(2001). "Embryonic mesencephalic transplantation for the treatment of advanced Parkinson's disease." Tecnologica MAP Suppl: 5-9. (2001). "Surgical treatment for Parkinson's disease." Tecnologica: 1, 3-7, 15. (2001). "Evaluation of dyskinesias in a pilot, randomized, placebo-controlled trial of remacemide in advanced Parkinson disease." Arch Neurol 58(10): 1660-8. CONTEXT: Long-term levodopa therapy for Parkinson disease commonly results in motor complications including "on-off" fluctuations and dyskinesias, but it is still unclear how best to assess treatment effects on dyskinesias in clinical trials. OBJECTIVE: To compare several methods of rating levodopa-induced dyskinesias to evaluate the effect of remacemide hydrochloride treatment in patients with advanced Parkinson disease. DESIGN: Two-week multicenter randomized, double-blind, placebo-controlled, parallel-group study. SETTING: Five academic sites of the Parkinson Study Group. PATIENTS: Thirty-nine subjects at least 30 years old with idiopathic Parkinson disease and disabling dyskinesias. INTERVENTIONS: Randomly received daily doses of 150 mg, 300 mg, or 600 mg of remacemide hydrochloride or matching placebo for 2 weeks. MAIN OUTCOME MEASURES: The dyskinesia rating scales used were the Modified Goetz Dyskinesia Rating scale (MGDRS), a newly created Lang-Fahn Activities of Daily Living Dyskinesia scale (LFADLDS), and diary dyskinesia ratings. RESULTS: Patient and investigator diaries showed excellent agreement in dyskinesia ratings. The MGDRS score correlated with clinic diary ratings of the percentage of "on" time with dyskinesias, and the LFADLDS score correlated with home and clinic diary assessments of percentage of on time with severe dyskinesias. The MGDRS score did not correlate highly with the LFADLDS score. This pilot study also validated previous results demonstrating the safety and tolerability of remacemide treatment for advanced Parkinson disease but did not result in any demonstrable improvement or worsening in dyskinesia measures. CONCLUSIONS: Diaries may provide a valid means of evaluating dyskinesias in clinical trials for Parkinson disease, but there remain other aspects of dyskinesias, as assessed by the MGDRS and LFADLDS, that are not reflected in diary ratings. (2001). "Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson's disease." N Engl J Med 345(13): 956-63. BACKGROUND: Increased neuronal activity in the subthalamic nucleus and the pars interna of the globus pallidus is thought to account for motor dysfunction in patients with Parkinson's disease. Although creating lesions in these structures improves motor function in monkeys with induced parkinsonism and patients with Parkinson's disease, such lesions are associated with neurologic deficits, particularly when they are created bilaterally. Deep-brain stimulation simulates the effects of a lesion without destroying brain tissue. METHODS: We performed a prospective, double-blind, crossover study in patients with advanced Parkinson's disease, in whom electrodes were implanted in the subthalamic nucleus or pars interna of the globus pallidus and who then underwent bilateral high-frequency deep-brain stimulation. We compared scores on the motor portion of the Unified Parkinson's Disease Rating Scale when the stimulation was randomly assigned to be turned on or off. We performed unblinded evaluations of motor function preoperatively and one, three, and six months postoperatively. RESULTS: Electrodes were implanted bilaterally in 96 patients in the subthalamic-nucleus group and 38 patients in the globus-pallidus group. Three months after the procedures were performed, double-blind, crossover evaluations demonstrated that stimulation of the subthalamic nucleus was associated with a median improvement in the motor score (as compared with no stimulation) of 49 percent, and stimulation of the pars interna of the globus pallidus with a median improvement of 37 percent (P<0.001 for both comparisons). Between the preoperative and six-month visits, the percentage of time during the day that patients had good mobility without involuntary movements increased from 27 percent to 74 percent (P<0.001) with subthalamic stimulation and from 28 percent to 64 percent (P<0.001) with pallidal stimulation. Adverse events included intracranial hemorrhage in seven patients and infection necessitating removal of the leads in two. CONCLUSIONS: Bilateral stimulation of the subthalamic nucleus or pars interna of the globus pallidus is associated with significant improvement in motor function in patients with Parkinson's disease whose condition cannot be further improved with medical therapy. (2001). "Loss of smell: how it happens and what it means." Harv Health Lett 26(11): 4-5. (2001). "Abstracts from the 2nd Congress Deutsche Parkinson-Gesellschaft e. V. Bochum, March 7-10, 2001." J Neural Transm 108(2): I-XXXVI. (2001). "[Pallidal and subthalamic stimulation in Parkinson's disease: lessons from the unsatisfactory results]." Neurologia 16(7): 298-302. BACKGROUND: Deep brain stimulation is being widely used in advanced Parkinson's disease (PD). Outcome determinants are not known. OBJECTIVE: Some relevant data about outcome may be obtained from the study of patients with unsatisfactory results. PATIENTS AND METHODS: We have retrospectively analyzed the number and causes of unsatisfactory results (insufficient improvement 6 months after the intervention) in 211 patients. RESULTS: Forty patients (18.9%) experienced an unsatisfactory result. Inadequate clinical selection by advanced age, abnormal MRI and levodopa unresponsive symptoms was the main cause in 28 cases. In 11 patients a misplacement of the electrode was reported. In 2 cases no cause was identified. Thirty-four out of the 40 patients corresponded to the early experience of the teams involved in the study. CONCLUSION: We conclude that the main factors responsible for a negative outcome are related to the inadequate clinical selection of the patients and the incorrect placement of the electrode. The experience of the team may also be a key factor. (2001). "Genetic epidemiology of Creutzfeldt-Jakob disease in Europe." Rev Neurol (Paris) 157(6-7): 633-7. The prion protein gene was studied in patients with definite or probable Creutzfeldt-Jakob disease (CJD) registered by national CJD units of 6 European countries. The role of genetic factors in CJD was also investigated by comparing the frequencies of a family history of dementia and Parkinson's disease in CJD cases and matched controls. Codon 129 genotype was examined in 337 CJD cases of whom 73.2 p. 100 were homozygous for methionine, 10.9 p. 100 were homozygous for valine and 15.7 p. 100 were heterozygous. The genotype frequencies were not statistically different across countries. Future differences, if any, would constitute a meaningful signal for the surveillance of CJD in Europe. A prion protein gene mutation was found in 14.5 p. 100 of CJD cases; only 40 p. 100 of them had a known family history of CJD. The case-control study showed that positive family histories of dementia and Parkinson's disease were both associated with CJD. Although recall bias is the most likely explanation for this finding, the hypothesis that neurodegenerative diseases might share unknown genetic risk factors can also be considered. (2001). "Initial treatment of Parkinson's disease: wait just a minute." Med Lett Drugs Ther 43(1108): 59-60. (2001). "[Parkinson patients. Normal life expectancy with selegiline?]." MMW Fortschr Med 143 Suppl 2: 93. (2001). "[L-dopa-induced movement disorders in Parkinson disease. Amantadine improves dyskinesia]." MMW Fortschr Med 143 Suppl 2: 93. (2001). "[Parkinson disease. Value of COMT inhibitors is verified]." MMW Fortschr Med 143(18): 51. (2001). "Gaining brain cells." Lab Anim (NY) 30(2): 12. (2001). "Parkinson's disease. New treatments, still no cure." Mayo Clin Health Lett 19(5): 1-3. (2001). "Prospects for Parkinson disease." Nat Med 7(4): 381. (2001). "Miracle cures and embryonic science." Nat Biotechnol 19(4): 287. (2001). "[Parkinson disease: diagnostic and therapeutic criteria]." Presse Med 30(8): 379-85. (2001). ""Management of behavioral and psychiatric problems in Parkinson's disease" by A. A. Rabinstein, L. M. Shulman. Parkinsonism & Related Disorders 7(1) pp. 41-50." 7(2): 161. (2001). "Health news. The sleeper syndrome." Harv Health Lett 26(3): 6. Aarsland, D., K. Andersen, et al. (2001). "Risk of dementia in Parkinson's disease: a community-based, prospective study." Neurology 56(6): 730-6. OBJECTIVE: To calculate the incidence of and determine possible risk factors for dementia in PD. BACKGROUND: Dementia has important clinical consequences for patients with PD and their caregivers, but the incidence is unknown. METHODS: A population-based cohort of nondemented patients with PD (n = 171) from the county of Rogaland, Norway, was assessed at baseline and 4.2 years later with a comprehensive evaluation of motor, cognitive, and neuropsychiatric symptoms. The diagnosis of dementia was made according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised (DSM-III-R) criteria, based on interview of the patient and a caregiver, cognitive rating scales, and neuropsychologic tests. A representative sample of 3,062 nondemented elderly subjects without PD served as control group. RESULTS: Forty-three patients with PD were demented at follow-up evaluation, equivalent to an incidence rate of 95.3 per 1,000 person-years (95% CI, 68.2 to 122.0). The risk for the development of dementia in patients with PD relative to the control subjects after adjusting for age, sex, and education was 5.9 (95% CI, 3.9 to 9.1). Predictive factors at baseline for dementia in PD in addition to age were Hoehn & Yahr score >2 (OR, 3.4; 95% CI, 1.3 to 8.6) and Mini-Mental State Examination score < 29 (OR, 3.3; 95% CI, 1.3 to 8.2). CONCLUSIONS: Patients with PD have an almost sixfold increased risk for becoming demented compared with subjects without PD. Aarsland, D., C. Ballard, et al. (2001). "A comparative study of psychiatric symptoms in dementia with Lewy bodies and Parkinson's disease with and without dementia." Int J Geriatr Psychiatry 16(5): 528-36. OBJECTIVES: To compare the frequency and clinical correlates of neuropsychiatric symptoms in patients with Parkinson's disease (PD) with and without dementia and in those with dementia with Lewy bodies (DLB). METHODS: Neuropsychiatric symptoms during the month prior to assessment were assessed in clinically diagnosed PD patients with dementia (PDD; n = 48) and without dementia (PDND; n = 83) and in 98 DLB patients (33% autopsy confirmed) using standardized instruments. RESULTS: Delusions and hallucinations were significantly more common in DLB (57% and 76%) than PDD (29% and 54%) and PDND (7% and 14%) patients (p < 0.001). In all groups, auditory and visual hallucinations and paranoid and phantom boarder delusions were the most common psychotic symptoms. Frequency of major depression and less than major depression did not differ significantly between the three groups. Clinical correlates of hallucinations in PD were dementia (odds ratio (OR) = 3.9; 95% confidence interval (CI) 1.5-10.4) and Hoehn-Yahr stage 3 or more (OR 3.4; 95% CI 1.0-12.0), whereas no significant clinical correlates of hallucinations were found in DLB patients. CONCLUSIONS: Delusions and hallucinations occur with increasing frequency in PDND, PDD and DLB patients, but the presentation of these symptoms is similar. These findings support the hypothesis that psychiatric symptoms are associated with cortical Lewy bodies or cholinergic deficits in the two disorders. Aarsland, D., C. Ballard, et al. (2001). "Comparison of extrapyramidal signs in dementia with lewy bodies and parkinson's disease." J Neuropsychiatry Clin Neurosci 13(3): 374-9. Extrapyramidal signs (EPS) were compared in 98 dementia with Lewy bodies (DLB) and 130 medication-responsive Parkinson's disease (PD) patients. DLB patients were older at assessment and at disease onset, were cognitively more impaired, and had a shorter duration of disease than PD patients. Sixty-seven DLB patients (68%) showed EPS. The 58 DLB patients with complete data had more severe action tremor, body bradykinesia, difficulty arising from a chair, and facial expression, gait, and rigidity symptoms than PD patients (all P<0.001). Abnormal posture and tremor at rest did not differ. Severity of EPS correlated with age, duration of disease, and cognitive impairment in PD patients but not in DLB patients. Studies of the clinical significance and management of EPS in DLB patients are needed. Aarsland, D., J. L. Cummings, et al. (2001). "Neuropsychiatric differences between Parkinson's disease with dementia and Alzheimer's disease." Int J Geriatr Psychiatry 16(2): 184-91. OBJECTIVE: To compare the profile of neuropsychiatric symptoms in patients with Parkinson's disease with dementia (PDD) and patients with Alzheimer's disease (AD). DESIGN: Cross-sectional survey of a population-based sample of patients with PDD and AD patients matched for age, sex, and Mini-Mental State Examination (MMSE) score. METHOD: Patients were diagnosed according to published criteria for PD and AD. The diagnosis of dementia in PD was made according to DSM-III-R, and was based on clinical interview of the patient and a relative, psychometric testing (including MMSE, Dementia Rating Scale and tests assessing memory, executive functions and visuospatial functioning) and physical examination. The Neuropsychiatric Inventory (NPI) was administered to all patients. RESULTS: One or more psychiatric symptoms was reported in 95% of AD and 83% of PDD patients. Hallucinations were more severe in PD patients, while aberrant motor behavior, agitation, disinhibition, irritability, euphoria, and apathy were more severe in AD. In PDD, apathy was more common in mild Hoehn and Yahr stages, while delusions increased with more severe motor and cognitive disturbances. In PDD, only delusions correlated with the MMSE score. CONCLUSIONS: Neuropsychiatric symptoms are common and severe in patients with PDD, with important implications for the management of these patients. AD and PDD patients have different neuropsychiatric profiles, suggesting different underlying mechanisms. Cognitive impairment, psychopathology, and motor features progress independently in PDD patients Copyright 2001 John Wiley & Sons, Ltd. Aarsland, D., I. Litvan, et al. (2001). "Neuropsychiatric symptoms of patients with progressive supranuclear palsy and Parkinson's disease." J Neuropsychiatry Clin Neurosci 13(1): 42-9. Neuropsychiatric symptoms are common in basal ganglia disorders and may have severe clinical consequences. The authors compared the neuropsychiatric manifestations of patients with Parkinson's disease (PD) and progressive supranuclear palsy (PSP). All 103 PD patients and 27 of the 61 PSP patients were taking dopaminergic agents. PSP patients showed significantly more apathy and disinhibition. Patients with PD had higher frequency of hallucinations, delusions, and depression. These results suggest that PSP patients show symptoms compatible with lesioned orbitofrontal and medial frontal circuits, such as disinhibition and apathy, whereas PD patients show symptoms associated with monoaminergic disturbances, such as psychosis and depression. Abbott, A. (2001). "Trials offer way forward for Parkinson's." Nature 410(6827): 401. Abbott, R. D., H. Petrovitch, et al. (2001). "Frequency of bowel movements and the future risk of Parkinson's disease." Neurology 57(3): 456-62. BACKGROUND: Constipation is frequent in PD, although its onset in relation to clinical PD has not been well described. Demonstration that constipation can precede clinical PD could provide important clues to understanding disease progression and etiology. The purpose of this report is to examine the association between the frequency of bowel movements and the future risk of PD. METHODS: Information on the frequency of bowel movements was collected from 1971 to 1974 in 6790 men aged 51 to 75 years without PD in the Honolulu Heart Program. Follow-up for incident PD occurred over a 24-year period. RESULTS: Ninety-six men developed PD an average of 12 years into follow-up. Age-adjusted incidence declined consistently from 18.9/10,000 person-years in men with <1 bowel movement/day to 3.8/10,000 person-years in those with >2/day (p = 0.005). After adjustment for age, pack-years of cigarette smoking, coffee consumption, laxative use, jogging, and the intake of fruits, vegetables, and grains, men with <1 bowel movement/day had a 2.7-fold excess risk of PD versus men with 1/day (95% CI: 1.3, 5.5; p = 0.007). The risk of PD in men with <1 bowel movement/day increased to a 4.1-fold excess when compared with men with 2/day (95% CI: 1.7, 9.6; p = 0.001) and to a 4.5-fold excess versus men with >2/day (95% CI: 1.2, 16.9; p = 0.025). CONCLUSIONS: Findings indicate that infrequent bowel movements are associated with an elevated risk of future PD. Further study is needed to determine whether constipation is part of early PD processes or is a marker of susceptibility or environmental factors that may cause PD. Abe, K. and H. Saito (2001). "Effects of basic fibroblast growth factor on central nervous system functions." Pharmacol Res 43(4): 307-12. Basic fibroblast growth factor (bFGF), initially identified as mitogens with prominent angiogenic properties, is now recognized as multifunctional growth factors with notable actions on neuronal cells. bFGF promotes the survival and neurite growth of brain neurons in vitro and in vivo, suggesting that it functions as a neurotrophic factor. This effect of bFGF could be beneficial for improving the survival of grafted neurons in transplantation. Furthermore, bFGF acutely modulates synaptic transmission in the hippocampus, suggesting that it has a role like a neurotransmitter or neuromodulator. In this article, we make a brief review of multiple biological activities of bFGF for brain neurons and discuss its potential usefulness for the treatment of neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. Abe, K., K. Taguchi, et al. (2001). "Stereoselective effect of (R)- and (S)-1-methyl-1,2,3,4-tetrahydroisoquinolines on a mouse model of Parkinson's disease." Brain Res Bull 56(1): 55-60. We carried out behavioral, pathological, and biochemical studies in order to determine whether the stereo-structure of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTIQ) affects the onset of Parkinson's disease-like symptoms, which are induced by 1,2,3,4-tetrahydroisoquinoline (TIQ) in mice. Pretreatment with (R)-1-MeTIQ or its racemate (RS)-1-MeTIQ prevented the TIQ-induced bradykinesia. Pretreatment with a combination of L-DOPA and carbidopa significantly prevented subsequent TIQ-induced bradykinesia. Furthermore, the pathological study demonstrated that either (R)-1-MeTIQ or its racemate protected against TIQ-induced loss of tyrosine hydroxylase-positive cells of the substantia nigra pars compacta. (R)-1-MeTIQ and its racemate also prevented the TIQ-induced reduction in the levels of dopamine and its metabolites in the striatum. Serotonin and its metabolite were not affected by repeated administration of (RS)-1-MeTIQ or its derivatives. On the other hand, (S)-1-MeTIQ induced moderate but significant bradykinesia, whereas (R)-1-MeTIQ did not induce this behavioral abnormality at all. In addition, (S)-enantiomer prevented the onset of TIQ-induced bradykinesia, though to a lesser extent than did either (R)-enantiomer or its racemate. However, (S)-enantiomer did not prevent the loss of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta. We concluded that (R)-1-MeTIQ, and not (S)-enantiomer, plays a crucial role in protection against TIQ-induced parkinsonism, a fact which suggests that enantiomeric biochemical events such as 1-MeTIQ biosynthesis may participate in the pathogenesis of Parkinson's disease. Abe, K., K. Taguchi, et al. (2001). "Biochemical and pathological study of endogenous 1-benzyl-1,2,3,4-tetrahydroisoquinoline-induced parkinsonism in the mouse." Brain Res 907(1-2): 134-8. We administered 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1-BnTIQ; 80 mg/kg, i.p.), an endogenous neurotoxin known to cause bradykinesia, the Parkinson's disease-like symptom, in order to obtain biochemical and pathological evidence of behavioral abnormalities. Immunohistochemical analysis demonstrated that 1-BnTIQ did not decrease the number of tyrosine hydroxylase-positive cells in the substantia nigra. Biochemical analysis demonstrated significantly increased striatal dopamine (DA) content, while DA metabolites in the striatum remained at control levels. We concluded that the 1-BnTIQ-induced bradykinesia has a different mechanism of action than that underlying the MPTP-induced depletion of striatal DA neurons. Abe, T., N. Tsuchida, et al. (2001). "[Comparison between the short program and the long program of post-operative rehabilitation of hip fracture for making the critical path]." Nippon Ronen Igakkai Zasshi 38(4): 514-8. Patients receiving operative treatment for fracture are good candidate for critical path management. Recently, we have developed a Short Program (SP) for post-operative rehabilitation of hip fractures. The purpose of this study was to evaluate the effectiveness, the safety and the cost efficiency of this SP, by comparing it with the former Long Program (LP) in terms of choosing the better program for the critical path. The enrolled patients were over 65 years old, had been able to walk by themselves with or without canes, were free from neurological diseases like hemiplegia and Parkinson's disease, and without pathological fractures. We enrolled 101 patients (mean age: 83.1) for the LP and 143 patients (mean age: 82.8) for the SP. The operative procedure for these patients was internal fixation with a sliding hip screw or prosthetic replacement for a femoral head. Length of hospitalization, the rate of recovering walking ability, medical expenses during hospitalization, and the types and incidence of complications were investigated to determine differences between the SP and the LP. Length of hospitalization was significantly shorter in SP patients (p < 0.01). The ratio of recovering walking ability was equal in both programs, while that among the patients with dementia was lower in the SP group. Medical expenses were significantly less in SP (p < 0.01). The SP had fever complications than the LP group (p < 0.05). As a result, the SP was superior to the LP in terms of effectiveness, safety and cost efficiency, thus it was considered to be suitable for critical path management of hip fracture cases. However, because recovery of walking ability was harder for patients over 85 years old with the SP than with the LP, a modified program is necessary for such older patients. Abell, C. W. and S. W. Kwan (2001). "Molecular characterization of monoamine oxidases A and B." Prog Nucleic Acid Res Mol Biol 65: 129-56. Monoamine oxidase A and B (MAO A and B) are the major neurotransmitter-degrading enzymes in the central nervous system and in peripheral tissues. MAO A and B cDNAs from human, rat, and bovine species have been cloned and their deduced amino acid sequences compared. Comparison of A and B forms of the enzyme shows approximately 70% sequence identity, whereas comparison of the A or B forms across species reveals a higher sequence identity of 87%. Within these sequences, several functional regions have been identified that contain crucial amino acid residues participating in flavin adenine dinucleotide (FAD) or substrate binding. These include a dinucleotide-binding site, a second FAD-binding site, a fingerprint site, the FAD covalent-binding site, an active site, and the membrane-anchoring site. The specific residues that play a role in FAD or substrate binding were identified by comparing sequences in wild-type and variants of MAO with those in soluble flavoproteins of known structures. The genes that encode MAO A and B are closely aligned on the X chromosome (Xp11.23), and have identical exon-intron organization. Immunocytochemical localization studies of MAO A and B in primate brain showed distribution in distinct neurons with diverse physiological functions. A defective MAO A gene has been reported to associate with abnormal aggressive behavior. A deleterious role played by MAO B is the activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a proneurotoxin that can cause a parkinsonian syndrome in mammals. Deprenyl, an inhibitor of MAO B, has been used for the treatment of early-stage Parkinson's disease and provides protection of neurons from age-related decay. Adamovich, S. V., M. B. Berkinblit, et al. (2001). "The interaction of visual and proprioceptive inputs in pointing to actual and remembered targets in Parkinson's disease." Neuroscience 104(4): 1027-41. We previously reported that Parkinson's disease patients could point with their eyes closed as accurately as normal subjects to targets in three-dimensional space that were initially presented with full vision. We have now further restricted visual information in order to more closely examine the individual and combined influences of visual information, proprioceptive feedback, and spatial working memory on the accuracy of Parkinson's disease patients. All trials were performed in the dark. A robot arm presented a target illuminated by a light-emitting diode at one of five randomly selected points composing a pyramidal array. Subjects attempted to "touch" the target location with their right finger in one smooth movement in three conditions: dark, no illumination of arm or target during movement; movement was to the remembered target location after the robot arm retracted; finger, a light-emitting diode on the pointing fingertip was visible during the movement but the target was extinguished; again, movement was to the remembered target location; and target, the target light-emitting diode remained in place and visible throughout the trial but there was no vision of the arm. In the finger condition, there is no need to use visual-proprioceptive integration, since the continuously visualized fingertip position can be compared to the remembered location of the visual target. In the target condition, the subject must integrate the current visible target with arm proprioception, while in the dark condition, the subject must integrate current proprioception from the arm with the remembered visual target. Parkinson's disease patients were significantly less accurate than controls in both the dark and target conditions, but as accurate as controls in the finger condition. Parkinson's disease patients, therefore, were selectively impaired in those conditions (target and dark) which required integration of visual and proprioceptive information in order to achieve accurate movements. In contrast, the patients' normal accuracy in the finger condition indicates that they had no substantial deficits in their relevant spatial working memory. Final arm configurations were significantly different in the two subject groups in all three conditions, even in the finger condition where mean movement endpoints were not significantly different. Variability of the movement endpoints was uniformly increased in Parkinson's disease patients across all three conditions.The current study supports an important role for the basal ganglia in the integration of proprioceptive signals with concurrent or remembered visual information that is needed to guide movements. This role can explain much of the patients' dependence on visual information for accuracy in targeted movements. It also underlines what may be an essential contribution of the basal ganglia to movement, the integration of afferent information that is initially processed through multiple, discrete modality-specific pathways, but which must be combined into a unified and continuously updated spatial model for effective, accurate movement. Adams, J. D., Jr., M. L. Chang, et al. (2001). "Parkinson's disease--redox mechanisms." Curr Med Chem 8(7): 809-14. Parkinson's disease occurs in 1% of people over the age of 65 when about 60% of the dopaminergic neurons in the substantia nigra of the midbrain are lost. Dopaminergic neurons appear to die by a process of apoptosis that is induced by oxidative stress. Oxygen radicals abstract hydrogen from DNA forming DNA radicals that lead to DNA fragmentation, activation of DNA protective mechanisms, NAD depletion and apoptosis. Oxygen radicals can be formed in dopaminergic neurons by redox cycling of MPP+, the active metabolite of MPTP. This redox cycling mechanism involves the reduction of MPP+ by a number of enzymes, especially flavin containing enzymes, some of which are found in mitochondria. Tyrosine hydroxylase is present in all dopaminergic neurons and is responsible for the synthesis of dopamine. However, tyrosine hydroxylase can form oxygen radicals in a redox mechanism involving its cofactor, tetrahydrobiopterin. Dopamine may be oxidized by monoamine oxidase to form oxygen radicals and 3,4-dihydroxyphenylacetaldehyde. This aldehyde may be oxidized by aldehyde dehydrogenase with the formation of oxygen radicals and 3,4-dihydroxyphenylacetic acid. The redox mechanisms of oxygen radical formation by MPTP, tyrosine hydroxylase, monoamine oxidase and aldehyde dehydrogenase will be discussed. Possible clinical applications of these mechanisms will be briefly presented. Aguirre, J. A., B. Andbjer, et al. (2001). "Group I mGluR antagonist AIDA protects nigral DA cells from MPTP-induced injury." Neuroreport 12(12): 2615-7. The effects of i.c.v. injection of AIDA, a group I mGluR antagonist, were studied on the nigral DA cells after MPTP-induced injury in the black mouse, using TH immunocytochemistry and unbiased stereology. MPTP reduced the total number of TH-IR neurons by 55.2% and non-TH-IR neurons by 27.5%. A 15 min AIDA pre-treatment (10 nmol) selectively counteracted the loss of TH-IR cells caused by MPTP as evaluated 10 days after the insult without changing the total number of non-neuronal cell nuclei. The results suggest that group I mGluR antagonists may have a neuroprotective role against MPTP-induced degeneration of DA neurons and thus probably also against neurodegenerative processes occurring in Parkinson's disease. Ahlbom, A. (2001). "Neurodegenerative diseases, suicide and depressive symptoms in relation to EMF." Bioelectromagnetics Suppl 5: S132-43. In 1979 the first study was published which indicated that environmental exposure to power frequency, electric and magnetic fields (EMF), might increase the risk of chronic disease. This was a study on cancer. However, this research area has gradually evolved and come also to include outcomes other than cancer. The purpose of this paper is to provide a better understanding of the literature on neurodegenerative diseases and on suicide and depressive symptoms in relation to EMF by using a meta-analysis technique. It is concluded that for amyotrophic lateral sclerosis, there are relatively strong data indicating that electric utility work may be associated with an increased risk. However, EMF exposure is only one of several possible explanations to this. For Alzheimer's disease the combined data on an association with EMF are weaker than that for ALS. For suicide an overall assessment yields the conclusion that the support for an association is weak. For depressive symptoms the assessment is more complex, but the overall conclusion is nevertheless that the evidence is relatively weak. For other diseases, such as Parkinson's, there is not enough information for an assessment. Ahlenius, S. and E. Ericson (2001). "Scopolamine does not restore normal conditioned avoidance performance in raclopride-treated rats." J Neural Transm 108(4): 415-30. Several studies have shown antagonism by anticholinergics of antipsychotic-induced suppression of conditioned avoidance behavior, as well as of catalepsy, in rats. These observations provide pharmacological evidence for these behaviors mediated via nigro-striatal dopaminergic projections, as well as known dopaminergic-cholinergic interactions in the neostriatum. The objective of the present study was to examine the quality of behavioral change produced by scopolamine (0.25-1.00 mgkg(-1) s.c.) on conditioned avoidance behavior, by itself, and in combination with raclopride (0.1 mgkg(-1) s.c.) in the rat. Adult male Wistar rats were trained to perform a conditioned avoidance response requiring a brightness discrimination. A two-way avoidance shuttle-box was used with the modification that there were two passages in the partition separating the two compartments of the shuttle-box. In order to make a correct avoidance in the response to white noise conditioned stimulus, the rat had to take background light into consideration. Correct passage under dim background conditions was to the left and, with increased background lights, to the right. A weak, intermittent, electric shock (approximately 0.2 mA) was used as unconditioned stimulus. Scopolamine by itself (0.25-1.00 mgkg(-1) s.c.) disrupted the visual discrimination without affecting avoidance performance. As expected, raclopride (0.1 mgkg(-1) s.c.) produced a suppression of conditioned avoidance behavior. A dose of 1.00 mgkg(-1) of scopolamine was needed to restore raclopride-induced suppression of conditioned avoidance behavior. Thus, restoration of the avoidance behavior by scopolamine treatment was not possible at doses that allow normal performance of the visual discrimination. It is concluded that anticholinergics do not restore normal behavior after neuroleptic-induced suppression of conditioned avoidance behavior. Ahlskog, J. E. (2001). "Parkinson's disease: medical and surgical treatment." Neurol Clin 19(3): 579-605, vi. It has been over three decades since the introduction of L-dihydroxyphenylalanine or levodopa therapy for Parkinson's disease (PD). The early levodopa trials were driven by recognition of a profound cerebral dopamine deficiency state in this disorder. Whereas dopamine fails to cross the blood brain barrier and hence is ineffective as therapy, the amino acid precursor, dopa, is transported across this barrier and provides a substrate for dopamine synthesis. Levodopa is converted to dopamine within the brain by dopa decarboxylase, replenishing central dopamine stores and potentially reversing the motor symptoms of PD. Ahlskog, J. E. and M. D. Muenter (2001). "Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature." Mov Disord 16(3): 448-58. There is no clear consensus regarding the frequency (and hence, the risk), of dyskinesias or motor fluctuations during chronic levodopa therapy for Parkinson's disease (PD). Multiple clinical series have tabulated these frequencies since the advent of levodopa over 30 years ago. We were interested in determining: (1) the aggregate frequency figures in the existing literature; and (2) how clinical series from the early levodopa era, which included patients with longer durations of parkinsonism, compare to more recent (modern era) series. We searched MEDLINE for all English language publications reporting the cumulative frequency of levodopa-induced dyskinesias or motor fluctuations during discrete intervals of treatment. This generated 2,478 publications spanning 1966 through September 2000. Papers with appropriate titles or abstracts were reviewed; reference lists from published clinical series were a source of additional papers for review. This ultimately yielded 74 publications with adequate data, relating to 112 intervals of levodopa treatment. Series that included patients with PD-onset well before levodopa availability (pre-levodopa era) were separately analyzed from all subsequent series. Series were grouped by duration of levodopa therapy and the median frequencies of dyskinesias and motor fluctuations were tabulated for each group. The data were analyzed both with and without adjustment for the number (N) in each series. Among series containing pre-levodopa era patients, the median dyskinesia frequency was already 50% by 5-6 months of treatment. This contrasts with the modern era series where dyskinesias were reported later in treatment. The median dyskinesia frequency was slightly less than 40% by 4-6 years of levodopa therapy among modern era patients. Motor fluctuations (wearing-off) were not tabulated in most of the early levodopa series. Among modern era reports, motor fluctuations were nil during the first year of levodopa therapy but were experienced by approximately 40% of patients by 4-6 years of treatment. Similar results were found when the analyses were restricted to only prospective studies where levodopa motor complications were targeted outcome measures. The conclusions reached were: (1) patients from the pre-levodopa era experienced dyskinesias much earlier during levodopa treatment than modern era patients, perhaps because of longer durations of pre-existing PD; (2) in the present era, patients treated with levodopa therapy for 4-6 years have approximately a 40% likelihood of experiencing motor fluctuations and a risk of dyskinesias just short of 40%; and (3) these findings represent incident data and the prevalence of clinically important morbidity may be substantially less. Ahmad, S. O., K. Mu, et al. (2001). "Meta-analysis of functional outcome in Parkinson patients treated with unilateral pallidotomy." Neurosci Lett 312(3): 153-6. Parkinson's disease (PD) profoundly affects activities of daily living (ADL) and quality of human life. Although unilateral pallidotomy has become a common surgical treatment for persons with advanced PD, functional outcome data from previous reports have failed to uniformly support this procedure. In the present investigation, results from 12 studies meeting specific inclusion criteria were subjected to meta-analysis. Only reports featuring unilateral pallidotomy as the exclusive surgery, a sample size of at least five patients, explicit assessment of ADL, and sufficient quantitative data were subjected to analysis. Type of research design was not a factor in the selection process. The results of our analysis suggest that unilateral pallidotomy successfully enhances functional outcome in patients with clinically advanced PD. Ahmed, M. E., A. S. Shatoor, et al. (2001). "Resting ECG abnormalities among asymptomatic Arab men and comparison with other ethnic populations." Ethn Dis 11(3): 446-53. The aim of this study was to detect the frequency of the resting electrocardiogram (ECG) abnormalities among asymptomatic Arab men in Saudi Arabia, since no similar studies had been conducted in this ethnic population. The ECG tracings of 314 men (mean age 44.2 years) who attended a health clinic in Abha, Southern Saudi Arabia, were analyzed according to the definitions of the major ECG textbooks and the Minnesota code. Abnormal ECG findings were encountered in 99 men (31.5%); 39 (12.4%) had non-specific changes, while 60 (19.1%) had potentiallysignificantabnormalities. Serious abnormalities, such as ischemic changes, left ventricular hypertrophy, and atrial fibrillation were seen in only 22 subjects (7%) and were associated with hypertension and an age greater than 40 years. On the other hand, early repolarization, the most frequent abnormality encountered, and Wolf-Parkinson-White syndrome (WPW) were mostly prevalent among young subjects. The significance of these ECG abnormalities with regard to long-term morbidity and mortality in asymptomatic subjects should be considered in relation to the age of the person and the presence of any underlying cardiovascular disease. Akamatsu, W. and H. Okano (2001). "[Neural stem cell, as a source of graft material for transplantation in neuronal disease]." No To Hattatsu 33(2): 114-20. Self-renewing and multipotent neural stem cells are present in the adult human brain. We successfully harvested neural stem cells from mice and humans using misexpressed EGFP proteins under the control of the nestin second intron enhancer. High-level EGFP expressors derived from mouse embryos included a distinct subpopulation of cells that were self-renewable and multipotent. Further, we obtained that neural progenitor cells from rat fetal spinal cords using a neurosphere technique, and demonstrated their ability to divide and differentiate into neurons in vivo, where they were integrated into the host tissue in the injured rat spinal cord with resultant behavioral improvement of the recipient rat. We also harvested tyrosine hydroxylase-positive neurons from a transgenic mouse expressing GFP under the control of the tyrosine hydroxylase promoter, and successfully transplanted them into the striatum of rats with parkinsonism with marked improvement of the neurological symptoms. Since neural stem cells can adapt well in the host CNS, studies should focus on their application as a vector in gene therapy and on the introduction in vivo or ex vivo of genes to control their proliferation and differentiation. Neural stem cells are a potential, useful source for developing new therapy for CNS disorders. Akerud, P., J. M. Canals, et al. (2001). "Neuroprotection through delivery of glial cell line-derived neurotrophic factor by neural stem cells in a mouse model of Parkinson's disease." J Neurosci 21(20): 8108-18. Neural stem cells (NSCs) have been proposed as tools for treating neurodegeneration because of their capacity to give rise to cell types appropriate to the structure in which they are grafted. In the present work, we explore the ability of NSCs to stably express transgenes and locally deliver soluble molecules with neuroprotective activity, such as glial cell line-derived neurotrophic factor (GDNF). NSCs engineered to release GDNF engrafted well in the host striatum, integrated and gave rise to neurons, astrocytes, and oligodendrocytes, and maintained stable high levels of GDNF expression for at least 4 months. The therapeutic potential of intrastriatal GDNF-NSCs grafts was tested in a mouse 6-hydroxydopamine model of Parkinson's disease. We found that GDNF-NSCs prevented the degeneration of dopaminergic neurons in the substantia nigra and reduced behavioral impairment in these animals. Thus, our results demonstrate that NSCs efficiently express therapeutic levels of GDNF in vivo, suggesting a use for NSCs engineered to release neuroprotective molecules in the treatment of neurodegenerative disorders, including Parkinson's disease. Akhmedova, S. N., A. K. Yakimovsky, et al. (2001). "Paraoxonase 1 Met--Leu 54 polymorphism is associated with Parkinson's disease." J Neurol Sci 184(2): 179-82. Two up-to-date known paraoxonase 1 (PON1) polymorphisms (Gln--Arg 191 and Leu--Met 54) affect the hydrolysis of toxic oxons and might intensify effects of pollutants, organophosphates and other environmental chemicals in development of Parkinson's disease (PD). We reported previously that PON1 G1n--Arg 191 polymorphism did not influence on the susceptibility to PD. In the present study we have investigated the PON1 Leu--Met 54 polymorphism in 117 patients with sporadic idiopathic PD. A new approach for Leu--Met 54 polymorphism genotyping has been developed. We have showed the frequency of the Met 54 allele of PON1 to be significantly increased in patients with PD compared with the controls (chi(2)=8.63, df=1, P<0.003). The relative risk of PD in the Met 54 allele carriers has been estimated to be 2.3 fold higher than in homozygotes for the L allele. Moreover it appeared to be even 5.15 higher in the subgroup of patients with early-onset PD. We suggest that the Met 54 allele may be considered to be an independent risk factor for PD. This mutation could probably cause PON1 impaired metabolism of environmental neurotoxins and might be responsible for neurodegeneration. Albanese, A., U. Bonuccelli, et al. (2001). "Consensus statement on the role of acute dopaminergic challenge in Parkinson's disease." Mov Disord 16(2): 197-201. Available evidence on the practice of acute pharmacological challenge tests in parkinsonian patients was reviewed by a committee of experts, which achieved a general consensus. The published data deal mainly with the acute administration of levodopa and apomorphine in Parkinson's disease. Such challenge may serve different purposes, e.g., research, diagnosis, or tailoring of treatment. Unique protocols describing the clinical setting and practice parameters are not available. The present paper describes the scientific background and supplies practical guidelines, whenever possible, to perform and evaluate acute challenge tests in parkinsonian syndromes. With the appropriate indication and setting, acute challenge tests are useful in diagnosis and therapy of Parkinson's disease and related disorders. Albani, G., G. Kunig, et al. (2001). "The role of language areas in motor control dysfunction in Parkinson's disease." Neurol Sci 22(1): 43-4. We evaluated the differences in motor control organization between parkinsonian patients with (seven cases) and without (ten cases) gait disorder. We used positron emission tomography (O15-H2O-PET) to measure regional cerebral blood flow as a correlate for local neuronal activation. This has been assessed during repetitive joystick movements of the right hand, externally triggered using a metronome as an auditory cue. In patients with Parkinson's disease (PD) without gait disorder, the contralateral supplementary motor cortex and the bilateral cerebellum were activated, while in PD patients with gait disorder the contralateral Broca's area, the contralateral sensory motor cortex and the homolateral cerebellum were activated. Our results suggest that PD patients with gait disorder creates an internal verbal cue in order to control the output of the movement of joystick, supplying the loss of control of the supplementary motor cortex that is activated in patients without gait disorder. Albers, D. S. and S. J. Augood (2001). "New insights into progressive supranuclear palsy." Trends Neurosci 24(6): 347-53. Increased oxidative damage and mitochondrial dysfunction have been suggested to play crucial roles in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. In this review, we will focus on progressive supranuclear palsy (PSP), a rare parkinsonian disorder with tau pathology. Particular emphasis is placed on the genetic and biochemical data that has emerged, offering new perspectives into the pathogenesis of this devastating disease, especially the contributory roles of oxidative damage and mitochondrial dysfunction. Alberts, J. L., C. H. Adler, et al. (2001). "Prehension patterns in restless legs syndrome patients." 7(2): 143-148. The pathogenesis of restless legs syndrome (RLS) is poorly understood. Previously we have shown that a reach-to-grasp task can be used to differentiate Parkinson's disease (PD) patients from healthy age-matched control subjects. The aim of this study was to determine if performance on this task could be used to differentiate between patients with RLS, PD patients, and healthy control subjects. Results indicated that RLS and control participants produced movement patterns that were nearly identical to one another, while movement patterns produced by the PD patients were significantly different from the other two groups. These results suggest RLS patients do not show any abnormalities in the performance of upper extremity prehension movements. Thus, these movements can be used to effectively differentiate between patients with Parkinson's Disease and Restless Legs Syndrome. While RLS patients respond favorably to dopaminergic therapies, this study suggests that PD and RLS may not share the same basal ganglia pathophysiology. Albin, R. L. (2001). "End of lines and boxes." Mov Disord 16(3): 405-6. Alegret, M., C. Junque, et al. (2001). "MRI atrophy parameters related to cognitive and motor impairment in Parkinson's disease." Neurologia 16(2): 63-9. BACKGROUND: Patients with Parkinson's disease (PD) show specific neuropsychological deficits in attention, memory, visuospatial or frontal lobe functions, which can arise from degeneration of different cerebral structures. OBJECTIVE: The aim of the present study was to analyze the role of focal degeneration (basal ganglia and substantia nigra) and diffuse cerebral atrophy (ventricular enlargement) in motor/cognitive impairment in PD. PATIENTS AND METHODS: We administered to 14 patients with advanced PD the following tests: Purdue Pegboard, Rey's Auditory-Verbal Learning test (RAVLT), Benton's Line Orientation, Trail Making, phonemic verbal fluency and Stroop test. Ventricular system, caudate and putamen nuclei and pars compacta of the substantia nigra were quantitatively measured by magnetic resonance imaging. Correlation analyses were carried out. RESULTS: The results showed that ventricular enlargement is negatively correlated with the performance on RAVLT and Stroop test. No relationship was found between caudate atrophy and cognitive deficits. Degeneration of putamen nucleus was found to be associated with motor deficits. CONCLUSION: Memory and frontal impairment are related to diffuse cerebral degeneration and the motor deficit is related to degeneration of the putamen nucleus. Alegret, M., C. Junque, et al. (2001). "Obsessive-compulsive symptoms in Parkinson's disease." J Neurol Neurosurg Psychiatry 70(3): 394-6. To systematically investigate obsessive-compulsive traits in Parkinson's disease, patients were administered the Maudsley obsessional-compulsive inventory (MOCI) and a modification of the Leyton obsessional inventory (LOI) to a sample of non-demented and non-depressed patients with Parkinson's disease. Patients with severe Parkinson's disease showed more obsessive traits than normal controls in MOCI and LOI total scores, and in the "checking", "doubting", and "cleaning" subscales of the MOCI. By contrast, patients with mild disease did not differ from controls. A significant correlation was found between severity and duration of illness and MOCI total score. These results support the involvement of basal ganglia in obsessive-compulsive symptomatology. As patients with mild Parkinson's disease did not differ from controls, obsessive-compulsive disorder does not seem to be directly related to the initial nigrostriatal dopaminergic deficiency which causes clinical Parkinson's disease symptomatology. The appearance of obsessive symptoms could be related to the subset of neurochemical changes taking place at the level of the basal ganglia circuitry as disease progresses. Alegret, M., C. Junque, et al. (2001). "Effects of bilateral subthalamic stimulation on cognitive function in Parkinson disease." Arch Neurol 58(8): 1223-7. BACKGROUND: Chronic bilateral subthalamic deep brain stimulation (STN-DBS) is known to improve motor function in patients with Parkinson disease (PD). However, the possible effects of STN-DBS on neuropsychological functions have been studied less. OBJECTIVE: To investigate the effects of STN-DBS on neuropsychological functions in PD. DESIGN: Before-after trial. PATIENTS AND METHODS: Fifteen consecutive patients were assessed before and 3 months after implantation of stimulators for STN-DBS (postsurgical assessment with the stimulators switched on). Both assessments were performed with patients in a drug-free condition. The neuropsychological battery consisted of tests measuring memory and visuospatial and frontal functions. RESULTS: The comparison between presurgical and postsurgical performance showed a moderate deterioration in verbal memory and prefrontal and visuospatial functions, and a moderate improvement in a prefrontal task and obsessive-compulsive traits. The motor state improved in all patients. CONCLUSION: Therapy with STN-DBS improves motor symptoms in PD without any clinically relevant neuropsychological deterioration. Alim, M. A., M. S. Hossain, et al. (2001). "Tubulin seeds alpha-synuclein fibril formation." J Biol Chem. Increasing evidence suggests that a-synuclein is a common pathogenic molecule in several neurodegenerative diseases, particularly in Parkinson's disease. To understand a-synuclein pathology, we investigated molecules that interact with a-synuclein in the human and rat brains, and identified tubulin as an a-synuclein binding/associated protein. Tubulin co-localized with a-synuclein in Lewy bodies and other a-synuclein-positive pathological structures. Tubulin initiated and promoted a-synuclein fibril formation under physiological conditions in vitro. These findings suggest that an interaction between tubulin and a-synuclein might accelerate a-synuclein aggregation in diseased brains, leading to formation of Lewy bodies. Alkhani, A. and A. M. Lozano (2001). "Pallidotomy for parkinson disease: a review of contemporary literature." J Neurosurg 94(1): 43-9. OBJECT: The authors conducted an evidence-based review of contemporary published articles on pallidotomy to obtain an appraisal of this procedure in the treatment of Parkinson disease (PD). METHODS: A search of the Pubmed database performed using the key word "pallidotomy" yielded 263 articles cited between January 1, 1992, and July 1, 1999. Articles that included original, nonduplicated descriptions of patients with PD treated with radiofrequency pallidotomy were selected. In 85 articles identified for critical review, 1959 patients with PD underwent pallidotomies at 40 centers in 12 countries. There were 1735 unilateral (88.6%) and 224 bilateral procedures (11.4%). The mean age of the patients was 61.4+/-3.6 years and the mean duration of PD symptoms in these patients was 12.3+/-1.9 years. Microelectrode recordings were used in 46.2% of cases. Outcomes were objectively documented using the Unified Parkinson Disease Rating Scale (UPDRS) in 501 (25.6%) of the cases at 6 months and in 218 (11.1%) of the cases at 1 year. There was a consensus on the benefits of pallidotomy for off period motor function and on period, drug-induced dyskinesias, with variations in the extent of symptomatic benefit across studies. At the 1-year assessment, the mean improvement in the UPDRS motor score during off periods was 45.3% and the mean improvement in contralateral dyskinesias during on periods was 86.4%. The overall mortality rate was 0.4% and the rate of persistent adverse effects was estimated at 14%. Major adverse events, including intracerebral hemorrhages, contralateral weakness, and visual field defects, occurred in 5.3% of patients reported. CONCLUSIONS: Unilateral pallidotomy is effective and relatively safe in the treatment of PD; however, limited data are available on the long-term outcome of this procedure. Allert, N., J. Volkmann, et al. (2001). "Effects of bilateral pallidal or subthalamic stimulation on gait in advanced Parkinson's disease." Mov Disord 16(6): 1076-85. Bilateral high-frequency stimulation of the internal globus pallidus (GPi) and the subthalamic nucleus (STN) both alleviate akinesia, rigidity, and tremor in idiopathic Parkinson's disease. To test the specific effect of these procedures on gait, we used quantitative gait analysis in addition to relevant subscores of the Unified Parkinson's Disease Rating Scale in a group of 10 patients with advanced Parkinson's disease treated by GPi stimulation and eight patients treated by STN stimulation. Patients were assessed before and 3 months after surgery. Thirty age-matched healthy subjects served as controls. The non-random selection allowed a descriptive but no direct statistical comparison of the respective procedure. Gait analysis showed significant stimulation-induced improvements of spatiotemporal gait and step parameters in both patient groups. Moreover, the effects on step length and cadence suggested a differential effect of both basal ganglia targets. Hence, the increase in gait velocity in the STN group was almost exclusively due to a significant increase in step length, while in the GPi group statistically non-significant increases in both step length and cadence contributed. Allman, K. C. (2001). "Metoprolol-induced changes in myocardial (123)I-metaiodobenzylguanidine uptake in Parkinson's disease." Circulation 104(7): E37. Alvarez, L., R. Macias, et al. (2001). "Dorsal subthalamotomy for Parkinson's disease." Mov Disord 16(1): 72-8. We report our experience of unilateral subthalamotomy in patients with Parkinson's disease (PD). Eleven patients were included in a pilot, open-labeled study to assess the effect of unilateral lesion of the subthalamic nucleus (STN) with a minimum of 12 months of follow-up. The guidelines of CAPIT (Core Assessment Program for Intracerebral Transplantation) were followed for recruitment into the study and follow-up assessment. Levodopa equivalents daily intake (mean 967 mg) were unchanged during the first 12 months in all but one patient who stopped medication. The sensorimotor region of the STN was defined by semimicrorecording and stimulation and a thermolytic lesion was placed accordingly. There was a significant reduction in both UPDRS parts II and III in the "off" state at 1-, 6-, and 12-month follow-up. This effect was maintained in four patients up to 24 months. The dyskinesia score did not change postoperatively. Lesion-induced dyskinesias were not a management problem except in one patient who developed a large infarction several days postsurgery. This initial study indicates that a lesion of the STN is not generally associated with hemiballismus in PD. Subthalamotomy may induce considerable motor benefit and could become another surgical option under specific circumstances. Alvarez, V., L. M. Guisasola, et al. (2001). "Early-onset Parkinson's disease associated with a new parkin mutation in a Spanish family." Neurosci Lett 313(1-2): 108-10. Mutations in the PARKIN gene are associated with early-onset (juvenile) Parkinson's disease. We analyzed the coding sequence of this gene (exons 1-12) in patients from a family with three affected siblings, born to first-degree consanguineous parents, with an onset before 23 years and foot dystonia as the initial clinical symptom. The three patients were alive without cognitive impairment at ages of 70, 69, and 65 years, showing a marked response to levodopa treatment. A 2 bp-deletion at exon 11 (1276-1277 del GA) was found. The three patients were homozygous for this frameshift mutation, which would introduce a Stop at codon 394. This is a new PARKIN-mutation that would produce a truncated protein, lacking exon 12 and most the 11th. This region includes the C-terminal ring-finger domain of parkin, essential for its function as a ubiquitin-protein ligase. Compared to patients from other families with truncating mutations, our patients had an earlier onset. In addition, the three patients had dystonia at onset. In conclusion, we described a new PARKIN truncating mutation associated with an early onset parkinsonism, and the presence of foot dystonia as the initial symptom. Aminoff, M. J. (2001). "Parkinson's disease." Neurol Clin 19(1): 119-28, vi. A number of changes have occurred in the management of Parkinson's disease in recent years, with the development of new therapeutic strategies based upon advances in pharmacotherapy and interventional procedures. The treatment of patients with Parkinson's disease is considered here with these advances in mind. Potential neuroprotective agents that might slow disease-progression are also considered, but at the present time these agents are more of academic interest than clinical relevance and their role remains to be established. Ablative surgery and stimulation procedures are also helpful in the management of Parkinson's disease, and the utility and limitations of these approaches are briefly summarized. Anagnostou, E., B. Sporer, et al. (2001). "Contraversive eye deviation during deep brain stimulation of the globus pallidus internus." Neurology 56(10): 1396-9. Clinical signs help determine correct electrode positioning during stereotactic implantation for chronic high-frequency pallidal stimulation in Parkinson's diease (PD). The authors describe a patient who had marked, sustained, contraversive eye deviation caused by stimulation during pallidal surgery. The underlying mechanism is probably an excitation of fibers in the internal capsule by volume-conducted current spread. Such conjugate eye deviation is thus not necessarily an indication of incorrect electrode placement. Andersen, J. K. (2001). "Does neuronal loss in Parkinson's disease involve programmed cell death?" Bioessays 23(7): 640-6. Recently it has been hypothesized that apoptotic cell death is involved in several neuropathological conditions including Parkinson's disease (PD). Initial morphological studies assessing the presence of apoptosis in Parkinsonian brain tissues yielded mixed results. Based on more recent studies in human PD brains as well in animal and cell culture models of the disease, a picture is emerging, however, that strongly suggests that many of the molecular players thought to participate in this type of neuronal cell death are active in the disease. The task of researchers in the field is now to deduce how these players may be interacting with one another to bring about cell death in PD and to design effective therapies to interfere with these processes. Andersen, J. K. (2001). "Do alterations in glutathione and iron levels contribute to pathology associated with Parkinson's disease?" Novartis Found Symp 235: 11-20; discussion 20-5. A growing body of evidence has implicated oxidative stress as an important factor in the neuropathology associated with Parkinson's disease. Dopaminergic nigrostriatal neurons, the predominant cells lost in Parkinson's, are believed to be highly prone to oxidative damage due to the propensity for dopamine to auto-oxidize and thereby produce elevated levels of hydrogen peroxide and catecholamine quinones. Hydrogen peroxide formed during this process can either be converted by iron to form highly reactive hydroxyl radicals or removed through reduction by glutathione. Glutathione can also conjugate with quinones formed during dopamine oxidation preventing them from facilitating the release of iron from the iron-storage molecule ferritin. Alterations in both iron and glutathione levels in the substantia nigra have been correlated with the neuronal degeneration accompanying Parkinson's disease but a direct causative role for either has yet to be definitively proved. We will discuss the use of genetically engineered cell and mouse lines generated in our laboratory as models to examine the role that alterations in iron and glutathione levels may play in neurodegeneration of dopaminergic neurons of the substantia nigra associated with Parkinson's disease, and how these two parameters may interact with one another to bring this about. Andersen-Ranberg, K., L. Vasegaard, et al. (2001). "Dementia is not inevitable: a population-based study of Danish centenarians." J Gerontol B Psychol Sci Soc Sci 56(3): P152-9. The authors evaluated the prevalence of dementia in centenarians. In this population-based survey, persons living in Denmark who turned 100 during the period April 1, 1995--May 31, 1996 (N = 276) were interviewed and examined at their residences. Additional health information was retrieved from medical files, including the National Discharge Registry. A participation rate was 75%, and no differences were found between participants and nonparticipants regarding sex and type of housing. The prevalence of mild to severe dementia in centenarians was 51%; 37% had no signs of dementia. Among the 105 demented centenarians, 13 (12%) had diseases (vitamin B12 and folic acid deficiencies, hypothyroidism, Parkinson's disease) that could contribute to a dementia diagnosis. Of the remaining 92 demented participants, 46 (50%) had 1 one or more cerebro- or cardiovascular diseases known to be risk factors in the development of dementia. The prevalence of these risk factors was the same in demented and nondemented participants, whereas hypertension was significantly more frequent in nondemented than demented participants. Dementia is common but not inevitable in centenarians. Cerebro- and cardiovascular diseases are equally common in demented and nondemented persons. Anderson, D. W., T. Neavin, et al. (2001). "Neuroprotective effects of pramipexole in young and aged MPTP-treated mice." Brain Res 905(1-2): 44-53. This study examined the effect of pramipexole (PPX), a selective dopamine (DA) D(3)/D(2) agonist, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced damage to the nigrostriatal dopamine system in young (8-week-old) and aged (12-month-old) mice. Co-administration of PPX and MPTP to young or aged mice, followed by 2 or 14 days of additional PPX treatment, significantly attenuated MPTP-induced striatal DA loss. Pramipexole treatment also significantly attenuated the loss of tyrosine hydroxylase immunoreactive neurons (TH-IR) within the substantia nigra pars compacta (SNc) in both young and aged animals. Effects of PPX administration on dopaminergic cell survival were confirmed in Nissl-stained sections and by quantitation of retrogradely labeled Fluorogold-positive SNc neurons. Protective effects of PPX on striatal DA levels and SNc DA neuron survival were similar in young and aged animals, although the magnitude of these effects was significantly less in aged animals. These findings support the early initiation of PPX therapy in Parkinson's disease patients. Anderson, W. F. (2001). "Excitement in gene therapy!" Hum Gene Ther 12(12): 1483-4. Andersson, I. and B. Sidenvall (2001). "Case studies of food shopping, cooking and eating habits in older women with Parkinson's disease." J Adv Nurs 35(1): 69-78. AIMS: The principal aim of this study was to investigate how married and single-living older women diagnosed with Parkinson's disease managed to shop for food, cook and carry out their meals; and to observe whether their nutritional needs were satisfied. A secondary aim was to identify women with severe motor problems and describe their food-related situation. BACKGROUND: Parkinson's disease is associated with motor and eating problems, which, combined with age-related declines in physical functioning, may affect activities of daily living and dietary intake. METHODS: Qualitative interviews and food survey were carried out in the homes of 10 women aged 67-80 years. The sample was recruited from outpatient registers. RESULTS: Decreased sense of smell, appetite and taste in combination with problems transporting food to the mouth and swallowing were risks for nutritional well-being. Food shopping was most difficult to manage, but six cooked even if their cooking style was changed. Married women with healthy husbands received support from their spouses. Single-living women suffering from motor problems had to call for help, which represented a threat to their well-being. Independence was given high priority. CONCLUSIONS: The whole situation - including psychosocial and stress factors - must be taken into account when discussing shopping, cooking and eating among old women with Parkinson's disease. A home-helper should not take over but facilitate procedures so that the woman can manage as long as possible. This gave them self-esteem. Andoh, T. (2001). "[Effects of general anesthetics on neuronal nicotinic acetylcholine receptors and their roles in the mechanism of anesthesia]." Masui 50(10): 1072-84. Neuronal nicotinic acetylcholine receptors (nAchRs) are widely expressed in the central and autonomic nervous systems and have subunit compositions with biophysical and pharmacological properties distinct from those of the receptors at the neuromuscular junction. They are thought to modulate synaptic transmission in the central nervous system (CNS) mainly by regulating the release of neurotransmitters. Although roles of neuronal nAchRs in the CNS are poorly understood, these receptors are involved in cognitive performance, nociception and psychoneurological disorders such as Alzheimer's and Parkinson disease. It is known that both central and peripheral neuronal nAchRs are sensitive to various types of anesthetics. Among those, barbiturates, ketamine, volatile and gaseous anesthetics depress neuronal nAchRs at or below clinical concentrations. Inhibition of neuronal nAchRs by barbiturates is unlikely to contribute to the anesthetic action of barbiturates, since this effect does not correlate with the anesthetic potencies of barbiturate stereoisomers. Relevance of inhibition of these receptors is controversial for anesthetic effects of other anesthetics, because conflicting results have been obtained from comparison of this effect with anesthetic actions of stereoisomers or structurally related compounds. However, it is possible that inhibition of central nAchRs contributes to secondary effects attributed to anesthesia such as impairment in memory and cognitive performance. Andreassen, O. A., R. J. Ferrante, et al. (2001). "Mice with a partial deficiency of manganese superoxide dismutase show increased vulnerability to the mitochondrial toxins malonate, 3-nitropropionic acid, and MPTP." Exp Neurol 167(1): 189-95. There is substantial evidence implicating mitochondrial dysfunction and free radical generation as major mechanisms of neuronal death in neurodegenerative diseases. The major free radical scavenging enzyme in mitochondria is manganese superoxide dismutase (SOD2). In the present study we investigated the susceptibility of mice with a partial deficiency of SOD2 to the neurotoxins 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), 3-nitropropionic acid (3-NP), and malonate, which are commonly used animal models of Parkinson's and Huntington's disease. Heterozygous SOD2 knockout (SOD2(+/-)) mice showed no evidence of neuropathological or behavioral abnormalities at 2-4 months of age. Compared to littermate wild-type mice, mice with partial SOD2 deficiency showed increased vulnerability to dopamine depletion after systemic MPTP treatment and significantly larger striatal lesions produced by both 3-NP and malonate. SOD2(+/-) mice also showed an increased production of "hydroxyl" radicals after malonate injection measured with the salicylate hydroxyl radical trapping method. These results provide further evidence that reactive oxygen species play an important role in the neurotoxicity of MPTP, malonate, and 3-NP. These findings show that a subclinical deficiency in a free radical scavenging enzyme may act in concert with environmental toxins to produce selective neurodegeneration. Andrews, L. W. (2001). "Working around PD." Environ Health Perspect 109(3): A114. Andrews, R. J. (2001). "Neuroprotection for the new millennium. Matchmaking pharmacology and technology." Ann N Y Acad Sci 939: 114-25. A major theme of the 1990s in the pathophysiology of nervous system injury has been the multifactorial etiology of irreversible injury. Multiple causes imply multiple opportunities for therapeutic intervention--hence the abandonment of the "magic bullet" single pharmacologic agent for neuroprotection in favor of pharmacologic "cocktails". A second theme of the 1990s has been the progress in technology for neuroprotection, minimally- or non-invasive monitoring as well as treatment. Cardiac stenting has eliminated the need, in many cases, for open heart surgery; deep brain stimulation for Parkinson's disease has offered significant improvement in quality of life for many who had exhausted cocktail drug treatment for their disease. Deep brain stimulation of the subthalamic nucleus offers a novel treatment for Parkinson's disease where a technological advance may actually be an intervention with effects that are normally expected from pharmacologic agents. Rather than merely "jamming" the nervous system circuits involved in Parkinson's disease, deep brain stimulation of the subthalamic nucleus appears to improve the neurotransmitter imbalance that lies at the heart of Parkinson's disease. It may also slow the progression of the disease. Given the example of deep brain stimulation of the subthalamic nucleus for Parkinson's disease, in future one may expect other technological or "hardware" interventions to influence the programming or "software" of the nervous system's physiologic response in certain disease states. Anichtchik, O. V., N. Peitsaro, et al. (2001). "Distribution and modulation of histamine H(3) receptors in basal ganglia and frontal cortex of healthy controls and patients with Parkinson's disease." Neurobiol Dis 8(4): 707-16. Parkinson's disease (PD) is a brain degenerative disorder with unknown etiology, and specific degeneration of mesencephalic dopaminergic cells is a morphological manifestation of the disease. The central histaminergic system appears to be activated in PD, since the histaminergic innervation is increased in the substantia nigra. The aim of the present study was to investigate the expression and function of histamine H(3) receptors in PD, using receptor mRNA in situ hybridization with oligonucleotide probes, receptor binding assay with a specific radioactive agonist, and GTP-gamma-[(35)S]-binding assay as a tool to study the activation of the receptor G-protein. H(3) receptor binding sites were detected using N-alpha-methylhistamine autoradiography in the basal ganglia and cortex, being most abundant in the substantia nigra and striatum. In PD substantia nigra we detected an increase of the receptor binding density. In situ hybridization study of the receptor mRNA revealed prominent sites of H(3) receptor synthesis in the putamen, cortex, and globus pallidus, whereas very low mRNA expression was seen in the substantia nigra. In the PD pallidum externum, H(3) receptor mRNA expression was elevated as compared with the normal brains. GTP-gamma-[(35)S]-binding assay did not reveal any significant difference between PD and normal brains, although the density values in PD substantia nigra tended to be lower than in the normal brain, and density values in PD striatum were higher. The dopaminergic neurons did not express significant amount of H(3) receptor mRNA, suggesting that the effects of H(3) receptor-mediated modulation of dopamine release are indirect. Our data indicates modulation of the histamine H(3) receptor in PD at the level of the mRNA expression in the striatum and receptor density in the substantia nigra. The receptor activity seems to be unchanged or decreased, as revealed by GTP-gamma-[(35)S]-binding assay. Modulation of the histamine H(3) receptor may influence the activity of other neurotransmitter systems, e.g., the GABAergic one, in the substantia nigra. Antman, K., S. Lagakos, et al. (2001). "Designing and funding clinical trials of novel therapies." N Engl J Med 344(10): 762-3. Antonini, A., R. De Notaris, et al. (2001). "Perfusion ECD/SPECT in the characterization of cognitive deficits in Parkinson's disease." Neurol Sci 22(1): 45-6. Cognitive abnormalities have been reported in a large percentage of patients with Parkinson's disease (PD). Often cognitive changes are sub-clinical and involve frontal lobe function. In other occasions they develop into full dementia. Functional neuroimaging may help characterize these abnormalities. We have studied brain perfusion with SPECT and the tracer ECD in 44 PD patients, 22 presenting with normal cognitive function and 22 with clinical and neuropsychological signs of dementia. Compared with 21 healthy controls, demented PD patients showed significant perfusion decrements in all cortical areas, particularly temporal and parietal regions; in the non-demented cohort reductions were limited to the frontal lobe area. These results suggest that brain perfusion abnormalities are present in PD patients. It is speculated that different pathological mechanisms underlie perfusion differences. Antonini, A., R. M. Moresco, et al. (2001). "The status of dopamine nerve terminals in Parkinson's disease and essential tremor: a PET study with the tracer [11-C]FE-CIT." Neurol Sci 22(1): 47-8. Neuroimaging studies of the striatal dopamine transporter (DAT) are useful in the assessment of the dopaminergic system in Parkinson's disease (PD). We used positron emisson tomography (PET) and the tracer [11C]FE-CIT to measure DAT binding in the caudate nucleus and putamen of 31 patients with PD, 5 with essential tremor and 8 healthy control subjects. Of the patients with PD, 17 were drug naive, while the others were either on levodopa or dopamine agonist monotherapy. DAT binding was significantly reduced in the caudate nucleus and to a greater extent in the putamen of PD patients compared to both healthy controls and essential tremor individuals. No overlap was observed between putamen values in PD and normals. No differences were found between controls and essential tremor subjects. These data confirm that measurements of DAT binding can provide an accurate and highly sensitive measure of degeneration in the dopamine system in PD. Aoi, M., I. Date, et al. (2001). "Single administration of GDNF into the striatum induced protection and repair of the nigrostriatal dopaminergic system in the intrastriatal 6-hydroxydopamine injection model of hemiparkinsonism." Restor Neurol Neurosci 17(1): 31-38. Purpose: Neurotrophic factor delivery into the brain is a promising approach in the treatment of Parkinson's disease. Glial cell line-derived neurotrophic factor (GDNF) is one of the most potent neurotrophic factors for dopaminergic neurons. Although multiple injections of GDNF into the brain are commonly performed in experimental studies, the present study investigates the efficacy of using a single injection of GDNF, which may be useful in elinically applying this treatment. Methods: Unilateral 6-hydroxydoparnine (6-OHDA) administration into the striatum was perforrned in Sprague-Dawley rats to create a partial lesion of the nigrostriatal DA system. These parkinsonian model rats received a single injection of human recombinant GDNF into the same portion of the striatum either 24 h before or 4 weeks after 6-OHDA treatrnent. Results: GDNF injected into the striatum before 6-OHDA administration potently protected the dopaminergic system, as shown by the numbers of mesencephalic dopaminergie neuron cell bodies and dopaminergic nerve terminal densities in the striatum. Dopaminergic neuron cell bodies and fiber densities were also significantly restored when GDNF was given after 6-OHDA administration, although the degree of restoration was lower than in the protective experiment. ODNF administration ameliorated apomorphine-induced rotational behavior in animals receiving it either before or after 6-OHDA treatment. However, the degree of improvement was less prominent when GDNF was iniected after 6-OHDA. Conclusion: Intracerebral GDNF adininistration exerts both protective and regenerative effects on the nigrostriatal dopaminergic system, a finding which may have implications for the development of new treatment strategies for Parkinson's disease. Aomi, Y., C. S. Chen, et al. (2001). "Cytoplasmic transfer of platelet mtDNA from elderly patients with Parkinson's disease to mtDNA-less HeLa cells restores complete mitochondrial respiratory function." Biochem Biophys Res Commun 280(1): 265-73. For determination of whether platelet mtDNA in patients with Parkinson's disease (PD) possesses some lesions to reduce respiratory enzyme activities, platelet mtDNA was transferred into mtDNA-less (rho0) HeLa cells from aged PD patients and age-matched normal subjects, since their activities were controlled by both mitochondrial and nuclear genomes. The resultant mtDNA-repopulated cybrid clones containing the HeLa nuclear genome as a common background were used for comparison of respiratory enzyme activities. Remarkable variations of the enzyme activities were observed in the cybrid clones, irrespective of whether their mtDNA was transferred from normal subjects or PD patients, and some of them showed 20% reduction of average activities. Thus, the mtDNA mutations responsible for inducing 20% reduction should be polymorphic rather than pathogenic. On the other hand, pathogenic control cybrid clones possessing mtDNA mutations from patients with mitochondrial disorders showed significant and specific decline of respiratory enzyme complex I activity beyond the normal range of the variations. These observations warrant reassessment of the conventional concept that complex I activity in platelets of PD patients is defective due to mtDNA mutations. Aoyama, K., K. Matsubara, et al. (2001). "Nicotinamide-N-methyltransferase is higher in the lumbar cerebrospinal fluid of patients with Parkinson's disease." Neurosci Lett 298(1): 78-80. Parkinson's disease (PD) may be initiated or precipitated by endogenous toxins with a structure similar to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in genetically-predisposed individuals. Nicotinamide N-methyltransferase (NNMT) catalyzes N-methylation of nicotinamide and other pyridines to form pyridinium ions. The protein amount of NNMT was measured in the lumbar cerebrospinal fluid of PD patients by immunoblot analysis using anti-human NNMT antibody. In younger (65 years old or younger) PD patients, the relative level of NNMT protein was significantly higher than that in younger controls. The NNMT protein was significantly affected by aging: the amount decreased along with aging in PD patients. These findings suggested that excess NNMT in the central nervous system might be implicated in the PD pathogenesis. Apartis, E., F. Tison, et al. (2001). "Fast orthostatic tremor in Parkinson's disease mimicking primary orthostatic tremor." Mov Disord 16(6): 1133-6. Leg tremor during standing is a rare feature in idiopathic Parkinson's disease (PD). Tremor during standing usually has a low frequency (range, 4-6 Hz), similar to PD rest tremor frequency, and is improved by levodopa. We describe three cases of fast orthostatic tremor (FoT) of legs and trunk mimicking primary orthostatic tremor (OT) in patients treated with levodopa for PD. Asymmetrical akinetorigid syndrome was accompanied by a rest tremor in two cases. We obtained electrophysiological parameters by electromyographic (EMG) polygraphic recording after 16 hours withdrawal of antiparkinsonian treatment and at the maximal effect of levodopa in order to investigate the effect of dopaminergic stimulation upon such cases of orthostatic tremor in PD. Electrophysiological parameters of orthostatic tremor, especially frequency (range 14-18 Hz), were similar to that seen in POT. Severity of tremor was independent of seriousness and duration of PD. Levodopa had no effect either on the handicap due to OT or on the amplitude and frequency of the EMG OT activity. In contrast, mild improvement of OT was obtained with benzodiazepines in two cases and parkinsonian syndrome was levodopa-sensitive. These findings suggest that FoT in PD would not be directly controlled by the dopaminergic system. However, increased rhythmicities in basal ganglia or in cerebello-thalamic loops at the rapid frequencies range seen in PD could favor the emergence of a primary orthostatic tremor-like tremor in PD patients. Arai, Y., M. Yamazaki, et al. (2001). "Alpha-synuclein-positive structures in cases with sporadic Alzheimer's disease: morphology and its relationship to tau aggregation." Brain Res 888(2): 287-296. Alzheimer's disease (AD) and Parkinson's disease share common clinical and pathological features. In this study, we examined the relationship between AD pathology and alpha-synuclein aggregation. The frequency and distribution of alpha-synuclein-positive structures were systematically investigated in 27 cases with sporadic AD by alpha-synuclein immuno-histochemistry. Thirteen (48.2%) of 27 cases had various alpha-synuclein-positive structures as well as Lewy bodies. The frequency and density of senile plaques and neurofibrillary tangles were not significantly different between cases with alpha-synuclein structures and those without. alpha-Synuclein-positive structures were found most frequently in the amygdala. The alpha-synuclein-positive inclusions that are different from Lewy bodies were observed at the highest rate in the hippocampus. The discovery of alpha-synuclein as the constituent of Lewy bodies facilitated the detection of Lewy-related structures even in AD cases with widespread and numerous neurofibrillary tangles. alpha-Synuclein-positive inclusions except for Lewy bodies are exposed, and the distribution of them indicates that Lewy body formation may be influenced by the degree of tau aggregation. This study also supports the suggestion that cases with AD pathology can be classified into two groups according to the existence or absence of alpha-synuclein aggregation. Araki, T., T. Mikami, et al. (2001). "Biochemical and immunohistological changes in the brain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse." Eur J Pharm Sci 12(3): 231-8. We investigated neurochemically and neuropathologically the utility of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice as a model of Parkinson's disease. The changes in dopamine D1 and D2 receptors and dopamine uptake sites were determined by quantitative autoradiography using [3H]SCH23390, [3H]raclopride and [3H]mazindol, respectively. Dopamine and 3,4-dihydroxyphenyl acetic acid (DOPAC) contents in the striatum were measured by high-performance liquid chromatography. The distribution of nigral neurons and reactive astrocytes was determined by immunohistochemical staining with antibody against tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP). The mice received four intraperitoneal injections of MPTP (10 mg/kg) at 1-h intervals and then the brains were analyzed at 3 and 7 days after the treatments. No significant change in dopamine D1 receptors was observed in the striatum and substantia nigra after acute treatment with MPTP. Dopamine D2 receptors were reduced significantly in the substantia nigra only 7 days after the MPTP treatment, whereas striatum showed no significant change in the binding throughout the experiments. In contrast, dopamine uptake sites were reduced markedly in the striatum and substantia nigra 3 and 7 days after the MPTP treatment. Dopamine and DOPAC content were also reduced in the striatum 3 and 7 days after the MPTP treatment. An immunohistochemical study indicated a loss of the number of TH-positive neurons in the substantia nigra 7 days after the MPTP treatment. In contrast, numerous GFAP-positive astrocytes were evident in the striatum 7 days after the MPTP treatment. These results provide valuable information for the pathogenesis of acute stage of Parkinson's disease. Araki, T., Y. Muramatsu, et al. (2001). "Riluzole (2-amino-6-trifluoromethoxy benzothiazole) attenuates MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity in mice." Neurosci Lett 312(1): 50-4. The protective effects of 2-amino-6-trifluoromethoxy benzothiazole (riluzole), a Na(+) channel blocker with antiglutamatergic activity were investigated in the model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced depletion of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in mice. The mice were injected intraperitoneally (i.p.) with four administrations of MPTP (10 mg/kg) at 1 h intervals and then the brains were analyzed at 3 and 7 days after the treatments. Dopamine, DOPAC and HVA levels were significantly decreased in the striatum 3 days after MPTP treatments. Riluzole dose-dependently antagonized the MPTP-induced decrease in dopamine, DOPAC and HVA levels in the striatum. MPTP treatment also caused a severe decrease in the amount of nigral tyrosine hydroxylase protein (TH) and microtuble-associated protein 2 (MAP 2) and produced a marked increase in the striatal glial fibrillary acidic protein (GFAP). Our immunohistochemical study with TH and MAP 2 staining showed that riluzole can protect against MPTP-induced neuronal damage in the substantia nigra. Furthermore, riluzole markedly increased the striatal GFAP-positive astrocytes 3 days after MPTP treatments. These results suggest that riluzole is effective against MPTP-induced neurodegeneration of the nigrostriatal dopaminergic neuronal pathway. Our findings also may provide a rationale for the identification of astrocytes as a prominent target for the development of new therapies of Parkinson's disease. Arciniegas, D. B., J. L. Topkoff, et al. (2001). "Psychosis Due to Neurologic Conditions." 3(4): 347-366. Psychosis arises with considerable frequency in a number of neurologic conditions. The treatment of such patients is often challenging, as many of the treatments for psychosis pose some risk of worsening the underlying neurologic condition. Although psychosis may emerge in the context of any neurologic condition that sufficiently disrupts the functioning of or connections between limbic, paralimbic, frontal, subcortical areas mediating complex sensory perception, interpretation, and thought or language organization, secondary psychoses are most often encountered in patients with Alzheimer's disease (Parkinson's disease receives dopaminomimetic therapies) and epilepsy. Psychosis, and particularly delusions and visual hallucinations, may arise in Alzheimer's disease. Based on the available literature, the first-line therapy for this problem is risperidone 0.5 to 3 mg per day. If this treatment proves unsuccessful, low-dose haloperidol or olanzapine should be considered next. If these treatments prove unsuccessful, quetiapine should then be considered. Finally, clozapine may be useful for treatment-refractory psychosis due to Alzheimer's disease, but due caution is warranted given its considerable anticholinergic properties and potential for worsening cognition in these patients. Although disease-emergent psychosis (paranoid delusions and visual hallucinations) may develop in patients with Parkinson's disease, psychosis due to dopaminomimetic therapy is much more common. When such symptoms develop, the accepted first step is to taper anti-parkinsonian medications were possible. Anticholinergic medications, amantadine, selegiline, and dopamine receptor agonists should be reduced or discontinued, provided that the patient can tolerate changes in motor symptoms attendant to such reductions. When these reductions are not feasible or fail to improve treatment-emergent psychosis, low-dose quetiapine or clozapine may be useful. The greatest body of evidence supports the effectiveness of these treatments and their relative lack of adverse effects on motor function. When psychosis develops in the context of epilepsy, the generally accepted first step is to maximize anticonvulsant therapy in an effort to reduce the possible contribution of electrophysiologic disturbances in the described areas to psychotic symptoms. When interictal psychosis persists despite such adjustments, initiation with low-dose atypical antipsychotics carries the least risk of lowering seizure threshold and should be considered. Armstrong, R. J., T. P. Harrower, et al. (2001). "Porcine neural xenografts in the immunocompetent rat: immune response following grafting of expanded neural precursor cells." Neuroscience 106(1): 201-16. Intracerebral neural xenografts elicit a host immune response that results in their rapid rejection. This forms a key barrier to the therapeutic use of xenogeneic tissue transplantation for conditions such as Parkinson's disease. The current study sought to provide insight into the cellular components of donor cell suspensions that are important in stimulating the host rejection response and thereby to suggest rational manipulations of xenogeneic donor tissue that might ultimately enhance its clinical utility. The neural stem cell mitogens, epidermal growth factor and fibroblast growth factor-2, have been used to isolate and expand populations of primordial neural precursor cells from the embryonic pig brain. The immune response elicited by these cells on transplantation into the non-immunosuppressed rat has been fully characterised.In the first experiments, expanded neural precursors were grafted into the hemi-parkinsonian, non-immunosuppressed Sprague-Dawley rat and graft status and host response examined 10, 21, 35 and 60 days post-transplantation. While equivalent primary tissue grafts were completely eliminated at 35 days, grafts of expanded neural precursors with healthy neurofilament-positive projections were present at all time-points, and two large grafts remained even at 60 days. Some grafts appeared to elicit minimal host immune responses at the time-points they were examined, although most did appear to be undergoing a rejection process since a co-ordinated response involving host cytotoxic T-lymphocytes, microglia/macrophages, immunoglobulin M and complement could be demonstrated to varying degrees.Subsequent experiments went on to demonstrate further that expanded precursor populations and primary tissue suspensions differed in their immunogenic profile. Firstly, when primary tissue was injected intraperitoneally into immunocompetent rats a vigorous primary humoral response was generated. No such response was detected following injection of expanded neural precursors. Secondly, flow cytometric analysis revealed small but significant levels of class II porcine major histocompatibility complex expression in primary cell suspensions but no such expression in expanded precursor populations.The results of this study therefore demonstrate that the immunogenicity of porcine neural cell suspensions used for intracerebral grafting is reduced when neural stem cell mitogens are used to expand precursor cells. The implications of these findings in the development of novel xenogeneic cellular therapies for neurodegenerative conditions such as Parkinson's disease are discussed. Arnott, W. L. and H. J. Chenery (2001). "Lexical decision in Parkinson's disease: a reply to Brown, McDonald, and Spicer (1999)." J Clin Exp Neuropsychol 23(2): 250-1. Arnott, W. L., H. J. Chenery, et al. (2001). "Semantic priming in Parkinson's disease: evidence for delayed spreading activation." J Clin Exp Neuropsychol 23(4): 502-19. Nineteen persons with Parkinson's disease (PD) and 19 matched control participants completed a battery of online lexical decision tasks designed to isolate the automatic and attentional aspects of semantic activation within the semantic priming paradigm. Results highlighted key processing abnormalities in PD. Specifically, persons with PD exhibited a delayed time course of semantic activation. In addition, results suggest that experimental participants were unable to implicitly process prime information and, therefore, failed to engage strategic processing mechanisms in response to manipulations of the relatedness proportion. Results are discussed in terms of the 'Gain/Decay' hypothesis (Milberg, McGlinchey-Berroth, Duncan, & Higgins, 1999) and the dopaminergic modulation of signal to noise ratios in semantic networks. Arnulf, I., M. Vidailhet, et al. (2001). "Blockade of cholecystokinin-A receptors has no effect on dyskinesias in Parkinson's disease." J Neurol Neurosurg Psychiatry 70(6): 812-3. Arvanitakis, Z. and Z. K. Wszolek (2001). "Recent advances in the understanding of tau protein and movement disorders." Curr Opin Neurol 14(4): 491-7. Tau plays an important role in movement disorders. The accumulation of pathological tau is a major substrate of frontotemporal dementia and parkinsonism linked to chromosome 17, progressive supranuclear palsy, and corticobasal degeneration. Over the past year, several new mutations on the tau gene have been found. These mutations have been classified into three groups: (i) mutations in constitutively spliced exons; (ii) mutations in the alternatively spliced exon 10; and (iii) mutations of the exon 10 5' splice site. Some patients presenting with frontotemporal dementia and parkinsonism linked to chromosome 17 transiently respond to levodopa therapy. The significance of Pick bodies was recognized by a recent study on kindred with the Glu342Val tau mutation. In sporadic cases of progressive supranuclear palsy, the presence of the H1 haplotype was found to be a risk factor. Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy. This opens the question of whether corticobasal degeneration represents a separate disorder or a spectrum of disease with progressive supranuclear palsy. However, distinguishing features are observed, and include oculomotor abnormalities, which may help to differentiate these two disorders on clinical grounds. Despite recent advances in the understanding of the tauopathies, there are still no curative therapies available. It is hoped that studies in transgenic tau animal models will lead to the development of successful treatments. Ascherio, A., S. M. Zhang, et al. (2001). "Prospective study of caffeine consumption and risk of Parkinson's disease in men and women." Ann Neurol 50(1): 56-63. Results of case-control studies and of a prospective investigation in men suggest that consumption of coffee could protect against the risk of Parkinson's disease, but the active constituent is not clear. To address the hypothesis that caffeine is protective against Parkinson's disease, we examined the relationship of coffee and caffeine consumption to the risk of this disease among participants in two ongoing cohorts, the Health Professionals' Follow-Up Study (HPFS) and the Nurses' Health Study (NHS). The study population comprised 47,351 men and 88,565 women who were free of Parkinson's disease, stroke, or cancer at baseline. A comprehensive life style and dietary questionnaire was completed by the participants at baseline and updated every two to four years. During the follow-up (10 years in men, 16 years in women), we documented a total of 288 incident cases of Parkinson's disease. Among men, after adjustment for age and smoking, the relative risk of Parkinson's disease was 0.42 (95% CI: 0.23-0.78; p for trend < 0.001) for men in the top one-fifth of caffeine intake compared to those in the bottom one-fifth. An inverse association was also observed with consumption of coffee (p for trend = 0.004), caffeine from noncoffee sources (p for trend < 0.001), and tea (p for trend = 0.02) but not decaffeinated coffee. Among women, the relationship between caffeine or coffee intake and risk of Parkinson's disease was U-shaped, with the lowest risk observed at moderate intakes (1-3 cups of coffee/day, or the third quintile of caffeine consumption). These results support a possible protective effect of moderate doses of caffeine on risk of Parkinson's disease. Ashburn, A., E. Stack, et al. (2001). "Predicting fallers in a community-based sample of people with Parkinson's disease." Gerontology 47(5): 277-81. BACKGROUND: The risk of people with Parkinson's disease (PD) falling is greater than that of the general population but to date, disease-specific predictors of falling have not been identified. OBJECTIVES: To identify one or more features, which would predict individuals at risk of falling during a 3-month prospective follow-up study. METHOD: A battery of standardised tests administered in the home and the laboratory with a 3-month follow-up telephone interview. RESULTS: Sixty-three people with PD were recruited from GP practices. Eleven interview variables and six gait laboratory variables were used with subsamples (55 and 44 subjects, respectively) to fit predictive models for identifying future fallers. The number of falls in the previous year was the most important variable, without exception, to be selected as a predictor in various logistic regression models. A history of two or more falls had a sensitivity of 86.4% (95% CI 67.3-96.2%) and a specificity of 85.7% (95% CI 71.2-94.2%) in predicting falling in the next 3 months. CONCLUSION: Healthcare workers should be asking their patients with PD regularly and carefully about falling, and should consider instigating programmes of fall management for patients with PD who have fallen two or more times in the previous 12 months. Ashburn, A., E. Stack, et al. (2001). "A community-dwelling sample of people with Parkinson's disease: characteristics of fallers and non-fallers." Age Ageing 30(1): 47-52. BACKGROUND: people with Parkinson's disease often fall. OBJECTIVES: to report the frequency of falls and characteristics of fallers and non-fallers in a community-based sample of people with Parkinson's disease. METHOD: we administered a battery of standardized tests in the home and the laboratory. RESULTS: we recruited 63 people with Parkinson's disease through general practices. Forty (64%, 95% confidence interval 51-74%) had fallen in the previous 12 months. Many factors associated with falling in the general population were associated with Parkinson's disease fallers (e.g. use of multiple medication and greater physical disability). Fallers were more likely to be depressed and anxious than non-fallers. Condition-specific factors associated with falling included greater disease severity (although there were exceptions) and more marked response to levodopa treatment, including more dyskinesia and on-off phenomena. Fallers took more steps to complete a test of mobility. They also had a shorter functional reach and greater postural sway whilst completing a dual task than non-fallers. CONCLUSION: this community-based study confirms the high risk of falling in Parkinson's disease. Our results suggest that disease-specific factors contribute to the increased risk and that there is scope for specific therapeutic interventions. Ashby, P., G. Paradiso, et al. (2001). "Potentials recorded at the scalp by stimulation near the human subthalamic nucleus." Clin Neurophysiol 112(3): 431-7. OBJECTIVE: To record the potentials evoked at the scalp by stimulation through electrodes targeted at the human subthalamic nucleus (STN) and to determine whether the responsible pathways continue to be excited or become blocked with high frequency stimulation. METHODS: We recorded the potentials evoked at the scalp in response to single and multiple stimuli delivered through STN contacts in 6 patients with Parkinson's disease. RESULTS: On 9/11 sides tested, single stimuli elicited a negative potential with latency of approximately 3 ms which was largest over the frontal region. Its short chronaxie (50 micros) and refractory period imply that it arose from the activation of low threshold neural elements, possibly myelinated axons. This potential could follow at 100 Hz. This early potential was sometimes followed by later negative potentials at approximately 5 ms (6/11 sides) and approximately 8 ms (8/11 sides). The responsible neural elements had the same short chronaxie. These potentials were augmented by paired stimuli at separations of 2-7 ms and by trains of stimuli at 200 Hz. CONCLUSIONS: Trains of stimuli delivered to the STN may excite low threshold neural elements which can transmit impulses at frequencies >100 Hz without blocking and which may produce postsynaptic facilitation at the cortex. Askenasy, J. M. (2001). "Approaching disturbed sleep in late Parkinson's Disease: first step toward a proposal for a revised UPDRS." 8(2): 123-131. A patient in stage 3-4 of the Unified Parkinson's Disease Rating Scale (UPDRS), or in stage 4-5 of Hoehn and Yahr staging scale, or a patient with 0-50% activities of daily living scale of Schwab and England is considered a Late Parkinson's Disease (LPD) patient. The prevalence of disturbed sleep in Parkinson's Disease (PD) was found to vary according to an objective rating, from 60 to 98%. The factors predicting the quality of life in PD patients are: depression, sleep disturbances and dependence. The present article proposes the insertion of the following items as a chapter in a revised UPDRS based on updated knowledge in sleep arousal disturbances in PD.Approaching the treatment of disturbed sleep in LPD means postponement of the institutionalization of the LPD patient, allowing the spouse or the caregiver a quiet nights sleep. This approach consists of three steps, each one of major importance. (1) Correct diagnosis based on detailed anamnesis of the patient, of the spouse or of the caregiver; a one week recording on a symptom diary (log) by the patient or the caregiver; excluding co morbidities. Then choosing the most appropriate sleep test, if necessary: polysomnography (PSG), multiple sleep latency test (MSLT), multiple wake latency test (MWLT), actigraphy or video-PSG. This first step allows the diagnosis of one of the above mentioned sleep-arousal disturbances. (2) The non-specific therapeutic approach consists of: (a) checking the sleep effect on motor performance: beneficial, worse or neutral. (b) Dopaminergic adjustment is necessary due to the progression of the nigrostriatal degeneration and the increased sensitivity of the terminals which alter the normal modulator mechanisms of motor centers in LPD patients. Among the many neurotransmitters of the nigro-striatal pathway one can distinguish two with a major influence on REM and non-REM sleep. REM sleep corresponds to an increased cholinergic receptor activity and a decreased dopaminergic activity. This is the reason why REM sleep deprivation by suppressing cholinergic receptor activity ameliorates LPD motor symptoms. L-Dopa and its agonists by suppressing cholinergic receptors suppress REM sleep. L-Dopa has also an arousal effect on Non-REM sleep, repeatedly awakening the patient and enhancing the fragmentation due to the involuntary movements. (c) Socio-physical assistance. (3) The specific therapy consists of: LFS-Sinemet CR, Tolcapone, Intranasal Desmopressin, Domperidon, Cisapride and neurosurgery; SRBD-CPAP, UPPP, nasal interventions, losing weight; RLS-PLM-Benzodiazepine (Clonazepam), Opioid, Apomorphine infusion; RBD-Clonazepam and dopaminergic agonists; SRH-Clozapine, Risperidone; SRPD-Nortriptyline, Clozapine, Olanzepine; SA-adjustment; EDS-arousing drugs. Each therapeutic approach must be tailored to the individual LPD patient. Awad-Granko, H. and P. J. Conn (2001). "Activation of groups I or III metabotropic glutamate receptors inhibits excitatory transmission in the rat subthalamic nucleus." Neuropharmacology 41(1): 32-41. The subthalamic nucleus (STN) is a key nucleus in the basal ganglia motor circuit that provides the major glutamatergic excitatory input to the basal ganglia output nuclei. The STN plays an important role in the normal motor function, as well as in pathological conditions such as Parkinson's disease. Development of a complete understanding of the role of the STN in motor control will require a detailed understanding of the mechanisms involved in the regulation of excitatory and inhibitory synaptic transmission in this nucleus. Here, we report that activation of groups I or III metabotropic glutamate (mGlu) receptors, but not group II, causes a depression of excitatory transmission in the STN. In contrast, mGlu receptor activation has no effect on the inhibitory transmission in this nucleus. Further characterization of the group I mGlu receptor-induced effect on EPSCs suggests that this response is mediated by mGlu1 and not mGlu5. Further, paired pulse studies suggest that both the mGlu1 receptor and the group III mGlu receptor-mediated effects are due to a presynaptic mechanism. If these receptors are involved in endogenous synaptic transmission in the STN, these results raise the exciting possibility that selective agents targeting mGlu receptors may provide a novel approach for the treatment of motor disorders involving the STN. Baas, H., F. Zehrden, et al. (2001). "Pharmacokinetic-pharmacodynamic relationship of levodopa with and without tolcapone in patients with Parkinson's disease." Clin Pharmacokinet 40(5): 383-93. OBJECTIVE: To investigate the effect of administration of the catechol-Omethyltransferase (COMT) inhibitor tolcapone on the concentration-effect relationship of levodopa in patients with advanced Parkinson's disease and on-off fluctuations. DESIGN: Nonblind single-group 2-period pharmacokinetic-pharmacodynamic study. PATIENTS AND PARTICIPANTS: 12 patients, mean age 59 years, with idiopathic Parkinson's disease and response fluctuations. METHODS: The pharmacokinetics [plasma concentrations of levodopa and 3-O-methyldopa (3-OMD)] and motor effects [global score of the Columbia University Rating Scale (CURSsigma)] of levodopa (plus the peripheral decarboxylase inhibitor benserazide 1:4) were determined for 4 consecutive dosage intervals (4 hours each, starting at 8.00am) in 12 patients before (day 1) and during (day 8) coadministration of tolcapone 100 mg 3 times daily for 7 days. RESULTS: Under tolcapone, exposure to levodopa [area under the plasma concentration-time for the dosage interval (AUCt)] observed for the separate doses increased by 1.6- to 2.2-fold, and peak plasma drug concentrations (Cmax) increased by 1.1 - to 2.1 -fold. 3-OMD concentrations at day 8 were reduced to about 20% of the values at day 1. At baseline (day 1, before the first levodopa dose), CURSsigma averaged 40 +/- 10 points. After the first levodopa dose. CURSsigma declined to 20 +/- 9 points. At day 8. the predose CURSsigma decreased to a final score of 31 +/-13 points, and the maximal decline after the first levodopa dose was to a final score of 16 +/- 8 points. Population analysis (NONMEM) of the concentration-effect relationship of levodopa according to a sigmoidal Emax model and over all dosage intervals did not show differences in levodopa responsiveness with or without tolcapone. The population mean of the 50% effective concentration (EC50) of levodopa was 1350 microg/L with an standard error of the population parameter estimate of 18%: adding tolcapone treatment as a covariate did not significantly change the population fit. Circadian influences on levodopa respon- siveness were not evaluable by the NONMEM model due to overparametrisation, but visual inspection of plotted data did not suggest differences in the concentration-effect relationship between the 4 consecutive dosage intervals on days 1 and 8. CONCLUSIONS: The gain in clinical improvement with levodopa under tolcapone can be fully explained by tolcapone-induced changes of peripheral levodopa pharmacokinetics. We suggest that this interaction study, performed in patients and using clinical data, excludes any central effects of tolcapone or any inhibiting effect of 3-OMD on levodopa permeation through the blood-brain barrier, which otherwise would have led to a decrease in the EC50 of levodopa. Baas, H. K. and P. Schueler (2001). "Efficacy of cabergoline in long-term use: results of three observational studies in 1,500 patients with Parkinson's disease." Eur Neurol 46 Suppl 1: 18-23. The tetracyclic ergoline derivative cabergoline was investigated in three studies to test its efficacy in treating the motor symptoms of Parkinson's disease. In two studies, it was used as an add-on agent to the previous medication regimen that included other parkinsonian drugs, including levodopa. In the third study, cabergoline was switched from another dopamine agonist. All studies proved this drug's effectiveness in treating such motor symptoms as akinesia, dyskinesia, and nocturnal akinesia. Quality of life and disability in activities of daily living assessments were measured by PDQ 39 or UPDRS VI. Treatment with cabergoline showed higher efficacy and greater safety than other parkinsonian drugs. Bai, O., M. Nakamura, et al. (2001). "Compensation of hand movement for patients by assistant force: relationship between human hand movement and robot arm motion." IEEE Trans Neural Syst Rehabil Eng 9(3): 302-7. As some functional diseases in the brain, such as cerebellum dysfunction and Parkinson's disease, cause the disability related to human movement control, a compensation method was developed for improving the performance of hand movement. The compensation can be carried out by adding assistant force, which is generated from artificial equipment attached to a human arm. From the experiment of visual target tracking, the tracking trajectories recorded from both healthy persons and patients with movement disability were analyzed. It was found that the tracking trajectories were represented sufficiently by a dynamic model of a robot arm in which the differences between healthy persons and patients were characterized by the model parameters. Based on the model, it was demonstrated that the hand movement of patients could be improved by introducing an appropriate compensation. The effectiveness of the proposed compensation method was verified from a simulation study of a robot arm. The design of artificial equipment for compensating the hand movement was also presented and discussed. Bair, J. D. and T. F. Oppelt (2001). "Warfarin and ropinirole interaction." Ann Pharmacother 35(10): 1202-4. OBJECTIVE: To report a case of increased international normalized ratio (INR) in a geriatric patient receiving warfarin and ropinirole. CASE SUMMARY: A 63-year-old African-American man with a history of Parkinson disease, Alzheimer disease, and status post-cardio-vascular accident was evaluated for symptoms of progressing stiffness and rigidity. Ropinirole was added to his current therapy for Parkinson disease, with a corresponding decrease in the dose of levodopa/carbidopa to allow levodopa sparing. On laboratory evaluation, he was noted to have an increased INR nine days after these adjustments; the INR had previously been stable. No other significant medication, social, or diet changes were noted. Warfarin was withheld for four days and restarted at approximately 75% of the previous weekly dose. The patient had no obvious signs of bleeding. Furthermore, the warfarin dose was again increased after discontinuation of ropinirole due to common gastrointestinal adverse effects. DISCUSSION: Warfarin is an oral anticoagulant whose narrow therapeutic index and potential for drug interaction is well documented. It is always possible that a change in blood coagulability can occur without an obvious contributable cause; however, an acute change in a previously stable INR with the addition of other medications always raises questions as to the possible mechanism of adverse reaction. No previously documented interaction of this precise nature has been identified. CONCLUSIONS: Ropinirole may elevate the anticoagulant effects of warfarin. Patients receiving warfarin should be considered for more frequent INR monitoring when ropinirole is added, adjusted, or discontinued from their medical regimen. Bakay, R. A. (2001). "Is transplantation to treat Parkinson's disease dead?" Neurosurgery 49(3): 576-80. Baker, H., N. Liu, et al. (2001). "Phenotypic differentiation during migration of dopaminergic progenitor cells to the olfactory bulb." J Neurosci 21(21): 8505-13. A possible source for transplantable neurons in Parkinson's disease are adult olfactory bulb (OB) dopamine (DA) progenitors that originate in the anterior subventricular zone and reach the OB through the rostral migratory stream. We used adult transgenic mice expressing a lacZ reporter directed by an 8.9 kb tyrosine hydroxylase (TH) promoter to investigate the course of DAergic differentiation. Parallel transgene and intrinsic TH mRNA expression occurred during migration of DA interneurons through the mitral and superficial granule cell layers before these cells reached their final periglomerular position. Differential transgene and calcium-calmodulin-dependent protein kinase IV expression distinguished two nonoverlapping populations of interneurons. Transgenic mice carrying a TH8.9kb/lacZ construct with a mutant AP-1 site demonstrated that this element confers OB DA-specific TH gene regulation. These results indicate that DA phenotypic determination is specific to a subset of mobile OB progenitors. Balas, I., C. Llumiguano, et al. (2001). "[Stereotactic thalamotomy for Parkinsonian and others types of tremor. Experiences of thalamic multiunit burst activity by means of semimicroelectrode]." Rev Neurol 32(6): 520-4. INTRODUCTION: Better understanding of the basic mechanism of disorders of movement, together with improvements in surgery and electrophysiological techniques have led to a resurge of interest in the surgical treatment of patients with tremor. Ventrolateral thalamotomy has been considered to be an alternative neurosurgical treatment for disabled persons including those with drug-resistant Parkinson s disease and other types of tremor. PATIENTS AND METHODS: Thirty four of 47 patients had Parkinson s disease (n= 23), essential tremor (n= 4), multiple sclerosis (n= 5), olivopontocerebellar lesion (n= 1) and posttraumatic tremor (n= 1) and did not show satisfactory improvement after drug treatment. The lesions were made in the thalamic nucleus. In 26 patients simultaneous recordings were made of nerve activity in the thalamus and of burst activity. RESULTS: In 23% of the cases the appropriate site for the final lesion could not be determined in accordance with electrostimulation of the empirical objective. In these patients the objective was determined after observation of the electrophysiological activity localized to the burst activity seen during the operation. The patients were followed-up for 6-24 months (average 12 months); 88% of them had no tremor or moderate contralateral tremor. The patients were assessed on a modified Fahn scale. Average scoring fell from a preoperative evaluation of 73.8 points to 34.0 after three months; 30.7 after six months, 32.0 after 9 months, 37.1 after 12 months and 35.2 points after 18 months. CONCLUSION: Of 47 thalamotomies done, 13 (29%) were successful and 5 (10%) maintained their original state, but no cases became worse or had serious complications. Ball, J. (2001). "Current advances in Parkinson's disease." Trends Neurosci 24(7): 367-9. Banaclocha, M. M. (2001). "Therapeutic potential of N-acetylcysteine in age-related mitochondrial neurodegenerative diseases." Med Hypotheses 56(4): 472-7. Increasing lines of evidence suggest a key role for mitochondrial damage in neurodegenerative diseases. Brain aging, Parkinson's disease, Alzheimer's disease, Huntington's disease and Friedreich's ataxia have been associated with several mitochondrial alterations including impaired oxidative phosphorylation. Mitochondrial impairment can decrease cellular bioenergetic capacity, which will then increase the generation of reactive oxygen species resulting in oxidative damage and programmed cell death. This paper reviews the mechanisms of N-acetylcysteine action at the cellular level, and the possible usefulness of this antioxidant for the treatment of age-associated neurodegenerative diseases. First, this thiol can act as a precursor for glutathione synthesis as well as a stimulator of the cytosolic enzymes involved in glutathione regeneration. Second, N-acetylcysteine can act by direct reaction between its reducing thiol group and reactive oxygen species. Third, it has been shown that N-acetylcysteine can prevent programmed cell death in cultured neuronal cells. And finally, N-acetylcysteine also increases mitochondrial complex I and IV specific activities both in vitro and in vivo in synaptic mitochondrial preparations from aged mice. In view of the above, and because of the ease of its administration and lack of toxicity in humans, the potential usefulness of N-acetylcysteine in the treatment of age-associated mitochondrial neurodegenerative diseases deserves investigation. Bandini, F., M. Pierantozzi, et al. (2001). "Parkinson's disease changes the balance of onset and offset visual responses: an evoked potential study." Clin Neurophysiol 112(6): 976-83. OBJECTIVES: We investigated whether the transient pattern onset and offset visual evoked potential (VEP) can distinguish between patients with Parkinson's disease (PD) and normal subjects. METHODS: Two horizontal sinusoidal gratings differing in spatial frequency, i.e. 1 and 4 cycles per degree, were presented to 17 patients with PD and 16 age-matched control subjects. We analyzed the responses in the time-domain and measured the latencies and amplitudes of N1 and P1 to the onset and the offset of the stimulus; we also derived the measures of offset N1 and P1 amplitude responses 'normalized' to onset N1 and P1 amplitude values, respectively (amplitude ratios). RESULTS: Absolute and normalized offset P1 amplitude is a distinguishing feature of PD patients from controls. Offset P1 amplitude was significantly larger in PD patients than in controls, particularly to the lower spatial frequency stimulus (P<0.01 for absolute and P<0.001 for normalized values, respectively). CONCLUSIONS: We conclude that the pattern onset/offset VEP amplitude provides a simple measure to evaluate visual processing deficits in PD and could contribute to an understanding of the pathophysiology of these changes. Bandopadhyay, R., R. de Silva, et al. (2001). "No pathogenic mutations in the synphilin-1 gene in Parkinson's disease." Neurosci Lett 307(2): 125-7. alpha-Synuclein is mutated in rare autosomal dominant forms of Parkinson's disease and is a major component of Lewy bodies and neurites. Synphilin-1, a novel protein interacts in vivo and co-localises with alpha-synuclein in Lewy bodies. We analysed the synphilin-1 gene in familial Parkinson's disease by single-strand conformation polymorphism (SSCP) and automated sequencing but found no coding mutations. However, we identified two novel intronic polymorphisms; an A/T polymorphism in intron 2, resulting in the introduction of an Alu1 site and a second G/T polymorphism in intron 4. We analysed the intron 2 polymorphism for allelic association as it was conducive to rapid screening but observed no changes in frequency between Parkinson's disease cases and controls. Banfield, M. J., R. L. Naylor, et al. (2001). "Specificity in Trk receptor:neurotrophin interactions: the crystal structure of TrkB-d5 in complex with neurotrophin-4/5." Structure (Camb) 9(12): 1191-9. BACKGROUND: The binding of neurotrophin ligands to their respective Trk cellular receptors initiates intracellular signals essential for the growth and survival of neurons. The site of neurotrophin binding has been located to the fifth extracellular domain of the Trk receptor, with this region regulating both the affinity and specificity of Trk receptor:neurotrophin interaction. Neurotrophin function has been implicated in a number of neurological disorders, including Alzheimer's disease and Parkinson's disease. RESULTS: We have determined the 2.7 A crystal structure of neurotrophin-4/5 bound to the neurotrophin binding domain of its high-affinity receptor TrkB (TrkB-d5). As previously seen in the interaction of nerve growth factor with TrkA, neurotrophin-4/5 forms a crosslink between two spatially distant receptor molecules. The contacts formed in the TrkB-d5:neurotrophin-4/5 complex can be divided into a conserved area similar to a region observed in the TrkA-d5:NGF complex and a second site-unique in each ligand-receptor pair-formed primarily by the ordering of the neurotrophin N terminus. CONCLUSIONS: Together, the structures of the TrkB-d5:NT-4/5 and TrkA-d5:NGF complexes confirm a consistent pattern of recognition in Trk receptor:neurotrophin complex formation. In both cases, the N terminus of the neurotrophin becomes ordered only on complex formation. This ordering appears to be directed largely by the receptor surface, with the resulting complementary surfaces providing the main determinant of receptor specificity. These features provide an explanation both for the limited crossreactivity observed between the range of neurotrophins and Trk receptors and for the high-affinity binding associated with respective ligand-receptor pairs. Barber, M., D. Stewart, et al. (2001). "Patient and carer perception of the management of Parkinson's disease after surgery." Age Ageing 30(2): 171-2. Barbieri, S., K. Hofele, et al. (2001). "Mouse models of alpha-synucleinopathy and Lewy pathology. Alpha-synuclein expression in transgenic mice." Adv Exp Med Biol 487: 147-67. Barbosa, E. R., M. D. Leiros da Costa, et al. (2001). "Parkinsonism after glycine-derivate exposure." Mov Disord 16(3): 565-8. This 54-year-old man accidentally sprayed himself with the chemical agent glyphosate, a herbicide derived from the amino acid glycine. He developed disseminated skin lesions 6 hours after the accident. One month later, he developed a symmetrical parkinsonian syndrome. Two years after the initial exposure to glyphosate, magnetic resonance imaging revealed hyperintense signal in the globus pallidus and substantia nigra, bilaterally, on T2-weighted images. Levodopa/benserazide 500/125 mg daily provided satisfactory clinical outcome. Barc, S., G. Page, et al. (2001). "Impairment of the neuronal dopamine transporter activity in MPP(+)-treated rat was not prevented by treatments with nitric oxide synthase or poly(ADP-ribose) polymerase inhibitors." Neurosci Lett 314(1-2): 82-6. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes, via its metabolite MPP(+), damages of the nigrostriatal dopaminergic pathway, similar to those observed in Parkinson's disease. An intranigral injection of 10 microg MPP(+) in rat induced a decrease of about 30% of the neuronal dopamine transporter (DAT) activity 21 days after lesion. Based on the hypothesis that MPTP/MPP(+) neurotoxicity involves the nitric oxide (NO) production and/or an activation of poly(ADP-ribose) polymerase (PARP), we investigated the preventive effects of a treatment either with L-Name, a NO synthase (NOS) inhibitor or 3-aminobenzamide, a PARP inhibitor on the reduction of dopamine uptake induced by MPP(+). Rats received a daily injection i.p. of 50 mg/kg L-Name or 10 mg/kg 3-aminobenzamide 3 days before and during 21 days after the MPP(+) lesion. The results showed that inhibitors of NOS and PARP did not prevent the alteration of DAT activity induced by 10 microg MPP(+), indicating that NO and PARP were not involved in the biochemical cascade leading to the inhibition of rat DAT activity by MPP(+) in our experimental conditions. Bar-Gad, I. and H. Bergman (2001). "Stepping out of the box: information processing in the neural networks of the basal ganglia." Curr Opin Neurobiol 11(6): 689-95. The Albin-DeLong 'box and arrow' model has long been the accepted standard model for the basal ganglia network. However, advances in physiological and anatomical research have enabled a more detailed neural network approach. Recent computational models hold that the basal ganglia use reinforcement signals and local competitive learning rules to reduce the dimensionality of sparse cortical information. These models predict a steady-state situation with diminished efficacy of lateral inhibition and low synchronization. In this framework, Parkinson's disease can be characterized as a persistent state of negative reinforcement, inefficient dimensionality reduction, and abnormally synchronized basal ganglia activity. Barker, S. J. and J. S. Polson (2001). "Fire in the operating room: a case report and laboratory study." Anesth Analg 93(4): 960-5. In July, 1998 a fire occurred in an operating room (OR) at the University Medical Center in Tucson, AZ. A patient was burned on the face, neck, and shoulders by the fire, which started during cranial burr-hole placement under monitored anesthesia care. This paper describes the actual case in some detail. The incident was simulated as accurately as possible in a laboratory experiment, in an attempt to determine specific risk factors for this event. The experiment found that a specific combination of factors was required to produce a fire similar in appearance to the one in the OR. The risk factors determined in these experiments are discussed in the context of previous reports of OR fires. Although other reports demonstrate some common characteristics of these events, the fire at the University Medical Center appears to be unique within the literature regarding the specific chain of events that led up to it. IMPLICATIONS: A patient was seriously burned in a fire that occurred during surgery. We performed laboratory experiments to re-create the fire, and found some of the key factors that led to this event. Barlas, O., H. A. Hanagasi, et al. (2001). "Do unilateral ablative lesions of the subthalamic nucleu in parkinsonian patients lead to hemiballism?" Mov Disord 16(2): 306-10. We report the safety results in nine patients with advanced idiopathic Parkinson's disease (PD) who underwent ablative surgery of unilateral subthalamic nucleus (STN). In eight patients, surgical objectives were attained without induction of abnormal involuntary movements or other adverse effects. One patient developed transient hemiballistic movements which improved within 2 weeks after surgery. Assessment at 2 weeks to 20 months postoperatively revealed no long-term adverse effects. We conclude that hemiballism following unilateral ablation of STN in patients with PD is a rare phenomenon, and unilateral ablative lesions of STN can be performed safely. Barnes, J. and A. S. David (2001). "Visual hallucinations in Parkinson's disease: a review and phenomenological survey." J Neurol Neurosurg Psychiatry 70(6): 727-33. OBJECTIVES: Between 8% and 40% of patients with Parkinson's disease undergoing long term treatment will have visual hallucinations during the course of their illness. There were two main objectives: firstly, to review the literature on Parkinson's disease and summarise those factors most often associated with hallucinations; secondly, to carry out a clinical comparison of ambulant patients with Parkinson's disease with and without visual hallucinations, and provide a detailed phenomenological analysis of the hallucinations. METHODS: A systematic literature search using standard electronic databases of published surveys and case-control studies was undertaken. In parallel, a two stage questionnaire survey was carried out based on members of a local branch of the Parkinson's Disease Society and followed up with a clinical interview. RESULTS: The review disclosed common factors associated with visual hallucinations in Parkinson's disease including greater age and duration of illness, cognitive impairment, and depression and sleep disturbances. The survey comprised 21 patients with visual hallucinations and 23 without. The hallucinators had a longer duration and a greater severity of illness, and tended to show more depressed mood and cognitive impairment. The typical visual hallucination in these patients is a complex visual image experienced while they are alert and have their eyes open. The image appears without any known trigger or voluntary effort, is somewhat blurred, and commonly moves. It stays present for a period of "seconds" or "minutes". The content can be variable within and between hallucinators, and includes such entities as people, animals, buildings, or scenery. These features resemble those highlighted in hallucinations in the visually impaired (Charles Bonnet's syndrome). CONCLUSION: A consistent set of factors are associated with visual hallucinations in Parkinson's disease. The results of the phenomenological survey and those of visual hallucinations carried out in other settings suggest a common physiological substrate for visual hallucinations but with cognitive factors playing an as yet unspecified role. Barquero-Jimenez, M. S. and M. Dominguez-Salgado (2001). "[Dementia in progressive supranuclear paralysis patients]." Rev Neurol 32(11): 1071-3. INTRODUCTION: Progressive supranuclear paralysis is difficult to detect in its initial stages. Its symptoms are not specific and often the patients are mistaken as Parkinson s disease patients, or even Alzheimer s ones. DEVELOPMENT: Initial features in progressive supranuclear paralysis are typically a gait disorder with frequent falls, behavioral disorder and often dysarthria. The gaze disorder, showing voluntary conjugate gase paralysis is characteristic, but it can appear late in the course of disease. Other motor signs are axial rigidity, bradykinesia, stiffness, and rarely chorea, ataxia, muscle weakness or myoclonus. Pseudobulbar paralysis is the more remarkable clinical finding. These motor symptoms are accompanied by cognitive disturbances, the typical ones of subcortical dementia, with mind slowness, apathy, depression, and, more often that in other primary dementias, psychotic features and relatively early behavioral disorders. A useful feature to distinguish the mental changes of progressive supranuclear paralysis with other primary subcortical dementias is a more remarkable impairment in visuospatial function, because of the need of a good gaze function to accomplish it. Progressive supranuclear paralysis patients work better in verbal tests that in visuospatial test. We try to describe clinical data and evolutive profile of this entity, whose cognitive disturbances as described by Albert in 1974 strongly stabilized the concept of subcortical dementia. Barraquer, I. B. L. (2001). "[Nightmares and behavior during REM sleep]." Neurologia 16(5): 214-20. This study reports the current neurobiologic data on REM sleep including psychoanalysis, distinguishing between the "instincts of pleasure" and the "instincts of death" (Beyond the principles of pleasure, S. Freud, 1920). The award and punishment systems are also reported and current data related to nightmares and mainly dream behavior during REM sleep without atonia are presented underlining the frequency of parasomnia in ponto-cerebellous atrophy and Parkinson's disease. The author emphasizes the need for establishing discussions among the different neuroscientific fields related to these questions. Barreto, W. J., S. R. Barreto, et al. (2001). "Interruption of the MnO2 oxidative process on dopamine and L-dopa by the action of S2O3(2-)." J Inorg Biochem 84(1-2): 89-96. The oxidation effects of Mn2+, Mn3+ or MnO2 on dopamine can be studied in vitro and, therefore, this offers a model of the auto-oxidation process that appears naturally in neurons causing Parkinson's disease. The use of MnO, as an oxidizer in aqueous solution at pH 7 causes the oxidation of catecholamines (L-dopa, dopamine, noradrenaline and adrenaline) to melanin. However, this work shows that, in water at pH 6-7, the oxidation of catecholamines by MnO2 in the presence of sodium thiosulphate (Na2S2O3) occurs by other mechanisms. For dopamine and L-dopa, MLCT complexes were formed with bands at 312, 350 (sh), 554 (sh) nm, and an intense band at 597 nm (epsilon approximately/= 4 x 10(3) M(-1) cm(-1)) and at ca. 336, 557 (sh) nm, and an intense band at 597 nm (epsilon approximately 6 x 10(3) M(-1) cm(-1)), respectively. The latter transitions were assigned to d(pi)-->pi*-SQ. Noradrenaline and adrenaline do not form this blue complex in solution, but generate soluble oxidized compounds. The resonance Raman spectra of these complexes in solution showed bands at 950, 1006, 1258, 1378, 1508 and 1603 cm(-1) for the complex derivation of L-dopa and at 948, 1010, 1255, 1373, 1510 and 1603 cm(-1) for the dopamine-derived compound. The most intense Raman band at ca. 1378 cm(-1) was assigned to C-O stretching with major C1-C2 characteristics and indicated that dopamine and L-dopa do not occur complexed with manganese in the catecholate or quinone form, but suggests an intermediate compound such as an anionic o-semiquinone (SQ-), forming a complex such as [Mn(II)(SQ-)3]-. All enhanced Raman frequencies are characteristic of the benzenic ring without the participation of the aminic nitrogen. A mechanism is proposed for the formation of the dopamine and L-dopa complexes and a computational simulation was performed to support it. Barrett, A. M., G. P. Crucian, et al. (2001). "Seeing trees but not the forest: limited perception of large configurations in PD." Neurology 56(6): 724-9. OBJECTIVE: To learn if Parkinson's disease (PD) is associated with a restricted attentional "floodlight." BACKGROUND: Different visual tasks may have different attentional requirements. Focused attention may be needed for some tasks; other tasks demand spatially distributed attention. Neglect after right cortical injury and dopamine depletion may limit the area over which attention can be spread. Although subjects with PD have dopamine depletion and can perform poorly on tests of visuospatial function, it is unclear if their attentional floodlight is restricted. METHODS: Eleven subjects with PD and 11 control subjects viewed different-sized letters on five printed stimulus sheets, 43 x 56 cm. On each sheet, four different large letters (14 cm2) were composed of four different medium-sized letters (2.5 cm2), which in turn were composed of four different small letters (0.4 cm2). Stimulus sheets were presented at 30- and 75-cm viewing distances. Subjects named "all the letters they could see." RESULTS: Subjects with PD named small- and medium-sized letters comparably to control subjects, but PD subjects named fewer large letters than control subjects (control = 65.68%, PD = 24.55%; group-by-letter-size interaction, p < 0.05). Subjects with PD who had undergone stereotactic pallidotomy named more letters than prepallidotomy PD subjects (p = 0.05). CONCLUSIONS: PD may affect the patient's ability to perceive large spatial configurations. As global configurations in subjects may be perceived preferentially over local patterns, it is possible that DA depletion induces an aberrant perceptual-attentional bias, such that patients have a narrowed attentional floodlight. Barthwal, M. K., N. Srivastava, et al. (2001). "Role of nitric oxide in a progressive neurodegeneration model of Parkinson's disease in the rat." Redox Rep 6(5): 297-302. This study was undertaken to investigate the nitric oxide synthase (NOS) activity in the striatum following 6-hydroxydopamine (6-OHDA) induced neurodegeneration in rats. Constitutive NOS (cNOS) activity remained unaltered at 3, 7 and 14 days after lesion, while a 43% and 45% decrease was observed at 30 and 50 days, respectively. Inducible NOS (iNOS) activity was detected only on the 3rd day after lesion and not in subsequent days or the control striatum. N(G)-nitro-L-arginine methyl ester (L-NAME) pretreatment blocked the amphetamine-induced rotations and inhibited the iNOS activity at the 3rd day after the 6-OHDA injection. L-NAME pretreatment also significantly restored the striatal dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in 6-OHDA treated rats. Thus a possible role of nitric oxide in 6-OHDA induced neurodegeneration is suggested. Barzilai, A., E. Melamed, et al. (2001). "Is there a rationale for neuroprotection against dopamine toxicity in Parkinson's disease?" Cell Mol Neurobiol 21(3): 215-35. Parkinson's disease is a progressive neurological disease caused by rather selective degeneration of the dopaminergic neurons in the substantia nigra. Though subject to intensive research, the etiology of this nigral loss is still undetermined and treatment is basically symptomatic. The current major hypothesis is that nigral neuronal death in PD is due to excessive oxidative stress generated by auto and enzymatic oxidation of the endogenous neurotransmitter dopamine (DA), the formation of neuromelanin (NM) and the presence of a high concentration of iron. In this review article although we concisely describe the effects of NM and iron on neuronal survival, we mainly focus on the molecular mechanisms of DA-induced apoptosis. DA exerts its toxic effects through its oxidative metabolites either in vitro or in vivo The oxidative metabolites then activate a very intricate web of signals, which culminate in cell death. The signal transduction pathways and genes, which are associated with DA toxicity are described in detail. Bas, J., M. Calopa, et al. (2001). "Lymphocyte populations in Parkinson's disease and in rat models of parkinsonism." J Neuroimmunol 113(1): 146-52. To assess the involvement of the immune system in Parkinson's disease we studied the phenotype of circulating lymphocytes in 30 untreated and 34 treated patients. We found a numeric decrease in helper T cells (higher in CD4(+)CD45RA(+) than in CD4(+)CD29(+)) and B cells, and a rise in activated, CD4(+)CD25(+) lymphocytes that was correlated with lymphocyte depletion. All these alterations were independent of levodopa treatment. In addition, we performed striatal dopamine depletion in rats with either MPP(+) or 6-OHDA, showing that MPP(+) but not 6-OHDA can increase CD4(+)CD25(+) lymphocytes. Thus, mechanisms other than dopamine deficit may explain the immune activation in Parkinson's disease. Basile, G., A. Epifanio, et al. (2001). "Cognitive and mood disorders in elderly patients with Parkinson's disease." Arch Gerontol Geriatr 33 Suppl 1: 33-36. Basson, R. (2001). "Sex and idiopathic Parkinson's disease." Adv Neurol 86: 295-300. Bauer, M., M. Meyer, et al. (2001). "Liposome-mediated gene transfer to fetal human ventral mesencephalic explant cultures." Neurosci Lett 308(3): 169-72. The feasibility of non-viral gene transfer using liposomes is described for human fetal nigral tissue. Ventral mesencephalic explants from 6 to 12 week old fetuses were grown as free-floating roller tube cultures. For the transfection, a vector coding for beta-galactosidase driven by the Rous Sarcoma Virus promoter was used. The developmental stage of the human tissue, time in vitro and the amount of vector DNA used significantly influenced the transfection efficiency. Optimal transfection results were obtained with tissue from a 10 week old fetus, cultured for 4 days and transfected with mixtures containing 4 microg vector DNA. Histological analysis suggested that a specific population of ventral mesencephalic precursor cells were the target for the gene transfer. This finding might have implications for gene delivery and cell replacement strategies in Parkinson's disease. Baufreton, J., M. Garret, et al. (2001). "Activation of GABA(A) receptors in subthalamic neurons in vitro: properties of native receptors and inhibition mechanisms." J Neurophysiol 86(1): 75-85. The subthalamic nucleus (STN) influences the output of the basal ganglia, thereby interfering with motor behavior. The main inputs to the STN are GABAergic. We characterized the GABA(A) receptors expressed in the STN and investigated the response of subthalamic neurons to the activation of GABA(A) receptors. Cell-attached and whole cell recordings were made from rat brain slices using the patch-clamp technique. The newly identified epsilon subunit confers atypical pharmacological properties on recombinant receptors, which are insensitive to barbiturates and benzodiazepines. We tested the hypothesis that native subthalamic GABA(A) receptors contain epsilon proteins. Applications of increasing concentrations of muscimol, a selective GABA(A) agonist, induced Cl(-) and HCO currents with an EC(50) of 5 microM. Currents induced by muscimol were fully blocked by the GABA(A) receptor antagonists, bicuculline and picrotoxin. They were strongly potentiated by the barbiturate, pentobarbital (+190%), and by the benzodiazepines, diazepam (+197%) and flunitrazepam (+199%). Spontaneous inhibitory postsynaptic currents were also significantly enhanced by flunitrazepam. Furthermore, immunohistological experiments with an epsilon subunit-specific antibody showed that the epsilon protein was not expressed within the STN. Native subthalamic GABA(A) receptors did not, therefore, display pharmacological or structural properties consistent with receptors comprising epsilon. Burst firing is a hallmark of Parkinson's disease. Half of the subthalamic neurons have the intrinsic capacity of switching from regular-firing to burst-firing mode when hyperpolarized by current injection. This raises the possibility that activation of GABA(A) receptors might trigger the switch. Statistical analysis of spiking activity established that 90% of intact neurons in vitro were in single-spike firing mode, whereas 10% were in burst-firing mode. Muscimol reversibly stopped recurrent electrical activity in all intact neurons. In neurons held in whole cell configuration, membrane potential hyperpolarized by -10 mV whilst input resistance decreased by 50%, indicating powerful membrane shunting. Muscimol never induced burst firing, even in neurons that exhibited the capacity of switching from regular- to burst-firing mode. These molecular and functional data indicate that native subthalamic GABA(A) receptors do not contain the epsilon protein and activation of GABA(A) receptors induces membrane shunting, which is essential for firing inhibition but prevents switching to burst-firing. They suggest that the STN, like many other parts of the brain, has the physiological and structural features of the widely expressed GABA(A) receptors consisting of alphabetagamma subunits. Beal, M. F. (2001). "Experimental models of Parkinson's disease." Nat Rev Neurosci 2(5): 325-34. Research into the pathogenesis of Parkinson's disease has been rapidly advanced by the development of animal models. Initial models were developed by using toxins that specifically targeted dopamine neurons, the most successful of which used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a toxin that causes parkinsonism in man. More recently, the identification of alpha-synuclein mutations as a rare cause of Parkinson's disease has led to the development of alpha-synuclein transgenic mice and Drosophila. Here, I discuss the merits and limitations of these different animal models in our attempts to understand the physiology of Parkinson's disease and to develop new therapies. Beal, M. F. and P. Hantraye (2001). "Novel therapies in the search for a cure for Huntington's disease." Proc Natl Acad Sci U S A 98(1): 3-4. Becker, G. and D. Berg (2001). "Neuroimaging in basal ganglia disorders: perspectives for transcranial ultrasound." Mov Disord 16(1): 23-32. Transcranial sonography is a new diagnostic tool, allowing not only the evaluation of cerebral arteries but also the two-dimensional display of the brain parenchyma. In this review we will summarize basics of the application, the ultrasound anatomy of the brain and sonographic findings in some movement disorders. While in normal adults basal ganglia nuclei are hypoechogenic, they are hyperechogenic in certain basal ganglia disorders. In Parkinson's disease, for example, the substantia nigra can be depicted as a distinctly echogenic area. An elevated echogenicity of the lentiform nuclei was noticed in patients with primary adult-onset dystonia. In both disorders the altered echogenicity may arise from higher heavy metal tissue content (i.e. iron in Parkinson's disease and copper in primary dystonia). Our findings converge to the hypothesis that transcranial ultrasound sensitively detects pathological metal accumulation not identified by other neuroimaging techniques (CT and MRI) and therefore provides new insights in the diagnosis of basal ganglia disorders. The implications of these findings for the understanding of the pathogenesis and its usefulness for the early diagnosis of movement disorders are outlined. Becker, G., D. Berg, et al. (2001). "Basal limbic system alteration in major depression: a hypothesis supported by transcranial sonography and MRI findings." Int J Neuropsychopharmacol 4(1): 21-31. The pathogenesis of major depression (MD) remains unclear despite intensive research in the last decades which brought up a multitude of findings illustrating the complexity of this disorder. In this paper we will summarize the evidence pointing towards a structural alteration of the basal limbic system in MD and depression in Parkinson's disease (PD). Transcranial ultrasound and MRI studies in both depressive syndromes revealed altered signal intensity of the brainstem midline comprising fibre tracts of the basal limbic system. The hypothesis of a structural disruption of the basal limbic system is supported by biochemical and histopathological findings. The similarity of findings in MD and depression in PD might reflect a relationship between MD and neurodegenerative disorders. Begley, S. (2001). "IV. Genes, cells, drugs. Cures for the future. Fountains of youth." Newsweek 138(11A): 84-6. Behari, M., A. K. Srivastava, et al. (2001). "Risk factors of Parkinson's disease in Indian patients." J Neurol Sci 190(1-2): 49-55. Epidemiological data on risk factors of Parkinson's disease (PD) are not available from India. In a case control study, we investigated environmental and genetic risk factors in the etiology of idiopathic Parkinson's disease. Three hundred seventy-seven patients of Parkinson disease (301 men, 76 women, mean+/-SD age 56.78+/-11.08 years) and equal number of age matched (+/-3 years) neurological controls (271 men, 106 women, mean+/-SD age 56.62+/-11.17 years) were included in the study. Conditional logistic regression model was used to determine the risk factors of PD. We found that male gender, family history of Parkinson's disease, past history of depression of up to 10-year duration and well water drinking of more than 10-year duration were significantly associated with occurrence of Parkinson's disease, whereas tobacco smoking of up to 20-year duration and exposure to pets had protective effect. However, tobacco smoking of more than 20-year duration, well water drinking of up to 10-year duration, vegetarian dietary habit, occupation involving physical exertion, rural living, farming, exposure to insecticides, herbicides, rodenticides, alcohol intake and family history of neurodegenerative diseases had no significant correlation with occurrence of PD in the patient population studied. Results of our study support the hypothesis of multifactorial etiology of PD with environmental factors acting on a genetically susceptible host. Beitner-Johnson, D., K. Seta, et al. (2001). "Identification of hypoxia-responsive genes in a dopaminergic cell line by subtractive cDNA libraries and microarray analysis." 7(3): 273-281. Transplantation of dopamine-secreting cells harvested from fetal mesencephalon directly into the striatum has had limited success as a therapy for Parkinson's disease. A major problem is that the majority of the cells die during the first 3 weeks following transplantation. Hypoxia in the tissue surrounding the graft is a potential cause of the cell death. We have used subtractive cDNA libraries and microarray analysis to identify the gene expression profile that regulates tolerance to hypoxia. An improved understanding of the molecular basis of hypoxia-tolerance may allow investigators to engineer cells that can survive in the hypoxic environment of the brain parenchyma following transplantation. Bekkering, H., S. F. Neggers, et al. (2001). "The preparation and execution of saccadic eye and goal-directed hand movements in patients with Parkinson's disease." Neuropsychologia 39(2): 173-83. The oculomotor and manual motor systems were studied in a two-segment movement task in a group of patients with Parkinson's disease and in age matched normal controls. In order to avoid reflexive motor movements the selection of the correct motor sequence was derived from the interpretation of symbolic (coloured) cues. The latencies and dynamics of eye and hand (pointing) movements performed during the first (fixed) movement segment were measured and the planning and execution processes were manipulated by varying the complexity of the second movement segment relative to the first (with regard to direction and amplitude). The results showed that the eye and hand movements made by patients with Parkinson's disease were not impaired in the initiation of the first movement segment. Interestingly, both Parkinson's patients and controls showed increased eye and hand reaction time latencies for the first movement when the second movement was in the direction opposite to the first. This indicates that the complexity of the second movement influences the execution of the first movement, and importantly that complexity affects motor initiation and execution processes in both normal subjects and in patients with Parkinson's disease. The execution of hand movements was found to be impaired in patients with Parkinson's disease as indicated by a reduced peak velocity of manual pointing responses when compared to age matched controls. By contrast, no differences were found in the dynamics of saccadic eye movements. This dissociation is consistent with the notion that the skeletomotor loop passes through the functionally corresponding portions of the basal ganglia independently of the oculomotor loop. Together, these results demonstrate that Parkinson's patients are able to generate multiple non-reflexive eye and hand movements and that the observed (manual) motor deficits are specific to the processes of motor execution. Benabid, A. L., A. Koudsie, et al. (2001). "Deep brain stimulation for Parkinson's disease." Adv Neurol 86: 405-12. Benabid, A. L., A. Koudsie, et al. (2001). "Deep brain stimulation of the corpus luysi (subthalamic nucleus) and other targets in Parkinson's disease. Extension to new indications such as dystonia and epilepsy." J Neurol 248 Suppl 3: III37-47. Chronic high frequency (130 Hz) stimulation (HFS) of the thalamic target Vim, first used in our group in 1987 as a treatment of tremor of various origins, has been used over the last ten years in 137 patients. Since 1993, this method has been extended to two other targets (subthalamic nucleus (STN): 137 patients and the medial pallidum (GPi): 12 patients), based on recent experimental data in rats and monkeys. STN appears to be a target of major interest, able to control the three cardinal symptoms and to allow the decrease or suppression of levodopa treatment, which then also suppresses levodopa induced dyskinesias. The stereotactic technique is based on the determination of the target using ventriculography, MRI and electrophysiology, with both microrecording of single neuron activity and microstimulation inducing therapeutic symptom suppression and side effects. Chronic electrodes are then placed bilaterally at the best physiologically defined location and then connected to implantable stimulators (either 2 Itrel II or the new double channel Kinetra), operated at 130-185 Hz, 60 ms pulse width, 2.5 to 3.5 volts. There was no operative mortality and permanent morbidity was observed in 3 patients. The mechanisms of action of HFS are not fully understood, but are definitely related to high frequency and are probably different depending on the target. Inhibition of cellular activity or of neural network functions could be induced, by jamming of a retroactive loop for tremor, or by shutdown of neurotransmitter release in STN. Mechanisms within an individual target are also probably different for tremor or for other symptom alleviation. All cardinal symptoms are alleviated from tremor to akinesia and rigidity. This strong improvement allows the decrease of the drug dosage to approximately 30% of the preoperative level, which suppresses the levodopa-induced dyskinesias. The off period dystonias are also suppressed as well as freezings and falls. The effects remain stable over more than 5 years and in the same period, the off stimulation-off medication UPDRS remains stable and does not increase at the usual rate The low rate of permanent complications, the minor side effects and their immediate reversibility, the possibility of bilateral implantation in one session and the long-term persistence of symptom relief are strong arguments which support chronic HFS of STN as the method of choice when a surgical procedure is indicated for the treatment of Parkinson's disease and even more when a bilateral procedure is necessary. Recent data show that STN stimulation could be useful in the treatment of dystonia as well as some forms of epilepsy. It is therefore possible that DBS in STN as well as in other targets could become a potent therapeutic tool in the near future for neurological disorders. Benarroch, E. E., A. M. Schmeichel, et al. (2001). "Depletion of cholinergic neurons of the medullary arcuate nucleus in multiple system atrophy." Auton Neurosci 87(2-3): 293-9. The human arcuate nucleus (ArcN) has been considered akin to the pontine precerebellar nuclei. However, there is anatomical, functional, and clinical evidence that the ArcN may be the homologue of chemosensitive areas of the ventral medullary surface involved in ventilatory responses to hypercarbia and cerebrospinal fluid acidosis. Acetylcholine has been involved in mechanisms of central chemosensitivity. Loss of ArcN neurons has been reported in patients with multiple system atrophy (MSA), a disorder characterized by disturbed automatic ventilation, but the neurochemical identity of these neurons is undetermined. We sought to determine whether the ArcN contains cholinergic neurons and whether these neurons are depleted in patients with MSA. Medullae were obtained from six patients with MSA, five patients with Parkinson's disease (PD) and six sex- and age-matched controls. Fifty-micron transverse sections obtained through the mid-olivary levels were processed for acetylcholinesterase (AchE), choline acetyltransferase (CAT), and alpha-synuclein immunoreactivity. We found that the ArcN contained CAT-positive neurons. There was a significant decrease in density of cholinergic ArcN neurons in MSA but not in PD patients. alpha-Synuclein-containing inclusions were present in the ArcN of MSA patients. Depletion of cholinergic neurons may provide a substrate for disturbances in automatic respiration in MSA patients. Benedetti, M. D., D. M. Maraganore, et al. (2001). "Hysterectomy, menopause, and estrogen use preceding Parkinson's disease: An exploratory case-control study." Mov Disord 16(5): 830-7. We studied the association of Parkinson's disease (PD) with type of menopause (natural or surgical), age at menopause, and postmenopausal estrogen replacement therapy using a case-control design. We used the medical records-linkage system of the Rochester Epidemiology Project to identify 72 women who developed PD in Olmsted County, MN, during the twenty years 1976-1995. Each incident case was matched by age (+/- 1 year) to a general population control subject. We collected exposure data through review of the complete medical records of cases and control subjects in the system. PD cases had undergone hysterectomy (with or without unilateral oophorectomy) significantly more often than control subjects (odds ratio [OR] = 3.36; 95% confidence interval [CI] = 1.05-10.77). In addition, PD cases had experienced early menopause (</= 46 years) more commonly than control subjects (OR = 2.18; 95% CI = 0.88-5.39). Finally, PD cases had used estrogens orally or parenterally for at least 6 months after menopause less frequently (8%) than control subjects (14%; OR = 0.47; 95% CI = 0.12-1.85). However, the findings for early menopause and estrogen replacement therapy were not statistically significant. Despite the limited sample size of this exploratory study, we hypothesize that there is an increased risk of PD in conditions causing an early reduction in endogenous estrogen. This hypothesis needs to be confirmed in a larger study. Ben-Jonathan, N. and R. Hnasko (2001). "Dopamine as a prolactin (PRL) inhibitor." Endocr Rev 22(6): 724-63. Dopamine is a small and relatively simple molecule that fulfills diverse functions. Within the brain, it acts as a classical neurotransmitter whose attenuation or overactivity can result in disorders such as Parkinson's disease and schizophrenia. Major advances in the cloning and characterization of biosynthetic enzymes, transporters, and receptors have increased our knowledge regarding the metabolism, release, reuptake, and mechanism of action of dopamine. Dopamine reaches the pituitary via hypophysial portal blood from several hypothalamic nerve tracts that are regulated by PRL itself, estrogens, and several neuropeptides and neurotransmitters. Dopamine binds to type-2 dopamine receptors that are functionally linked to membrane channels and G proteins and suppresses the high intrinsic secretory activity of the pituitary lactotrophs. In addition to inhibiting PRL release by controlling calcium fluxes, dopamine activates several interacting intracellular signaling pathways and suppresses PRL gene expression and lactotroph proliferation. Thus, PRL homeostasis should be viewed in the context of a fine balance between the action of dopamine as an inhibitor and the many hypothalamic, systemic, and local factors acting as stimulators, none of which has yet emerged as a primary PRL releasing factor. The generation of transgenic animals with overexpressed or mutated genes expanded our understanding of dopamine-PRL interactions and the physiological consequences of their perturbations. PRL release in humans, which differs in many respects from that in laboratory animals, is affected by several drugs used in clinical practice. Hyperprolactinemia is a major neuroendocrine-related cause of reproductive disturbances in both men and women. The treatment of hyperprolactinemia has greatly benefited from the generation of progressively more effective and selective dopaminergic drugs. Bennett, D. H. and M. C. Hall (2001). "Coronary sinus diverticulum containing posteroseptal accessory pathway." Heart 86(5): 539. Ben-Paz, H., H. Bergman, et al. (2001). "Synchrony of rest tremor in multiple limbs in parkinson's disease: evidence for multiple oscillators." J Neural Transm 108(3): 287-96. Recent evidence points to involvement of central nervous system oscillators in Parkinson's disease (PD) rest tremor. It remains unknown whether one or multiple oscillators cause tremor in multiple limbs. Based on the prediction that multiple oscillators would cause low coherence even with similar average frequency, we studied 22 PD patients using accelerometers on multiple limbs. Records were digitized and spectral analysis was performed. Peak frequencies in the arms, legs, and chin were similar, indicating that biomechanical factors did not determine the frequency. Coherence between different axes of individual accelerometers and between different segments of the same limb was high. However, coherence between tremor in different limbs was low. There was no consistent pattern across patients of ipsi- vs. contralateral predominance of coherence. These data suggest that tremor in PD is generated by multiple oscillatory circuits, which operate on similar frequencies. Ben-Shlomo, Y. and A. Lees (2001). "Selegiline and mortality in subjects with Parkinson's disease: a longitudinal community study." Neurology 57(2): 369; discussion 369-70. Berardelli, A., J. C. Rothwell, et al. (2001). "Pathophysiology of bradykinesia in Parkinson's disease." Brain 124(Pt 11): 2131-46. Bradykinesia means slowness of movement and is one of the cardinal manifestations of Parkinson's disease. Weakness, tremor and rigidity may contribute to but do not fully explain bradykinesia. We argue that bradykinesia results from a failure of basal ganglia output to reinforce the cortical mechanisms that prepare and execute the commands to move. The cortical deficit is most apparent in midline motor areas. This leads to particular difficulty with self-paced movements, prolonged reaction times and abnormal pre-movement EEG activity. Movements are often performed with normally timed EMG bursts but the amount of EMG activity is underscaled relative to the desired movement parameters. There are also abnormalities in sensory scaling and sensorimotor integration. The brain appears to be able to compensate to some degree for the basal ganglia deficit. There is overactivity in the lateral premotor areas during task performance and movements can be speeded by giving sensory cues. Attention to movement is also beneficial. However, we propose that the engagement of compensatory processes may also lead to reduced performance in other tasks. For example, patients' problems in performing more than one task at the same time could result from lack of sufficient resources both to compensate for their basal ganglia deficit and to run two tasks simultaneously. Surgical therapies are unlikely to work solely by normalizing basal ganglia output to that seen in healthy individuals. It seems more plausible that surgery removes an interfering signal that allows more efficient compensation by other structures. Berciano, J. (2001). "[Genetics in Parkinson's disease: toward a new nosological era]." Med Clin (Barc) 116(16): 614-6. Berding, G., P. Odin, et al. (2001). "Resting regional cerebral glucose metabolism in advanced Parkinson's disease studied in the off and on conditions with [(18)F]FDG-PET." Mov Disord 16(6): 1014-22. Studies of resting regional cerebral glucose consumption (rCMRGlc) in nondemented patients with Parkinson's disease (PD) have produced conflicting results, reporting both reduced and normal metabolism in advanced disease and reduced or normal metabolism after dopaminergic therapy. To investigate these issues, [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) was performed in 11 nondemented PD patients with advanced disease and 10 age-matched controls. PD patients were studied after withdrawal of all dopaminergic medication to produce a practically defined off condition, and a second time 1 hour after levodopa, resulting in a clinical on state. Dynamic PET scans and simultaneous arterialised venous blood samples of [(18)F] acticvity were obtained. A graphical approach was used to generate parametric images of rCMRGlc and statistical parametric mapping to localise significant metabolic changes in PD. Compared with controls, global rCMRGlc was reduced in the on but not in the off condition in PD. In both states, significant regional reductions of glucose uptake were found in the parietal, frontal, temporal cortex, and caudate nucleus. Reductions correlated with the severity of disability in frontal and temporal cortex. Direct comparison between on and off conditions revealed relatively greater reductions of uptake in the ventral/orbital frontal cortex and the thalamus during on. Results suggest that cortical and caudate hypometabolism are common in advanced PD and that caution is mandatory if [(18)F]FDG PET is being used to differentiate advanced PD from dementia and progressive supranuclear palsy where similar reductions are seen. Furthermore, in PD, administration of levodopa is associated with further hypometabolism in orbitofrontal cortex; an area known to be relevant for reversal learning where performance is typically impaired after dopaminergic treatment. Berendse, H. W., J. Booij, et al. (2001). "Subclinical dopaminergic dysfunction in asymptomatic Parkinson's disease patients' relatives with a decreased sense of smell." Ann Neurol 50(1): 34-41. By the time a clinical diagnosis of Parkinson's disease (PD) is made, a significant loss of dopaminergic neurons has already occurred. Identifying patients in the period between the presumed onset of dopaminergic cell loss and the appearance of clinical parkinsonism may be of major importance in the development of effective neuroprotective treatment strategies. In an effort to develop a feasible strategy to detect preclinical PD, a combination of olfactory processing tasks, including odor detection, odor identification, and odor discrimination was used to select groups of hyposmic and normosmic individuals from a total of 250 relatives (parents, siblings, or children) of subjects with PD. Single photon emission computed tomography (SPECT) with [123I]beta-CIT as a dopamine transporter ligand was used to assess nigrostriatal dopaminergic function in 25 hyposmic and 23 normosmic relatives of PD patients. An abnormal reduction in striatal dopamine transporter binding was found in 4 out of 25 hyposmic relatives of PD patients, two of whom subsequently developed clinical parkinsonism, and in none of the 23 normosmic relatives. These observations demonstrate that subclinical reductions in dopamine transporter binding can be detected in asymptomatic relatives of sporadic PD patients by means of [123I]beta-CIT and SPECT. The results further indicate that olfactory deficits may precede clinical motor signs in PD. Berg, D., G. Becker, et al. (2001). "Morphine in tardive and idiopathic dystonia (short communication)." J Neural Transm 108(8-9): 1035-41. Opioids have been shown to improve L-Dopa induced dyskinesias in patients with Parkinson's disease. In this pilot trial of five patients with tardive and four patients with idiopathic dystonia we tested the effect of morphinsulfate in a retarded form with a dosage of 20-60 mg per day. A substantial improvement of dystonic movements could be observed in four patients with tardive and one patient with idiopathic dystonia. The effect was only transient in tardive dystonia while pain relief mediated by morphine overlasted the effect on involuntary movements. Berg, D., M. Gerlach, et al. (2001). "Brain iron pathways and their relevance to Parkinson's disease." J Neurochem 79(2): 225-36. A central role of iron in the pathogenesis of Parkinson's disease (PD), due to its increase in substantia nigra pars compacta dopaminergic neurons and reactive microglia and its capacity to enhance production of toxic reactive oxygen radicals, has been discussed for many years. Recent transcranial ultrasound findings and the observation of the ability of iron to induce aggregation and toxicity of alpha-synuclein have reinforced the critical role of iron in the pathogenesis of nigrostriatal injury. Presently the mechanisms involved in the disturbances of iron metabolism in PD remain obscure. In this review we summarize evidence from recent studies suggesting disturbances of iron metabolism in PD at possibly different levels including iron uptake, storage, intracellular metabolism, release and post-transcriptional control. Moreover we outline that the interaction of iron with other molecules, especially alpha-synuclein, may contribute to the process of neurodegeneration. Because many neurodegenerative diseases show increased accumulation of iron at the site of neurodegeneration, it is believed that maintenance of cellular iron homeostasis is crucial for the viability of neurons. Berg, D., B. Jabs, et al. (2001). "Echogenicity of substantia nigra determined by transcranial ultrasound correlates with severity of parkinsonian symptoms induced by neuroleptic therapy." Biol Psychiatry 50(6): 463-7. BACKGROUND: Increased echogenicity of the substantia nigra (SN) detected by transcranial sonography is a characteristic ultrasound feature of Parkinson's disease. This ultrasound feature can also be detected in a subgroup of healthy adults. In recent studies, healthy subjects with this ultrasound feature showed a reduced [(18)F]-Dopa uptake on positron emission tomography (PET), indicating a subclinical alteration of the nigrostriatal system. This study was designed to evaluate whether the severity of neuroleptic side effects is related to the echo-feature of the SN. METHODS: In the retrospective part of the study, 93 psychiatric patients with either definite and severe parkinsonism after neuroleptic treatment (n = 52) or with no or minimal parkinsonian symptoms (n = 41) were included and underwent transcranial sonography to measure the extension of hyperechogenic areas at the SN. In addition, in the prospective part 11 patients with an acute psychotic episode requiring first-ever neuroleptic treatment underwent ultrasound examination. Subsequently, neuroleptic-induced parkinsonian signs were assessed prospectively. RESULTS: In the retrospective part of the study, patients with severe neuroleptic-induced parkinsonism had more extended echogenic signals at the SN than those with low echogenic SN (U-test; p <.01). The prospective part of the study showed that the severity of parkinsonian symptoms correlated with the echogenicity of the substantia nigra (Spearman's rank: p <.01). CONCLUSIONS: Increased echogenicity of the substantia nigra is associated with impaired function of the nigrostriatal system that can be disclosed by neuroleptic drugs. Berg, D., C. Siefker, et al. (2001). "Echogenicity of the substantia nigra in Parkinson's disease and its relation to clinical findings." J Neurol 248(8): 684-9. Recently an increased echogenicity of the substantia nigra (SN) in patients with Parkinson's disease (PD) was demonstrated by transcranial ultrasound (TCS). In this study we set out to compare SN echogenicitiy with disease characteristics (time of onset, duration, toxin exposure) in a large patients sample. Patients' history and exposure to toxins were recorded from 112 PD patients who underwent a thorough neurological examination including assessment of disease stage according to Hoehn and Yahr and CURS (Columbia University Rating Scale). Personality was assessed according to the Freiburg Personality Inventory. In all patients the area of SN echogenicity was encircled and measured by TCS. All except 9 patients had hyperechogenic SN areas exceeding the mean plus standard deviation values of an age matched control group (0.19 cm2). The age of disease onset was lower in patients who displayed an area of SN echogenicity above this value. The area of SN echogenicity was larger contralateral to the side with more severe symptoms. None of the other characteristics correlated with ultrasound findings. We conclude that SN hyperechogenicity is a typical finding in PD. The cause of hyperechogenicity is so far unknown. Investigation of the underlying reason might disclose a pathogenic factor in PD. Berg, D., C. Siefker, et al. (2001). "Relationship of substantia nigra echogenicity and motor function in elderly subjects." Neurology 56(1): 13-7. BACKGROUND: Patients with Parkinson's disease (PD) exhibit an increased echogenicity of the substantia nigra (SN) on transcranial sonography. Some healthy adults with the same echo characteristics showed a reduced 18fluorodopa uptake on PET, indicating a subclinical alteration of the nigrostriatal system. OBJECTIVES: To determine whether the sonographic phenotype of hyperechogenic SN has any relevance for motor function in elderly subjects and whether an increased echogenicity of the SN is associated with an impaired motor function. METHOD: In a population-based, cross-sectional study, 93 subjects older then 60 years without history of extrapyramidal disorder underwent sonographic and neurologic examinations, with a quantitative motor assessment. RESULTS: Elderly healthy subjects without prediagnosed extrapyramidal disorder but with SN hyperechogenicity had more frequent and more severe parkinsonian symptoms and a slower finger tapping than those with a regular echogenicity of the SN (p < 0.05, U test). CONCLUSION: With increasing age, subjects with SN hyperechogenicity develop a more substantial slowing of movements than subjects without this echo pattern, stressing the functional relevance of this sonographic finding. The authors speculate that hyperechogenicity of the SN may be detected by transcranial sonography early in life and may serve as a risk marker for nigral injury, although only a minority of these subjects will develop the full clinical picture of PD. Berke, J. D., V. Sgambato, et al. (2001). "Dopamine and glutamate induce distinct striatal splice forms of Ania-6, an RNA polymerase II-associated cyclin." Neuron 32(2): 277-87. Control of neuronal gene expression by drugs or neurotransmitters is a critical step in long-term neural plasticity. Here, we show that a gene induced in the striatum by cocaine or direct dopamine stimulation, ania-6, is a member of a novel family of cyclins with homology to cyclins K/T/H/C. Further, different types of neurotransmitter stimulation cause selective induction of distinct ania-6 isoforms, through alternative splicing. The longer Ania-6 protein colocalizes with nuclear speckles and is associated with key elements of the RNA elongation/processing complex, including the hyperphosphorylated form of RNA polymerase II, the splicing factor SC-35, and the p110 PITSLRE cyclin-dependent kinase. Distinct types of neuronal stimulation may therefore differentially modulate nuclear RNA processing, through altered transcription and splicing of ania-6. Bermejo, F., R. Gabriel, et al. (2001). "Problems and issues with door-to-door, two-phase surveys: an illustration from central Spain." Neuroepidemiology 20(4): 225-31. In 1994-1995, a screening and examination survey was conducted to ascertain the prevalence of dementia, Parkinson's disease and stroke in two urban communities and one rural community of central Spain. We use this survey to illustrate many nonclinical aspects of conducting two-phase prevalence surveys. Special emphasis is given to two common weaknesses in such surveys: screening nonparticipation and screening validation. Bertoni, J. M., J. L. Prendes, et al. (2001). "Long-term Medical Treatment for Parkinson's Disease." Curr Treat Options Neurol 3(6): 495-506. The authors of this paper view Parkinson's disease (PD) as a clinically defined progressive syndrome of resting limb tremor, bradykinesia, muscle rigidity, and a shuffling unsteady gait that responds well to dopaminergic medications. Parkinson's disease is a not a single entity, but rather a syndrome with diverse causes, with both genetic and environmental risk factors. The clinician's concern is to rule out other entities, especially those having another specific treatment, and to give PD patients the best short- and long-term benefit, with the least possible unwanted side effects. Beyer, M. K., K. Herlofson, et al. (2001). "Causes of death in a community-based study of Parkinson's disease." Acta Neurol Scand 103(1): 7-11. INTRODUCTION: The aim of this community-based study of Parkinson's disease (PD) was to investigate the causes of death among PD patients over a 4-year period and to examine the quality of death certificates with regard to PD. PATIENTS AND METHODS: A total of 245 patients were diagnosed with PD on Jan 1st 1993 in a defined geographical area in Norway. This patient cohort was followed from 1993 until Dec 31st 1996. Some 84 patients died in the 4-year period of follow-up. Their death certificates were collected, and causes of death were registered. A control group with the same age and sex distribution as the decedents, from the same geographical area, were also examined for causes of death. RESULTS: We found that the deceased PD patients at baseline were older, had a higher Unified Parkinson's Disease Rating Scale (UPDRS) score and Hoehn and Yahr staging than those patients who did not die during the observation period. Twice as many PD patients (20%) as controls (9%) died from pneumonia, whereas more controls than patients died from ischemic heart disease. There was a trend towards more deaths from malignant neoplasms in the control group than among PD patients. Only 56% of the death certificates of the deceased patients had PD registered as either underlying or contributing cause of death. CONCLUSION: We found that in an unselected group of PD patients there is a significant increase in deaths from pneumonia. The low frequency of PD on deceased patients' death certificates show that research based on these certificates should be evaluated with caution. Bezard, E., T. Boraud, et al. (2001). "Pallidal border cells: an anatomical and electrophysiological study in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkey." Neuroscience 103(1): 117-23. A dopamine transporter-radioligand binding study demonstrated a dopaminergic innervation around the pallidal complex in the normal monkey (n=5), i.e. where a subpopulation of pallidal neurons known as "border cells" is classically identified. Surprisingly, this peripallidal binding persists in monkeys rendered parkinsonian (n=5) with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment. The border cell electrophysiological activity was then analysed in normal and parkinsonian monkeys (n=2), either in the untreated state or following administration of levodopa. Pallidal border cell firing frequency was significantly decreased after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment (8.9+/-0.7 vs 31.4+/-1.6Hz, P<0.05). This decrease was partly corrected by levodopa administration (19.2+/-1.0Hz, P<0.05 vs both normal and parkinsonian situations). The peripallidal dopaminergic innervation suggests that pallidal border cells are under a direct dopaminergic control, arising from the ventral tegmental area and/or the basal forebrain magnocellular complex, the role of which remains unknown. Moreover, the relative sparing of these dopaminergic fibers in parkinsonian monkeys suggests that they would exhibit specific adaptive properties totally different from those described in the nigrostriatal pathway. Bezard, E., J. M. Brotchie, et al. (2001). "Pathophysiology of levodopa-induced dyskinesia: potential for new therapies." Nat Rev Neurosci 2(8): 577-88. Involuntary movements--or dyskinesias--are a debilitating complication of levodopa therapy for Parkinson's disease, and is experienced in most patients. Despite the importance of this problem, little was known about the cause of dyskinesia until recently; however, this situation has changed significantly in the past few years. Our increased understanding of levodopa-induced dyskinesia is not only valuable for improving patient care, but also in providing us with new insights into the functional organization of the basal ganglia and motor systems. Bezard, E., A. R. Crossman, et al. (2001). "Structures outside the basal ganglia may compensate for dopamine loss in the presymptomatic stages of Parkinson's disease." Faseb J 15(6): 1092-4. Bezard, E., S. Dovero, et al. (2001). "Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease." J Neurosci 21(17): 6853-61. The concept of a threshold of dopamine (DA) depletion for onset of Parkinson's disease symptoms, although widely accepted, has, to date, not been determined experimentally in nonhuman primates in which a more rigorous definition of the mechanisms responsible for the threshold effect might be obtained. The present study was thus designed to determine (1) the relationship between Parkinsonian symptom appearance and level of degeneration of the nigrostriatal pathway and (2) the concomitant presynaptic and postsynaptic striatal response to the denervation, in monkeys treated chronically with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine according to a regimen that produces a progressive Parkinsonian state. The kinetics of the nigrostriatal degeneration described allow the determination of the critical thresholds associated to symptom appearance, these were a loss of 43.2% of tyrosine hydroxylase-immunopositive neurons at the nigral level and losses of 80.3 and 81.6% DA transporter binding and DA content, respectively, at the striatal level. Our data argue against the concept that an increase in DA metabolism could act as an efficient adaptive mechanism early in the disease progress. Surprisingly, the D(2)-like DA receptor binding showed a biphasic regulation in relation to the level of striatal dopaminergic denervation, i.e., an initial decrease in the presymptomatic period was followed by an upregulation of postsynaptic receptors commencing when striatal dopaminergic homeostasis is broken. Further in vivo follow-up of the kinetics of striatal denervation in this, and similar, experimental models is now needed with a view to developing early diagnosis tools and symptomatic therapies that might enhance endogenous compensatory mechanisms. Bezard, E., P. Ravenscroft, et al. (2001). "Upregulation of striatal preproenkephalin gene expression occurs before the appearance of parkinsonian signs in 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine monkeys." Neurobiol Dis 8(2): 343-50. GABA and enkephalin-utilizing efferents from the striatum to the external segment of the pallidal complex (GPe) are thought to be overactive in Parkinson's disease (PD). This overactivity is generally held to play a major role in the genesis of parkinsonian symptoms, which are thought to appear when dopaminergic neuronal death exceeds a critical threshold. Little is known, however, regarding the activity of this pathway during disease progression and more particularly, prior to the emergence of parkinsonian symptoms. In order to test the hypothesis that an upregulation of striatal preproenkephalin-A (PPE-A) mRNA levels occurs before the appearance of parkinsonian motor disabilities, the present study assessed PPE-A mRNA expression and striatal dopamine (DA) content following a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration protocol in monkeys that produces a progressive parkinsonian state. Groups ranged from normal to full parkinsonian through asymptomatic lesioned monkeys. The key finding of this study is that PPE-A expression is already upregulated in asymptomatic-lesioned monkeys showing a marked DA depletion (56%). Importantly, this up-regulation is restricted to motor regions of the basal ganglia circuitry. The increased PPE-A mRNA expression observed in asymptomatic, but DA-depleted animals, supports our initial hypothesis of such an upregulation occurring before the appearance of parkinsonian motor disabilities. Furthermore, when considered with recent electrophysiological and histochemical data, these findings question the functional significance of upregulated enkephalin transmission in the indirect striatopallidal pathway. Bhatia, K., D. J. Brooks, et al. (2001). "Updated guidelines for the management of Parkinson's disease." Hosp Med 62(8): 456-70. New data on diagnosis, drug therapy, surgery and psychosocial concerns have emerged since the publication of the 1998 Guidelines for the Management of Parkinson's Disease. This article reviews new data and addresses issues left unanswered in the previous guidelines. Biemans, M. A., J. Dekker, et al. (2001). "The internal consistency and validity of the Self-Assessment Parkinson's Disease Disability Scale." Clin Rehabil 15(2): 221-8. OBJECTIVE: To test the consistency and validity of the Self-assessment Parkinson's Disease Disability Scale in patients with Parkinson's disease living at home. DESIGN: Patients with Parkinson's disease responded to a set of questionnaires. In addition, an observation of the performance of daily activities was carried out on a subgroup. SETTING AND SUBJECTS: Patients with Parkinson's disease living at home (n = 142). MEASURES: The Self-assessment Parkinson's Disease Disability Scale (SPDDS), the Hoehn & Yahr Rating Scale (H&Y), and the Sickness Impact Profile (SIP68). The observation concerned nine activities that correspond to items of the SPDDS questionnaire. RESULTS: Internal consistency of the SPDDS was very high (Cronbach's alpha = 0.97; reliability rho = 0.97). The items of the SPDDS are hierarchical (Loevinger's H = 0.64): patients had least difficulty with 'washing' and 'brushing teeth' and most difficulty with 'turning in bed', 'travelling by public transport' and 'writing a letter'. Validity of the SPDDS was good: the relationship between the SPDDS questionnaire and the H&Y rating scale, the SIP68 and the results of the observation was strong and significant. CONCLUSION: The SPDDS is a unidimensional instrument measuring disabilities in Parkinson's disease patients living at home. Bjarkam, C. R., J. C. Sorensen, et al. (2001). "New strategies for the treatment of Parkinson's disease hold considerable promise for the future management of neurodegenerative disorders." Biogerontology 2(3): 193-207. Neurodegenerative diseases are often considered incurable with no efficient therapies to modify or halt the progress of disease, and ultimately lead to reduced quality of life and to death. Our knowledge of the nervous system in health and disease has, however, increased considerably during the last fifty years and today, neuroscience reveals promising new strategies to deal with disorders of the nervous system. Some of these results have been implemented with success in the treatment of Parkinson's disease, a common neurodegenerative illness affecting approximately 1% of the population aged seventy or more. Parkinson's disease is characterized by a massive loss of dopaminergic neurons in the substantia nigra, leading to severe functional disturbance of the neuronal circuitry in the basal ganglia. A thorough description of basal ganglia circuitry in health and disease is presented. We describe how the functional disturbances seen in Parkinson's disease may be corrected at specific sites in this circuitry by medical treatment or, in advanced stages of Parkinson's disease, by neurosurgical methods. The latter include lesional surgery, neural transplantation and deep brain stimulation, together with future treatment strategies using direct or indirect implantation of genetically modified cell-lines capable of secreting neurotrophic factors or neurotransmitters. Advantages and disadvantages are briefly mentioned for each strategy and the implications for the future and the possible use of these interventions in other neurodegenerative diseases are discussed, with special emphasis on deep brain stimulation. Blair, E., C. Redwood, et al. (2001). "Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis." Hum Mol Genet 10(11): 1215-20. Familial hypertrophic cardiomyopathy (HCM) has been widely studied as a genetic model of cardiac hypertrophy and sudden cardiac death. HCM has been defined as a disease of the cardiac sarcomere, but mutations in the known contractile protein disease genes are not found in up to one-third of cases. Further, no consistent changes in contractile properties are shared by these mutant proteins, implying that an abnormality of force generation may not be the underlying mechanism of disease. Instead, all of the sarcomeric mutations appear to result in inefficient use of ATP, suggesting that an inability to maintain normal ATP levels may be the central abnormality. To test this hypothesis we have examined candidate genes involved in energy homeostasis in the heart. We now describe mutations in PRKAG2, encoding the gamma(2) subunit of AMP-activated protein kinase (AMPK), in two families with severe HCM and aberrant conduction from atria to ventricles in some affected individuals (pre-excitation or Wolff-Parkinson-White syndrome). The mutations, one missense and one in-frame single codon insertion, occur in highly conserved regions. Because AMPK provides a central sensing mechanism that protects cells from exhaustion of ATP supplies, we propose that these data substantiate energy compromise as a unifying pathogenic mechanism in all forms of HCM. This conclusion should radically redirect thinking about this disorder and also, by establishing energy depletion as a cause of myocardial dysfunction, should be relevant to the acquired forms of heart muscle disease that HCM models. Blakely, R. D. (2001). "Neurobiology. Dopamine's reversal of fortune." Science 293(5539): 2407-9. Blanco Lezcano, L., N. Pavon Fuentes, et al. (2001). "[Microdialysis cerebral. Main application of this technique]." Rev Neurol 33(5): 464-71. INTRODUCTION. Microdialysis cerebral technique has been widely employed in order to study the neurotransmitter release. DEVELOPMENT. This technique present numerous advantages such as: allow to work with sample in vivo from animals freely moving, by means of microdialysis can be infused simultaneously different drugs in different points implanted probes in several coordinates; also allow carry out pharmacokinetics studies that show correlation with behavior patter as well as to study metabolic changes, which is not possible when this determination are carry out in tissue, in post mortem stadio. CONCLUSIONS. In the present work is carry out a review about the main results obtaining in the sensitization and abstinence to several drug study and approach to biochemical characteristics to Parkinson s disease (PD) by means of microdialysis technique. In relation to sensibilization studies, the temporal changes in different behavior pattern that modify after amphetamine administration have been studied. Microdialysis study allowed correlationate dopamine concentration with behavior pattern above mentioned. In relation with PD, dopamine concentration after systemic and central (intracerebral) administration of levodopa and another dopaminergic drugs have been studied in different nucleus of basal ganglia as well as its respectively behavior correlates. Blandini, F., R. Fancellu, et al. (2001). "Plasma homocysteine and l-dopa metabolism in patients with Parkinson disease." Clin Chem 47(6): 1102-4. Blandini, F., G. Nappi, et al. (2001). "Subthalamic infusion of an NMDA antagonist prevents basal ganglia metabolic changes and nigral degeneration in a rodent model of Parkinson's disease." Ann Neurol 49(4): 525-9. Using permanent cannulas connected to subcutaneous pumps, we infused selective glutamate antagonists into the subthalamic nucleus of rats. Pumps were implanted immediately after the intrastriatal injection of 6-hydroxydopamine and delivered micro-quantities of the Nmethyl-D-aspartate antagonist MK-801 or the alpha-amino-3-hydroxy-5-methylisoxazole antagonist NBQX for 4 weeks. Subthalamic infusion of MK-801, but not of NBQX, prevented the basal ganglia metabolic changes and motor abnormalities caused by nigrostriatal lesion. Animals treated with MK-801 also exhibited marked reduction of nigral cell loss. We conclude that pharmacological modulation of subthalamic activity may have both symptomatic and neuroprotective effects in Parkinson's disease. Blass, J. P. (2001). "Brain metabolism and brain disease: is metabolic deficiency the proximate cause of Alzheimer dementia?" J Neurosci Res 66(5): 851-6. The potential of impairments in oxidative/energy metabolism to cause diseases of the brain had been proposed even before the major pathways of oxidative/energy metabolism were described. Deficiencies associated with disease are known in all the pathways of oxidative/energy metabolism and are associated with some of the most common disorders of the nervous system, including Alzheimer's disease (AD) and Parkinson's disease. A common mechanism in these conditions appears to be a downward mitochondrial spiral, involving abnormalities in energy metabolism, calcium metabolism, and free radicals (reactive oxygen and nitrogen species). In AD, the spiral appears to interact with abnormalities in the metabolism of the Alzheimer amyloid precursor protein (APP) and its Abeta fragment. Several lines of evidence indicate that the mitochondrial spiral may be a proximate cause of the clinical disabilities in AD. Decreases in cerebral metabolic rate (CMR) characteristically occur in AD and in other dementias. Inducing decreases in CMR leads to clinical disabilities characteristically associated with AD and with analogous problems in experimental animals. Treatments directed toward normalizing CMR appear to help at least some patients. Further studies of this possibility and of treatments designed to ameliorate the mitochondrial spiral may prove useful for treating AD and perhaps some other dementing disorders. Block, F. and C. M. Kosinski (2001). "[Glutamate antagonists in neurology]." Nervenarzt 72(6): 393-405. Glutamate is the major excitatory neurotransmitter of the central nervous system. Besides its importance in many physiological processes, increased glutamate release and subsequent excessive stimulation of the various glutamate receptors are thought to play critical roles in the pathophysiological mechanisms underlying many neurologic diseases. Experimental data suggest that blockade of glutamate receptors or inhibition of glutamate release has positive effects in many disease models. Glutamate antagonists are already in clinical use for the treatment of Parkinson's disease, epilepsy, spasticity, and neuropathic pain. Overall, glutamate antagonists have not been found clinically effective for neuroprotective treatment of cerebral ischemia or chronic neurodegenerative diseases, with one exception. Side effects of glutamate antagonists can be mainly attributed to central mechanisms and include psychosis, agitation, and disorientation. It is to be hoped that further development of new glutamate antagonists that block disease-relevant subtypes of glutamate receptors will lead to more effective drugs with fewer side effects. Bloem, B. R., Y. A. Grimbergen, et al. (2001). "Prospective assessment of falls in Parkinson's disease." J Neurol 248(11): 950-8. We studied prospectively the epidemiology, clinical impact and prediction of falls in 59 moderately affected patients with Parkinson's disease (PD) (mean UPDRS motor score 31.5; mean age 61 years) and 55 controls (mean age 60 years). At baseline, balance and gait were evaluated extensively. The retropulsion test (response to sudden shoulder pull) was executed first unexpectedly and five more times following prior warning. All persons used standardised scoring forms to document their falls during six months. Thirty patients (50.8 %) and eight controls (14.5%) fell at least once (relative risk [RR] 6.1; 95% confidence interval [CI] 2.5-15.1, p < 0.001). Recurrent (> or = 2) falls occurred in 15 patients (25.4%), but in only two controls (RR 9.0; 95 % CI 2.0-41.7; p=0.001). Recurrent falls were more common among persons taking benzodiazepines (RR 5.0; 95% CI 1.6-15.5; p < 0.01). Sixty-two percent of the falls in patients caused soft tissue injuries, but no fractures occurred. A fear of future falls was common (45.8 % of patients) and was accompanied by restriction of daily activities (44.1 % of patients). Seventy percent of falls reported by patients were'intrinsic' (due to patient-related factors), but falls in controls were mainly (50%) 'extrinsic' (due to environmental factors). None of the baseline posture and gait variables predicted falls adequately. The first 'unexpected' retropulsion test was more often abnormal than all subsequent (predictable) tests. Irrespective of its method of execution, the retropulsion test did not predict falls. A combination of asking for prior falls, disease severity and the Romberg test yielded the best overall diagnostic utility (sensitivity 65 % and specificity 98 %). Recurrent fallers were best predicted by disease severity (RR for Hoehn and Yahr stage 3 was > 100; 95% CI 3.1-585) and asking for prior falls (RR 5.0; 95% CI 1.2-20.9). We conclude that falls are common and disabling, even in relatively early stage PD. Recurrent fallers were best predicted by disease severity and presence of prior falls. Strategies to prevent falls in PD should particularly focus at intrinsic (patient-related) factors, such as minimising the use of benzodiazepines. Bloem, B. R., V. V. Valkenburg, et al. (2001). "The multiple tasks test. Strategies in Parkinson's disease." Exp Brain Res 137(3-4): 478-86. The clinical balance tests presently used cannot predict falls in Parkinson's disease (PD), perhaps because they probe fairly isolated "components" of postural control. The Multiple Tasks Test (MTT) is a new balance test that simultaneously assesses multiple components of postural control. We investigated whether this MTT can detect postural abnormalities in PD patients. Fifty young controls (mean age 27.6 years), 20 elderly controls (mean age 62.5 years), and 20 PD patients (mean age 61.8 years, mean Hoehn and Yahr stage 2.2) participated. The MTT consisted of eight separate tasks of increasing complexity, which were executed sequentially. These tasks were composed of several motor components (standing up, walking, avoiding obstacles, touching the floor, turning around, and sitting down) and one cognitive component (answering serial questions). Four additional components included carrying an empty or loaded tray, wearing slippery shoes, and reduced illumination. All components within each task had to be performed simultaneously or directly sequentially. Errors were defined as Hesitations (slowed performance) or Blocks (complete cessation), which were scored separately for execution of the motor and cognitive components. Speed of performance was not stressed, but we did measure the time taken to complete all tasks. The complete MTT was performed by all subjects, except for a subgroup of seven patients and seven elderly controls who performed a shortened version, with only three of the eight sequential tasks (simple, intermediate, and most difficult). The number of subjects that produced Hesitations or Blocks for the motor components differed between the three groups [two-way repeated measures MANOVA, F(2.7) = 20.56; P < 0.001], patients making more errors than young and elderly controls. Furthermore, the number of subjects that made motor errors increased as the tasks became more complex [F(2.7) = 6.69; P < 0.001]. This increase differed across the three groups [significant interaction effect; F(2.7) = 3.31; P < 0.001] because particularly patients produced motor errors during the more complex tasks. In both control groups, 62% performed all eight consecutive tasks without errors in the motor components. In contrast, only 8% of the patients completed all tasks without motor errors (log rank test, P < 0.0001). This difference between patients and controls disappeared if the cognitive component was also scored, because more controls made cognitive errors during complex tasks than patients. Controls apparently gave priority to execution of the motor components, which they performed significantly faster than the patients. Both patients and controls made more errors during the shortened MTT, suggesting that learning effects (gain in performance through practice) influenced performance on the complete test. The MTT is a new balance test that clearly discriminates between healthy subjects and PD patients. Unlike controls, PD patients lend less priority to motor tasks over cognitive tasks. In addition, impaired motor learning may partially explain the higher error rate in PD. Future studies must determine if impaired MTT performance can predict actual falls in daily life. Bloem, B. R., V. V. Valkenburg, et al. (2001). "The Multiple Tasks Test: development and normal strategies." Gait Posture 14(3): 191-202. Simultaneous challenge of posture and cognition ("dual tasks") may predict falls better than tests of isolated components of postural control. We describe a new balance test (the Multiple Tasks Test, MTT) which (1) is based upon simultaneous assessment of multiple (>2) postural components; (2) represents everyday situations; and (3) can be applied by clinicians. Relevant risk factors for falls and actual fall circumstances (identified from a prospective survey in Parkinson's disease) were used to design functional tests (or postural "components") that resembled everyday situations. We distinguished a "cognitive" component (answering serial questions) from largely "motor" components (standing up, sitting down, turning around, walking, avoiding obstacles, and touching the floor). Four additional components included carrying an empty or loaded tray, wearing shoes with slippery soles and reduced illumination. These components were combined to yield eight separate tasks of increasing complexity that were executed sequentially. The first and simplest task consisted of standing up, undisturbed walking, turning around and sitting down. For each of the next tasks, a new component was added to the earlier and otherwise identical task. All components within each task had to be performed simultaneously. Errors were defined as Hesitations (slowed performance) or Blocks (complete cessation), which were scored separately for execution of motor and cognitive components. Speed of performance was not stressed, but was measured for all tasks. The MTT was administered to 50 young healthy subjects (mean age 27.6 years) and 13 elderly subjects (mean age 62.0 years). To study learning effects, 20 different young subjects (mean age 21.0 years) received the MTT in order of gradually decreasing complexity. For subjects who received the MTT in order of increasing difficulty, 62% in both age groups performed all eight tasks without any Errors in the motor components. Among those making Errors, the proportion of subjects that made motor Errors increased significantly as the tasks became more complex (F(1,7)=2.66, P<0.05). This increase differed across the two groups (significant interaction of Group by Task; F(1,7)=3.07, P=0.01) because more elderly subjects produced motor Errors during the most complex tasks. Cognitive Errors increased even more than motor Errors with task complexity, and this increase was most pronounced in young subjects (significant interaction of Group by Error Type by Task; F(1,1,7)=3.85, P=0.001). Only eight young (16%) and four elderly subjects (30.8%) performed the MTT without any motor or cognitive Errors, again suggesting that more young subjects made cognitive Errors. Among subjects who received the MTT in reverse order, motor errors were more common than among subjects who received the MTT in order of increasing complexity (F(1,7)=5.90, P<0.05), particularly during the two most difficult tasks. The elderly performed all tasks slower than the young subjects. We conclude that the MTT is a new balance test based upon a multiple task design that resembles everyday situations. Performance by healthy subjects revealed interesting insights into normal postural strategies. For complex postural tasks, healthy subjects favour execution of motor components over execution of a cognitive component ("posture first" strategy). Young subjects were more inclined than elderly subjects to use this strategy. Motor learning influenced performance among subjects who received the MTT in order of increasing difficulty. Further studies must determine whether the MTT can be used to evaluate balance disorders. Bloem, B. R., J. P. van Vugt, et al. (2001). "Postural instability and falls in Parkinson's disease." Adv Neurol 87: 209-23. Blum, D., S. Torch, et al. (2001). "Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson's disease." Prog Neurobiol 65(2): 135-72. Parkinson's disease (PD) is a neurodegenerative disorder characterized by a preferential loss of the dopaminergic neurons of the substantia nigra pars compacta. Although the etiology of PD is unknown, major biochemical processes such as oxidative stress and mitochondrial inhibition are largely described. However, despite these findings, the actual therapeutics are essentially symptomatical and are not able to block the degenerative process. Recent histological studies performed on brains from PD patients suggest that nigral cell death could be apoptotic. However, since post-mortem studies do not allow precise determination of the sequence of events leading to this apoptotic cell death, the molecular pathways involved in this process have been essentially studied on experimental models reproducing the human disease. These latter are created by using neurotoxic compounds such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or dopamine (DA). Extensive study of these models have shown that they mimick, in vitro and in vivo, the histological and/or the biochemical characteristics of PD and thus help to define important cellular actors of cell death presumably critical for the nigral degeneration. This review reports recent data concerning the biochemical and molecular apoptotic mechanisms underlying the experimental models of PD and correlates them to the phenomena occurring in human disease. Bocquet, A., G. Lorent, et al. (2001). "Failure of GPI compounds to display neurotrophic activity in vitro and in vivo." Eur J Pharmacol 415(2-3): 173-80. The aim of this study was to evaluate the neurotrophic and neuroprotective properties of a series of immunophilin ligands and to assess the potential involvement of FK506 Binding Protein 12 kDa (FKBP12) rotamase inhibition in this activity. Both FK506 and rapamycin induced a potent inhibition of the FKBP12 rotamase activity (pIC(50) values of 7.3 and 7.4, respectively) but only a modest inhibition was observed with 1-(3,3-dimethyl-2-oxo-pentanoyl)-pyrrolidine-2-carboxylic acid S-3-pyridin-3-yl-propyl ester (GPI 1046) (5.8), its N-oxide (5.4) and thioester (6.3) analogues. Compared to nerve growth factor, all these immunophilin ligands only induced marginal increases in neurite outgrowth of rat dissociated newborn dorsal root ganglia cells. Furthermore, systemic administration of GPI 1046 and its N-oxide and thioester analogues failed to prevent striatal dopamine depletion induced by acute or chronic i.p. treatment with 1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine (MPTP). These results suggest that inhibition of FKBP12 rotamase activity is not predictive for neurotrophic and neuroprotective properties of immunophilin ligands and question their therapeutic utility in neurodegenerative diseases like Parkinson's disease. Bodenmann, P., J. Ghika, et al. (2001). "[Neurological comorbidity in parkinsonism]." Rev Neurol (Paris) 157(1): 45-54. We studied the neurological comorbidity of parkinsonism in 368 consecutive patients from the Lausanne Movement Disorders Registry. Only 6 patients had no neurological comorbidity. We found that 23p.100 of our patients had ischemic strokes, especially large vessel strokes, i.e three times more than in an age-matched control study performed in a recent survey in our country, which is a new finding in contradiction with previous reports mentioning that Parkinson's disease may be a protective factor against stroke. This finding opens new directions for further studies concerning some shared mechanisms in both diseases associated with age. Predominantly tremulous parkinsonism (46p.100) and progressive supranuclear palsy patients (PSP) (40p.100) had the highest prevalence of cerebrovascular disease of all subgroups of parkinsonism, especially lacunar infarcts, which is in accord with a higher frequency of hypertension in these subgroups according to a recent study of ours. Transient ischemic attacks or hemorrhages were not more frequent than in the general population. We did not find a higher frequency of head trauma except for Parkinson's disease, but a trend for a higher frequency of headache and migraine. Brain tumors were more frequent in Parkinson's disease and hydrocephalus and radiculopathies in parkinsonism in general when compared to age-matched populations from the literature. Polyneuropathies were more frequently observed in familial parkinsonism only, but myopathies and cranial neuropathies were not more frequent in our patients. Epilepsy was significantly less frequent in parkinsonism, especially in Parkinson's disease, infectious diseases of the nervous system were rarely encountered, and restless legs syndrome was surprisingly not more frequent than in a normal population. Dementia was associated in 20p.100, but multiple sclerosis is noticeably absent. Boeve, B. F., M. H. Silber, et al. (2001). "Association of REM sleep behavior disorder and neurodegenerative disease may reflect an underlying synucleinopathy." Mov Disord 16(4): 622-30. Our objective was to examine whether rapid eye movement (REM) sleep behavior disorder occurs in disproportionally greater frequency in multiple system atrophy (MSA), Parkinson's disease (PD), and dementia with Lewy bodies (DLB), collectively known as the synucleinopathies, compared to other nonsynucleinopathy neurodegenerative disorders. In study 1, we reviewed the clinical records of 398 consecutive patients evaluated at Mayo Clinic Rochester for parkinsonism and/or cognitive impairment. The frequency of suspected and polysomnogram (PSG)-confirmed REM sleep behavior disorder (RBD) among subjects with the synucleinopathies MSA, PD, or DLB was compared to the frequency among subjects with the nonsynucleinopathies Alzheimer's disease (AD), frontotemporal dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), mild cognitive impairment (MCI), primary progressive aphasia (PPA), and posterior cortical atrophy (PCA). In study 2, we reviewed the clinical records of 360 consecutive patients evaluated at Mayo Clinic Jacksonville for parkinsonism and/or cognitive impairment. The frequency of probable RBD among patients with PD and DLB was compared to the frequency among patients with AD and MCI. In study 3, we reviewed the brain biopsy or postmortem autopsy diagnoses of 23 Mayo Clinic Rochester patients who had been clinically examined for possible RBD and a neurodegenerative disorder. In study 1, patients with MSA, PD, or DLB were more likely to have probable and PSG-confirmed RBD compared to subjects with the nonsynucleinopathies (probable RBD 77/120=64% vs. 7/278=3%, p < 0.01; PSG-confirmed RBD 47/120=39% vs. 1/278=0%, p < 0.01). In study 2, patients with PD and DLB were more likely to have probable RBD compared to those with AD and MCI (56% vs. 2%, p < 0.01). In study 3, of the 23 autopsied patients who had been questioned about possible RBD, 10 were clinically diagnosed with RBD. The neuropathologic diagnoses in these 10 included Lewy body disease in nine, and MSA in one. Of the other 13 cases, 12 did not have a history suggesting RBD, and the one case who did had normal electromyographic atonia during REM sleep on PSG and autopsy findings of PSP. Only one of these 13 had a synucleinopathy. The positive predictive values for RBD indicating a synucleinopathy for studies 1-3 were 91.7%, 94.3%, and 100.0%, respectively. Clinically suspected and PSG-proven RBD occurs with disproportionally greater frequency in MSA, PD, and DLB compared to other neurodegenerative disorders. In the setting of degenerative dementia and/or parkinsonism, we hypothesize that RBD is a manifestation of an evolving synucleinopathy. Bonelli, R. M., L. Kenner, et al. (2001). "Compactotomy in Huntington's chorea." Med Hypotheses 57(4): 491-6. Advances in neuroradiological and neurosurgical techniques have lead to a growing interest in functional neurosurgical interventions for medically intractable movement disorders. The majority of these procedures are performed in patients with hypokinetic movement disorders, especially Parkinson's disease. However, relatively few interventions were done in hyperkinetic disorders such as Huntington's disease (HD), mainly owing to the lack of an adequate target nucleus. We have recently described the case of a reversible chorea in a genetically confirmed HD patient. We subsequently identified a marked bilateral degeneration of the substantia nigra as the probable reason for choreatic cessation. We therefore suggest that primary striatal atrophy causing hyperkinesia and secondary substantia nigra atrophy favouring hypokinesia were balanced in this patient, thus resulting in a close-to-physiologic GABAergic basal ganglia output. We postulate that deep brain stimulation of the substantia nigra pars compacta may ameliorate hyperkinesia in choreatic movement disorders, thus representing the first effective therapy in Huntington's chorea. Several lines of evidence in recent neurophysiological research support our hypothesis and are discussed below. Bonifati, V. (2001). "Monogenic Parkinsonisms and the genetics of Parkinson's disease." Funct Neurol 16(1): 35-44. Bonifati, V., G. De Michele, et al. (2001). "The parkin gene and its phenotype. Italian PD Genetics Study Group, French PD Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease." Neurol Sci 22(1): 51-2. Mutations of the parkin gene on chromosome 6 cause autosomal recessive, early onset parkinsonism. This is the most frequent form of monogenic parkinsonism so far identified. The associated phenotypical spectrum encompasses early onset, levodopa-responsive parkinsonism (average onset in the early 30s in Europe), and it overlaps with dopa-responsive dystonia in cases with the earliest onset, and with clinically typical Parkinson's disease in cases with later onset. Despite clinical features, Lewy bodies are not found at autopsy in brains of patients with parkin mutations. The parkin protein possesses ubiquitin ligase activity, which is abolished by the pathogenic mutations. Bonini, N. M. (2001). "Drosophila as a genetic approach to human neurodegenerative disease." 7(3): 171-175. Polyglutamine disease is a class of human neurodegenerative diseases characterized by late-onset, progressive neural degeneration. The molecular mechanism is expansion, within the coding region of the respective genes, of a CAG repeat encoding glutamine. The expanded polyglutamine domain confers dominant toxicity on the disease protein, leading to neuronal dysfunction and degeneration. In order to develop Drosophila as a model system to approach and study such human diseases, a human gene encoding an expanded polyglutamine protein was introduced into the fly. Expression of this protein with a pathogenic polyglutamine domain causes late-onset, progressive degeneration of cells in the fly, as it does in humans with disease and mouse transgenic models. Moreover, the protein shows abnormal protein aggregation in flies, similar to human disease tissue. These studies indicate that molecular mechanisms of polyglutamine-induced neurodegeneration are conserved in Drosophila. Through these studies and additional studies to develop fly models for other human neurodegenerative diseases, including Parkinson's disease, the power of Drosophila genetics can be brought to bear toward the molecular understanding and treatment of human neurodegeneration. Booij, J., P. Bergmans, et al. (2001). "Imaging of dopamine transporters with [123I]FP-CIT SPECT does not suggest a significant effect of age on the symptomatic threshold of disease in Parkinson's disease." Synapse 39(2): 101-8. Parkinson's disease (PD) is characterized neuropathologically by degeneration of the nigrostriatal dopaminergic pathway. With natural aging there is loss of dopaminergic cells in the substantia nigra and, consequently, loss of dopamine transporters in the striatum. It has been suggested that PD is caused by an accelerated rate of cell death. Conceptually, symptoms in idiopathic PD become apparent after a critical level of cell loss, the "symptom threshold." It has been suggested that this symptom threshold is independent of age. In this study, [123I]FP-CIT SPECT was used to assess the effect of aging on the density of striatal dopamine transporters in vivo in controls (n = 36) and early, drug-naive, patients with PD (n = 32). We found a significant age-associated decline of [123I]FP-CIT binding to striatal dopamine transporters in controls, but not in parkinsonian patients. This finding might give further support for the existence of an age-independent threshold in PD. In a subgroup of patients with hemi-PD, we found a significant loss of dopamine transporters bilaterally in the caudate nucleus and putamen. This loss was more pronounced in the putamen than in the caudate nucleus and the contralateral binding was significantly lower than the ipsilateral binding. By using age-corrected data, we estimated that in our particular patient group motor signs started when the loss of [123I]FP-CIT binding ratios in the putamen was 46-64%. Booij, J., J. D. Speelman, et al. (2001). "The clinical benefit of imaging striatal dopamine transporters with [123I]FP-CIT SPET in differentiating patients with presynaptic parkinsonism from those with other forms of parkinsonism." Eur J Nucl Med 28(3): 266-72. [123I]FP-CIT (N-omega-fluoropropyl-2 beta-carbomethoxy-3 beta-(4-iodophenyl)nortropane) has been developed successfully as a radioligand for single-photon emission tomography (SPET) imaging of dopamine transporters, which are situated in the membrane of dopaminergic neurons. Imaging of these transporters has shown promise as a clinical tool to detect degeneration of the dopaminergic nigrostriatal pathway. Several "presynaptic parkinsonian" syndromes, such as Parkinson's disease or multiple system atrophy, are characterised by degeneration of the nigrostriatal pathway. [123I]FP-CIT SPET imaging studies have shown the ability to detect loss of striatal dopamine transporters in such syndromes. However, in clinical practice it is sometimes difficult, but important, to discriminate patients with "presynaptic parkinsonism" from those with other forms of parkinsonism not characterised by loss of presynaptic dopaminergic cells (e.g. psychogenic parkinsonism or drug-induced postsynaptic parkinsonism). In these inconclusive cases, it may be of value to confirm or exclude the existence of degeneration of nigrostriatal dopaminergic cells by using imaging techniques such as [123I]FP-CIT SPET. Using [123I]FP-CIT SPET, we have imaged the striatal dopamine transporters in a group of patients with inconclusive forms of parkinsonism, and, moreover, have been able to perform clinical follow-up of these patients 2-4 years after imaging. In 33 inconclusive cases, ratios of specific to non-specific binding were calculated for the caudate nucleus and putamen following [123I]FP-CIT SPET imaging and compared with ratios obtained in healthy controls. In nine of the patients, degeneration of the nigrostriatal pathway was found scintigraphically and in all these cases, presynaptic parkinsonism was confirmed by clinical follow-up. In the other 24 subjects no degeneration was found scintigraphically. Forms of parkinsonism other than the presynaptic were confirmed at follow-up in 19 cases, and in three cases no conclusive diagnosis was established, but presynaptic parkinsonism was excluded clinically. A clinical diagnosis of presynaptic parkinsonism was established in two cases: one case of multiple system atrophy (in this patient loss of dopamine D2 receptors was found with [123I]iodobenzamide SPET performed 2 weeks after [123I]FP-CIT imaging) and one case of Parkinson's disease. Our data suggest that the positive predictive value of [123I]FP-CIT imaging is very high, and although the negative predictive value is lower, dopamine transporter imaging offers the prospect of a quick, objective method to confirm or exclude presynaptic parkinsonism in inconclusive cases. Borbely, K. (2001). "[In Process Citation]." Orv Hetil 142(43): 2347-55. Positron Emission Tomography (PET) and Single Photon Emission. Computed Tomography (SPECT) highly contribute to the management of patients with movement disorders by measuring regional cerebral metabolism/blood flow and dopamine receptors. Imaging of the dopaminergic system is a powerful tool for distinguishing patients with neurodegenerative disorders, such as Parkinson's disease. Parkinsonism is most of the time caused by idiopathic Parkinson's disease. Considering the differences in therapeutic response and prognosis, differentiation between Parkinson's disease and "parkinsonism-plus syndromes" is important. Visualisation of pre- and post-synaptic D2 dopamine receptors by using receptor ligands helps to discriminate between Parkinson's disease and "parkinsonism-plus syndromes" as Parkinson's disease is a presynaptic disease. Early disease detection in subjects suspected at risk for developing Parkinson's disease has become possible using ligands for the dopamine transporter. Functional imaging modalities are useful in the management of patients with movement disorders, are able to monitor in an objective way the efficacy of new pharmacological therapies, can document the effect of neuronal grafting for Parkinson's disease, and delineate the progression of these diseases. Borlongan, C. V., T. P. Su, et al. (2001). "Delta opioid peptide augments functional effects and intrastriatal graft survival of rat fetal ventral mesencephalic cells." Cell Transplant 10(1): 53-8. Delta enkephalin analogue [D-Ala(2),D-Leu(5)]enkephalin (DADLE) has been shown to protect dopamine transporters from methamphetamine-induced neurotoxicity. In the present study, we demonstrate that exposure of embryonic ventral mesencephalic cells to DADLE (0.01 g/ml), prior to intrastriatal transplantation, enhanced functional recovery and graft survival in 6-hydroxydopamine-induced hemiparkinsonian rats. At 6 and 8 weeks posttransplantation, animals that received DADLE-treated cell grafts exhibited significantly higher (near normal) spontaneous locomotor behaviors, as well as trends of greater reversal of motor asymmetrical behaviors compared with animals that received nontreated cell grafts. Histological examination revealed that animals transplanted with DADLE-treated cell grafts exhibited about twice the number of surviving tyrosine hydroxylase-immunoreactive grafted neurons compared with those animals that received nontreated cell grafts. These results suggest that DADLE should be considered as an adjunctive agent for neural transplantation therapy in Parkinson's disease. Bostantjopoulou, S., Z. Katsarou, et al. (2001). "Clinical features of parkinsonian patients with the alpha-synuclein (G209A) mutation." Mov Disord 16(6): 1007-13. The motor and neuropsychological abnormalities in eight Greek patients with Parkinson's disease (PD) carrying the alpha-synuclein gene mutation (G209A) were studied. These patients (five men, three women) belonged to six different families. Their symptoms started between 32-50 years of age (mean +/- SD, 39.7 +/- 7.6 years) and they had a mean disease duration of 5.4 +/- 2.1 years (range, 2-9 years) at the time of examination. Rigidity and bradykinesia predominated both at disease onset as well as in the later stages and rest tremor was relatively uncommon. Neuropsychological assessment showed that one patient was mildly demented while another had impairment in memory, visuoconstructive abilities, and executive function. Depression was present in only one patient. Our findings indicate that genetic forms of parkinsonism share common motor and cognitive characteristics with sporadic PD but raise the possibility that greater cognitive impairment and the relative rarity of tremor may be distinctive features worthy of further investigation. Bostantjopoulou, S., G. Kiosseoglou, et al. (2001). "Concurrent validity of the Test of Nonverbal Intelligence in Parkinson's disease patients." J Psychol 135(2): 205-12. The Test of Nonverbal Intelligence (TONI-2; L. Brown, R. J. Sherbenou, & S. Johnsen, 1990) and Raven's Colored Progressive Matrices (RCPM; J. C. Raven, 1965) are defined as language-free measures of cognitive ability. The purpose of the present study was to investigate the relation between the RCPM and the TONI-2 for samples of patients with Parkinson's disease (n = 75) and controls (n = 47). A regression equation was computed to evaluate the relation of the RCPM scores to the TONI-2 quotient. Regression equation results indicate that there is a significant overlapping linear variance between the two measures in both patients and controls. Boules, M., L. Warrington, et al. (2001). "Antiparkinson-like effects of a novel neurotensin analog in unilaterally 6-hydroxydopamine lesioned rats." Eur J Pharmacol 428(2): 227-33. Parkinson's disease is a neuropathological disorder involving the degeneration of dopamine neurons in the substantia nigra, with the resultant loss of their terminals in the striatum. This dopamine loss causes most of the motor disturbances associated with the disease. One animal model of Parkinson's disease involves destruction of the nigrostriatal pathway with a neurotoxin (6-hydroxydopamine) injected into this pathway. In unilaterally lesioned animals, injection of D-amphetamine causes rotation towards the lesioned side, while injection of apomorphine acting upon supersensitive postsynaptic dopamine receptors causes rotation away from the lesioned side. In this study, we tested the effects of acute and subchronic injection of a neurotensin analog (NT69L) on the rotational behavior induced by D-amphetamine (5 mg/kg) or apomorphine (600 microg/kg) in unilaterally 6-hydroxydopamine lesioned rats. Pretreatment of animals with intraperitoneal injections of NT69L (1 mg/kg) resulted in a significant reduction of apomorphine-induced contralateral rotation and D-amphetamine-induced ipsilateral rotation in these lesioned rats with an ED(50) of 40 and 80 microg/kg, respectively. After three daily injections of NT69L, its effects on this rotational behavior were unchanged, suggesting that no tolerance develops to this effect of NT69L. Boulu, R. G., C. Mesenge, et al. (2001). "[Neuronal death: potential role of the nuclear enzyme, poly (ADP-ribose) polymerase]." Bull Acad Natl Med 185(3): 555-63; discussion 564-5. Poly(ADP-ribose) polymerase (PARP, EC 2.4.2.30) is known as a nuclear enzyme that is activated by DNA strand breaks to participate in DNA repair. It is also called poly(ADP-ribose) synthase (PARS) or poly(ADP-ribose) transferase (PADRT). In physiological conditions, PARP plays an important role in maintaining genomic stability. However, for several pathological situations, which include massive DNA injury (brain ischemia for example), excessive activation of PARP can deplete stores of nicotinamide adenine dinucleotide (NAD+), the PARP substrate, which, with the subsequent ATP depletion, leads to cell death. PARP activation appears to play a major role in neuronal death induced by cerebral ischemia, traumatic brain injury, Parkinson disease and other pathologies. PARP inhibitors (3-aminobenzamide and other compounds) and PARP gene deletion induced dramatic neuroprotection in experimental animals (rats, mice). Accordingly, these data suggest that PARP inhibitors could provide a novel therapeutic approach in a wide range of neurodegenerative disorders including cerebral ischemia and traumatic brain injury. Boyce, S., N. M. Rupniak, et al. (2001). "Differential effects of D1 and D2 agonists in MPTP-treated primates: functional implications for Parkinson's disease. 1990." Neurology 57(10 Suppl 3): S27-33. Boylan, L. S., S. L. Pullman, et al. (2001). "Repetitive transcranial magnetic stimulation to SMA worsens complex movements in Parkinson's disease." Clin Neurophysiol 112(2): 259-64. OBJECTIVES: To evaluate the therapeutic potential of repetitive transcranial magnetic stimulation (rTMS) for Parkinson's disease (PD) by delivering stimulation at higher intensity and frequency over longer time than in previous research. Promising beneficial effects on movement during or after rTMS have been reported. METHODS: Ten patients with idiopathic PD were enrolled in a randomized crossover study comparing active versus sham rTMS to the supplementary motor area (SMA). Assessments included reaction and movement times (RT/MT), quantitative spiral analysis, timed motor performance tests, United Parkinson's Disease Rating Scale (UPDRS), patient self-report and guess as to stimulation condition. RESULTS: Two of 10 patients could not tolerate the protocol. Thirty to 45 min following stimulation, active rTMS as compared with sham stimulation worsened spiral drawing (P=0.001) and prolonged RT in the most affected limb (P=0.030). No other significant differences were detected. CONCLUSIONS: We sought clinically promising improvement in PD but found subclinical worsening of complex and preparatory movement following rTMS to SMA. These results raise safety concerns regarding the persistence of dysfunction induced by rTMS while supporting the value of rTMS as a research tool. Studies aimed at understanding basic mechanisms and timing of rTMS effects are needed. Braak, E., D. Sandmann-Keil, et al. (2001). "alpha-synuclein immunopositive Parkinson's disease-related inclusion bodies in lower brain stem nuclei." Acta Neuropathol (Berl) 101(3): 195-201. Advanced silver stains and immunohistochemical reactions against alpha-synuclein were used to detect Parkinson's disease-related cytoskeletal abnormalities in select lower brain stem nuclei. Various types of inclusion bodies including inconspicuous and heretofore unnoted granular particles and thread-like Lewy neurites were visualized. Of the nuclei investigated (gigantocellular reticular nucleus, bulbar raphe nuclei, coeruleus-subcoeruleus area), only lipofuscin- or neuromelanin-laden neuronal types showed a propensity to develop the pathological changes. Neuronal types devoid of pigment deposits remained free of the cytoskeletal abnormalities. Fine, dust-like particles and small globular Lewy bodies were encountered solely within the limits of intraneuronal lipofuscin or neuromelanin deposits. Braak, H., K. Del Tredici, et al. (2001). "Nerve cells expressing heat-shock proteins in Parkinson's disease." Acta Neuropathol (Berl) 102(5): 449-54. A distinctive histopathological feature of several neurodegenerative diseases, including corticobasal degeneration, argyrophilic grain disease, progressive supranuclear palsy, and Pick's disease, are achromatic nerve cells that express small heat-shock proteins, such as alphaB-crystallin or hsp-27, and develop in specific telencephalic cortical areas and subcortical nuclei. Here, we point to the consistent presence of such cells in Parkinson's disease. In this disorder, the neurons under consideration remain immunonegative for phosphorylated neurofilaments or for ubiquitin, thus exhibiting an immunocytochemical profile different from that shown by alphaB-crystallin-positive neurons in other neurodegenerative disorders. In severe cases of Parkinson's disease, the alphaB-crystallin-positive neurons are dispersed throughout the cerebral cortex, amygdala, and ventral claustrum. In cases showing relatively mild involvement of the telecephalon, these neurons occur chiefly within the reaches of the anterior temporal and insular mesocortex. These telencephalic predilection sites are nearly identical with those of the alpha-synuclein pathology. Nevertheless, most of the telencephalic alphaB-crystallin-immunopositive neurons refrain from developing Lewy bodies and Lewy neurites and, vice versa, most of the nerve cells containing Lewy bodies do not accumulate alphaB-crystallin. Branston, N. M. and W. el-Deredy (2001). "Movement discrimination by single cells in the human pallidum characterised by hidden Markov models." Exp Brain Res 137(1): 117-21. In patients undergoing pallidotomy for Parkinson's disease, we recorded extracellularly from single neurons in the two internal segments (GPii, GPie) and the external segment (GPe) of the globus pallidus (GP) in response to active (cued) movements of the contralateral wrist, elbow or ankle. The patterns of cell activity occurring both before and after movement onset were analysed using hidden Markov models (HMMs) and clustered by movement type using the generative topographical mapping algorithm. Cluster separation was quantified in order to measure a cell's ability to discriminate between movements. Statistical analysis of variance indicated a significant regional gradient (GPii > GPie > GPe) of movement discrimination, while cells in all regions differentiated better between movements of different joints (wrist, elbow or ankle) than between flexion and extension of the same joint. We found that GP cells generally showed distinguishable firing patterns corresponding to more than one type of movement per cell, in support of the hypothesis that cells in these regions of the basal ganglia are not involved in preparation or execution of a single type of movement but participate in many different movements, analogous to the hidden units of a neural network. Our results also indicate that cell activity both preceding a movement and during its execution may be modelled by HMMs with only a small number of states. Brattstrom, L. (2001). "Plasma homocysteine and MTHFR C677T genotype in levodopa-treated patients with PD." Neurology 56(2): 281; discussion 281-2. Breitenstein, C., D. Van Lancker, et al. (2001). "Impaired perception of vocal emotions in Parkinson's disease: influence of speech time processing and executive functioning." Brain Cogn 45(2): 277-314. Little is known about the underlying dimensions of impaired recognition of emotional prosody that is frequently observed in patients with Parkinson's disease (PD). Because patients with PD also suffer from working memory deficits and impaired time perception, the present study examined the contribution of (a) working memory (frontal executive functioning) and (b) processing of the acoustic parameter speech rate to the perception of emotional prosody in PD. Two acoustic parameters known to be important for emotional classifications (speech duration and pitch variability) were systematically varied in prosodic utterances. Twenty patients with PD and 16 healthy controls (matched for age, sex, and IQ) participated in the study. The findings imply that (1) working memory dysfunctions and perception of emotional prosody are not independent in PD, (2) PD and healthy control subjects perceived vocal emotions categorically along two acoustic manipulation continua, and (3) patients with PD show impairments in processing of speech rate information. Brevig, T., M. Meyer, et al. (2001). "Neural xenotransplantation: pretreatment of porcine embryonic nigral tissue with anti-Gal antibodies and complement is not toxic for the dopaminergic neurons." Cell Transplant 10(1): 25-30. The immunogenicity of porcine tissue is a major obstacle to its use as donor material in xenotransplantation for neurodegenerative diseases. We are currently evaluating a novel strategy for reducing the immunogenicity, in which the alpha-galactosyl epitope (Galalpha1,3Galbeta1,4GlcNAc-R) is used as a target for antibody- and complement-mediated removal of microglia. In the present study, our aim was to determine whether a pretreatment with antibodies against the alpha-galactosyl epitope (anti-Gal) and complement would lyse or otherwise damage dopaminergic neurons in porcine embryonic ventral mesencephalon (VM), the donor tissue for treatment of Parkinson's disease by xenotransplantation. Cell suspensions prepared from VM tissue from 27-day-old pig embryos were incubated with anti-Gal, purified from normal human serum by affinity chromatography, or medium only (control), and subsequently with rabbit complement. After these pretreatments, the cell suspensions were transplanted into the right striatum of 14 adult rats (two groups of 7 animals). The animals were sacrificed 20 days after transplantation, the brains were processed for histology, and the sections were stained for Nissl substance, porcine neurofilament, tyrosine hydroxylase, and rat CD45 to determine graft volume, presence of porcine neurons, content of dopaminergic cells, and leukocyte infiltration, respectively. The VM tissue pretreated with anti-Gal and complement gave rise to dopaminergic grafts that were indistinguishable from those derived from VM tissue given the control pretreatment. In 5 of the 14 animals, the grafts were infiltrated by host leukocytes, but in two of these recipients, the infiltration was only minimal. We conclude that anti-Gal and complement can be applied to porcine embryonic VM tissue without damaging the dopaminergic neurons and their precursors. Brevig, T., M. Meyer, et al. (2001). "Xenotransplantation for brain repair: reduction of porcine donor tissue immunogenicity by treatment with anti-Gal antibodies and complement." Transplantation 72(2): 190-6. BACKGROUND: Transplantation of embryonic neural tissue is a potential treatment for Parkinson's disease. Because human donor material is in short supply, porcine xenografts are considered a useful alternative. Current immunosuppressive therapies fail, however, to protect intracerebral neural xenografts from host CD4 T lymphocytes. To reduce the immunogenicity of porcine donor tissue, we attempted to remove microglial cells with antibodies against the alpha-galactosyl epitope (Galalpha1,3Galbeta1,4GlcNAc-R), or anti-Gal, and complement, and studied whether this pretreatment can reduce direct and indirect T-cell responses to the tissue. METHODS: Brain tissue from 27-day-old pig embryos was dissociated and treated with human anti-Gal and rabbit complement. The microglial content was analyzed by flow cytometry. [3H]thymidine incorporation in cocultures of the brain cells and purified human CD4 T cells was used to determine direct T-cell responses. Indirect T-cell responses were studied by grafting pretreated and control-pretreated (no anti-Gal) nigral tissue into the lesioned striatum of immunocompetent rats with 6-hydroxydopamine-induced hemiparkinsonism. Amphetamine-induced circling behavior was used to measure graft function. RESULTS: Anti-Gal and complement reduced the microglial content to 11-24% of control and abolished the ability of the brain cells to induce human CD4 T-cell proliferation. Pretreated nigral tissue reduced hemiparkinsonism by more than 50% in five of eight rats at some point during the 10-week follow-up. Rats receiving control-pretreated nigral tissue did not display this degree of improvement. CONCLUSIONS: Pretreatment with anti-Gal and complement can reduce the immunogenicity of porcine neural tissue, and might, therefore, be a valuable alternative or supplement to immunosuppression in neural xenotransplantation. Briand, K. A., W. Hening, et al. (2001). "Automatic orienting of visuospatial attention in Parkinson's disease." Neuropsychologia 39(11): 1240-9. The basal ganglia are involved in not only motor behavior, but also other more cognitive processes, such as attention. We tested Parkinson's disease (PD) patients in a task that measures reflexive orienting of spatial attention. Seven patients with idiopathic PD and eight control subjects performed a covert orienting task where spatial attention was directed by means of exogenous cues (luminance increments) with no predictive validity for target position. The subjects' task was to make a speeded saccade to a visual target, which appeared a variable time after onset of the cue either in the cued or an uncued spatial position. There was no overall difference between PD patients and control subjects in terms of the initial facilitation following reflexive cues, and later inhibition of return (IOR). However, PD patients differed from control subjects in two important respects. First, they were significantly faster than were control subjects on this reflexive visual-orienting task. Second, disease severity correlated with attentional performance; more advanced patients showed less initial facilitation but greater IOR. Thus PD patients show better performance on a reflexive saccade task and, for more advanced patients, greater IOR than control subjects. These findings are consistent with the possibility that reflexive attentional processes in PD patients may be more active. Brody, J. A. and M. D. Grant (2001). "Age-associated diseases and conditions: implications for decreasing late life morbidity." Aging (Milano) 13(2): 64-7. We discuss two types of age-associated diseases; aging-dependent such as Alzheimer's disease and congestive heart failure which increase logarithmically with age, versus age-dependent such as multiple sclerosis and amyotrophic lateral sclerosis which occur at proscribed ages, and then occurrence of new cases ceases or diminishes with further aging. Prevention strategies with both types emphasize postponement or delay of onset. The non-fatal aging-dependent diseases and conditions are an accumulating burden as we age, and increase overall morbidity in late years. These include Alzheimer's disease and other dementias, Parkinson's disease, loss of vision and hearing, incontinence, osteoporosis and hip fracture, osteoarthritis and depression. With mortality postponed, we will be living for many years at old and vulnerable ages. Life's quality will be reasonable for most. Still, increasing the chance that all will experience this desirable outcome requires pursuing the means to delay the onset of the physical and social events which we categorize as the non-fatal aging-dependent diseases and conditions. We must recognize that each added year occurs at the tip of an exponential curve where risk is maximal. Broggi, G., A. Franzini, et al. (2001). "Effect of bilateral subthalamic electrical stimulation in Parkinson's disease." Surg Neurol 56(2): 89-94; discussion 94-6. BACKGROUND: Bilateral high frequency subthalamic stimulation has been reported to be effective in the treatment of Parkinson's disease and levodopa-induced dyskinesias. To analyze the results of this surgical procedure we critically reviewed 17 parkinsonian patients with advanced disease complicated by motor fluctuations and dyskinesias. METHODS: Between January 1998 and June 1999 these 17 consecutive patients (age 48-68 years; illness duration 8-27 years) underwent bilateral stereotactically guided implantation of electrodes into the subthalamic nucleus in the Department of Neurosurgery of the Istituto Nazionale Neurologico "C. Besta." Parameters used for continuous high-frequency stimulation were: frequency 160 Hz, pulse width 90 microsec, mean amplitude 2.05 +/- 0.45 V. Parts II and III of the UPDRS were used to assess motor performance before and after operation by the neurologic team. The follow-up ranged between 6 and 18 months. RESULTS: At latest examination, mean UPDRS II and III scores had improved by 30% (on stimulation, off therapy) with mean 50% reduction in daily off time. Peak dyskinesias and early morning dystonias also improved in relation to therapy reduction. Side effects were persistent postoperative supranuclear oculomotor palsy and postural instability in one case, worsened off-medication hypophonia in three, and temporary nocturnal confusion episodes in three. Postoperative MRI revealed a clinically silent intracerebral haematoma in one case. One electrode required repositioning. CONCLUSIONS: Continuous high frequency STN stimulation is an effective treatment for advanced PD. A functionally useful and safe electrode placement can be performed without microrecording. Brooks, D. J. (2001). "Functional imaging studies on dopamine and motor control." J Neural Transm 108(11): 1283-98. In this review, the insights that PET and MR activation studies have given us concerning the role of dopamine in motor control are reviewed. Regional cerebral blood flow (rCBF) changes when normal subjects and Parkinson's disease patients perform simple finger movements, motor sequence learning, problem solving, and tasks financially rewarded according to success are compared. Additionally, dopamine release during rewarded and unrewarded actions, as reflected by relative levels of striatal binding of the reversible dopamine antagonist 11C-raclopride, are contrasted. It is argued that during unrewarded familiar actions tonic dopamine release in the basal ganglia acts to focus and filter cortical output so optimising the running of motor programmes. During motor learning, novel, and financially rewarded tasks additional dopamine is phasically released, acting to both alert the subject and to reinforce motor learning. Brooks, D. J. (2001). "Cerebral blood flow activation studies in Parkinson's disease." Adv Neurol 86: 225-35. Brooks, D. J. and M. Doder (2001). "Depression in Parkinson's disease." Curr Opin Neurol 14(4): 465-70. Brooksbank, C. (2001). "Protein degradation: Parkin finds a partner and a victim." Nat Rev Mol Cell Biol 2(1): 4-5. Brown, J. M., G. R. Hanson, et al. (2001). "Regulation of the vesicular monoamine transporter-2: a novel mechanism for cocaine and other psychostimulants." J Pharmacol Exp Ther 296(3): 762-7. The plasmalemmal dopamine (DA) transporter (DAT) is a principal site of action for cocaine. This report presents the novel finding that in addition to inhibiting DAT function, cocaine administration rapidly alters vesicular DA transport. Specifically, cocaine treatment abruptly and reversibly increased both the V(max) of DA uptake and the B(max) of vesicular monoamine transporter-2 (VMAT-2) ligand (dihydrotetrabenazine) binding, as assessed ex vivo in purified rat striatal synaptic vesicles. Selective inhibitors of the DAT (amfonelic acid and GBR12935), but not the plasmalemmal serotonin transporter (fluoxetine), also increased vesicular DA uptake. Moreover, DA depletion resulting from administration of the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine had cocaine-like effects. Conversely, administration of the DA-releasing agent methamphetamine rapidly decreased vesicular uptake. Taken together, these data demonstrate for the first time ex vivo that cocaine treatment rapidly alters vesicular monoamine transport, and suggest that alterations in cytoplasmic DA concentrations contribute to stimulant-induced changes in vesicular DA uptake. Hence, the VMAT-2 may be an important target for developing strategies to treat not only cocaine addiction but also other disorders involving alterations in neuronal DA disposition, including Parkinson's disease. Brown, P., J. Marsden, et al. (2001). "Intermuscular coherence in Parkinson's disease: relationship to bradykinesia." Neuroreport 12(11): 2577-81. We hypothesised that bradykinesia may be partly due to the failure of the corticomuscular system to engage in high frequency oscillatory activity in Parkinson's disease (PD). In healthy subjects such oscillations are evident in coherence between active muscles at 15--30 Hz. We therefore investigated the effects of therapeutic stimulation of the basal ganglia on this coherence and related it to changes in bradykinesia in the contralateral arm. Increases in coherence at 15--30 Hz and improvements in bradykinesia upon stimulation were correlated (r = 0.564, p < 0.001). This suggests that the basal ganglia modulate oscillatory activity in the corticomuscular system and that impairment of the motor system's ability to engage in synchronised oscillations at high frequency may contribute to bradykinesia in PD. Brown, P., A. Oliviero, et al. (2001). "Dopamine dependency of oscillations between subthalamic nucleus and pallidum in Parkinson's disease." J Neurosci 21(3): 1033-8. The extent of synchronization within and between the nuclei of the basal ganglia is unknown in Parkinson's disease. The question is an important one because synchronization will increase postsynaptic efficacy at subsequent projection targets. We simultaneously recorded local potentials (LPs) from the globus pallidus interna (GPi) and subthalamic nucleus (STN) in four awake patients after neurosurgery for Parkinson's disease. Nuclei from both sides were recorded in two patients so that a total of six ipsilateral GPi-STN LP recordings were made. Without medication, the power within and the coherence between the GPi and STN was dominated by activity with a frequency <30 Hz. Treatment with the dopamine precursor levodopa reduced the low-frequency activity and resulted in a new peak at approximately 70 Hz. This was evident in the power spectrum from STN and GPi and in the coherence between these nuclei. The phase relationship between the nuclei varied in a complex manner according to frequency band and the presence of exogenous dopaminergic stimulation. Synchronization of activity does occur between pallidum and STN, and its pattern is critically dependent on the level of dopaminergic activity. Bruck, A., R. Portin, et al. (2001). "Positron emission tomography shows that impaired frontal lobe functioning in Parkinson's disease is related to dopaminergic hypofunction in the caudate nucleus." Neurosci Lett 311(2): 81-4. We examined the relation between the dopaminergic function and the cognitive performance of patients with Parkinson's disease (PD). The subject sample consisted of ten patients in the early course of PD and with no previous antiparkinsonian medication. The dopaminergic function of the caudate nucleus and the putamen was studied with [(18)F]fluorodopa positron emission tomography, and the cognitive performance with a comprehensive battery of neuropsychological tests including tests sensitive to frontal lobe function. The decreased [(18)F]fluorodopa uptake in the right caudate nucleus was found to be related to slow processing time, measured as the difference between the incongruent and the congruent subtests of the Stroop Test (r=-0.85, P=0.002), a similar trend was seen in the left caudate (r=-0.60, P=0.07). Similar correlation was not detected in the putamen. The present findings provide evidence that the decreased dopaminergic function in the right caudate nucleus is related to the impaired performance in tests sensitive to frontal lobe function in patients at an early stage of PD and with no antiparkinsonian medication. Bruet, N., F. Windels, et al. (2001). "High frequency stimulation of the subthalamic nucleus increases the extracellular contents of striatal dopamine in normal and partially dopaminergic denervated rats." J Neuropathol Exp Neurol 60(1): 15-24. The subthalamic nucleus (STN) has come under focus in Parkinson disease (PD) because of recent advances in the understanding of the functional organization of the basal ganglia in normal and pathological conditions. Manipulations of the STN have been described to compensate for some imbalance in motor output of the basal ganglia in animal models of PD and have been proposed as a potential therapeutic target in humans. Indeed, high frequency stimulation (HFS) (130 Hz) of the STN has beneficial effects in severe parkinsonian patients but the precise mechanisms underlying these clinical results remain to be elucidated. To date, very little is known concerning the effect of HFS-STN on striatal dopaminergic transmission. Since it has been reported that dopaminergic medication may be reduced in PD patients under HFS-STN, our goal was to study the effect of HFS-STN on striatal dopamine (DA) transmission by using intracerebral microdialysis in normal and partially DA denervated rats. Our results show that HFS STN induces a significant increase of extracellular DA in the striatum of normal and partially DA lesioned rats while striatal extracellular levels of DOPAC were not affected. We conclude that HFS-STN acts directly and/or indirectly on striatal DA levels in control or partially DA lesioned rats. Brundin, P., S. Dunnett, et al. (2001). "Transplanted dopaminergic neurons: more or less?" Nat Med 7(5): 512-3. Brune, M., G. Gerlach, et al. (2001). "[A case of delusional jealousy in Parkinson disease ]." Nervenarzt 72(3): 224-6. Delusional jealousy has been reported in organic and "functional" psychotic disorders. In organic psychoses, delusional jealousy is usually associated with impaired orientation or other cognitive disturbances. Delusional jealousy in Parkinson's disease has rarely been reported in the scientific literature. A case of a 49-year-old man suffering from this pathology in the course of Parkinson's disease is presented as to clinical picture, therapy, course, and outcome. Buervenich, S., L. Olson, et al. (2001). "Nestin-like immunoreactivity of corpora amylacea in aged human brain." Brain Res Mol Brain Res 94(1-2): 204-8. Corpora amylacea (CA) are spherical bodies routinely observed throughout the aged human brain, normally found at high frequencies under the ependymal lining of the ventricles. We identified clusters of CA under the ependyma of the lateral and fourth ventricles in post-mortem brain material from Parkinson patients as well as age-matched controls. Using a monoclonal antibody we found CA to be immunoreactive for nestin, a marker of neural stem cells, while no other structures in the investigated brain areas were labeled by this antibody. Nestin filaments are therefore possible structural components of CA, a finding which may trigger new hypotheses regarding their biogenesis and function. Buervenich, S., F. Xiang, et al. (2001). "Identification of four novel polymorphisms in the calcitonin/alpha-CGRP (CALCA) gene and an investigation of their possible associations with Parkinson disease, schizophrenia, and manic depression." Hum Mutat 17(5): 435-6. We identified novel polymorphisms in the calcitonin/CGRPalpha (CALCA) gene by direct sequencing of genomic DNA and subsequent genotyping by RFLP (restriction fragment length polymorphism) detection and investigated association with neurological or psychiatric disease. Four novel polymorphic alleles were found: two (g.979G>A and g.4218T>C) represented single nucleotide polymorphisms (SNPs), one consisted of two coupled SNPs in close vicinity to each other (g.1210T>C and g.1214C>G), and one was an intronic 16-bp microdeletion (2919-2934del16). One of the SNPs (g.4218T>C) causes a non-synonymous amino acid change (Leu66Pro) in the third exon, an exon common to both procalcitonin and pro-alpha-CGRP. In a subsequent association study, frequencies of the identified polymorphisms in Parkinson and schizophrenia patients were compared with frequencies in the normal population. No statistically significant association was found in our material. The 16-bp microdeletion polymorphism was present in a family with multiple cases of unipolar or bipolar depressive disorder. Using this polymorphism as marker, cosegregation with the phenotype was observed in the majority of individuals. Burke, R. E. (2001). "alpha-Synuclein and parkin: coming together of pieces in puzzle of Parkinson's disease." Lancet 358(9293): 1567-8. Burkhard, P., P. Dominici, et al. (2001). "Structural insight into Parkinson's disease treatment from drug-inhibited DOPA decarboxylase." Nat Struct Biol 8(11): 963-7. DOPA decarboxylase (DDC) is responsible for the synthesis of the key neurotransmitters dopamine and serotonin via decarboxylation of L-3,4-dihydroxyphenylalanine (L-DOPA) and L-5-hydroxytryptophan, respectively. DDC has been implicated in a number of clinic disorders, including Parkinson's disease and hypertension. Peripheral inhibitors of DDC are currently used to treat these diseases. We present the crystal structures of ligand-free DDC and its complex with the anti-Parkinson drug carbiDOPA. The inhibitor is bound to the enzyme by forming a hydrazone linkage with the cofactor, and its catechol ring is deeply buried in the active site cleft. The structures provide the molecular basis for the development of new inhibitors of DDC with better pharmacological characteristics. Burn, D. J. and E. Jaros (2001). "Multiple system atrophy: cellular and molecular pathology." Mol Pathol 54(6): 419-26. Multiple system atrophy is an adult onset neurodegenerative disease, featuring parkinsonism, ataxia, and autonomic failure, in any combination. The condition is relentlessly progressive and responds poorly to treatment. Death occurs on average six to seven years after the onset of symptoms. No familial cases of multiple system atrophy have been reported, and no environmental factors have been robustly implicated as aetiological factors. However, analytical epidemiological studies are hampered because the condition is relatively rare. The discovery of the glial cytoplasmic inclusion (GCI) in 1989 helped to define multiple system atrophy as a clinicopathological entity, and drew attention to the prominent, if not primary, role played by the oligodendrocyte in the pathogenesis of the condition. Subsequently, GCIs were shown to be positive for alpha-synuclein, with immunostaining for this protein indicating that white matter pathology was more widespread than had previously been recognised. The presence of alpha-synuclein in GCIs provides a link with Parkinson's disease, dementia with Lewy bodies, and neurodegeneration with brain iron accumulation, type 1 (or Hallervorden-Spatz syndrome), in which alpha-synuclein is also found within Lewy bodies. This has led to the term "synucleinopathy" to embrace this group of conditions. The GCIs of multiple system atrophy contain a range of other cytoskeletal proteins. It is unknown how fibrillogenesis occurs, and whether there is primary oligodendrocytic dysfunction, which then disrupts the neurone/axon as a consequence of the glial pathology, or whether the oligodendrocytic changes merely represent an epiphenomenon. Further research into this devastating condition is urgently needed to improve our understanding of the pathogenesis, and also to produce new treatment approaches. Bush, A. I. and L. E. Goldstein (2001). "Specific metal-catalysed protein oxidation reactions in chronic degenerative disorders of ageing: focus on Alzheimer's disease and age-related cataracts." Novartis Found Symp 235: 26-38; discussion 38-43. Abnormalities of protein aggregation and deposition may play an important role in the pathophysiology of a diverse set of chronically progressive degenerative disorders including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease and age-related cataracts. We propose that aberrant metalloprotein reactions may be a common denominator in these diseases. In these instances, an abnormal reaction between a protein and redox active metal ions (especially copper or iron) promotes the generation of reactive oxygen species, and possibly, protein radicalization. These products then lead to chemical modification of the protein, alterations in protein structure and solubility, and oxidative damage to surrounding tissue. In this review, we explore these ideas by focusing on two common diseases of ageing, Alzheimer's disease and age-related cataracts. Understanding the metalloprotein biochemistry in both diseases may lead to a better understanding of the underlying pathophysiology in both disorders and suggest novel targets for therapeutic agents. Bussell, R., Jr. and D. Eliezer (2001). "Residual structure and dynamics in Parkinson's disease-associated mutants of alpha-synuclein." J Biol Chem 276(49): 45996-6003. alpha-Synuclein (alpha S) is a pre-synaptic protein that has been implicated as a possible causative agent in the pathogenesis of Parkinson's disease (PD). Two autosomal dominant missense mutations in the alpha S gene are associated with early onset PD. Because alpha S is found in an aggregated fibrillar form in the Lewy body deposits characteristic of Parkinson's patients, aggregation of the protein is believed to be related to its involvement in the disease process. The wild type (WT) and early onset mutants A30P and A53T display diverse in vitro aggregation kinetics even though the gross physicochemical and morphological properties of the mutants are highly similar. We used high resolution solution NMR spectroscopy to compare the structural and dynamic properties of the A53T and A30P mutants with those of WT alpha S in the free state. We found that the A30P mutation disrupts a region of residual helical structure that exists in the WT protein, whereas the A53T mutation results in a slight enhancement of a small region around the site of mutation with a preference for extended conformations. Based on these results and on the anticipated effects of these mutations on elements of secondary structure, we proposed a model of how these two PD-linked mutations influence alpha S fibril formation that is consistent with the documented differences in the fibrillization kinetics of the two mutants. Butterfield, D. A. and J. Kanski (2001). "Brain protein oxidation in age-related neurodegenerative disorders that are associated with aggregated proteins." Mech Ageing Dev 122(9): 945-62. Protein oxidation, one of a number of brain biomarkers of oxidative stress, is increased in several age-related neurodegenerative disorders or animal models thereof, including Alzheimer's disease, Huntington's disease, prion disorders, such as Creutzfeld-Jakob disease, and alpha-synuclein disorders, such as Parkinson's disease and frontotemporal dementia. Each of these neurodegenerative disorders is associated with aggregated proteins in brain. However, the relationship among protein oxidation, protein aggregation, and neurodegeneration remain unclear. The current rapid progress in elucidation of mechanisms of protein oxidation in neuronal loss should provide further insight into the importance of free radical oxidative stress in these neurodegenerative disorders. Byerly, M. J., M. T. Weber, et al. (2001). "Antipsychotic medications and the elderly: effects on cognition and implications for use." Drugs Aging 18(1): 45-61. Despite being frequently prescribed in the elderly, antipsychotic medications are commonly associated with adverse effects in this population, including sedative, orthostatic and extrapyramidal adverse effects. Growing evidence suggests that antipsychotics can also cause deleterious cognitive effects in some elderly patients. Preclinical and growing clinical evidence indicates that inhibitory effects on dopaminergic, cholinergic and histaminergic neurochemical systems may account for antipsychotic-associated cognitive impairment in the elderly. A review of published reports of the cognitive effects of antipsychotics in the elderly suggests that newer antipsychotic medications may possess a more favourable cognitive profile than that of traditional agents in this population. The cognitive effect that a specific antipsychotic will have in the elderly, however, is likely better predicted by considering the pharmacodynamic action of an individual agent in combination with the pathophysiology of the condition being treated. Agents with relatively weak dopamine inhibiting effects (e.g. clozapine and quetiapine), for example, would theoretically have a cognitive profile superior to that of agents with higher degrees of dopaminergic inhibition (all traditional agents, risperidone, olanzapine and ziprasidone) when used for conditions associated with diminished dopamine function (e.g. idiopathic Parkinson's disease). Drugs with weak anticholinergic effects (high-potency traditional agents, risperidone, quetiapine and ziprasidone) would theoretically be less likely to cause cognitive impairment than agents with high degrees of cholinergic receptor blocking actions (clozapine and olanzapine) when treating patients with impaired cholinergic function (e.g. Alzheimer's disease). Cholinergic agonist effects of clozapine and olanzapine may, however, mitigate potential adverse cognitive effects associated with the cholinergic blocking actions of these agents. Large, rigorous trials comparing the cognitive effects of antipsychotics with diverse pharmacodynamic actions are lacking in the elderly and are needed. Caap-Ahlgren, M. and O. Dehlin (2001). "Insomnia and depressive symptoms in patients with Parkinson's disease. Relationship to health-related quality of life. An interview study of patients living at home." Arch Gerontol Geriatr 32(1): 23-33. The objectives of this study were to describe the prevalence of insomnia and depressive symptoms in patients with Parkinson's disease (PD) and to relate those symptoms to health-related quality of life. A total of 102 patients living at home, most of them moderately to severely disabled, were interviewed. Of them 43 patients were women with a mean age of 70 (range 58-79). The mean age for the men was 71 (range 56-80). Time since diagnosis was <2 years for 57%, 2-10 years for 31% and >10 years for 12%. The geriatric depression scale (GDS) and Livingston's insomnia scale were used. The results were related to quality of life as measured with the SF-36 health survey. The prevalence of insomnia was 80%. Moderate depressive symptoms were found in 47% and severe depressive symptoms in 5%. Patients with insomnia or with depressive symptoms had a significantly impaired quality of life on all eight scales of the SF-36. In a stepwise regression analysis the presence of pain and ache and depressive symptoms were significantly related to insomnia. The variables most related to depressive symptoms were Hoehn and Yahr group and insomnia. Hoehn and Yahr groups (more disability) were significantly related to insomnia and depressive symptoms. Thus, insomnia and depressive symptoms are prevalent in PD and influence quality of life and should, therefore, be considered when evaluating patients with PD. Cadet, J. L. (2001). "Molecular neurotoxicological models of Parkinsonism: focus on genetic manipulation of mice." 8(2): 85-90. Parkinson's disease is a neurodegenerative disorder that affects mainly the nigrostriatal dopaminergic system in humans. Several propositions have been put forward to explain the cellular and molecular pathobiology of this syndrome. Initial attempts were made through the use of various agents to manipulate the deleterious effects of toxins that destroy dopaminergic cells both in vitro and in vivo. These studies led to the idea that oxidative stress is an important factor in killing these cells. More recent attempts have made use of genetically modified mice to eliminate or over-express genes of interest. These experiments have suggested that the destruction of dopaminergic cells might be the result of the convergence of dependent and independent molecular pathways and that trigger cellular events might lead to the demise of these dopaminergic cells. Calabrese, V., G. Scapagnini, et al. (2001). "Mitochondrial involvement in brain function and dysfunction: relevance to aging, neurodegenerative disorders and longevity." Neurochem Res 26(6): 739-64. It is becoming increasingly evident that the mitochondrial genome may play a key role in neurodegenerative diseases. Mitochondrial dysfunction is characteristic of several neurodegenerative disorders, and evidence for mitochondria being a site of damage in neurodegenerative disorders is partially based on decreases in respiratory chain complex activities in Parkinson's disease, Alzheimer's disease, and Huntington's disease. Such defects in respiratory complex activities, possibly associated with oxidant/antioxidant balance perturbation, are thought to underlie defects in energy metabolism and induce cellular degeneration. Efficient functioning of maintenance and repair process seems to be crucial for both survival and physical quality of life. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of genes termed vitagenes. A promising approach for the identification of critical gerontogenic processes is represented by the hormesis-like positive effect of stress. In the present review, we discuss the role of energy thresholds in brain mitochondria and their implications in neurodegeneration. We then review the evidence for the role of oxidative stress in modulating the effects of mitochondrial DNA mutations on brain age-related disorders and also discuss new approaches for investigating the mechanisms of lifetime survival and longevity. Callizot, N., J. L. Guenet, et al. (2001). "The frissonnant mutant mouse, a model of dopamino-sensitive, inherited motor syndrome." Neurobiol Dis 8(3): 447-58. The frissonnant (fri) mutation is an autosomic recessive mutation which spontaneously appeared in the stock of C3H mice. fri mutant mice have locomotor instability and rapid tremor. Since tremor ceases when mutant mice have sleep or are anaesthetized, and because of their obvious stereotyped motor behavior, these mice could represent an inherited Parkinsonian syndrome. We show here that the fri/fri mouse fulfills two out of the three criteria required to validate an experimental model of human disease, that is isomorphism, homology and predictivity. Indeed, fri/fri mice present an important motor deficit accompanying visible tremor and stereotypies. They display some memory deficits as in human Parkinson's desease. l-Dopa and apomorphine (dopaminergic agonists), ropinirole (selective D2 agonist), and selegiline (an monoamino-oxidase B [MAO-B] inhibitor) improve their clinical status. However, neither anatomopathological evidence of nigrostriatal lesion, nor decrease in tyrosine hydroxylase production could be seen. Calon, F., N. Lavertu, et al. (2001). "Effect of MPTP-induced denervation on basal ganglia GABA(B) receptors: Correlation with dopamine concentrations and dopamine transporter." Synapse 40(3): 225-34. We investigated the effect of MPTP-induced lesion of the substantia nigra pars compacta (SNpc) dopaminergic neurons on GABA(B) receptors in the basal ganglia of mice and monkeys using receptor autoradiography and in situ hybridization. The extent of the lesion was measured with striatal catecholamine content, striatal binding of (125)I-RTI-121 to dopamine transporter (DAT), and DAT expression in the SNpc. GABA(B) receptors in mice brain were evaluated using (3)H-CGP54626 and its expression was measured with oligonucleotides probes targeting the mRNAs of GABA(B(1a+b)), GABA(B(1a)), GABA(B(1b)), GABA(B(2)) subunits. In monkeys, (125)I-CGP64213 and selective probes for GABA(B(1a+b)) and GABA(B(2)) mRNAs were used. In mice, dopamine content, (125)I-RTI-121 binding, and DAT expression were reduced by 44%, 40%, and 39% after a dose of 40 mg/kg of MPTP and 74%, 70%, and 34% after 120 mg/kg of MPTP, respectively. In monkeys, dopamine content and DAT expression were decreased by more than 90% and 80%, respectively. In the striatum and the subthalamic nucleus, GABA(B) receptors were unchanged following MPTP in both species. In the SNpc of mice, MPTP (120 mg/kg) induced a significant decrease of (3)H-CGP54626 binding (-10%) and of the expression of GABA(B(1a+b)) mRNA (-13%). The decrease of the expression of GABA(B(1a+b)) mRNA was correlated with dopamine content, (125)I-RTI-121 binding and DAT expression. In MPTP-treated monkeys, (125)I-CGP64213 binding (-40%), GABA(B(1a+b)) mRNA (-69%) and GABA(B(2)) mRNA (-66%) were also significantly decreased in the SNpc. Our results suggest that MPTP-induced denervation is associated with a decrease of GABA(B) receptors restricted to the SNpc. These observations may be relevant to the pathophysiology of motor disorders involving dysfunction of the basal ganglia such as Parkinson disease. Camicioli, R., S. J. Grossmann, et al. (2001). "Discriminating mild parkinsonism: methods for epidemiological research." Mov Disord 16(1): 33-40. Methods for the efficient and accurate detection of parkinsonism are essential for epidemiological studies. We sought to determine whether parkinsonism could be detected by a neurologist from a videotaped assessment and whether neurobehavioral methods (motor, cognitive, and sensory) discriminated between patients with Parkinson's disease (PD) and controls. Fifteen patients with mild PD (Hoehn and Yahr I-III) were compared to 15 age-, sex-, and education- matched controls. Each participant underwent a videotaped neurological examination (based on the Unified Parkinson's Disease Rating Scale, UPDRS), administered by a trained technician, and reviewed by a neurologist, as well as a series of neurobehavioral tests. The neurologist identified PD patients with 86% sensitivity and 100% specificity. Among the neurobehavioral tests, finger tapping, combined with one or more among olfaction, visual contrast sensitivity, or Paired Associates Learning, correctly classified 90%, or more, of subjects. Individual psychological tests did not discriminate reliably between groups. We conclude that videotaped assessments of parkinsonism or objective tests of motor and sensory function can accurately detect patients with PD. Both approaches have potential for identifying PD cases, but the latter may be more efficient for screening. Camicioli, R., E. Lea, et al. (2001). "Methylphenidate increases the motor effects of L-Dopa in Parkinson's disease: a pilot study." Clin Neuropharmacol 24(4): 208-13. We determined whether methylphenidate, a dopamine transporter blocker, modifies motor, cognitive, or affective responses to L-Dopa in Parkinson's disease (PD). Five patients who reported benefit from L-Dopa/carbidopa and motor fluctuations were admitted and withdrawn from their usual antiparkinsonian medications. On 3 consecutive days in a randomized double-blinded fashion, they took 0.2 mg/kg oral methylphenidate or placebo followed 30 minutes later by a 1-hour intravenous L-Dopa (2 mg/kg per h) or placebo infusion. Vital signs, tapping, walking, dyskinesias, mood, anxiety, concentration, and arousal were monitored every 30 minutes. Cognitive testing was performed before and following the infusion. Methylphenidate combined with L-Dopa led to greater peak right-hand tapping speed than either alone. Dyskinesia severity increased most when methylphenidate and L-Dopa were co-administered. There were no differences between conditions on the Stroop test, digit ordering, simple reaction time, or covert orienting of attention validity effect. Methylphenidate alone led to improvement in choice reaction time. Change in self-assessed analogue ratings of mood, anxiety, arousal, or concentration did not differ between conditions. Methylphenidate increased the motor effects of L-Dopa with minimal effects on cognitive or affective functions, suggesting a physiologic role for the dopamine transporter in patients with PD with motor fluctuations. Campbell, B. C., C. A. McLean, et al. (2001). "The solubility of alpha-synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson's disease." J Neurochem 76(1): 87-96. Intracellular inclusions containing alpha-synuclein (alpha SN) are pathognomonic features of several neurodegenerative disorders. Inclusions occur in oligodendrocytes in multiple system atrophy (MSA) and in neurons in dementia with Lewy bodies (DLB) and Parkinson's disease (PD). In order to identify disease-associated changes of alpha SN, this study compared the levels, solubility and molecular weight species of alpha SN in brain homogenates from MSA, DLB, PD and normal aged controls. In DLB and PD, substantial amounts of detergent-soluble and detergent-insoluble alpha SN were detected compared with controls in grey matter homogenate. Compared with controls, MSA cases had significantly higher levels of alpha SN in the detergent-soluble fraction of brain samples from pons and white matter but detergent-insoluble alpha SN was not detected. There was an inverse correlation between buffered saline-soluble and detergent-soluble levels of alpha SN in individual MSA cases suggesting a transition towards insolubility in disease. The differences in solubility of alpha SN between grey and white matter in disease may result from different processing of alpha SN in neurons compared with oligodendrocytes. Highly insoluble alpha SN is not involved in the pathogenesis of MSA. It is therefore possible that buffered saline-soluble or detergent-soluble forms of alpha SN are involved in the pathogenesis of other alpha SN-related diseases. Canals, S., M. J. Casarejos, et al. (2001). "Glutathione depletion switches nitric oxide neurotrophic effects to cell death in midbrain cultures: implications for Parkinson's disease." J Neurochem 79(6): 1183-95. Nitric oxide (NO) exerts neurotrophic and neurotoxic effects on dopamine (DA) function in primary midbrain cultures. We investigate herein the role of glutathione (GSH) homeostasis in the neurotrophic effects of NO. Fetal midbrain cultures were pretreated with GSH synthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO), 24 h before the addition of NO donors (diethylamine/nitric oxide-complexed sodium and S-nitroso-N-acetylpenicillamine) at doses tested previously as neurotrophic. Under these conditions, the neurotrophic effects of NO disappeared and turned on highly toxic. Reduction of GSH levels to 50% of baseline induced cell death in response to neurotrophic doses of NO. Soluble guanylate cyclase (sGC) and cyclic GMP-dependent protein kinase (PKG) inhibitors protected from cell death for up to 10 h after NO addition; the antioxidant ascorbic acid also protected from cell death but its efficacy decreased when it was added after NO treatment (40% protection 2 h after NO addition). The pattern of cell death was characterized by an increase in chromatin condensed cells with no DNA fragmentation and with breakdown of plasmatic membrane. The inhibition of RNA and protein synthesis and of caspase activity also protected from cell death. This study shows that alterations in GSH levels change the neurotrophic effects of NO in midbrain cultures into neurotoxic. Under these conditions, NO triggers a programmed cell death with markers of both apoptosis and necrosis characterized by an early step of free radicals production followed by a late requirement for signalling on the sGC/cGMP/PKG pathway. Cannas, A., A. Spissu, et al. (2001). "Chronic delusional hallucinatory psychosis in early-onset Parkinson's disease: drug-induced complication or sign of an idiopathic psychiatric illness?" Neurol Sci 22(1): 53-4. Chronic delusional psychosis with hallucinations (CDHP) is commonly assumed to complicate the later stages of Parkinson's disease, as a side effect of antiparkinsonian medication. We studied 7 patients with early onset PD, who had developed psychiatric manifestations consisting in CDHP after a few years of antiparkinsonian therapy. All patients underwent a neurological, psychiatric and brain imaging (CT or MRI) evaluation. Detailed clinical history was recorded in order to reveal prior psychiatric illness and to analyse the relationship between neurological disease, cognitive impairment and psychosis. Our findings suggest that CDHP occurring in patients with early onset PD, normal or slightly impaired cognitive functions and normal CT/MRI scans is invariably the expression of a coexisting psychiatric illness which prior to onset of the neurologic disease had not been correctly diagnosed and which has been disclosed by dopaminergic therapy. Capka, V. and Y. Xu (2001). "Simultaneous determination of enantiomers of structurally related anticholinergic analogs in human serum by liquid chromatography-electrospray ionization mass spectrometry with on-line sample cleanup." J Chromatogr B Biomed Sci Appl 762(2): 181-92. Trihexyphenidyl, biperiden and procyclidine are anticholinergic drugs produced as racemates for the treatment of Parkinson's disease. This paper describes a simple and sensitive LC-MS method for the simultaneous determination of these compounds in human serum. An on-line sample clean-up procedure was used, where serum samples were directly injected into a "restricted-access media" pre-column. After the exclusion of the serum proteins, the drug molecules were eluted to a beta-cyclodextrin analytical column for chiral separation. The quantitation was done by electrospray ionization MS using diphenidol as an internal standard. The method developed has limits of detection of 1 ng/ml, at least two-orders-of-magnitude linear dynamic ranges (r>0.999), and RSDs of less than 10%. The system can be completely automated for increased sample throughput and unattended analyses. Capus, L., A. Melatini, et al. (2001). "Chronic bilateral electrical stimulation of the subthalamic nucleus for the treatment of advanced Parkinson's disease." Neurol Sci 22(1): 57-8. Preliminary reports in patients with Parkinson's disease (PD) showed that subthalamic nucleus (STN) stimulation was able to reverse parkinsonian state. Since 1998 we evaluated the safety and the efficacy of STN stimulation in 7 patients affected by advanced PD. All patients were included using CAPIT protocol. Motor functions and quality of life were evaluated, before and after surgery, with UPDRS and PDQ38, respectively. At the 6-month follow-up, the off medication/on stimulation UPDRS motor score improved by 50.6% and the on medication/on stimulation by 20.3%. Motor fluctuations were reduced by 57.2% and dyskinesias by 73.5%. The total L-dopa equivalent daily dose was reduced by 40.7%. PDQ38 ameliorated by 49.9%. We did not observe any perioperatory complication and only mild and tolerable side effects after stimulation. Caraceni, T. and M. Musicco (2001). "Levodopa or dopamine agonists, or deprenyl as initial treatment for Parkinson's disease. A randomized multicenter study." 7(2): 107-114. Objectives: levodopa improves the quality of life in parkinsonian patients, however long term response is compromised by the emergence of motor fluctuations and dyskinesias. The aim of this study was to compare the occurrence of motor fluctuations and dyskinesias in previously untreated patients assigned to receive levodopa, a dopamine agonist or deprenyl.Thirty-five neurological departments in Italian hospitals participated in this randomized open trial. Patients with Parkinson's disease, who required the initiation of an effective antiparkinsonian treatment, were randomly assigned to receive levodopa, dopamine agonists or deprenyl. The end-points were motor dyskinesias and motor fluctuations occurring in a median follow-up period of about 3years.After a median follow-up of 34months, motor fluctuations and dyskinesias were less frequent in patients assigned to a dopamine agonist or deprenyl than in patients assigned to levodopa (relative risk [RR] 0.5, 95% confidence interval [95% CI] 0.3-0.8, and RR=0.6, 95% CI 0.3-0.9, respectively), but dopamine agonists were less effective and less well tolerated than levodopa. The lower frequency of motor fluctuations in patients assigned to deprenyl was no longer statistically significant when prognostic predictors were considered in a multivariable analysis. Long-term mortality did not differ in the three arms of the study. Dopamine agonists and deprenyl can be considered as an alternative to levodopa for starting treatment in Parkinson's disease patients. However, on clinical grounds, only small advantages are expected over the traditional therapy initiation with levodopa. Carboncini, M. C., D. Manzoni, et al. (2001). "The relation between EMG activity and kinematic parameters strongly supports a role of the action tremor in parkinsonian bradykinesia." Mov Disord 16(1): 47-57. The kinematics characteristics of an upper arm extension of large amplitude (90 degrees) performed in the horizontal plane and the simultaneous activity of the shoulder muscles were recorded in 12 parkinsonian patients and in six normal control subjects. The movement, triggered by an acoustic "go" signal, was preceded by an isometric adduction. Within the whole population of individuals (n = 18) a strong, positive correlation was observed between the root mean square value of agonist EMG activity, evaluated during the acceleration phase of the movement, and both peak velocity and acceleration. In six patients tremor bursts at the frequency of 8-14 Hz (action tremor) were observed during the movement phase in the anterior, middle, and posterior deltoid: all these patients showed low root mean square values and were bradykinetic with respect to the control subjects. The remaining six patients did not show this action tremor during the movement phase. All but one had an agonist activation of normal duration and amplitude, showed high root mean square values, and performed well in the range of control subjects. We conclude that the inability to suppress the activity of pathological oscillator(s) responsible for the action tremor plays a fundamental role in the bradykinesia associated with Parkinson's disease. Carella, F., S. Genitrini, et al. (2001). "Acute effects of bilateral subthalamic nucleus stimulation on clinical and kinematic parameters in Parkinson's disease." Mov Disord 16(4): 651-5. After implantation with subthalamic stimulators, nine patients with advanced Parkinson's disease were studied on the task of tracing out, as accurately as possible, the four corners of a square with the dominant hand. The task was performed in four treatment conditions: on stimulation-off medication, off stimulation-off medication, off stimulation-on medication, and on stimulation-on medication. Movement times and peak velocities improved significantly only in the on stimulation-on medication condition compared to off stimulation-off medication. The improvement in clinical parameters with stimulation only (relative to off stimulation off medication) was of borderline significance, while consistent and significant clinical improvement was only obtained with addition of medication (on medication-on stimulation). This study provides quantitative evidence of the effect of subthalamic stimulation on kinematic measures in Parkinson's disease (PD) and suggests that combined treatment (medication and stimulation) is superior to either treatment alone. Caronti, B., G. Antonini, et al. (2001). "Dopamine transporter immunoreactivity in peripheral blood lymphocytes in Parkinson's disease." J Neural Transm 108(7): 803-7. There is increasing interest in the identification of biological markers for the early diagnosis of Parkinson's disease (PD). Previous studies indicate changes of dopamine content, tyrosine hydroxylase immunoreactivity and dopamine receptors in peripheral blood lymphocytes (PBL) in PD. Here we demonstrate a reduction of dopamine transporter immunoreactivity in PBL in the early clinical stages of the disease. These findings contribute to our understanding of the peripheral dopamine system in PD. Carpenter, D. O. (2001). "Effects of metals on the nervous system of humans and animals." Int J Occup Med Environ Health 14(3): 209-18. Several metals have toxic actions on nerve cells and neurobehavorial functioning. These toxic actions can be expressed either as developmental effects or as an increased risk of neurodegenerative diseases in old age. The major metals causing neurobehavioral effects after developmental exposure are lead and methylmercury. Lead exposure in young children results in a permanent loss of IQ of approximately 5 to 7 IQ points, and also results in a shortened attention span and expression of anti-social behaviors. There is a critical time period (<2 years of age) for development of these effects, after which the effects do not appear to be reversible even if blood lead levels are lowered with chelation. Methylmercury has also been found to have effects on cognition at low doses, and prenatal exposure at higher levels can disrupt brain development. Metals have also been implicated in neurodegenerative diseases, although it is unlikely that they are the sole cause for any of them. Elevated aluminum levels in blood, usually resulting from kidney dialysis at home with well water containing high aluminum, result in dementia that is similar to but probably different from that of Alzheimer's disease. However, there is some epidemiological evidence for elevated risk of Alzheimer's in areas where there is high concentration of aluminum in drinking water. Other metals, especially lead, mercury, manganese and copper, have been implicated in amvotrophic lateral sclerosis and Parkinson's disease. Carta, A., S. Fenu, et al. (2001). "Alterations in GAD67, dynorphin and enkephalin mRNA in striatal output neurons following priming in the 6-OHDA model of Parkinson's disease." Neurol Sci 22(1): 59-60. In the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease, administration of a dopaminergic agonist sensitizes rats to a subsequent administration of dopaminergic drugs given days apart (priming). In situ hybridization was used to evaluate changes on striatal gene expression of rats primed three days previously with either L-dopa, SKF38393 or quinpirole. Double labeling was used to identify the neuronal population in which such alterations occurred. GAD67 and enkephalin mRNA were increased by the lesion whereas dynorphin mRNA was decreased as compared to the intact striatum. Priming with L-dopa and SKF38393 significantly increased GAD67 mRNA in the lesioned striatum and reversed dynorphin mRNA reduction, as compared to drug-naive rats, whereas quinpirole failed to produce any effect. Enkephalin mRNA was not affected by priming. Results suggest that 6-OHDA lesion-induced adaptive changes on striatal gene expression are modified by priming. Priming brings striatal output neurons to a higher level of activity, which may explain the sensitized behavioral response observed following a dopaminergic agonist challenge. These changes are in relation to the different types of dopamine agonists utilized and suggest that modifications in gene expression induced by priming might be predictive of the dyskinetic potential of a drug. Carvalho, G. A. and G. Nikkhah (2001). "Subthalamic nucleus lesions are neuroprotective against terminal 6-OHDA-induced striatal lesions and restore postural balancing reactions." Exp Neurol 171(2): 405-17. Inactivation of the subthalamic nucleus (STN) by deep brain stimulation or lesioning can ameliorate symptoms in Parkinson' disease (PD) and may alter the underlying progressive degenerative process. We evaluated the effects of STN lesions in a terminal lesion model of PD in rats. Multiple intrastriatal 6-OHDA injections (4 x 7 microg) resulted in a partial loss of striatal TH-positive innervation (-30 to -40%) and nigral dopaminergic neurons (-60%), which was associated with behavioral deficits as observed in drug-induced rotational asymmetry, side-stepping, and postural balancing reactions. Unilateral ibotenic acid lesions of the STN did produce a 50-60% loss of STN neurons based on stereological analysis, which did not induce a functional impairment in rotational asymmetry or spontaneous sensorimotor behaviors. When STN lesions were performed 1 week prior to the 6-OHDA terminal striatal lesions, a significant rescue effect (+23%) on nigral dopaminergic neurons against terminal 6-OHDA neurotoxicity could be demonstrated, whereas striatal TH-positive fiber loss was not attenuated in these animals. In addition, animals with combined STN and striatal lesions exhibited a significant recovery in postural balancing reactions induced by 6-OHDA terminal lesions and did not show a significant impairment in any of the other behavioral parameters examined. Taken together, STN lesions can exert neuroprotective effects on nigral dopamine neurons in a partial lesion model of PD which result in recovery of spontaneous sensorimotor behavior. These findings may therefore provide new insights into the functional interaction between the glutamatergic and the dopaminergic neurotransmitter systems and foster novel therapeutic concepts for the early and middle phases of Parkinson's disease. Carvey, P. M., Z. D. Ling, et al. (2001). "A clonal line of mesencephalic progenitor cells converted to dopamine neurons by hematopoietic cytokines: a source of cells for transplantation in Parkinson's disease." Exp Neurol 171(1): 98-108. Neural progenitor cells potentially provide a limitless, on-demand source of cells for grafting into patients with Parkinson's disease (PD) if the signals needed to control their conversion into dopamine (DA) neurons could be identified. We have recently shown that cytokines which instruct cell division and differentiation within the hematopoeitic system may provide similar functions in the central nervous system. We have shown that mitotic progenitor cells can be isolated from embryonic rat mesencephalon and that these cells respond to a combination of interleukin-1, interleukin-11, leukemia inhibitory factor, and glial cell line-derived neurotrophic factor yielding a tyrosine hydroxylase-immunoreactive (THir) phenotype in 20-25% of total cells. In the present study, 24 clonal cell lines derived from single cells of mesencephalic proliferation spheres were examined for their response to the cytokine mixture. The clone yielding the highest percentage of THir neurons (98%) was selected for further study. This clone expressed several phenotypic characteristics of DA neurons and expression of Nurr1. The response to cytokines was stable for several passages and after cryopreservation for several months. When grafted into the striatum of DA-depleted rats, these cells attenuated rotational asymmetry to the same extent as freshly harvested embryonic DA neurons. These data demonstrate that mesencephalic progenitor cells can be clonally expanded in culture and differentiated in the presence of hematopoietic cytokines to yield enriched populations of DA neurons. When transplanted, these cells provide significant functional benefit in the rat model of PD. Carvey, P. M., S. O. McGuire, et al. (2001). "Neuroprotective effects of D3 dopamine receptor agonists." 7(3): 213-223. The effects of D(3) receptor activation are unresolved at this time, but may have practical implications in the treatment of Parkinson's disease (PD). As a result of assessing the neuroprotective effects of the direct-acting D(3) preferring dopamine (DA) agonist pramipexole (PPX), we have observed that drugs which psossess D(3) affinity increase the production of a DA neurotrophic factor in tissue culture. This molecule is increased by treatment with PPX, is constitutively produced by DA neurons in culture, and possesses a molecular weight of approximately 35kDa. It is hypothesized that this molecule may be the so-called DA autotrophic factor referred to by many authors over the past two decades. Interestingly, the protein is oxidant-labile and, therefore, D(3) agonists which increase its production and also possess antioxidant capacity would provide unique neuroprotective benefits to patients with PD. However, many questions remain. Although the data supporting this notion are strong, it is clear that other unknown characteristics of DA agonists, including increased production of anti-apoptotic proteins, are also involved. This manuscript will review this concept in the context of tissue culture strategies of neuroprotection. Although no conclusion can be made at this time, it is clear that direct comparisons of the neuroprotective effects of direct-acting DA agonists in mesencephalic culture can provide considerable insight into the mechanistic actions of anti-dopaminergic drugs. Casali, C., V. Bonifati, et al. (2001). "Mitochondrial myopathy, parkinsonism, and multiple mtDNA deletions in a Sephardic Jewish family." Neurology 56(6): 802-5. The authors describe a family of Sephardic Jews with progressive external ophthalmoparesis, skeletal muscle weakness, and parkinsonism. Autosomal recessive inheritance was suggested by many consanguineous marriages, although a dominant disorder could not be excluded. No linkage to known progressive external ophthalmoparesis locus was found. The presence of cytochrome c oxidase-negative ragged-red fibers, biochemically reduced respiratory chain complexes, and multiple mitochondrial DNA deletions in muscle biopsies from four patients suggested a new mitochondrial disorder of intergenomic communication. Cassidy, M. and P. Brown (2001). "Task-related EEG-EEG coherence depends on dopaminergic activity in Parkinson's disease." Neuroreport 12(4): 703-7. We investigated whether functional coupling between different cortical areas is impaired in Parkinson's disease, using corticocortical coherence as a surrogate measure of coupling. We recorded scalp EEG from different sites in seven parkinsonian patients while they tracked a visual target using their wrist, or copied the same movement from memory. Differences in EEG-EEG coherence between the tracking and copying tasks and their respective controls, visual tracking alone and fixation of a stationary target, were determined on and off levodopa. After levodopa we found extensive task-specific and broad band cortico-cortical coherence. Off levodopa cortico-cortical coherence was much reduced. Ascending dopaminergic projections from the ventral mesencephalon may therefore be important in determining the pattern and extent of corticocortical coupling during executive tasks. Castagnoli, K. P., S. J. Steyn, et al. (2001). "Neuroprotection in the MPTP Parkinsonian C57BL/6 mouse model by a compound isolated from tobacco." Chem Res Toxicol 14(5): 523-7. Epidemiological evidence suggests a lower incidence of Parkinson's disease in smokers than in nonsmokers. This evidence, together with the lower levels of brain monoamine oxidase (MAO) activity in smokers and the potential neuroprotective properties of MAO inhibitors, prompted studies which led to the isolation and characterization of 2,3,6-trimethyl-1,4-naphthoquinone (TMN), an MAO-A and MAO-B inhibitor which is present in tobacco and tobacco smoke. Results of experiments reported here provide evidence that this compound protects against the MPTP-mediated depletion of neostriatal dopamine levels in the C57BL/6 mouse. These results support the hypothesis that the inhibition of MAO by constituents of tobacco smoke may be related to the decreased incidence of Parkinson's disease in smokers. Castell, J. A., B. T. Johnston, et al. (2001). "Manometric abnormalities of the oesophagus in patients with Parkinson's disease." Neurogastroenterol Motil 13(4): 361-4. Dysphagia in Parkinson's disease (PD) is known to correlate with abnormalities of oropharyngeal function. Oesophageal abnormalities have not been previously demonstrated to correlate with dysphagia. The aim of the study was to determine if motor dysfunction of the oesophageal body correlates with dysphagia or disease severity in PD. Twenty-two patients with PD were assessed for the severity of their dysphagia (scale of 1-7) and severity of PD (Hoehn and Yahr scale 1-4). All underwent oesophageal manometry. Dysphagia was present daily in 10 patients (45%). Parkinson's disease was graded as severe (Hoehn and Yahr > or =3) in eight (36%) patients. Oesophageal manometry was abnormal in 16 (73%) patients. Thirteen patients had either complete aperistalsis or multiple simultaneous contractions (diffuse oesophageal spasm). These findings were significantly more common in patients with daily dysphagia (90% vs. 33%; P < 0.005), and were not related to duration or severity of PD. We conclude that the presence of aperistalsis or multiple simultaneous contractions in the oesophagus does correlate with dysphagia and is independent of PD severity or duration. This may reflect selective involvement of either the dorsal motor nucleus of the vagus or the oesophageal myenteric plexus. Castro, D. S., E. Hermanson, et al. (2001). "Induction of cell cycle arrest and morphological differentiation by Nurr1 and retinoids in dopamine MN9D cells." J Biol Chem 276(46): 43277-84. Dopamine cells are generated in the ventral midbrain during embryonic development. The progressive degeneration of these cells in patients with Parkinson's disease, and the potential therapeutic benefit by transplantation of in vitro generated dopamine cells, has triggered intense interest in understanding the process whereby these cells develop. Nurr1 is an orphan nuclear receptor essential for the development of midbrain dopaminergic neurons. However, the mechanism by which Nurr1 promotes dopamine cell differentiation has remained unknown. In this study we have used a dopamine-synthesizing cell line (MN9D) with immature characteristics to analyze the function of Nurr1 in dopamine cell development. The results demonstrate that Nurr1 can induce cell cycle arrest and a highly differentiated cell morphology in these cells. These two functions were both mediated through a DNA binding-dependent mechanism that did not require Nurr1 interaction with the heterodimerization partner retinoid X receptor. However, retinoids can promote the differentiation of MN9D cells independently of Nurr1. Importantly, the closely related orphan receptors NGFI-B and Nor1 were also able to induce cell cycle arrest and differentiation. Thus, the growth inhibitory activities of the NGFI-B/Nurr1/Nor1 orphan receptors, along with their widespread expression patterns both during development and in the adult, suggest a more general role in control of cell proliferation in the developing embryo and in adult tissues. Castro, M. G., A. David, et al. (2001). "Gene therapy for Parkinson's disease: recent achievements and remaining challenges." Histol Histopathol 16(4): 1225-38. Gene therapy is the use of nucleic acids as drugs. Thus, ways had to be developed to deliver this new generation of drugs to target tissues. Various viral and non-viral vectors have been engineered to carry potentially therapeutic nucleic acids into diseased organs or target cells. The brain offers a particular challenge for gene delivery to its constituent cells: it is encased by the skull, separated from the general circulation by the blood brain barrier, and made up of mostly non-dividing cells. The skull limits direct injection of vectors into the brain, the blood brain barrier inhibits the easy entry of vectors injected into the bloodstream, and post mitotic target cells restrict what type of vector can be used to deliver genes to the brain. We will discuss the main challenges faced by gene delivery to the brain, i.e. immune responses to the delivery vectors and therapeutic transgenes and length of duration of the therapy specifically as applied to Parkinson's disease. We will also discuss therapeutic strategies, which could be implemented to treat Parkinson's disease, and the models in which they have been tested. Catalan-Alonso, M. J. and J. Del Val (2001). "[Dopaminomimetic psychosis in Parkinson's disease: first symptom of early dementia?]." Rev Neurol 32(11): 1085-7. INTRODUCTION: Parkinson s disease (PD) is caused by an abnormal degeneration of the dopamine producing cells in the substantia nigra and ventral tegmental area. When PD advances, degeneration of the nigroestriatal tracts may expand and involve other pathways (mesolimbic and frontal), and also serotonergic and cholinergic systems. This degeneration leads to a multitude of motor and non motor behavioral disturbances. DEVELOPMENT: On the background of progressive degeneration, chronic levodopa and dopaminergic agonist administration may cause pulsatile non physiologic overstimulation of dopaminergic receptors. This may induce perturbations in limbic and frontal cortex structures and overstimulation of serotonergic, cholinergic and other neurotransmitter systems. These events are the basis of parkinsonian psychosis, perhaps in the setting of early dementia. The treatment of this psychosis is difficult. The reduction or withdrawal of dopaminomimetic agents may improve psychosis with worsening of parkinsonian disability. The recommended order to discontinue antiparkinsonian drugs, when is required, is anticholinergic, selegiline, amantadine and dopamine agonist. Levodopa should be reduced to a tolerable minimum to compensate the motor disturbances. At this point, it may be necessary to add an atypical neuroleptic such as clozapine, quetirapine or olanzapine to improve the symptomatology. CONCLUSIONS: More studies are needed to asses the relationship between parkinsonian psychosis and early dementia. Additional, the development of new drugs could be helpful to control these psychotic symptoms in PD without serious secondary effects. Ceravolo, M. G., L. Paoloni, et al. (2001). "Rehabilitation of parkinsonian patients." Funct Neurol 16(2): 157-62. Cesaro, P., M. Peschanski, et al. (2001). "Treatment of Parkinson's disease by cell transplantation." Funct Neurol 16(1): 21-7. Chacon Pena, J. R. and E. Duran Ferreras (2001). "[Parkinsonism probably induced by manganese]." Rev Neurol 33(5): 434-7. INTRODUCTION. In all cases of young persons with clinical Parkinson s disease it should be suspected that it is secondary to some primary disorder. Therefore a battery of diagnostic tests should be done before classification as idiopathic Parkinson s disease. CLINICAL CASE. A 31 year old woman whose only previous illness had been Graves disease. She complained of difficulty with movements of her right arm and leg for some months (she had problems with walking and with rapid, repeated movements of her right hand). She also complained of tremor of her right limbs at rest. She denied taking drugs, having dysphagia, dysarthria, visual changes or sphincter disorders. Neurological examination showed her to have monotonous speech, slight facial hypomimia, slight reduction in spontaneous blinking, walking with less swing of her right arm; postural tremor of both arms, worse on the right; bradykinesia (2/4) of both right limbs and rigidity (1/4), axial and of the right limbs. The results of all the investigations done to rule out secondary Parkinsonism were normal, except for the plasma manganese level which was raised, although it returned to normal when the probable source of exposure to this metal was removed. However, the alterations of movement only disappeared after treatment with levodopa was started. CONCLUSION. In cases of Parkinsonism in young adults secondary causes should always be rules out, such as exposure to certain metals. Chan, D. K. (2001). "Parkinson disease and its differentials. Diagnoses made easy." Aust Fam Physician 30(11): 1053-6. BACKGROUND: Parkinson disease is a common neurological disorder that is both underdiagnosed and inaccurately diagnosed. There is no reliable biological marker or test that can differentiate between causes of parkinsonism. Even for experienced clinicians, the clinical diagnostic accuracy compared to post mortem findings is about 80%. OBJECTIVE: To discuss the clinical features that differentiate Parkinson disease from other important causes of parkinsonism. DISCUSSION: Although Parkinson disease is a common cause of parkinsonism, other candidates such as drug reactions, benign essential tremor, vascular disease and Lewy body dementia need to be differentiated. Incorrect diagnosis can result in complications related particularly to the use of levodopa and antipsychotic agents. Diagnostic accuracy is important to ensure appropriate management, to avoid complications and to assist patients to have realistic expectations and prognostic information about their condition. Chan, D. K., M. Dunne, et al. (2001). "Pilot study of prevalence of Parkinson's disease in Australia." Neuroepidemiology 20(2): 112-7. Parkinson's disease is a common neurological disease and its prevalence increases with age. Because of an ageing population and changing environment compared to the last epidemiological study done in Australia over 30 years ago, we have conducted a door-to-door pilot survey which looked at the latest prevalence as well as putative risk factors in a random population. We used a two-phase investigation method (screening followed by detailed examination) in a random community sample of 2,820 households (with 527 individuals aged 55 and over) along with 203 residents in aged care facilities (single-phase examination for residents aged 55 and above) in the Randwick area of Sydney, New South Wales. We had a 75% participation rate in the community and a 94% in the aged care facilities. The results of the survey in this sample of 730 subjects indicated that the crude prevalence of Parkinson's disease was between 3.6 and 4.9% (higher in the aged care facilities). The putative risk factors positively identified using chi-square method were 'family history' (p < 0.01) and 'exposure to chemicals at work or in surrounding environment' (p < 0.05). The age-adjusted prevalence rate of Parkinson's disease revealed at least a 42.5% increase in the disease compared to 1966. We conclude that there may be an increase in the disease in Australia due to ageing and other risk factors. Chan, D. T., V. C. Mok, et al. (2001). "Surgical management of Parkinson's disease: a critical review." Hong Kong Med J 7(1): 34-9. Parkinson's disease is a progressive disabling movement disorder that is characterised by three cardinal symptoms: resting tremor, rigidity, and bradykinesia. Before the availability of effective medical treatment with levodopa and stereotactic neurosurgery, the objective of surgical management was to alleviate symptoms such as tremor at the expense of motor deficits. Levodopa was the first effective medical treatment for Parkinson's disease, and surgical treatment such as stereotactic thalamotomy became obsolete. After one decade of levodopa therapy, however, drug-induced dyskinesia had become a source of additional disability not amenable to medical treatment. Renewed interest in stereotactic functional neurosurgery to manage Parkinson's disease has been seen since the 1980s. Local experience of deep-brain stimulation is presented and discussed in this paper. Deep-brain stimulation of the subthalamic nucleus is an effective treatment for advanced Parkinson's disease, although evidence from randomised control trials is lacking. Chan, P. L. and N. H. Holford (2001). "Drug treatment effects on disease progression." Annu Rev Pharmacol Toxicol 41: 625-59. Degenerative diseases are characterized by a worsening of disease status over time. The rate of deterioration is determined by the natural rate of progression of the disease and by the effect of drug treatments. A goal of drug treatment is to slow disease progression. Drug treatments can be categorized as symptomatic or protective. Symptomatic treatments do not affect the rate of disease progression whereas protective treatments have the ability to slow disease progression down. Many current methods for describing disease progression have two common drawbacks: a linear relationship between time and disease status is assumed, and within- and between-subject variability is ignored. Disease progress models combined with pharmacokinetic pharmacodynamic models and hierarchical random effects statistical models provide insights into understanding the time course and management of degenerative disease. Chase, T. N., S. Konitsiotis, et al. (2001). "Striatal molecular mechanisms and motor dysfunction in Parkinson's disease." Adv Neurol 86: 355-60. Chassain, C., A. Eschalier, et al. (2001). "Assessment of motor behavior using a video system and a clinical rating scale in parkinsonian monkeys lesioned by MPTP." J Neurosci Methods 111(1): 9-16. The best current model of Parkinson's disease is the primate treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Quantification of animal movement is important for the study of severity of parkinsonian syndrome induced by MPTP and response to drug treatments. Both require clinical rating scales that measure motor behavior with well-defined objective items. However, evaluations using these scales depend on the observer scoring the different items, according to his/her experience. The video image analyzer system, which produces an activity curve in correlation with the visual study of animal motor behavior, offers an automatic evaluation method that is observer-independent and reproducible. Using such an system we defined items correlated with those used in clinical rating scales that are sensitive to animal motor changes, decrease in movements with MPTP intoxication and alleviation afforded by levodopa: global locomotor activity and specific activities (climbing, social interactions, eating and drinking behaviors). Chaudhuri, K. R. (2001). "Twenty-four-hour symptom control in Parkinson's disease, with emphasis on management of nocturnal disabilities." Eur Neurol 46 Suppl 1: 1-2. Chaudhuri, K. R. (2001). "Autonomic dysfunction in movement disorders." Curr Opin Neurol 14(4): 505-11. Dysfunction of the autonomic nervous system is an under-recognised but important aspect of the aetiological and clinical manifestation of primary degenerative dysautonomias such as multiple system atrophy (MSA) and Parkinson's disease (PD). Although the clinical presentation of dysautonomia in these two disorders may overlap, yet pathological and in vivo imaging studies suggest considerable differences. Functional imaging studies suggest that selective cardiac sympathetic denervation may occur early in PD but not in other parkinsonian syndromes. The clinical implication of this apparently disease specific peripheral dysautonomia is unknown and would be the subject of much interest in future years. Dysautonomia in degenerative disorders also affect respiration, genitourinary function and sleep. Sleep related disorders such as rapid eye movement behaviour disorder and urinary voiding dysfunction appear to precede the development of PD related symptoms while patients with sporadic ataxia have been shown to progress to develop MSA. Dysautonomia has also been recognised in other movement disorders, examples being the combination of dystonia and complex regional pain syndrome with elevated HLA-DR13 and late onset Huntington's disease presenting with dominant parkinsonism and minimal chorea. These studies have helped progress in various diagnostic and management parameters in relation to autonomic dysfunction and movement disorders. Chaudhuri, K. R., S. Pal, et al. (2001). "Achieving 24-hour control of Parkinson's disease symptoms: use of objective measures to improve nocturnal disability." Eur Neurol 46 Suppl 1: 3-10. Sleep-related problems are common in Parkinson's disease (PD) and may occur due to the disease process, alteration in sleep architecture or nocturnal motor problems such as akinesia and dystonia. Neuropsychiatric problems and nocturia can also cause significant sleep disruption in PD. Poor sleep may lead to daytime consequences such as excessive daytime sleepiness or fatigue. As there are no PD-specific sleep scales, we have devised a simple visual analogue scale - the Parkinson's disease sleep scale (PDSS) which is aimed at formal quantification of various aspects of nocturnal sleep disturbance in PD. In this paper, we discuss the development of this scale, its clinical use and how the scale could be used to devise targeted treatment strategies for nocturnal problems in PD. Chauhan, N. B., G. J. Siegel, et al. (2001). "Depletion of glial cell line-derived neurotrophic factor in substantia nigra neurons of Parkinson's disease brain." J Chem Neuroanat 21(4): 277-88. The distribution of nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic factor (GDNF), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) in substantia nigra pars compacta (SNc) of Parkinson's disease (PD) brains was investigated by immunofluorescence. Cases studied included four 69-77 year old neurologically normal male controls and four 72-79 year old male PD patients. Integrated optical densities (IODs) of immunofluorescence over individual neuromelanin-containing neurons and in areas of neuropil and the number of neurons on H & E stained adjacent sections were quantitated with the use of the BioQuant Image Analyzer. Data were statistically analyzed by ANOVA, including the unpaired two-tailed Student t-test and the Mann-Whitney test. The results showed 55.8% (P<0.0001) dropout of SNc neurons in PD brains compared to age-matched controls. Despite considerable neuronal dropout, immunofluorescent NTFs in the PD brains showed differential reductions that were consistent within the group as compared to age-matched controls: reductions were GDNF, 19.4%/neuron (P<0.0001), 20.2%/neuropil (P<0.0001); CNTF, 11.1%/neuron (P<0.0001), 9.4%/neuropil (P<0.0001); BDNF, 8.6%/neuron (P<0.0001), 2.5%/neuropil. NGF, NT-3 and NT-4 showed no significant differences within surviving neurons or neuropil. Since the depletion of GDNF both within surviving neurons and neuropil was twice as great as that of CNTF and BDNF and since the other NTFs showed no changes, GDNF, of the tested NTFs, is probably the most susceptible and the earliest to decrease in the surviving neurons of SNc. These observations suggest a role for decreased availability of GDNF in the process of SNc neurodegeneration in PD. Chazot, P. L. (2001). "Safinamide (Newron Pharmaceuticals)." Curr Opin Investig Drugs 2(6): 809-13. Safinamide (formerly PNU-151774E), a sodium and calcium channel modulator that also inhibits monoamine oxidase B (MAOB), is under development by Newron Pharmaceuticals for the potential treatment of epilepsy, Parkinson's disease (PD), pain and stroke [345222], [348351]. Phase I trials for epilepsy and PD have been completed, and dose-finding studies for both indications had commenced in March 2001 [401685]. The compound was previously developed by Pharmacia & Upjohn (P&U) for the potential treatment of epilepsy, an indication for which it initially reached phase I trials [294891], [345007]. Newron acquired the rights to safinamide from P&U at the end of 1998. Results from two phase I trials of the compound (single ascending dose and steady state at three doses), completed in March 2000, demonstrated that the drug is well tolerated with good bioavailability and linear pharmacokinetics [359652]. Chen, C. H., C. C. Hung, et al. (2001). "Debrisoquine 4-hydroxylase (CYP2D6) genetic polymorphisms and susceptibility to schizophrenia in Chinese patients from Taiwan." Psychiatr Genet 11(3): 153-5. Debrisoquine 4-hydroxylase (CYP2D6) is one of the cytochrome P450 enzyme families that metabolize many compounds. Polymorphic activities of debrisoquine 4-hydroxylase were suggested to be associated with some complex diseases, such as cancer and Parkinson's disease. Schizophrenia is also a complex disorder, and hence we are interested in understanding if the CYP2D6 gene is a susceptibility gene for schizophrenia in Chinese. We determined the genotype and allele frequencies of four molecular variants of CYP2D6 gene (i.e. 188C/T, 1934G/A, 2938C/T and 4268C/G) in 162 Chinese schizophrenic patients and 94 non-psychotic control subjects from Taiwan. No significant differences of allele or genotype frequencies of three polymorphisms (i.e. 188T/C, 2938C/T and 4268C/G) were detected between patients and control subjects. The 1934A allele, which accounts for the majority of poor metabolizers in Caucasians, was not detected in either patients or control subjects, indicating that the 1934A allele is very rare in Chinese. Our data suggest that the CYP2D6 gene may not be a susceptibility gene for schizophrenia in Chinese schizophrenic patients. Chen, J. F., K. Xu, et al. (2001). "Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson's disease." J Neurosci 21(10): RC143. Recent epidemiological studies have established an association between the common consumption of coffee or other caffeinated beverages and a reduced risk of developing Parkinson's disease (PD). To explore the possibility that caffeine helps prevent the dopaminergic deficits characteristic of PD, we investigated the effects of caffeine and the adenosine receptor subtypes through which it may act in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin model of PD. Caffeine, at doses comparable to those of typical human exposure, attenuated MPTP-induced loss of striatal dopamine and dopamine transporter binding sites. The effects of caffeine were mimicked by several A(2A) antagonists (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5 -c]pyrimidine (SCH 58261), 3,7-dimethyl-1-propargylxanthine, and (E)-1,3-diethyl-8 (KW-6002)-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione) (KW-6002) and by genetic inactivation of the A(2A) receptor, but not by A(1) receptor blockade with 8-cyclopentyl-1,3-dipropylxanthine, suggesting that caffeine attenuates MPTP toxicity by A(2A) receptor blockade. These data establish a potential neural basis for the inverse association of caffeine with the development of PD, and they enhance the potential of A(2A) antagonists as a novel treatment for this neurodegenerative disease. Chen, L. W., L. C. Wei, et al. (2001). "Differential expression of AMPA receptor subunits in dopamine neurons of the rat brain: a double immunocytochemical study." Neuroscience 106(1): 149-60. We have examined the distribution of dopamine neurons expressing alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor subunits (glutamate receptors 1, 2/3 and 4) in the A8-A15 regions of the rat brain using double immunofluorescence. The distribution of glutamate receptor 1- or 2/3-like immunoreactive neurons completely overlapped that of tyrosine hydroxylase-like immunoreactive neurons in dopamine cell groups in the retrorubral field (A8), the substantia nigra (A9), the ventral tegmental area and the nucleus raphe linealis (A10), and the rostral hypothalamic periventricular nucleus (A14, A15). In the caudal hypothalamic periventricular nucleus (A11), arcuate nucleus (A12) and zona incerta (A13), the distribution was partially overlapping. Neurons double-labeled for tyrosine hydroxylase and glutamate receptor 1 or 2/3 immunoreactivities were, however, exclusively found in certain dopamine cell regions: in areas A14-A15, 85-88% of tyrosine hydroxylase-containing neurons expressed glutamate receptor 1 and 22-25% expressed glutamate receptor 2/3, while in areas A8-A10, 20-43% expressed glutamate receptor 1 and 63-84% expressed glutamate receptor 2/3. In contrast, the double-labeled neurons were hardly detected in the A11-A13 regions. No tyrosine hydroxylase-positive neurons displayed glutamate receptor 4 immunoreactivity, though a partially overlapping distribution of tyrosine hydroxylase- and glutamate receptor 4-immunopositive neurons was also seen in regions A8-10, A11 and A13.The present study has demonstrated the morphological evidence for direct modulation of dopamine neurons via AMPA receptors in rat mesencephalon and hypothalamus. This distribution may provide the basis for a selective dopamine neuron loss in neurodegenerative disorders, such as Parkinson's disease. Chen, M. T., M. Morales, et al. (2001). "In vivo extracellular recording of striatal neurons in the awake rat following unilateral 6-hydroxydopamine lesions." Exp Neurol 171(1): 72-83. The purpose of this study was to further understand the functional effects of dopaminergic input to the dorsal striatum and to compare the effects of dopaminergic lesions in awake and anesthetized animals. We examined the effects of unilateral 6-hydroxydopamine (6-OHDA) lesions of the ascending dopaminergic bundle on the firing properties of dorsal striatal neurons in the awake freely moving rat using chronically implanted microwire electrode arrays. We recorded extracellular activity of striatal neurons under baseline conditions and following the systemic injection of apomorphine in awake and anesthetized subjects. Firing rates were higher in the hemisphere ipsilateral to the 6-OHDA lesion compared to rates of neurons from the contralateral unlesioned hemisphere. Striatal firing rates from sham and no-surgery control rats were, in general, higher than those from the contralateral unlesioned striatum of experimental subjects. Apomorphine (0.05 mg/kg, sc) normalized the differences in firing rates in lesioned animals by increasing firing of neurons within the contralateral unlesioned side, while simultaneously decreasing firing of neurons within the ipsilateral lesioned side. Mean firing rates were substantially higher in awake animals than in subjects anesthetized with chloral hydrate, perhaps reflecting anesthesia-induced decreases in excitatory input to striatal neurons. Chloral hydrate anesthesia decreased firing rates of neurons in the lesioned, unlesioned, and control striata to a similar degree, although absolute firing rates of neurons from the 6-OHDA-lesioned striata remained elevated over all other groups. Unilateral 6-OHDA lesions also altered the pattern of spike output in the awake animal as indicated by an increase in the number of bursts per minute following dopaminergic deafferentation. This and other burst parameters were altered by apomorphine. Our findings show that effects of dopaminergic deafferentation can be measured in the awake behaving animal; this model should prove useful for testing the behavioral and functional effects of experimental manipulations designed to reduce or reverse the effects of dopaminergic cell loss. In addition, these results suggest that the contralateral changes in striatal function which occur in the unilateral dopaminergic lesion model should be considered when evaluating experimental results. Chen, R., R. R. Garg, et al. (2001). "Effects of internal globus pallidus stimulation on motor cortex excitability." Neurology 56(6): 716-23. BACKGROUND: Deep brain stimulation is a promising treatment for PD, but its physiologic effects and mechanisms of action remain poorly understood. Magnetic stimulation studies have revealed abnormalities in several different excitatory and inhibitory circuits in the motor cortex in PD. METHODS: The physiologic effects of internal globus pallidus (GPi) stimulation in seven patients with PD and seven age-matched healthy volunteers were studied. The stimulators were set at the optimal parameters (ON), at half the optimal amplitude (Half-Amp), or switched off (OFF) in random order. Patients were taking their usual medications. Magnetic stimulation was applied to the motor cortex, and motor evoked potentials (MEP) were recorded from the contralateral first dorsal interosseous muscle. Several excitatory and inhibitory pathways that have been found to be abnormal in PD were tested. RESULTS: The motor threshold (MT), MEP recruitment curve (stimulus intensities from 100 to 150% of MT), short and long interval intracortical inhibition, and intracortical facilitation were similar in the three stimulator conditions tested both at rest and during voluntary contraction. The silent period (SP) was longer in the OFF and Half-Amp conditions than in normal control subjects. In the stimulator ON condition, the SP was significantly reduced compared with the OFF condition and became similar to that in normal control subjects. CONCLUSIONS: GPi stimulation while on dopaminergic medications reduced the SP following magnetic stimulation but did not change corticospinal excitability or other measures of intracortical inhibition and facilitation. The reduction of SP may be related to the antidyskinetic and levodopa-blocking effects of ventral GPi stimulation. Chen, R., S. Kumar, et al. (2001). "Impairment of motor cortex activation and deactivation in Parkinson's disease." Clin Neurophysiol 112(4): 600-7. OBJECTIVES: To examine the time course of corticospinal excitability before and after voluntary movement in Parkinson's disease (PD). METHODS: We studied 9 mild PD patients at least 12 h off medications and 11 healthy volunteers in a simple reaction time (RT) paradigm. Suprathreshold transcranial magnetic stimulation was delivered to the left motor cortex at intervals covering the periods before and after movement. RESULTS: PD patients (284+/-90 ms) and normal subjects (282+/-56 ms) had similar median RT. The time courses of both the premovement increase and the postmovement decrease in corticospinal excitability were significantly different between PD patients and normal subjects. The increase in motor-evoked potential (MEP) amplitudes began earlier for PD patients (200 ms before electromyographic (EMG) onset) than for normal subjects (150 ms before EMG onset), but the rate of increase was slower in PD patients than controls. After EMG offset, MEP amplitudes were increased for about 150 ms in normal subjects, but in PD patients this period was prolonged to about 350 ms. CONCLUSIONS: Impairment of motor cortex activation and deactivation is an early feature of PD and may be a physiological correlate of bradykinesia. The normal RT in our patients may be related to the earlier occurrence of the premovement increase in corticospinal excitability compensating for the slower rate of rise. Chen, R. C., S. F. Chang, et al. (2001). "Prevalence, incidence, and mortality of PD: a door-to-door survey in Ilan county, Taiwan." Neurology 57(9): 1679-86. BACKGROUND: The reported prevalence and incidence rates of PD were significantly lower in China than those in Western countries. People in China and Taiwan have a similar ethnic background. OBJECTIVE: To investigate the prevalence, incidence, and mortality rate of PD in Taiwan. METHOD: The authors conducted a population-based survey using a two-stage door-to-door approach for patients aged 40 years or older in Ilan, Taiwan. Patients were diagnosed with PD by having at least two of the four cardinal signs of parkinsonism and exclusion of seconddary parkinsonism. To identify new cases of PD after the survey, patients with negative results of parkinsonism in the first stage were matched to the information on clinical diagnosis of PD from the Bureau of National Health Insurance toward the end of December 31, 1997. All cases of PD were linked to the Taiwan mortality registration to ascertain causes of deaths until December 31, 1999. RESULTS: The participation rate was 88.1% among the 11,411 contacted individuals. Thirty-seven cases of PD were identified. The age-adjusted prevalence rate of PD for all age groups was 130.1 per 100,000 population after being adjusted to the 1970 US census, assuming no cases of PD would be found among those younger than 40 years of age. Of 9972 non-PD subjects in the first screen, 15 new cases of PD were ascertained. The age-adjusted incidence rate was 10.4 per 100,000 population for all age groups. The case fatality rate of PD after a 7-year follow-up was 40.4% (21 deaths in 52 patients with PD). The relative risk of death for PD cases versus non-PD cases was 3.38 (95% CI: 2.05-4.34). The 5-year cumulative survival rate in PD cases (78.85%) was statistically lower than that in non-PD cases (92.84%). CONCLUSION: The prevalence and incidence rates of PD in Taiwan were much higher than those reported in China, but closer to those in Western countries. These results suggest that environmental factors may be more important than racial factors in the pathogenesis of PD. Chiang, Y., M. Morales, et al. (2001). "Fetal intra-nigral ventral mesencephalon and kidney tissue bridge transplantation restores the nigrostriatal dopamine pathway in hemi-parkinsonian rats." Brain Res 889(1-2): 200-7. We have previously demonstrated that intranigral transplantation of fetal ventral mesencephalic (VM) tissue and nigrostriatal administration of glial cell line-derived neurotrophic factor (GDNF) restores striatal dopamine input in hemiparkinsonian rats. Since it has been found that GDNF is highly expressed in fetal kidney, we examined the possibility that fetal kidney tissue may provide trophic support, similar to GDNF, to an intranigral dopamine (DA) transplant and restore the nigrostriatal pathway. Adult Sprague-Dawley rats were anesthetized and unilaterally injected with 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. Completeness of the lesion was evaluated by measuring amphetamine-induced rotation. One month after 6-OHDA lesioning, fetal VM cells were grafted into the lesioned nigral area followed by transplantation of fetal kidney tissue or vehicle along a pathway from nigra to striatum. Animals receiving these transplants showed a significant decrease both in amphetamine-induced rotation and in postural asymmetry 1 to 3 months after grafting. Immunocytochemical studies demonstrated tyrosine hydroxylase (TH) positive fiber tracts in the lesioned striatum. Control animals that received vehicle injection after the intranigral graft or no transplantation showed no alterations in amphetamine-induced turning and no TH-positive fibers in the lesioned striatum. These results indicate that combinations of fetal nigral and kidney transplants may restore the nigrostriatal DA pathway in Parkinsonian rats. As fetal kidney contains a variety of trophic proteins, it may provide a synergistic admixture to optimally promote DA fiber outgrowth. Chiba-Falek, O. and R. L. Nussbaum (2001). "Effect of allelic variation at the NACP-Rep1 repeat upstream of the alpha-synuclein gene (SNCA) on transcription in a cell culture luciferase reporter system." Hum Mol Genet 10(26): 3101-9. Mutations in the alpha-synuclein gene (SNCA) have been implicated in familial Parkinson's disease (PD) while certain polymorphic alleles at a microsatellite repeat, NACP-Rep1, located approximately 10 kb upstream of the gene, have been associated with sporadic PD. In order to study the regulation of the human alpha-synuclein gene, we performed a deletion analysis of 10.7 kb upstream of the translational start site, using the luciferase reporter assay in 293T cells and the neuroblastoma cell line SH-SY5Y. The shortest fragment, 400 bp upstream of the transcriptional start site, was sufficient for transcription in both cell lines. The other constructs led to variable expression levels, with some showing maximum expression and others showing nearly complete extinction of expression. An 880 bp fragment located approximately 10 kb upstream of the gene and containing the NACP-Rep1 polymorphism, was shown to be necessary for normal expression. Additional analysis of the NACP-Rep1 locus and surrounding DNA suggested that two domains flanking the repeat interact to enhance expression while the repeat acts as a negative modulator. Next, we measured the activity of the entire 10.7 kb upstream region in the luciferase reporter assay when each of our different NACP-Rep1 alleles were present. The expression levels varied very significantly among the different alleles over a 3-fold range in the SH-SY5Y cells but showed little or no significant variation in the 293T cells. Given that even small changes in alpha-synuclein expression may, over many decades, predispose to PD, the association of different NACP-Rep1 alleles with PD may be a consequence of polymorphic differences in transcriptional regulation of alpha-synuclein expression resulting from different NACP-Rep1 alleles. Chinopoulos, C. and V. Adam-Vizi (2001). "Mitochondria deficient in complex I activity are depolarized by hydrogen peroxide in nerve terminals: relevance to Parkinson's disease." J Neurochem 76(1): 302-6. Deficiency of complex I in the respiratory chain and oxidative stress induced by hydrogen peroxide occur simultaneously in dopaminergic neurones in Parkinson's disease. Here we demonstrate that the membrane potential of in situ mitochondria (Delta Psi m), as measured by the fluorescence change of JC-l (5,5',6,6'-tetrachloro-1,1,3,3'-tetraethylbezimidazolyl-carbocyani ne iodide), collapses when isolated nerve terminals are exposed to hydrogen peroxide (H(2)O(2), 100 and 500 microM) in combination with the inhibition of complex I by rotenone (5 nM-1 microM). H(2)O(2) reduced the activity of complex I by 17%, and the effect of H(2)O(2) and rotenone on the enzyme was found to be additive. A decrease in Delta Psi m induced by H(2)O(2) was significant when the activity of complex I was reduced to a similar extent as found in Parkinson's disease (26%). The loss of Delta Psi m observed in the combined presence of complex I deficiency and H(2)O(2) indicates that when complex I is partially inhibited, mitochondria in nerve terminals become more vulnerable to H(2)O(2)-induced oxidative stress. This mechanism could be crucial in the development of bioenergetic failure in Parkinson's disease. Choi, P., N. Golts, et al. (2001). "Co-association of parkin and alpha-synuclein." Neuroreport 12(13): 2839-43. Parkin and alpha-synuclein are two proteins that are associated with the pathophysiology of Parkinson's disease (PD). Parkin is present in Lewy bodies and axonal spheroids in brains affected by PD, and mutations in parkin cause hereditary forms of Parkinsonism. Alpha-synuclein is a major component of Lewy bodies and is associated with rare cases of PD. We now show that parkin binds to alpha-synuclein, including conditions associated with alpha-synuclein aggregation. Parkin and alpha-synuclein complexes were observed in BE-M17 cells under basal conditions, in BE- M17 cells under oxidative conditions and in brains from control or PD donors. Double staining of PD brains shows parkin and alpha-synuclein co-localize to the same pathological structures (both Lewy bodies and axonal spheroids). These results suggest that parkin interacts with alpha-synuclein and could contribute to the pathophysiology of PD more generally than was previously considered. Chollet, F., I. Loubinoux, et al. (2001). "[Pharmacologic modification of cerebral activity: value of functional neuroimaging]." Rev Neurol (Paris) 157(8-9 Pt 1): 827-31. Chong, R. K., J. Barbas, et al. (2001). "Does balance control deficit account for walking difficulty in Parkinson's disease?" Int J Clin Pract 55(6): 411-2. Patients with Parkinson's disease (PD) walk slowly, in part to compensate for their balance control deficit. We tested the effect of balance support to determine if walking performance in PD patients would improve. The sample consisted of unmedicated older adults with idiopathic Parkinson's disease who had poor balance control but no stooped posture, arthritis or muscle weakness. There was no difference in walking speed between unsupported and supported walking. The speeds were between those reported for disease-free older adults and older adults with muscle weakness and a history of falling. PD patients' walking difficulties, even while using a balance aid, may be partly explained by their set-changing problems. They frequently hold the cane off the ground when walking, suggesting their set-changing difficulty may be severe enough that using it aggravates their walking difficulty. Treatment of walking difficulty in PD patients should consider interventions other than those dealing only with balance control. Chou, S. M. and L. Gutmann (2001). "Deteriorating parkinsonism and subdural hematomas." Neurology 57(7): 1295. Chouker, M., K. Tatsch, et al. (2001). "Striatal dopamine transporter binding in early to moderately advanced Parkinson's disease: monitoring of disease progression over 2 years." Nucl Med Commun 22(6): 721-5. Imaging of striatal dopamine transporter binding allows differentiation between patients with Parkinson's disease and controls. We investigated the use of this technique to monitor disease progression. We used N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(4-chlorophenyl) tropane (IPT) and single photon emission computed tomography (SPECT) to determine dopamine transporter function in eight patients with Parkinson's disease Hoehn and Yahr stage I to III over time. Patients were recruited from the movement disorder clinic and were studied at entry and after a follow-up period of 1 and 2 years. Specific striatal IPT binding was measured with a manual region of interest technique. At entry, all patients showed a reduction of striatal IPT uptake of approximately 50% compared to controls, with a mean striatum to background ratio of 3.61 +/- 0.72 (controls, 7.34 +/- 1.18). Putamen to background ratios were initially measured as 2.42 +/- 0.74 and caudate to background ratios as 5.00 +/- 0.73 (controls, 6.46 +/- 1.22 for putamen and 8.58 +/- 1.36 for caudate). Specific striatal IPT binding decreased by a mean of 6.6% in the first year and another 5.3% in the second year. Changes of specific IPT binding over time were similar in caudate and putamen. In patients with clinically asymmetric disease, differences between the rate of decline in the ipsilateral and contralateral sides could not be detected. The findings suggest that IPT SPECT can quantify the reduction of dopamine transporter binding over time. This technique seems to be a useful tool in monitoring the intra-individual progression of dopaminergic cell loss in patients with Parkinson's disease and may help to follow the effects of putative neuroprotective drugs in future clinical trials. Christoforidis, G. A., E. M. Spickler, et al. (2001). "Lacunar infarct during pallidotomy: case report." Neuroradiology 43(4): 321-4. A symptomatic lacunar infarct is an unusual complication which may develop during stereotactically guided pallidotomy using radiofrequency thermoablation. We describe a 54-year-old man with Parkinson's disease involving predominantly the right side, progressively deteriorating under medical management. He underwent stereotactically guided radiofrequency thermoablation of the posteroventral globus pallidus interna. Despite intraoperative microelectrode recording and stimulation, the patient developed right facial weakness and pronator drift during the procedure. MRI showed a small lacunar infarct in the left internal capsule, in addition to the appropriately placed ablative lesion. We discuss the potential mechanisms for this type of injury. Christova, L. G., A. S. Alexandrov, et al. (2001). "Comparative analyse of single motor unit pattern in healthy subjects and patients with neuromuscular disorders." Acta Physiol Pharmacol Bulg 26(1-2): 59-62. OBJECTIVE: The motor unit (MU) spike trains in human muscle contractions are an object to new mathematical processing. The aim is to identify the interspike interval relations characterizing normal and changed physiological states (neuro-muscular disorders). METHODS: MU activities in healthy subjects and patients with Schwartz-Jampel syndrome, neuromiotonia and Parkinson disease were investigated. Motor unit action potentials (MUAPs) were recorded by surface multielectrode with small leading-off area without provoking a burst of activity, as usually was observed during the needle electromyography study in patients with Schwartz-Jampel syndrome and neuromiotonia. RESULTS: Different single motor unit activity in healthy subjects and patients was observed. Discharge pattern of patients was basically changed. Disturbance of different parts of the motor system leads to the changes of temporal order of interspike interval. This permit us to suppose that the pattern of repetative neuronal discharges suggests an influence at a higher level than the muscle in all investigated patients but the reason of multiple discharges with an interimpulse interval of 2 to 10 ms probably originated in the muscle membrane. CONCLUSIONS: The comparative analysis of MU patterns in healthy subjects and patients with neuro-muscular disorders can help us to disclose inapparent connections between cortical and spinal level of motor control. Chuang, C., R. S. Kocen, et al. (2001). "Case with both multiple system atrophy and primary progressive multiple sclerosis with discussion of the difficulty in their differential diagnosis." Mov Disord 16(2): 355-8. Chun, H. S., G. E. Gibson, et al. (2001). "Dopaminergic cell death induced by MPP(+), oxidant and specific neurotoxicants shares the common molecular mechanism." J Neurochem 76(4): 1010-21. Recent etiological study in twins (Tanner et al. 1999) strongly suggests that environmental factors play an important role in typical, non-familial Parkinson's disease (PD), beginning after age 50. Epidemiological risk factor analyses of typical PD cases have identified several neurotoxicants, including MPP(+) (the active metabolite of MPTP), paraquat, dieldrin, manganese and salsolinol. Here, we tested the hypothesis that these neurotoxic agents might induce cell death in our nigral dopaminergic cell line, SN4741 (Son et al. 1999) through a common molecular mechanism. Our initial experiments revealed that treatment with both MPP(+) and the other PD-related neurotoxicants induced apoptotic cell death in SN4741 cells, following initial increases of H(2)O(2)-related ROS activity and subsequent activation of JNK1/2 MAP kinases. Moreover, we have demonstrated that during dopaminergic cell death cascades, MPP(+), the neurotoxicants and an oxidant, H(2)O(2) equally induce the ROS-dependent events. Remarkably, the oxidant treatment alone induced similar sequential molecular events: ROS increase, activation of JNK MAP kinases, activation of the PITSLRE kinase, p110, by both Caspase-1 and Caspase-3-like activities and apoptotic cell death. Pharmacological intervention using the combination of the antioxidant Trolox and a pan-caspase inhibitor Boc-(Asp)-fmk (BAF) exerted significant neuroprotection against ROS-induced dopaminergic cell death. Finally, the high throughput cDNA microarray screening using the current model identified downstream response genes, such as heme oxygenase-1, a constituent of Lewy bodies, that can be the useful biomarkers to monitor the pathological conditions of dopaminergic neurons under neurotoxic insult. Chun, H. S., H. Lee, et al. (2001). "Manganese induces endoplasmic reticulum (ER) stress and activates multiple caspases in nigral dopaminergic neuronal cells, SN4741." Neurosci Lett 316(1): 5-8. Chronic exposure to manganese causes Parkinson's disease (PD)-like clinical symptoms (Neurotoxicology 5 (1984) 13; Arch. Neurol. 46 (1989) 1104; Neurology 56 (2001) 4). Occupational exposure to manganese is proposed as a risk factor in specific cases of idiopathic PD (Neurology 56 (2001) 8). We have investigated the mechanism of manganese neurotoxicity in nigral dopaminergic (DA) neurons using the DA cell line, SN4741 (J. Neurosci. 19 (1999) 10). Manganese treatment elicited endoplasmic reticulum (ER) stress responses, such as an increased level of the ER chaperone BiP, and simultaneously activated the ER resident caspase-12. Peak activation of other major initiator caspases-like activities, such as caspase-1, -8 and -9, ensued, resulting in activation of caspase-3-like activity during manganese-induced DA cell death. The neurotoxic cell death induced by manganese was significantly reduced in the Bcl-2-overexpressing DA cell lines. Our findings suggest that manganese-induced neurotoxicity is mediated in part by ER stress and considerably ameliorated by Bcl-2 overexpression in DA cells. Chung, K. K., Y. Zhang, et al. (2001). "Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease." Nat Med 7(10): 1144-50. Parkinson disease is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons and the presence of intracytoplasmic-ubiquitinated inclusions (Lewy bodies). Mutations in alpha-synuclein (A53T, A30P) and parkin cause familial Parkinson disease. Both these proteins are found in Lewy bodies. The absence of Lewy bodies in patients with parkin mutations suggests that parkin might be required for the formation of Lewy bodies. Here we show that parkin interacts with and ubiquitinates the alpha-synuclein-interacting protein, synphilin-1. Co-expression of alpha-synuclein, synphilin-1 and parkin result in the formation of Lewy-body-like ubiquitin-positive cytosolic inclusions. We further show that familial-linked mutations in parkin disrupt the ubiquitination of synphilin-1 and the formation of the ubiquitin-positive inclusions. These results provide a molecular basis for the ubiquitination of Lewy-body-associated proteins and link parkin and alpha-synuclein in a common pathogenic mechanism through their interaction with synphilin-1. Ciechanover, A. (2001). "Linking ubiquitin, parkin and synphilin-1." Nat Med 7(10): 1108-9. Clarke, C. E., J. A. Cooper, et al. (2001). "A randomized, double-blind, placebo-controlled, ascending-dose tolerability and safety study of remacemide as adjuvant therapy in Parkinson's disease with response fluctuations." Clin Neuropharmacol 24(3): 133-8. The objective of this study was to establish the maximum tolerated dose of the low affinity non-competitive N-methyl-D-aspartate receptor antagonist remacemide in patients who have Parkinson's disease with response fluctuations or dyskinesias, or both. A total of 33 patients were randomly assigned in a 3-to-1 ratio to receive remacemide or placebo. Remacemide was administered orally at 150 mg twice daily, increasing incrementally by 100 mg (50 mg twice daily) at 2-week intervals to a final daily regimen of 400 mg twice daily or until a maximum tolerated dose was identified. The maximum total treatment period was 12 weeks. Of the 23 patients randomly selected to receive remacemide, four completed the study at the maximum permitted dose, compared with four of the 10 patients given placebo. The median maximum tolerated dose of remacemide was 450 mg/d. There was no clinically relevant change in percentage of "on" time between baseline and maximum tolerated dose in either group. At the maximum tolerated dose of remacemide for each patient, the mean Unified Parkinson's Disease Rating Scale (UPDRS) motor examination score (part III) decreased from 33 (SD = 18) to 26 (SD = 13) compared with a decrease from 28 (SD = 12) to 27 (SD = 8) in the placebo group. There was a decrease in the mean UPDRS "complications of therapy" score (part IV) in the remacemide group from 8 (SD = 4) to 6 (SD = 4), and the placebo group remained unchanged at 6 (SD = 4). The most common adverse events associated with remacemide were nausea, vomiting, dizziness, headache, abnormal vision, and hypokinesia. Remacemide was well tolerated at a dose level of 400 mg/d. There was a trend suggesting that remacemide was effective in improving symptoms at patients' individual maximum tolerated doses. These improvements occurred without exacerbating levodopa-induced dyskinesias. Clarke, C. E. and K. D. Deane (2001). "Cabergoline versus bromocriptine for levodopa-induced complications in Parkinson's disease." Cochrane Database Syst Rev 1: CD001519. BACKGROUND: Long term levodopa therapy in Parkinson's disease is associated with the development of motor complications including abnormal involuntary movements and a shortening response to each dose (wearing off phenomenon). It is thought that dopamine agonists can reduce the duration of immobile off periods and the need for levodopa therapy whilst maintaining or improving motor impairments and only minimally increasing dopaminergic adverse events. OBJECTIVES: To compare the efficacy and safety of adjuvant cabergoline therapy versus bromocriptine in patients with Parkinson's disease, already established on levodopa and suffering from motor complications. SEARCH STRATEGY: Electronic searches of MEDLINE, EMBASE and the Cochrane Controlled Trials Register. Handsearching of the neurology literature as part of the Cochrane Movement Disorders Group's strategy. Examination of the reference lists of identified studies and other reviews. Contact with Pharmacia Upjohn Limited. SELECTION CRITERIA: Randomised controlled trials of cabergoline versus bromocriptine in patients with a clinical diagnosis of idiopathic Parkinson's disease and long-term complications of levodopa therapy. DATA COLLECTION AND ANALYSIS: Data were abstracted independently by the authors and differences settled by discussion. The outcome measures used included Parkinson's disease rating scales, levodopa dosage, off time measurements and the frequency of withdrawals and adverse events. MAIN RESULTS: Cabergoline has been compared with bromocriptine in five randomised, double-blind, parallel group studies including 1071 patients. Only one of the phase II studies was medium term (36 weeks), the others all being short term (12 -15 weeks). The non-significant difference in off time reduction produced by cabergoline compared with bromocriptine was 0.29 hours/day in favour of the former (weighted mean difference; 95% CI -0.10, 0.68; p = 0.15). Dyskinesia reported as an adverse event was significantly increased with cabergoline compared with bromocriptine (Peto odds ratio 1.57; 95% CI 1.05, 2.35; p = 0.03). Motor impairment and disability were measured in four of the studies using the UPDRS rating scale but the small differences in UPDRS ADL (part II) and motor (part III) scores were not statistically significant in any study. Similarly, no significant difference in Schwab and England score was seen. The number of patients rated as much or very much improved on a clinician's global impression scale was similar with both agonists. Levodopa dose reduction was no different between cabergoline and bromocriptine. There was more confusion with cabergoline (Peto odds ratio 2.02; 95% CI 1.09, 3.76; p = 0.03). Otherwise, dopaminergic adverse events were comparable with these agonists and no significant difference in all cause withdrawal rate was found. REVIEWER'S CONCLUSIONS: Cabergoline produces similar benefits to bromocriptine in off time reduction, motor impairment and disability ratings, and levodopa dose reduction over the first three months of therapy. Dyskinesia and confusion were increased with cabergoline but otherwise the frequency of adverse events and withdrawals from treatment were similar with the two agonists. Clarke, C. E. and K. H. Deane (2001). "Cabergoline for levodopa-induced complications in Parkinson's disease." Cochrane Database Syst Rev 1: CD001518. BACKGROUND: Long term levodopa therapy in Parkinson's disease is associated with the development of motor complications including abnormal involuntary movements and a shortening response to each dose (wearing off phenomenon). It is thought that dopamine agonists can reduce the duration of immobile off periods and the need for levodopa therapy whilst maintaining or improving motor impairments and only minimally increasing dopaminergic adverse events. OBJECTIVES: To compare the efficacy and safety of adjuvant cabergoline therapy versus placebo in patients with Parkinson's disease, already established on levodopa and suffering from motor complications. SEARCH STRATEGY: Electronic searches of MEDLINE, EMBASE and the Cochrane Controlled Trials Register. Handsearching of the neurology literature as part of the Cochrane Movement Disorders Group's strategy. Examination of the reference lists of identified studies and other reviews. Contact with Pharmacia Upjohn Limited. SELECTION CRITERIA: Randomised controlled trials of cabergoline versus placebo in patients with a clinical diagnosis of idiopathic Parkinson's disease and long-term complications of levodopa therapy. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by the authors and differences settled by discussion. The outcome measures used included Parkinson's disease rating scales, levodopa dosage, off time measurements and the frequency of withdrawals and adverse events. MAIN RESULTS: Cabergoline has been compared with placebo in two phase II (6 - 12 weeks) and one phase III randomised controlled trials (24 weeks). These were double-blind, parallel group, multicentre studies including 268 patients with Parkinson's disease and motor complications. The reduction of 1.14 hours (WMD; 95% CI -0.06, 2.33; p = 0.06) in off time in favour of cabergoline was not statistically significant. Inadequate data on dyskinesia was collected either on rating scales or as adverse event reporting to allow a conclusion to be drawn. A small but statistically significant advantage of cabergoline over placebo was seen in one study for UPDRS ADL (part II) score and UPDRS motor score. No such advantage was seen in one other study due to small numbers of patients and the comparatively low doses of cabergoline used. No significant differences in Schwab and England scale were seen in two studies. Levodopa dose reduction was significantly greater with cabergoline (WMD 149.6 mg/d; 95% CI 94.1, 205.1; p < 0.00001). There was a trend towards more dopaminergic adverse events with cabergoline but this did not reach statistical significance at the p < 0.01 level. However, there was a trend towards fewer withdrawals from cabergoline. REVIEWER'S CONCLUSIONS: In the management of the motor complications seen in Parkinson's disease, cabergoline can be used to reduce levodopa dose and modestly improve motor impairment and disability with an acceptable adverse event profile. These conclusions are based on, at best, medium term evidence. Clarke, C. E. and K. H. Deane (2001). "Ropinirole versus bromocriptine for levodopa-induced complications in Parkinson's disease." Cochrane Database Syst Rev 1: CD001517. BACKGROUND: Long-term levodopa therapy for Parkinson's disease is complicated by the development of motor fluctuations and abnormal involuntary movements. One approach is to add a dopamine agonist at this stage of the disease to reduce the time the patient spends immobile or off and to reduce the dose of levodopa in the hope of reducing such problems in the future. OBJECTIVES: To compare the efficacy and safety of adjuvant ropinirole therapy with bromocriptine in patients with Parkinson's disease already established on levodopa therapy and suffering from motor complications. SEARCH STRATEGY: Electronic searches of MEDLINE, EMBASE and the Cochrane Controlled Trials Register. Handsearching of the neurology literature as part of the Cochrane Movement Disorders Group's strategy. Examination of the reference lists of identified studies and other reviews. Contact with SmithKline Beecham. SELECTION CRITERIA: Randomised controlled trials of ropinirole versus bromocriptine in patients with a clinical diagnosis of idiopathic Parkinson's disease and long-term complications of levodopa therapy. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by the authors and differences settled by discussion. The outcome measures used included Parkinson's disease rating scales, levodopa dosage, 'off' time measurements and the frequency of withdrawals and adverse events. MAIN RESULTS: In the 3 trials identified, no significant differences between ropinirole and bromocriptine were found in off time reduction, dyskinesia as an adverse event, motor impairment and disability, or levodopa dose reduction. Withdrawal rates and adverse event frequency were similar with the two agents apart from significantly less nausea with ropinirole (odds ratio 0.50; 0.29, 0.84 95% CI; p =0.01). REVIEWER'S CONCLUSIONS: Ropinirole is at least as good as bromocriptine in patients with Parkinson's disease with motor complications in terms of improving off time and reducing levodopa dose, without increasing adverse events including dyskinesia. However, these comparitor studies may have been underpowered to detect clinically meaningful differences between the agonists. Further, much larger, phase IV studies are required to examine the efficacy, effectiveness, and safety of all of the dopamine agonists as adjuvant therapy in Parkinson's disease. Clarke, C. E. and K. H. Deane (2001). "Ropinirole for levodopa-induced complications in Parkinson's disease." Cochrane Database Syst Rev 1: CD001516. BACKGROUND: Long-term levodopa therapy for Parkinson's disease is complicated by the development of motor fluctuations and abnormal involuntary movements. One approach is to add a dopamine agonist at this stage of the disease to reduce the time the patient spends immobile or off and to reduce the dose of levodopa in the hope of reducing such problems in the future. OBJECTIVES: To compare the efficacy and safety of adjuvant ropinirole therapy versus placebo in patients with Parkinson's disease already established on levodopa therapy and suffering from motor complications. SEARCH STRATEGY: Electronic searches of MEDLINE, EMBASE and the Cochrane Controlled Trials Register. Handsearching of the neurology literature as part of the Cochrane Movement Disorders Group's strategy. Examination of the reference lists of identified studies and other reviews. Contact with SmithKline Beecham. SELECTION CRITERIA: Randomised controlled trials of ropinirole versus placebo in patients with a clinical diagnosis of idiopathic Parkinson's disease and long-term complications of levodopa therapy. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by the authors and differences settled by discussion. The outcome measures used included Parkinson's disease rating scales, levodopa dosage, 'off' time measurements and the frequency of withdrawals and adverse events. MAIN RESULTS: Three double-blind, parallel group, randomised, controlled trials have been conducted on 263 patients. The two phase II studies were relatively small, were conducted over the short term (12 weeks), and used relatively low doses of ropinirole (mean administered doses 3.3 and 3.5 mg/d) in a twice daily regime. In view of this clinical heterogeneity and some statistical heterogeneity, the results of these trials have not been included in a meta-analysis. The conclusions of this review are based on the evidence from a single phase III study which was medium term (26 weeks) and used ropinirole doses in line with the current UK licensed maximum in a thrice daily regime. In view of difficulties in assessing changes in off time in ~~ Leiberman 98~~, caused by the initial imbalance between the arms of the trial, it is unsafe to draw any firm conclusion about the effect of ropinirole on off time. However, as an adverse event, dyskinesia was significantly increased in those who received ropinirole (~~ Leiberman 98~~; odds ratio 2.90; 1.36, 6.19 95% CI; Table 8). Measurements of motor impairments and disability were poor in this study with incomplete information available. Levodopa dose could be reduced in ~~ Leiberman 98~~ with a significantly larger reduction on ropinirole than on placebo (weighted mean difference 180 mg/d; 106, 253 95% CI; Table 2). No significant differences in the frequency of adverse event reports were noted between ropinirole and placebo apart from the increase in dyskinesia with ropinirole. There was a trend towards fewer withdrawals from ropinirole in ~~ Leiberman 98~~ but this did not reach statistical significance. REVIEWER'S CONCLUSIONS: Ropinirole therapy can reduce levodopa dose but at the expense of increased dyskinetic adverse events. No clear effect on off time reduction was found but this may have been due to the under-powering of the single evaluable trial. Inadequate data on motor impairments and disability was collected to assess these outcomes. These conclusions apply to short and medium term treatment, up to 26 weeks. Further longer term trials are required, with measurements of effectiveness, and also studies to compare the newer with the older dopamine agonists. Clarke, C. E. and M. Lowry (2001). "Systematic review of proton magnetic resonance spectroscopy of the striatum in parkinsonian syndromes." Eur J Neurol 8(6): 573-7. It has been suggested that proton magnetic resonance spectroscopy (MRS) of the striatum can differentiate between parkinsonian syndromes. The present study aims to examine this claim by performing a systematic review of the existing literature. A MEDLINE search was performed between 1966 and October 1999, along with searches of conference abstracts and reference lists of papers identified. Eleven groups have used MRS to examine metabolite ratios in the striatum in Parkinsonian syndromes. A number of these have shown reduced N-acetylaspartate/choline (NAA/Cho) and/or N-acetylaspartate/creatine (NAA/Cr) ratios in either idiopathic Parkinson's disease (IPD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP) or corticobasal degeneration. However, the heterogeneity in the results precludes the use of any of these findings in differential diagnosis at the present time. The only group to use absolute metabolite concentrations rather than ratios showed that the decreased NAA/Cho ratio in IPD was because of an increase in choline which is of uncertain biological significance. Further large multicentre trials are required using absolute quantitation of tissue metabolite concentrations and a standardized technique. The patients entering such studies must be rigorously assessed to establish the diagnosis of the type of parkinsonism as accurately as possible. Any discriminatory abnormality must be tested in a large prospective study of newly presenting parkinsonian patients with long-term clinical follow up and ultimate pathological confirmation of the diagnosis as far as possible. Clarkson, E. D. (2001). "Fetal tissue transplantation for patients with Parkinson's disease: a database of published clinical results." Drugs Aging 18(10): 773-85. Over the past 13 years approximately 300 patients with Parkinson's disease have received transplants of human fetal dopamine cells in an attempt to reduce or control disease symptoms. Many of these patients have had improvements in their motor skills and a reduction in their daily levodopa administration. However, improvements are far from guaranteed and questions need to be answered before this technique can be widely applied. To help address some of these issues, a search of all the published results of patients with Parkinson's disease transplanted with human fetal tissue was conducted. This generated a database of 70 transplant recipients who had their levodopa administration and clinical benefit reported both prior to transplant and at least 6 months post-transplant. Furthermore, the number of years of disease onset prior to transplant was available for all recipients. This database was examined for motor improvement and reduction in levodopa dosage for up to 2 years post-transplant to determine the effects of time on transplant outcome. The database showed that most recipients had significant improvements in motor skills and levodopa administration, and that most benefits were observed in the first 6 months post-transplant. In addition, the database demonstrated that the number of years of disease onset prior to transplantation was not a predictor of patient outcome 1-year post-transplant. Current and future directions in fetal tissue transplantation research and replacements for fetal tissue are discussed. Clostre, F. (2001). "[Mitochondria: recent pathophysiological discoveries and new therapeutic perspectives]." Ann Pharm Fr 59(1): 3-21. Until about a decade ago, few researchers in clinical or evolutionary biology paid much attention to mitochondria. But over the years, as technological advances in molecular biology made nuclear functions more accessible to them, interest in mitochondria began to revive. First, geneticists started tracing certain rare inherited disorders to mutations in the mitochondria's circular genome. More recently, other researchers have speculated that mitochondria might contribute to aging, either by releasing tissue-damaging reactive oxygen molecules or by impairing and depriving the cell of the energy it needs to function. One the most important recent developments has been the recognition that mitochondria play a central role in the regulation of programmed cell death, or apoptosis. Now, we know that mitochondria play a decisive role in life-death decisions for the cell and may choose between the apoptotic and necrotic pathways. Mitochondria can trigger cell death in a number of ways: by disrupting electron transport and energy metabolism, by activating the mitochondrial permeability transition, by releasing and/or activating proteins that mediate apoptosis. Any or all of these mechanisms may help to explain how mitochondrial defects contribute to the pathogenesis of neuronal death or dysfunction in ischemia/reperfusion injury as well as in human degenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. This has opened up new avenues for understanding the pathogenesis of neurodegeneration and may lead to new and more effective therapeutic approaches to these diseases. Clower, W. T. (2001). "Lesions as therapy: rigidity and Parkinson's disease." J Hist Neurosci 10(1): 93-106. Since James Parkinson (1817) first characterized the shaking palsy as a unique condition, significant confusion has remained concerning the causes and treatments of Parkinson's disease (PD). Through the 19th century, a wide variety of approaches were attempted in an effort to reduce its cardinal signs--rigidity, tremor, and bradykinesia--but to little effect. Today, approaching 200 years after Parkinson's seminal work, this disorder is commonly treated by surgical means, inducing a lesion in one specific portion of a small nucleus in the central nervous system (Desaloms et al., 1998, Lang et al., 1999). The notion of providing a lesion to the nervous system as a therapy for PD, however, began in earnest at the beginning of the 20th century. The first attempt to alleviate the symptoms of PD through surgical means involved a section of the dorsal roots of the spinal cord supplying the affected limb (also known as dorsal rhizotomy). Although ultimately resulting in disastrous effects, these early surgical attempts proceeded from a firm body of clinical and experimental research on both the central and peripheral nervous systems. After briefly reviewing the use and failure of dorsal rhizotomy as a treatment for parkinsonian rigidity, this paper will examine the manner in which clinicians and scientists justified the procedure. Coccia, R., C. Foppoli, et al. (2001). "Interaction of enkephalin derivatives with reactive oxygen species." Biochim Biophys Acta 1525(1-2): 43-9. The oxidation of opioid peptides by tyrosinase in the presence of an excess of a thiol gives rise to cysteinyldopa derivatives. The major products arising from the reaction between Leu-enkephalin and cysteine are represented by 5-S-cysteinyldopaenkephalin (5-CDenk) and 2-S-cysteinyldopaenkephalin (2-CDenk). The interaction of 5-CDenk and 2-CDenk with reactive oxygen species (ROS) has been studied. These compounds are able to scavenge superoxide anion, hydroxyl and peroxyl radicals as well as to reduce the lipid peroxidation rate induced by ABAP. The scavenging activities in all instances are dose-dependent. In some cases CDenks are more active than compounds recognized as strong radical scavengers, such as Trolox and mannitol. As a result of the action of the Fenton system, the CDenks (as well as the Enks) are oxidized into pigmented derivatives. The possible implications of the interaction of CDenks and Enks with ROS on melanization process in Parkinson's disease are discussed. Cole, N. B., D. D. Murphy, et al. (2001). "Lipid droplet binding and oligomerization properties of the Parkinson's disease protein alpha-synuclein." J Biol Chem. alpha-Synuclein is a major component of the fibrillary lesion known as Lewy bodies (LBs) and Lewy neurites (LNs) that are the pathologic hallmarks of Parkinson's disease (PD). In addition, point mutations in the alpha-synuclein gene implicate alpha-synuclein dysfunction in the pathology of inherited forms of PD. alpha-Synuclein is a member of a family of proteins found primarily in the brain and is concentrated within presynaptic terminals. Here, we address the localization and membrane binding characteristics of wild type and PD mutants of alpha synuclein in cultured cells. In cells treated with high concentrations of fatty acids, wild type alpha-synuclein accumulated on phospholipid monolayers surrounding triglyceride-rich lipid droplets, and was able to protect stored triglycerides from hydrolysis. PD mutant synucleins showed variable distributions on lipid droplets and were less effective in regulating triglyceride turnover. Chemical crosslinking demonstrated that synuclein formed small oligomers within cells, primarily dimers and trimers, that preferentially associated with lipid droplets and cell membranes. Our results suggest that the initial phases of synuclein aggregation may occur on the surfaces of membranes, and that pathological conditions that induce crosslinking of synuclein may enhance the propensity for subsequent synuclein aggregation. Conn, K. J., M. D. Ullman, et al. (2001). "Decreased expression of the NADH:ubiquinone oxidoreductase (complex I) subunit 4 in 1-methyl-4-phenylpyridinium -treated human neuroblastoma SH-SY5Y cells." Neurosci Lett 306(3): 145-8. Oxidative stress and mitochondrial dysfunction have been implicated in Parkinson's disease (PD) pathology. NADH:ubiquinone oxidoreductase (complex I) (EC 1.6.99.3) enzyme activity is aberrant in both PD and 1-methyl-4-phenylpyridinium (MPP(+)) models of PD. Reverse transcription polymerase chain reaction of RNA isolated from MPP(+)-treated human neuroblastoma SH-SY5Y cells identified changes in steady-state mRNA levels of the mitochondrial transcript for subunit 4 of complex I (ND4). Expression of ND4 decreased to nearly 50% after 72 h of MPP(+) (1 mM) exposure. The expression of other mitochondrial transcripts did not change significantly under the same conditions. Pre-incubation of cells with the free-radical spin-trap, N-tert-butyl-alpha-(2-sulfophenyl)-nitrone prior to MPP(+) exposure, prevented decreases in cell viability and ND4 expression. This suggests that functional defects in complex I enzyme activity in PD and MPP(+) toxicity may result from changes in steady-state mRNA levels and that free radicals may be important in this process. Connor, B. (2001). "Adenoviral vector-mediated delivery of glial cell line-derived neurotrophic factor provides neuroprotection in the aged parkinsonian rat." Clin Exp Pharmacol Physiol 28(11): 896-900. 1. The long-term delivery of neurotrophic factors to specific regions of the central nervous system via gene therapy offers a new strategy for the treatment of neurodegenerative disorders. 2. The neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) is a potent dopaminergic (DA) trophic factor that ameliorates the behavioural and histological consequences of lesioning DA neurons in rodent and primate models of Parkinson's disease. 3. Glial cell line-derived neurotrophic factor gene therapy may have a potential use in the clinical treatment of Parkinson's disease. 4. We examined whether injection of an adenoviral vector encoding human GDNF preproprotein (Ad GDNF) could protect the rat nigrostriatal DA system from progressive neuronal degeneration. Because Parkinson's disease occurs primarily in the elderly population, we studied the effect of GDNF gene delivery in an aged rat model of Parkinson's disease. 5. In the aged (20 month) Fischer 344 rat, Ad GDNF was injected either near DA cell bodies in the substantia nigra (SN) or at the DA terminals in the striatum. One week following gene delivery, the neurotoxin 6-hydroxydopamine (6-OHDA) was injected unilaterally into the striatum to cause progressive degeneration of the DA neurons. 6. Injection of GDNF vector into either the striatum or the SN provided significant cell protection against 6-OHDA. However, only striatal injection of Ad GDNF protected against the development of behavioural and neurochemical changes that occur in the DA-depleted brain. 7. The results of this study are reviewed here and the behavioural and cellular effects of GDNF gene delivery into striatal versus mesencephalic sites are discussed. Connor, B., D. A. Kozlowski, et al. (2001). "Glial cell line-derived neurotrophic factor (GDNF) gene delivery protects dopaminergic terminals from degeneration." Exp Neurol 169(1): 83-95. Previously, we observed that injection of an adenoviral (Ad) vector expressing glial cell line-derived neurotrophic factor (GDNF) into the striatum, but not the substantia nigra (SN), prior to a partial 6-OHDA lesion protects dopaminergic (DA) neuronal function and prevents the development of behavioral impairment in the aged rat. This suggests that striatal injection of AdGDNF maintains nigrostriatal function either by protecting DA terminals or by stimulating axonal sprouting to the denervated striatum. To distinguish between these possible mechanisms, the present study examines the effect of GDNF gene delivery on molecular markers of DA terminals and neuronal sprouting in the aged (20 month) rat brain. AdGDNF or a control vector coding for beta-galactosidase (AdLacZ) was injected unilaterally into either the striatum or the SN. One week later, rats received a unilateral intrastriatal injection of 6-OHDA on the side of vector injection. Two weeks postlesion, rats injected with AdGDNF into either the striatum or the SN exhibited a reduction in the area of striatal denervation and increased binding of the DA transporter ligand [(125)I]IPCIT in the lesioned striatum compared to control animals. Furthermore, injections of AdGDNF into the striatum, but not the SN, increased levels of tyrosine hydroxylase mRNA in lesioned DA neurons in the SN and prevented the development of amphetamine-induced rotational asymmetry. In contrast, the level of T1 alpha-tubulin mRNA, a marker of neuronal sprouting, was not increased in lesioned DA neurons in the SN following injection of AdGDNF either into the striatum or into the SN. These results suggest that GDNF gene delivery prior to a partial lesion ameliorates damage caused by 6-OHDA in aged rats by inhibiting the degeneration of DA terminals rather than by inducing sprouting of nigrostriatal axons. Connor, B., W. M. van Roon-Mom, et al. (2001). "Stem cells and neurodegenerative diseases." N Z Med J 114(1142): 477-9. Contin, M., R. Riva, et al. (2001). "Pharmacodynamic modeling of oral levodopa in Parkinson's disease." Ann Neurol 50(5): 687-8. Conway, K. A., J. C. Rochet, et al. (2001). "Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct." Science 294(5545): 1346-9. The substantia nigra in Parkinson's disease (PD) is depleted of dopaminergic neurons and contains fibrillar Lewy bodies comprising primarily alpha-synuclein. We screened a library to identify drug-like molecules to probe the relation between neurodegeneration and alpha-synuclein fibrilization. All but one of 15 fibril inhibitors were catecholamines related to dopamine. The inhibitory activity of dopamine depended on its oxidative ligation to alpha-synuclein and was selective for the protofibril-to-fibril conversion, causing accumulation of the alpha-synuclein protofibril. Adduct formation provides an explanation for the dopaminergic selectivity of alpha-synuclein-associated neurotoxicity in PD and has implications for current and future PD therapeutic and diagnostic strategies. Cools, R., R. A. Barker, et al. (2001). "Enhanced or impaired cognitive function in Parkinson's disease as a function of dopaminergic medication and task demands." Cereb Cortex 11(12): 1136-43. We investigated how dopamine (DA) systems contribute to cognitive performance in the domain of learning and attentional flexibility by examining effects of withdrawing DA-ergic medication in patients with Parkinson's disease (PD). Medication remediated impairments in switching between two tasks, thought to depend on circuitry connecting the dorsolateral prefrontal cortex and the posterior parietal cortex to the dorsal caudate nucleus, which is profoundly DA-depleted in PD. By contrast, the same medication impaired probabilistic reversal learning that implicates orbitofrontal cortex- ventral striatal circuitry, which is relatively spared of DA loss in PD. Hence, DA-ergic medication improves or impairs cognitive performance depending on the nature of the task and the basal level of DA function in underlying cortico-striatal circuitry. Cools, R., R. A. Barker, et al. (2001). "Mechanisms of cognitive set flexibility in Parkinson's disease." Brain 124(Pt 12): 2503-12. Previous research on cognitive set shifting in patients with Parkinson's disease has often been confounded by concept formation, rule learning, working memory and/or general slowing of cognitive processes. To circumvent this problem, the present study used the task-set switching procedure in which good performance was independent of rule learning, and in which working memory load was reduced by explicitly cueing the task switches. Our results provide strong evidence for a specific cognitive set shifting deficit in patients with mild Parkinson's disease in a non-learning context, which also cannot be explained by general slowing of cognitive processes. Moreover, the deficit was robust in a small sample of patients at the earliest stages of the disease. Finally, the impairment in task-set switching was only apparent when competing information was present, i.e. when the load on selection mechanisms was increased. Cooper, A. J. and I. M. Stanford (2001). "Dopamine D2 receptor mediated presynaptic inhibition of striatopallidal GABA(A) IPSCs in vitro." Neuropharmacology 41(1): 62-71. The modulation of GABA release within the globus pallidus (GP) by dopamine was studied using whole-cell patch clamp recordings from visually identified neurones. In sagittal slices, single shock electrical stimulation in the striatum evoked GABA(A) inhibitory postsynaptic currents (IPSCs), which were inhibited by dopamine in a dose-dependent manner (0.3-30 microM) with an IC(50) value of 0.7 microM. The inhibition was accompanied by an increase in paired pulse facilitation, indicative of a presynaptic effect. In coronal slices, stimulation within the GP adjacent to the recording site evoked GABA(A) IPSCs which were relatively unaffected by dopamine indicating the lack of modulation of GABA release from terminals of local GP axon collaterals. No consistent changes in holding current, membrane potential, firing rate or the frequency of spontaneous IPSCs was observed.Tetrodotoxin-resistant miniature (m)IPSCs were recorded in chloride-loaded cells. Dopamine (3-30 microM) reduced the frequency of mIPSCs, but was without effect on mIPSC amplitude, confirming a presynaptic effect. The addition of the "D2 like" agonist quinpirole (3 microM), but not the "D1 like" agonist SKF 38393 (10 microM), mimicked these effects. The "D2 like" antagonist sulpiride (10 microM), while having no effect alone, blocked the action of dopamine. In contrast the dopamine D4 selective antagonist L745, 870 (1 microM) or D1 antagonist SCH 23390 (10 microM) were without effect.These results indicate that dopamine acts on presynaptic D2 receptors on striatopallidal terminals to reduce the release of GABA in the GP. Attenuation of this mechanism following the depletion of dopamine may contribute to the changes in GP neuronal activity observed in animal models of Parkinson's disease. Cooper, S. D., H. A. Ismail, et al. (2001). "Case report: successful use of rectally administered levodopa-carbidopa." Can Fam Physician 47: 112-3. Copland, D. A., H. J. Chenery, et al. (2001). "Discourse priming of homophones in individuals with dominant nonthalamic subcortical lesions, cortical lesions and Parkinson's disease." J Clin Exp Neuropsychol 23(4): 538-56. An on-line priming experiment was used to investigate discourse-level processing in four matched groups of subjects: individuals with nonthalamic subcortical lesions (NSL) (n = 10), normal control subjects (n = 10), subjects with Parkinson's disease (PD) (n = 10), and subjects with cortical lesions (n = 10). Subjects listened to paragraphs that ended in lexical ambiguities, and then made speeded lexical decisions on visual letter strings that were: nonwords, matched control words, contextually appropriate associates of the lexical ambiguity, contextually inappropriate associates of the ambiguity, and inferences (representing information which could be drawn from the paragraphs but was not explicitly stated). Targets were presented at an interstimulus interval (ISI) of 0 or 1000 ms. NSL and PD subjects demonstrated priming for appropriate and inappropriate associates at the short ISI, similar to control subjects and cortical lesion subjects, but were unable to demonstrate selective priming of the appropriate associate and inference words at the long ISI. These results imply intact automatic lexical processing and a breakdown in discourse-based meaning selection and inference development via attentional/strategic mechanisms. Cordivari, C., V. P. Misra, et al. (2001). "Treatment of dystonic clenched fist with botulinum toxin." Mov Disord 16(5): 907-13. Fourteen patients with "dystonic clenched fist" (three with Corticobasal Ganglionic Degeneration, seven with Parkinson's disease, and four with Dystonic-Complex Regional Pain Syndrome) were treated with botulinum toxin A (BTXA, Dysport(R)). The muscles involved were identified by the hand posture and EMG activity recorded at rest and during active and passive flexion/extension movements of the finger and wrist. EMG was useful in distinguishing between muscle contraction and underlying contractures and to determine the dosage of BTX. All patients had some degree of flexion at the proximal metacarpophalangeal joints and required injections into the lumbricals. The response in patients depended on the severity of the deformity and the degree of contracture. All patients had significant benefit to pain, with accompanying muscle relaxation, and palmar infection, when present, was eradicated. Four patients with Parkinson's disease and one patient with Dystonia-Complex Regional Pain Syndrome obtained functional benefit. Corti, O. and A. Brice (2001). "Parkin and Parkinson's: more than homonymy?" Ann Neurol 50(3): 283-5. Costa, G., J. A. Abin-Carriquiry, et al. (2001). "Nicotine prevents striatal dopamine loss produced by 6-hydroxydopamine lesion in the substantia nigra." Brain Res 888(2): 336-342. While the work of several groups has shown the neuroprotective effects of nicotine in vitro, evidences for the same effects in vivo are controversial, mainly regarding neuroprotection in experimental models of Parkinson's disease. In this context, we investigated the capability of various systemic administration schedules of nicotine to prevent the loss of striatal dopamine levels produced by partial or extensive 6-hydroxydopamine (6-OHDA) lesion of rat substantia nigra (SN). Eight days after 6- and 10-microg injections of 6-OHDA in the SN there was a significant decrease of dopamine concentrations in the corpus striatum (CS) and a concomitant increase in dopamine turnover. While 10 microg 6-OHDA produced an almost complete depletion of dopamine in the SN, 6 microg decreased dopamine levels by 50%. Subcutaneous nicotine (1 mg/kg) administered 4 h before and 20, 44 and 68 h after 6 microg 6-OHDA, prevented significantly the striatal dopamine loss. Administered only 18 or 4 h before or only 20, 44 and 68 h after, nicotine failed to counteract the loss of dopamine or the increase in dopamine turnover observed in the CS. Nicotine also failed to prevent significantly the decrease of striatal dopamine levels produced by the 10-microg 6-OHDA intranigral dose. Chlorisondamine, a long-lasting nicotinic acetylcholine receptor antagonist, reverted significantly the nicotinic protective effects on dopamine concentrations. These results are showing that putative neuroprotective effects of nicotine in vivo depend on an acute intermittent administration schedule and on the extent of the brain lesion. Costantini, L. C., D. Cole, et al. (2001). "Immunophilin ligands can prevent progressive dopaminergic degeneration in animal models of Parkinson's disease." Eur J Neurosci 13(6): 1085-92. Slowing or halting the progressive dopaminergic (DA) degeneration in Parkinson's disease (PD) would delay the onset and development of motor symptoms, prolong the efficacy of pharmacotherapies and decrease drug-induced side-effects. We tested the potential of two orally administered novel immunophilin ligands to protect against DA degeneration in two animal models of PD. First, in an MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model, we compared an immunophilin ligand (V-10,367) documented to bind the immunophilin FKBP12 with V-13,661, which does not bind FKBP12. Both molecules could prevent the loss of striatal DA innervation in a dose-dependent fashion during 10 days of oral administration. Second, to determine whether an immunophilin ligand can protect against progressive and slow DA degeneration typical of PD, an intrastriatal 6-hydroxydopamine-infusion rat model was utilized. Oral treatment with the FKBP12-binding immunophilin ligand began on the day of lesion and continued for 21 days. At this time point, post mortem analyses revealed that the treatment had prevented the progressive loss of DA innervation within the striatum and loss of DA neurons within the substantia nigra, related to functional outcome as measured by rotational behaviour. Notably, DA fibres extending into the area of striatal DA denervation were observed only in rats treated with the immunophilin ligand, indicating neuroprotection or sprouting of spared DA fibres. This is the first demonstration that immunophilin ligands can prevent a slow and progressive DA axonal degeneration and neuronal death in vivo. The effects of orally administered structurally related immunophilin ligands in acute and progressive models of DA degeneration are consistent with the idea that these compounds may have therapeutic value in PD. Counihan, T. J., L. A. Shinobu, et al. (2001). "Outcomes following staged bilateral pallidotomy in advanced Parkinson's disease." Neurology 56(6): 799-802. The authors assessed clinical outcome for up to one year after staged bilateral pallidotomy in 14 patients with advanced PD. One year after surgery, dyskinesias were virtually abolished and there were significant reductions in "off" time (67%) and activities of daily living "off" scores (24%), as well as nonsignificant reduction in "off" motor score (39%); "on" scores were unchanged. One patient developed a visual field deficit; two had transient confusion. Staged bilateral pallidotomy improves motor function in selected patients with advanced PD. Couzin, J. (2001). "Parkinson's disease. Dopamine may sustain toxic protein." Science 294(5545): 1257-8. Cowan, W. M. and E. R. Kandel (2001). "Prospects for neurology and psychiatry." Jama 285(5): 594-600. Neurological and psychiatric illnesses are among the most common and most serious health problems in developed societies. The most promising advances in neurological and psychiatric diseases will require advances in neuroscience for their elucidation, prevention, and treatment. Technical advances have improved methods for identifying brain regions involved during various types of cognitive activity, for tracing connections between parts of the brain, for visualizing individual neurons in living brain preparations, for recording the activities of neurons, and for studying the activity of single-ion channels and the receptors for various neurotransmitters. The most significant advances in the past 20 years have come from the application to the nervous system of molecular genetics and molecular cell biology. Discovery of the monogenic disorder responsible for Huntington disease and understanding its pathogenesis can serve as a paradigm for unraveling the much more complex, polygenic disorders responsible for such psychiatric diseases as schizophrenia, manic depressive illness, and borderline personality disorder. Thus, a new degree of cooperation between neurology and psychiatry is likely to result, especially for the treatment of patients with illnesses such as autism, mental retardation, cognitive disorders associated with Alzheimer and Parkinson disease that overlap between the 2 disciplines. Cowley, G. (2001). "The new animal farm." Newsweek 137(14): 44-5. Cranston, R. E. (2001). "Competency to consent to medical treatment in cognitively impaired patients with Parkinson's disease." Neurology 56(12): 1782-3. Craven, R. (2001). "Disappointment for Parkinson's disease patients." Trends Pharmacol Sci 22(5): 221. Creighton, C. J., C. H. Reynolds, et al. (2001). "Conformational analysis of the eight-membered ring of the oxidized cysteinyl-cysteine unit implicated in nicotinic acetylcholine receptor ligand recognition." J Am Chem Soc 123(50): 12664-9. Nicotinic acetylcholine receptors (nAChRs) are membrane-bound, pentameric ligand-gated ion channels associated with a variety of human disorders such as Alzheimer's disease, Parkinson's disease, schizophrenia, and pain. Most known nAChRs contain an unusual eight-membered disulfide-containing cysteinyl-cysteine ring, ox-[Cys-Cys], as does the soluble acetylcholine binding protein (AChBP) found in the snail Lymnaea stagnalis. The cysteinyl-cysteine ring is located in a region implicated in ligand binding, and conformational changes involving this ring may be important for modulation of nAChR function. We have studied the preferred conformations of Ac-ox-[Cys-Cys]-NH(2) by NMR in water and computationally by Monte Carlo simulations using the OPLS-AA force field and GB/SA water model. ox-[Cys-Cys] adopts four distinct low-energy conformers at slightly above 0 degrees C in water. Two populations are dependent on the peptide omega(2) dihedral angle, with the trans amide favored over the cis amide by a ratio of ca. 60:40. Two ox-[Cys-Cys] conformers with a cis amide bond (C+ and C-) differ from each other primarily by variation of the chi(3) dihedral angle, which defines the orientation of the helicity about the S-S bond (+/- 90 degrees ). Two trans amide conformers have the same S-S helicity (chi(3) approximately -90 degrees ), but are distinguished by a backbone rotation about phi(2) and psi(1) (T- and T'-). The ratio of T-/T'-/C+/C- is 47:15:29:9. The orientation of the pendant moieties from the eight-membered ring is more compact for the major trans conformer (T-) than for the extended conformations adopted by T'-, C+, and C-. These conformational preferences are also observed in tetrapeptide and undecapeptide fragments of the human alpha(7) subtype of the nAChR that contains the ox-[Cys-Cys] unit. Conformer T- is nearly identical to the conformation seen in the X-ray structure of ox-[Cys(187)-Cys(188)] found in the unliganded AChBP, and is a Type VIII beta-turn. Crocker, S. J., N. Wigle, et al. (2001). "NAIP protects the nigrostriatal dopamine pathway in an intrastriatal 6-OHDA rat model of Parkinson's disease." Eur J Neurosci 14(2): 391-400. Parkinson's disease (PD) is a progressive neurodegenerative disorder of the basal ganglia, associated with the inappropriate death of dopaminergic neurons of the substantia nigra pars compacta (SNc). Here, we show that adenovirally mediated expression of neuronal apoptosis inhibitor protein (NAIP) ameliorates the loss of nigrostriatal function following intrastriatal 6-OHDA administration by attenuating the death of dopamine neurons and dopaminergic fibres in the striatum. In addition, we also addressed the role of the cysteine protease caspase-3 activity in this adult 6-OHDA model, because a role for caspases has been implicated in the loss of dopamine neurons in PD, and because NAIP is also a reputed inhibitor of caspase-3. Although caspase-3-like proteolysis was induced in the SNc dopamine neurons of juvenile rats lesioned with 6-OHDA and in adult rats following axotomy of the medial forebrain bundle, caspase-3 is not induced in the dopamine neurons of adult 6-OHDA-lesioned animals. Taken together, these results suggest that therapeutic strategies based on NAIP may have potential value for the treatment of PD. Crucian, G. P., L. Huang, et al. (2001). "Emotional conversations in Parkinson's disease." Neurology 56(2): 159-65. OBJECTIVE: To learn how PD influences verbal description of emotional events. BACKGROUND: Individuals with PD exhibit emotional processing deficits. Emotional experience likely involves several dimensions (e.g., valence, arousal, motor activation) subserved by a distributed modular network involving cortical, limbic, basal ganglia, diencephalic, and mesencephalic regions. Although the neurodegeneration in PD likely affects components in this network, little is known about how PD influences emotional processing. Because PD is associated with activation deficits, one could predict that the discourse of emotional experiences involving high activation would be reduced in patients with PD compared to control subjects. Alternatively, because patients with PD exhibit paradoxical sensitivity to externally evoked motor activation (kinesia paradoxica), it is possible that emotional stimuli may facilitate verbal emotional expression more so in patients with PD than in control subjects. METHODS: The authors measured verbal descriptions of personal emotional experiences in subjects with PD and normal controls. RESULTS: Compared with control subjects, individuals with PD showed a relative increase in the number of words spoken and in discourse duration when talking about emotional experiences that are usually associated with high levels of arousal and motor activation. Although the authors did not measure arousal or activation, prior research has shown that, when asked to recall an emotional experience, people will often re-experience the emotion previously experienced during that episode. CONCLUSIONS: Recalling emotional episodes induces verbal kinesia paradoxica in patients with PD. Although recall of these emotional episodes may have been associated with increased arousal and activation, the mechanism underlying emotional verbal kinesia paradoxica is unclear. Cubo, E., J. M. Gracies, et al. (2001). "Early morning off-medication dyskinesias, dystonia, and choreic subtypes." Arch Neurol 58(9): 1379-82. BACKGROUND: Abnormal involuntary movements (dyskinesias) are common in patients with Parkinson disease (PD) as a consequence of the disease and dopaminergic replacement therapy. Early morning off-medication choreic dyskinesias have been recently reported after fetal dopaminergic cell transplantations in patients with advanced PD. OBJECTIVE: To determine the frequency and severity of the early morning off-medication dyskinesias in consecutive patients with advanced PD and an insufficient response to medical management before they undergo neurosurgery. METHODS: Consecutive patients with advanced idiopathic PD were examined and videotaped before undergoing neurosurgery that included pallidotomy, fetal transplantation, or deep brain stimulation. The examination took place in the morning in the practically defined off state, at least 12 hours after the last dose of dopaminergic drugs. Parkinson disease was characterized using the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr stage. Dyskinesias were rated with the Abnormal Involuntary Movements Scale and the Rush Dyskinesia Rating Scale. Patients' characteristics and medications were compared using the Wilcoxon rank sum and the Fisher exact tests. RESULTS: Of 68 consecutive patients (44 [65%] men and 24 [35%] women), 11 (16%) had early morning off-medication dyskinesia, with a 95% upper confidence limit of 24%. Focal dystonia was the most common off-medication dyskinesia, and occurred in 10 patients (15%), with a 95% upper confidence limit of 22%; and off-choreic dyskinesia occurred in 1 patient (1.5%), with a 95% upper confidence limit of 4%. There was no difference in PD medications between the patients with and those without dyskinesias. CONCLUSIONS: The most common form of off-medication dyskinesia seen in patients with advanced PD is dystonia. Early morning off-medication choreic dyskinesias are rare but do occur in patients with advanced PD before surgical intervention. The presence and type of off-medication dyskinesias should be monitored in clinical and surgical studies in patients with PD as part of the safety and evaluation of clinical benefits. Cullinane, C. A., R. Jarrahy, et al. (2001). "Asymptomatic renal neoplasms in the rectal cancer patient." Am Surg 67(12): 1162-4. Although cancers of the rectum and kidney are common malignancies the incidence of coexistent rectal and renal primary tumors is unclear. Our objective was to determine the true incidence of synchronous neoplasms of the rectum and kidney. The computed tumor registry database at the City of Hope National Medical Center was queried for patients with synchronous rectal cancer and renal neoplasms presenting between August 1990 and August 2000. During the 10-year period there were 182 patients presenting for treatment of rectal carcinoma. Of these seven (3.8%) were found to have an asymptomatic renal neoplasm. Four patients underwent synchronous resection. Three patients underwent staged renal and rectal resections. The pathology of the renal lesions included renal cell carcinoma in six and an oncocytoma in one patient. Rectal lesions were all adenocarcinomas and all were within 10 cm of the dentate line. Three patients required abdominoperineal resections and four were treated with low anterior resections. Two patients presented with hepatic metastasis at the time of diagnosis. Five patients remain free of disease. Two patients died of persistent and recurrent disease 6 months and 40 months after operation. With the exception of one patient who required prolonged intubation because of severe Parkinson's disease there were no major complications after simultaneous resection of both renal and rectal disease. Simultaneous asymptomatic renal neoplasms may be found in up to 3.8 per cent of patients with rectal cancer. Synchronous lesions may be treated simultaneously without significant morbidity. Cummings, C. J., Y. Sun, et al. (2001). "Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice." Hum Mol Genet 10(14): 1511-8. Many neurodegenerative diseases are caused by gain-of-function mechanisms in which the disease-causing protein is altered, becomes toxic to the cell, and aggregates. Among these 'proteinopathies' are Alzheimer's and Parkinson's disease, prion disorders and polyglutamine diseases. Members of this latter group, also known as triplet repeat diseases, are caused by the expansion of unstable CAG repeats coding for glutamine within the respective proteins. Spinocerebellar ataxia type 1 (SCA1) is one such disease, characterized by loss of motor coordination due to the degeneration of cerebellar Purkinje cells and brain stem neurons. In SCA1 and several other polyglutamine diseases, the expanded protein aggregates into nuclear inclusions (NIs). Because these NIs accumulate molecular chaperones, ubiquitin and proteasomal subunits--all components of the cellular protein re-folding and degradation machinery--we hypothesized that protein misfolding and impaired protein clearance might underlie the pathogenesis of polyglutamine diseases. Over-expressing specific chaperones reduces protein aggregation in transfected cells and suppresses neurodegeneration in invertebrate animal models of polyglutamine disorders. To determine whether enhancing chaperone activity could mitigate the phenotype in a mammalian model, we crossbred SCA1 mice with mice over-expressing a molecular chaperone (inducible HSP70 or iHSP70). We found that high levels of HSP70 did indeed afford protection against neurodegeneration. Cunningham, D. A., C. Herring, et al. (2001). "Analysis of patients treated with living pig tissue for evidence of infection by porcine endogenous retroviruses." Trends Cardiovasc Med 11(5): 190-6. The use of pigs as a source of cells and organs for transplantation has the potential to reduce the current chronic shortage of organs for the treatment of many end-stage diseases. The risk of transmission of infectious agents across the species barrier (zoonoses) has to be assessed. Many such agents can be eliminated from the pig herd. However, porcine endogenous retroviruses, which are carried within the pig genome, are not easily eliminated. They can infect primary and immortalized human cells in vitro, but to date no evidence for in vivo infection has been found in retrospective studies of humans exposed to viable porcine cells. Small-scale clinical trials using porcine cells for the treatment of Parkinson's and Huntington's disease are currently in progress. The prospective monitoring of these patients in conjunction with further research into the biology of this virus will help address safety issues. Cunnington, R., G. F. Egan, et al. (2001). "Motor imagery in Parkinson's disease: A PET study." Mov Disord 16(5): 849-57. We used positron emission tomography (PET) with (15)O-labelled water to record patterns of cerebral activation in six patients with Parkinson's disease (PD), studied when clinically "off" and after turning "on" as a result of dopaminergic stimulation. They were asked to imagine a finger opposition movement performed with their right hand, externally paced at a rate of 1 Hz. Trials alternating between motor imagery and rest were measured. A pilot study of three age-matched controls was also performed. We chose the task as a robust method of activating the supplementary motor area (SMA), defects of which have been reported in PD. The PD patients showed normal degrees of activation of the SMA (proper) when both "off" and "on." Significant activation with imagining movement also occurred in the ipsilateral inferior parietal cortex (both "off" and when "on") and ipsilateral premotor cortex (when "off" only). The patients showed significantly greater activation of the rostral anterior cingulate and significantly less activation of the left lingual gyrus and precuneus when performing the task "on" compared with their performance when "off." PD patients when imagining movement and "off" showed less activation of several sites including the right dorsolateral prefrontal cortex (DLPFC) when compared to the controls performing the same task. No significant differences from controls were present when the patients imagined when "on." Our results are consistent with other studies showing deficits of pre-SMA function in PD with preserved function of the SMA proper. In addition to the areas of reduced activation (anterior cingulate, DLPFC), there were also sites of activation (ipsilateral premotor and inferior parietal cortex) previously reported as locations of compensatory overactivity for PD patients performing similar tasks. Both failure of activation and compensatory changes are likely to contribute to the motor deficit in PD. Cunnington, R., W. Lalouschek, et al. (2001). "A medial to lateral shift in pre-movement cortical activity in hemi-Parkinson's disease." Clin Neurophysiol 112(4): 608-18. OBJECTIVE: Recent evidence suggests that cortical activity associated with voluntary movement is relatively shifted from medial to lateral premotor areas in Parkinson's disease. This shift occurs bilaterally even for unilateral responses. It is not clear whether the shift in processing reflects an overall change in movement strategy, thereby involving alternate cortical areas, or reflects a compensatory change whereby, given the appropriate conditions, less impaired cortical areas are able to provide a similar function in compensation for those areas which are more impaired. This issue was examined in patients with hemi-Parkinson's disease, in whom basal ganglia impairment is most pronounced in one hemisphere. METHODS: Fourteen patients with hemi-Parkinson's disease and 15 age-matched control subjects performed a Go/NoGo finger movement task and the contingent negative variation (CNV) was recorded from 21 scalp positions. RESULTS AND CONCLUSIONS: Maximal CNV amplitudes were found over central medial regions for control subjects, but were shifted more frontally for Parkinson's disease patients, reduced in amplitude over the midline and lateralized towards the side ipsilateral to the greatest basal ganglia impairment. This shift in cortical activity from medial to lateral areas in Parkinson's disease patients appears to reflect a compensatory mechanism operating predominantly on the side of greatest basal ganglia impairment. Currie, L. J., M. B. Harrison, et al. (2001). "Maternal age is not a risk factor for Parkinson's disease." J Neurol Neurosurg Psychiatry 71(1): 130-1. Da Cunha, C., M. S. Gevaerd, et al. (2001). "Memory disruption in rats with nigral lesions induced by MPTP: a model for early Parkinson's disease amnesia." Behav Brain Res 124(1): 9-18. Intra-nigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) caused a lesion in the substantia nigra, compact part (SNc) and a specific loss of dopamine and its metabolites in the striatum of rats. The animals were then tested in the two-way active avoidance task. MPTP-treated animals presented lower learning scores in the training and test sessions, an effect that was not caused by motor impairment or by a decreased sensitivity to footshock since their reaction time to the footshock (unconditioned stimulus - UCS) was not reduced. These lower scores were also not attributable to lower acoustic sensitivity or to a slowing in the association of the sound cue (conditioned stimulus - CS) with the UCS since the reaction time to the CS in the active avoidance response did not differ between MPTP-treated and control groups. Therefore, these results are more properly attributable to an impairment of the memory acquisition and retention processes. In addition, this study is presented as a model of early Parkinson's Disease amnesia and is discussed in terms of the importance of the nigrostriatal pathway to memory acquisition and storage processes. Dabbeni-Sala, F., S. Di Santo, et al. (2001). "Melatonin protects against 6-OHDA-induced neurotoxicity in rats: a role for mitochondrial complex I activity." Faseb J 15(1): 164-170. Unilateral injection into the right substantia nigra of the catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) produces extensive loss of dopaminergic cells ('hemi-parkinsonian rat'). The pineal hormone melatonin, which is a potent antioxidant against different reactive oxygen species and has been reported to be neuroprotective in vivo and in vitro, was evaluated for potential anti-Parkinson effects in this model. Imbalance in dopaminergic innervation between the striata produced by intranigral administration of 6-OHDA results in a postural asymmetry causing rotation away from the nonlesioned side. Melatonin given systemically prevented apomorphine-induced circling behavior in 6-OHDA-lesioned rats. Reduced activity of mitochondrial oxidative phosphorylation enzymes has been suggested in some neurodegenerative diseases; in particular, selective decrease in complex I activity is observed in the substantia nigra of Parkinson's disease patients. Analysis of mitochondrial oxidative phosphorylation enzyme activities in nigral tissue from 6-OHDA-lesioned rats by a novel BN-PAGE histochemical procedure revealed a clear loss of complex I activity, which was protected against in melatonin-treated animals. A good correlation between behavioral parameters and enzymatic (complex I) analysis was observed independent of melatonin administration. A deficit in mitochondrial complex I could conceivably contribute to cell death in parkinsonism via free radical mechanisms, both directly via reactive oxygen species production and by decreased ATP synthesis and energy failure. Melatonin may have potential utility in the treatment of neurodegenerative disorders where oxidative stress is a participant. Dagher, A. (2001). "Functional imaging in Parkinson's disease." Semin Neurol 21(1): 23-32. This article reviews the applications of functional neuroimaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) to the diagnosis and treatment of Parkinson's disease (PD). PET measurements with [18F]deoxyglucose to measure glucose metabolism or with various markers of the pre- and postsynaptic dopamine systems may distinguish idiopathic PD from other conditions presenting with an akinetic-rigid state. Moreover, PET has been used to gain new insights into mechanisms of cell death and the role of heredity in Parkinson's disease. Finally, we discuss the use of functional neuroimaging to study the role of the basal ganglia in movement and cognition in PD. Dagher, A., A. M. Owen, et al. (2001). "The role of the striatum and hippocampus in planning: a PET activation study in Parkinson's disease." Brain 124(Pt 5): 1020-32. Previous work has identified the prefrontal cortex (PFC) and striatum as participating in the planning and selection of movements. We compared the brain activation patterns during planning in Parkinson's disease patients and age-matched controls using H(2)(15)O-PET and the Tower of London (TOL) task. In this study, our mildly affected Parkinson's disease group performed as well as the control group but showed a different pattern of neuronal activation. In the two groups, overlapping areas of the PFC were activated but, whereas the right caudate nucleus was activated in the control group, this was not evident in the Parkinson's disease patients. This suggests that normal normal frontal lobe activation can occur in Parkinson's disease despite abnormal processing within the basal ganglia. Moreover, right hippocampus activity was suppressed in the controls and enhanced in the Parkinson's disease patients. This could represent a shift to the declarative memory system in Parkinson's disease during performance of the TOL task, possibly resulting from insufficient working memory capacity within the frontostriatal system. Dal-Pizzol, F., F. Klamt, et al. (2001). "Neonatal iron exposure induces oxidative stress in adult Wistar rat." Brain Res Dev Brain Res 130(1): 109-14. Oxidative stress and excess of iron in the brain has been implicated in a variety of acute and chronic neurological conditions. The neonatal period is critical for the establishment of normal iron content in the adult brain. In the present study, the long-term oxidative effects of iron exposure during this period were assessed by treating Wistar rats orally with 0, 7.5 or 15 mg Fe(+2)/kg of body weight on postnatal days 10-12. Thiobarbituric acid reactive species, protein carbonyl, superoxide dismutase activity were measured at the age of 3 months. It was found that there was an increase in thiobarbituric acid reactive species and protein carbonyl in the substantia nigra of iron treated rats. In contrast, oxidative stress in the striatum was decreased. Superoxide dismutase activity was decreased in the substantia nigra iron treated rats. There were no differences in cerebellum measures among the groups. Our results demonstrated that iron supplementation in a critical neonatal period induced oxidative stress and modulated SOD activity in the adult life in selective brain regions. Damier, P., J. L. Houeto, et al. (2001). "The role of the pallidum in Parkinson's disease gait. Lessons from pallidal stimulation." Adv Neurol 87: 283-8. D'Andrea, M. R., S. Ilyin, et al. (2001). "Abnormal patterns of microtubule-associated protein-2 (MAP-2) immunolabeling in neuronal nuclei and Lewy bodies in Parkinson's disease substantia nigra brain tissues." Neurosci Lett 306(3): 137-40. Parkinson's disease (PD) is a neurodegenerative disorder associated with the appearance of cytoplasmic Lewy bodies (LBs) in dopaminergic neurons of the substantia nigra and the progressive loss of these neurons. Cytoskeleton alterations and associated impairments of neuronal transport may contribute to neuronal death. Microtubule-associated protein-2 (MAP-2), a cytoskeleton protein is localized primarily in neuronal dendrites and is known to stabilize microtubule assembly and mediate their interactions with other neuronal cell components. To determine if alterations in MAP-2 morphology are present in PD neurons, we used single and double immunohistochemical and immunofluorescent techniques to characterize MAP-2 in PD neuronal tissues. We report abnormal MAP-2 immunolabeling in some neurons of the substantia nigra of PD brain tissues, which were not observed in the normal, age-matched, control brain tissues. Furthermore, MAP-2 was co-localized with alpha-synuclein and ubiquitin in cytoplasmic LBs of neurons. Surprisingly, MAP-2 was also found to form fibrous aggregates and crystal-like structures within neuronal nuclei. These PD-associated alterations in MAP-2 morphology and distribution suggest that impaired neuronal transport may contribute to the progression of neuronal loss in the brains of PD patients. Danielsen, E. H., D. Smith, et al. (2001). "Acute neuroleptic stimulates DOPA decarboxylase in porcine brain in vivo." Synapse 41(2): 172-5. The activity of DOPA decarboxylase measured in homogenates from rat striatum, or calculated from the rate of tracer decarboxylation measured ex vivo, is stimulated following acute treatment with antagonists of dopamine D2-like receptors. We used compartmental kinetics to test the hypothesis that utilization of the DOPA decarboxylase substrate [(18)F]fluorodopa is potentiated in living striatum following acute treatment with a typical neuroleptic. The kinetics of the tracer uptake were determined in eight anesthetized female pigs (40 kg) and in three animals receiving an infusion of haloperidol (75 microg kg(-1) h(-1)) for 1 h prior to tracer administration and throughout the 2-h positron emission recording. The relative activity of DOPA decarboxylase in striatum was increased threefold by the treatment. This potentiation of DOPA decarboxylation after pharmacological blockade of dopamine D2-like receptors may be used to optimize the utilization of exogenous DOPA in the treatment of Parkinson's disease. Danoff, S. K., M. E. Grasso, et al. (2001). "Pleuropulmonary disease due to pergolide use for restless legs syndrome." Chest 120(1): 313-6. Pergolide is an ergot-derived dopamine agonist used in Parkinson's disease and, increasingly, in restless legs syndrome. We report a patient with a 2.5-year history of weight loss, pleuropulmonary fibrosis, and exudative pleural effusion that developed insidiously while taking this medication. The extensive and invasive workup that preceded the diagnosis highlights the difficulty in attributing such a process to a drug reaction. This is the second report of such a reaction to pergolide, which is one of the increasing number of ergot-derived compounds in common clinical use. Danysz, W. (2001). "Neurotoxicity as a mechanism for neurodegenerative disorders: basic and clinical aspects." Expert Opin Investig Drugs 10(5): 985-9. This three day meeting focused on chronic neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and amylotrophic lateral sclerosis (ALS). It attracted 69 participants from 10 countries with dominance of Chile and USA. Neurodegeneration and its prevention increasingly gain in importance as the number of people affected increases year-by-year. The meeting addressed various basic aspects having pragmatic implications such as: oxidative stress, inflammatory reaction, glial activation, role of glutamatergic system and apoptosis using a plethora of in vitro and in vivo methods. Date, I., T. Shingo, et al. (2001). "Grafting of encapsulated genetically modified cells secreting GDNF into the striatum of parkinsonian model rats." Cell Transplant 10(4-5): 397-401. In order to deliver glial cell line-derived neurotrophic factor (GDNF) into the brain, we have established a cell line that produces GDNF in a continuous fashion by genetic engineering. These cells were encapsulated and grafted into parkinsonian model rats that had received unilateral intrastriatal injection of 6-hydroxydopamine 2 weeks earlier. Neurochemical analysis showed that GDNF has been produced from the capsule for 6 months after grafting and histological analysis revealed good survival of GDNF-producing cells in the capsule 6 months after grafting. The density of nigrostriatal dopaminergic fibers in the striatum as well as the number of dopaminergic cell bodies in the substantia nigra recovered significantly after GDNF-producing cell grafting. These results suggest the possible application of GDNF-producing cell grafting for the treatment of Parkinson's disease. Datla, K. P., S. B. Blunt, et al. (2001). "Chronic L-DOPA administration is not toxic to the remaining dopaminergic nigrostriatal neurons, but instead may promote their functional recovery, in rats with partial 6-OHDA or FeCl(3) nigrostriatal lesions." Mov Disord 16(3): 424-34. In this study, we have examined the effects of chronic L-3,4-dihydroxyphenylalanine (L-DOPA) administration on the remaining dopaminergic neurons in rats with 6-hydroxydopamine (6-OHDA) or buffered FeCl(3) partial lesions to the nigrostriatal tract. L-DOPA administration increased the turnover of dopamine in the striatum. L-DOPA administration for 1 week produced an increase in the level of striatal RTI-121 binding, a specific marker for dopamine uptake sites on the dopaminergic nerve terminals in the striatum. However, longer periods of L-DOPA treatment decreased the level of RTI-121 binding in the striatum. In the partial 6-OHDA lesion model, L-DOPA treatment had a time-dependent effect on the number of neurons demonstrating a dopaminergic phenotype i.e., neurons that are tyrosine hyrdoxylase (TH)-immunopositive, on the lesioned side of the brain. In the first few weeks of treatment, L-DOPA decreased the number of TH-positive neurons but with long-term treatment, i.e., 24 weeks, L-DOPA increased the number of neurons demonstrating a dopaminergic phenotype. Even in the buffered FeCl(3) infusion model, where the levels of iron were increased, L-DOPA treatment did not have any detrimental effects on the number of TH-positive neurons on the lesioned side of the brain. Consequently, chronic L-DOPA treatment does not have any detrimental effects to the remaining dopaminergic neurons in rats with partial lesions to the nigrostriatal tract; indeed in the 6-OHDA lesion model, long-term L-DOPA may increase the number of neurons, demonstrating a dopaminergic phenotype. Datla, K. P., M. Christidou, et al. (2001). "Tissue distribution and neuroprotective effects of citrus flavonoid tangeretin in a rat model of Parkinson's disease." Neuroreport 12(17): 3871-5. Neuroprotective effects of a natural antioxidant tangeretin, a citrus flavonoid, were elucidated in the 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson's disease (PD), after bioavailability studies. Following the chronic oral administration (10 mg/kg/day for 28 days), significant levels of tangeretin were detected in the hypothalamus, striatum and hippocampus (3.88, 2.36 and 2.00 ng/mg, respectively). The levels in the liver and plasma were 0.59 ng/mg and 0.11 ng/ml respectively. Unilateral infusion of the dopaminergic neurotoxin, 6-hydroxydopamine (6-OHDA; 8 microg), onto medial forebrain bundle significantly reduced the number of tyrosine hydroxylase positive (TH+) cells in the substantia nigra and decreased striatal dopamine content in the vehicle treated rats. Sub-chronic treatment of the rats with high doses of tangeretin (20 mg/kg/day for 4 days; p.o.) before 6-OHDA lesioning markedly reduced the loss of both TH+ cells and striatal dopamine content. These studies, for the first time, give evidence that tangeretin crosses the blood-brain barrier. The significant protection of striato-nigral integrity and functionality by tangeretin suggests its potential use as a neuroprotective agent. Davey, P., N. Rajan, et al. (2001). "Cost-effectiveness of pergolide compared to bromocriptine in the treatment of Parkinson's disease: a decision-analytic model." Value Health 4(4): 308-15. OBJECTIVE: To develop a decision-analytic model to assess the cost-effectiveness of pergolide versus bromocriptine in the treatment of Parkinson's disease (PD). METHODS: A Markov decision-analytic model is used to examine cost-effectiveness. The model ran for 20 cycles of 6 months' duration, and the patients progress through six stages: Hoehn-Yahr stages 1-5 and death. The transitional probabilities for each stage are derived from a 12-year longitudinal study of patients with PD. The costs in the model are derived from an expert panel containing six Australian neurologists. A review of the randomized controlled trials comparing the efficacy and safety of pergolide versus bromocriptine was undertaken. Five studies were identified, with four showing that pergolide offers superior efficacy when compared to bromocriptine. The Mizuno et al. (1995) study was the largest of the controlled trials and also measured patient Hoehn-Yahr status before and after treatment. This was identified as the most appropriate source of relative efficacy data for the model. The model examined various scenarios based on alternate durations of superior clinical benefit with pergolide compared to bromocriptine. The main analysis assumed that patients in each arm of the model would have identical Hoehn-Yahr status by the fifth year. Sensitivity analysis was used to determine cost-effectiveness in the case where the therapeutic benefit was of a shorter duration. RESULTS: The Mizuno study indicates that an additional 19.09% of patients improved by at least one stage on pergolide over bromocriptine, with an odds ratio of 2.26 (p < .01). The total health care cost per patient over the 10-year period was $46,323 in the pergolide treatment arm and $47,351 in the bromocriptine treatment arm, an incremental saving of $1028. Patients also spent extra time in Hoehn-Yahr stages 1, 2, and 3. In sensitivity analyses, when the benefit from pergolide expired between 6 months and 5 years after treatment cessation, cost savings ranged from $68 to $2535. CONCLUSION: Pergolide is cost saving and more efficacious than bromocriptine, and is therefore cost-effective. Davidson, C., A. J. Gow, et al. (2001). "Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment." Brain Res Brain Res Rev 36(1): 1-22. Research into methamphetamine-induced neurotoxicity has experienced a resurgence in recent years. This is due to (1) greater understanding of the mechanisms underlying methamphetamine neurotoxicity, (2) its usefulness as a model for Parkinson's disease and (3) an increased abuse of the substance, especially in the American Mid-West and Japan. It is suggested that the commonly used experimental one-day methamphetamine dosing regimen better models the acute overdose pathologies seen in humans, whereas chronic models are needed to accurately model human long-term abuse. Further, we suggest that these two dosing regimens will result in quite different neurochemical, neuropathological and behavioral outcomes. The relative importance of the dopamine transporter and vesicular monoamine transporter knockout is discussed and insights into oxidative mechanisms are described from observations of nNOS knockout and SOD overexpression. This review not only describes the neuropathologies associated with methamphetamine in rodents, non-human primates and human abusers, but also focuses on the more recent literature associated with reactive oxygen and nitrogen species and their contribution to neuronal death via necrosis and/or apoptosis. The effect of methamphetamine on the mitochondrial membrane potential and electron transport chain and subsequent apoptotic cascades are also emphasized. Finally, we describe potential treatments for methamphetamine abusers with reference to the time after withdrawal. We suggest that potential treatments can be divided into three categories; (1) the prevention of neurotoxicity if recidivism occurs, (2) amelioration of apoptotic cascades that may occur even in the withdrawal period and (3) treatment of the atypical depression associated with withdrawal. Davis, K. M. and J. Y. Wu (2001). "Role of glutamatergic and GABAergic systems in alcoholism." J Biomed Sci 8(1): 7-19. The pharmacological effects of ethanol are complex and widespread without a well-defined target. Since glutamatergic and GABAergic innervation are both dense and diffuse and account for more than 80% of the neuronal circuitry in the human brain, alterations in glutamatergic and GABAergic function could affect the function of all neurotransmitter systems. Here, we review recent progress in glutamatergic and GABAergic systems with a special focus on their roles in alcohol dependence and alcohol withdrawal-induced seizures. In particular, NMDA-receptors appear to play a central role in alcohol dependence and alcohol-induced neurological disorders. Hence, NMDA receptor antagonists may have multiple functions in treating alcoholism and other addictions and they may become important therapeutics for numerous disorders including epilepsy, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's chorea, anxiety, neurotoxicity, ischemic stroke, and chronic pain. One of the new family of NMDA receptor antagonists, such as DETC-MESO, which regulate the redox site of NMDA receptors, may prove to be the drug of choice for treating alcoholism as well as many neurological diseases. de Bie, R. M., P. R. Schuurman, et al. (2001). "Outcome of unilateral pallidotomy in advanced Parkinson's disease: cohort study of 32 patients." J Neurol Neurosurg Psychiatry 71(3): 375-82. OBJECTIVES: In a randomised trial to study the efficacy of unilateral pallidotomy in patients with advanced Parkinson's disease, patients having pallidotomy within 1 month after randomisation were compared with patients having pallidotomy 6 months after the primary outcome assessment. Of the 37 patients enrolled 32 had a unilateral pallidotomy. The follow up study of these patients is presented to report (1) clinical outcome; (2) adverse effects; (3) cognitive and behavioural effects; (4) relation between lesion location and outcome; and (5) preoperative patient characteristics predictive for good outcome. METHODS: Outcome measures were the motor section of the unified Parkinson's disease rating scale (UPDRS), levodopa induced dyskinesias, disability, quality of life, and a comprehensive neuropsychological assessment. Multivariate logistic regression was used to identify preoperative patient characteristics independently associated with good outcome. RESULTS: Off phase assessment showed a reduction in parkinsonism from 49 to 36.5 points on the UPDRS 6 months after surgery. Improvements were also demonstrated for activities of daily living and quality of life. In the on phase dyskinesias were reduced. All effects lasted up to 12 months after surgery. Three patients had major permanent adverse effects. Besides worsening of verbal fluency after left sided surgery, systematic cognitive deterioration was not detected. Patients taking less than 1000 levodopa equivalent units (LEU)/day were more likely to improve. CONCLUSIONS: The positive effects of unilateral pallidotomy are stable up to 1 year after surgery. Patients taking less than 1000 LEU per day were most likely to improve. De Broe, S., F. Christopher, et al. (2001). "The role of specialist nurses in multiple sclerosis: a rapid and systematic review." Health Technol Assess 5(17): 1-47. BACKGROUND: Multiple sclerosis (MS) is a disease of the central nervous system. The cause is unknown. There are about 80-160 people with MS per 100,000 population, with twice as many women affected as men. The management of individuals with MS includes treatment of acute relapses and chronic symptoms. The care of MS patients is provided by various healthcare professionals, such as general practitioners (GPs), neurologists, physiotherapists, occupational therapists and nurses. Some MS patients have access to an MS specialist nurse, although this provision varies geographically. OBJECTIVES: The aim of this report is to assess the effectiveness and relative cost-effectiveness of MS specialist nurses in improving care and outcomes for patients with MS. METHODS: A systematic review of the literature, involving a range of databases, was performed. Full details are described in the main report. RESULTS: Only one study was identified that tried to evaluate the benefit of MS specialist nurses. The study concluded that MS patients and their carers found the MS specialist nurse to be helpful, particularly in improving their knowledge of MS, ability to cope, mood and confidence about the future. GPs also reported finding the nurse to be helpful with their MS patients, and 40% of the GPs stated they would purchase the services of an MS specialist nurse if their practices became fundholding. However, there were considerable methodological weaknesses inherent in the study design, and it was unclear whether the results of the study could be extrapolated to other settings or to other MS patient groups. RESULTS - ONGOING RESEARCH: There are two ongoing research studies regarding MS specialist nurses. One of these studies involves the provision of MS nurses to several areas, but also has two control populations to allow evaluation of the health benefits of the nurses to MS patients and their carers. This study will help to fill the evidence gap. RESULTS - COSTS: The costs of providing MS specialist nurses consist of their yearly salary (usually NHS grade G), as well as additional costs for travelling, administration, computer and telephone use, a pension scheme, National Insurance and study leave. The MS Society of Great Britain and Northern Ireland allows a generous total yearly cost to the employer of 40,000 pounds. CONCLUSIONS: The present evidence does not make it possible to comment with any certainty on the value of specialist nurses in MS. The best evidence available to the authors is specialist opinion from neurologists and nurses, and comments from patients with MS; this opinion supports the provision of MS specialist nurses. CONCLUSIONS - RECOMMENDATIONS FOR RESEARCH: Further research is needed before it will be feasible to make firm recommendations on the value of MS specialist nurses relative to other possible uses of funds. de Carle, A. J. and R. Kohn (2001). "Risk factors for falling in a psychogeriatric unit." Int J Geriatr Psychiatry 16(8): 762-7. OBJECTIVE: To identify risk factors associated with falls in a psychogeriatric inpatient population. DESIGN: Retrospective cohort study. SETTING: A psychogeriatric inpatient unit in a Brown University affiliated psychiatric hospital. PARTICIPANTS: A total of 1834 men and women who represented all admissions to the psychogeriatric inpatient unit between January 1992 and December 1995. RESULTS: Over the study period a total of 175 falls were recorded, giving a fall rate of 9.5%. Using a logistic regression model, six variables were found to be independently associated with an increased risk of falling: female gender, electroconvulsive therapy (ECT), mood stabilizers, cardiac arrhythmias, Parkinson's syndrome and dementias. Falls and ECT were associated with longer hospital stay, when adjusted for confounders including ECT. CONCLUSIONS: These findings support previous results and identify ECT as a possible risk factor for falling in a hospital setting. de Goede, C. J., S. H. Keus, et al. (2001). "The effects of physical therapy in Parkinson's disease: a research synthesis." Arch Phys Med Rehabil 82(4): 509-15. OBJECTIVE: To present a critical review and meta-analysis of studies evaluating the effects of physical therapy in patients suffering from Parkinson's disease (PD), in terms of neurologic signs, activities of daily living (ADLs), and walking ability. DATA SOURCES: Articles published from 1966 to May 1999 were compiled by means of MEDLINE, Cochrane register of controlled trials, and CINAHL using combinations of the key words Parkinson's disease, exercise, exercise therapy, physical therapy, and group training. References presented in relevant publications were also examined. Articles written in English, German, or Dutch were included. STUDY SELECTION: Studies had to meet the following selection criteria: (1) patients with PD were included in the intervention study, (2) the effects of physical therapy (PT) were evaluated, (3) the study could be classified as true or quasi-experiment, and (4) the study was published in a journal or book. DATA EXTRACTION: Two reviewers assessed independently the methodologic quality of the data of each included study. One reviewer extracted relevant meta-analysis data. DATA SYNTHESIS: For each outcome measure the estimated effect size and the summary effect size (SES) were calculated, using fixed (ie, Hedges's g) and random effects models. The meta-analysis resulted in a significant homogeneous SES with regard to ADLs (.40; confidence interval [CI] = .17-.64) and stride length (.46; CI = .12-.82). The SES with regard to walking speed showed a significant heterogeneous SES, which remained significant after applying a random effects model (.49; CI = .21-.77). The SES with regard to neurologic signs was not significant (.22; CI = -.08 to .52). The small number of studies included and the shortcomings of the methodologic quality of these studies, however, bias the results of the present study. CONCLUSIONS: The results of the present research synthesis support the hypothesis that Parkinson patients benefit from PT added to their standard medication. de la Fuente-Fernandez, R. and D. B. Calne (2001). "Familial aggregation of Parkinson's disease." N Engl J Med 344(15): 1168. de La Fuente-Fernandez, R., A. S. Lim, et al. (2001). "Apomorphine-induced changes in synaptic dopamine levels: positron emission tomography evidence for presynaptic inhibition." J Cereb Blood Flow Metab 21(10): 1151-9. The authors developed a novel positron emission tomography method to estimate changes in the synaptic level of dopamine ([DA]) induced by direct dopamine agonists (for example, apomorphine) in patients with Parkinson disease. The method is based on the typical asymmetry of the nigrostriatal lesion that often occurs in Parkinson disease. Using the between-side difference (ipsilateral (I) and contralateral (C) putamen to the more affected body side) of the inverse of the putamen [11C]raclopride binding potential (BP), the authors obtained [equation: see text] at baseline (that is, before apomorphine administration) and [equation: see text] after apomorphine administration (assuming the concentration of apomorphine is equal in both putamina). The between-side difference in the estimated synaptic concentration of dopamine (diff[DA]) should remain constant unless apomorphine affects dopamine release differently between the two sides. The authors found that apomorphine given subcutaneously at doses of 0.03 and 0.06 mg/kg induced significant changes in their estimate of diff[DA] (P < 0.05). Such changes were more pronounced when only patients with a stable response to levodopa were considered (P < 0.01). These findings provide in vivo evidence that direct dopamine agonists can inhibit the release of endogenous dopamine. The authors propose that this effect is mainly mediated by the activation of presynaptic D2/D3 dopamine receptors. de la Fuente-Fernandez, R., J. Q. Lu, et al. (2001). "Biochemical variations in the synaptic level of dopamine precede motor fluctuations in Parkinson's disease: PET evidence of increased dopamine turnover." Ann Neurol 49(3): 298-303. Motor fluctuations are a major disabling complication in the treatment of Parkinson's disease. To investigate whether such oscillations in mobility can be attributed to changes in the synaptic levels of dopamine, we studied prospectively patients in the early stages of Parkinson's disease with a follow-up after at least 3 years of levodopa treatment. At baseline, 3 positron emission tomography (PET) scans using [11C]raclopride before and after (1 hour and 4 hours) orally administered levodopa were performed on the same day for each patient. Patients who developed "wearing-off" fluctuations during the follow-up period had a different pattern of levodopa-induced changes in [11C]raclopride binding potential (BP) from that observed in patients who were still stable by the end of the follow-up. Thus, 1 hour post-levodopa the estimated increase in the synaptic level of dopamine was 3 times higher in fluctuators than in stable responders. By contrast, only stable responders maintained increased levels of synaptic dopamine in the PET scan performed after 4 hours. These results indicate that fluctuations in the synaptic concentration of dopamine precede clinically apparent "wearing-off" phenomena. The rapid increase in synaptic levels of dopamine observed in fluctuators suggests that increased dopamine turnover might play a relevant role in levodopa-related motor complications. de la Fuente-Fernandez, R., T. J. Ruth, et al. (2001). "Expectation and dopamine release: mechanism of the placebo effect in Parkinson's disease." Science 293(5532): 1164-6. The power of placebos has long been recognized for improving numerous medical conditions such as Parkinson's disease (PD). Little is known, however, about the mechanism underlying the placebo effect. Using the ability of endogenous dopamine to compete for [11C]raclopride binding as measured by positron emission tomography, we provide in vivo evidence for substantial release of endogenous dopamine in the striatum of PD patients in response to placebo. Our findings indicate that the placebo effect in PD is powerful and is mediated through activation of the damaged nigrostriatal dopamine system. de Luis, D. A., G. Cabezas, et al. (2001). "[Evaluation of a dessert in patients with deglutition changes, one more step in advanced basic feeding]." Nutr Hosp 16(2): 55-8. BACKGROUND: Decrease in the capacity to deglutition solids and liquids is a problem in many people, this problem decreases quality of life. The objective of our work is to evaluate the acceptance degree of a dessert (stewed fruit) (including in the normal diet of the Hospital) in a group of patients with dysphagia. METHODS: Forty seven patients were studied in Hospital Universitario del Rio Hortega (Valladolid) in July of 2000. The main pathology of these patients was; (n = 12) 25.5% acute stroke, (n = 16) 34% aerodigestive tumors (Jarynx carcinoma (n = 5), cavum carcinoma (n = 9), oesophagus carcinoma (n = 2)) and 40.4% (n = 19) chronic neurologic disease (Alzheimer, vascular dementia, and parkinson). All patients took a oral triturated diet, a dessert with apple and pear (Resource fruits Instant). All patients took a portion of the dessert and after that a acceptance questionnaire was filled. RESULTS: Global acceptance of the product was 7.25 +/- 1.5, this punctuation was higher in the tumoral group 8 +/- 1.1 points, 6.86 +/- 1.4 in patients with acute stroke and 6.7 +/- 1.5 in patients with chronic neurologic disease (p < 0.05). Different organoleptic characteristics were analyzed, mean punctuation in texture was 1.79 +/- 0.6, color 2.2 +/- 0.5, smell 2.24 +/- 0.59 and taste 1.95 +/- 0.61, in a scale of 1 (very good) until 5 (very bad), a total of 57.9% patients responded very good (1) or good (2) in texture scale, 71.1% in color scale, 60.5% in smell scale and 63.2% in taste scale. CONCLUSIONS: Acceptance of this product in patients with dysphagia has been elevated, showing useful in these patients with nutrition alterations. De Salles, A. A., W. P. Melega, et al. (2001). "Radiosurgery performed with the aid of a 3-mm collimator in the subthalamic nucleus and substantia nigra of the vervet monkey." J Neurosurg 95(6): 990-7. OBJECT: Radiosurgery for functional neurosurgery performed using a linear accelerator (LINAC) has not been extensively characterized in preclinical studies. In the present study, the properties of a newly designed 3-mm-diameter collimator were evaluated in a dedicated LINAC, which produced lesions in the basal ganglia of vervet monkeys. Lesion formation was determined in vivo in three animals by examining magnetic resonance (MR) images to show the dose-delivery precision of targeting and the geometry and extent of the lesions. Postmortem immunohistochemical studies were conducted to determine the extent of lesion-induced radiobiological effects. METHODS: In three male vervet monkeys, the subthalamic nucleus (STN; one animal) and the pars compacta of the lateral substantia nigra (SN; two animals) were targeted by a Novalis Shaped Beam Surgery System that included a 3-mm collimator and delivered a maximum dose of 150 Gy. Magnetic resonance images obtained 4, 5, and 9 months posttreatment were reviewed, and the animals were killed so that immunohistological characterizations could be made. CONCLUSIONS: The generation of precise radiosurgical lesions by a 3-mm collimator was validated in studies that targeted the basal ganglia of the vervet monkey. The extent of the lesions created in all animals remained restricted in diameter (< 3 mm) throughout the duration of the studies, as assessed by reviewing MR images. Histological studies showed that the lesions were contained within the STN and SN target areas and that there were persistent increases in glial fibrillary acidic protein immunoreactivity. Increases in immunoreactivity for tyrosine hydroxylase, the serotonin transporter, and the GluR1 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate glutamate receptor in penumbral regions of the lesion were suggestive of compensatory neuronal adaptations. This radiosurgical approach may be of particular interest for the induction of lesions of the STN and SN in studies of experimental parkinsonism, as well as for the development of potential radiosurgical treatments for Parkinson disease. Deane, K. H., C. Ellis-Hill, et al. (2001). "Occupational therapy for patients with Parkinson s disease (cochrane review)." Cochrane Database Syst Rev 3: CD002813. BACKGROUND: Despite drug and surgical therapies for Parkinson's disease, patients develop progressive disability. The role of the occupational therapist is to support the patient and help them maintain their usual level of self-care, work and leisure activities for as long as possible. When it is no longer possible to maintain their usual activities, occupational therapists support individuals in changing and adapting their relationship with their physical and social environment to develop new valued activities and roles. OBJECTIVES: To compare the efficacy and effectiveness of occupational therapy with placebo or no interventions (control group) in patients with Parkinson's disease. SEARCH STRATEGY: Relevant trials were identified by electronic searches of MEDLINE, EMBASE, CINAHL, ISI-SCI, AMED, MANTIS, REHABDATA, REHADAT, GEROLIT, Pascal, LILACS, MedCarib, JICST-EPlus, AIM, IMEMR, SIGLE, ISI-ISTP, DISSABS, Conference Papers Index, Aslib Index to Theses, the Cochrane Controlled Trials Register, the CentreWatch Clinical Trials listing service, the metaRegister of Controlled Trials, ClinicalTrials.gov, CRISP, PEDro, NIDRR and NRR; and the reference lists of identified studies and other reviews were examined. SELECTION CRITERIA: Only randomised controlled trials (RCT) were included, however those trials that allowed quasi-random methods of allocation were allowed. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by two authors and differences were settled by discussion. MAIN RESULTS: Two trials were identified with 84 patients in total. Although both trials reported a positive effect from occupational therapy, all of the improvements were small. The trials did not have adequate placebo treatments, used small numbers of patients and the method of randomisation and concealment of allocation was not specified in one trial. These methodological problems could potentially lead to bias from a number of sources reducing the strength of the studies further. REVIEWER'S CONCLUSIONS: Considering the significant methodological flaws in the studies, the small number of patients examined, and the possibility of publication bias, there is insufficient evidence to support or refute the efficacy of occupational therapy in Parkinson's disease. There does not appear to be a consensus as to the best practice in occupational therapy when treating people with Parkinson's disease. A survey of therapists is needed to determine what methods of occupational therapy are currently being used by therapists to treat Parkinson's disease, and whether there is a consensus as to 'best-practice'. Large well designed placebo-controlled RCTs are needed to demonstrate occupational therapy's effectiveness in Parkinson's disease. Outcome measures with particular relevance to patients, carers, occupational therapists and physicians should be chosen and the patients monitored for at least six months to determine the duration of benefit. The trials should be reported using CONSORT guidelines. Deane, K. H., D. Jones, et al. (2001). "A comparison of physiotherapy techniques for patients with Parkinson's disease." Cochrane Database Syst Rev 1: CD002815. BACKGROUND: Despite optimal medical and surgical therapies for Parkinson's disease, patients develop progressive disability. The role of the physiotherapist is to maximise functional ability and minimise secondary complications through movement rehabilitation within a context of education and support for the whole person. What form of physiotherapy is most effective in the treatment of Parkinson's disease remains unclear. OBJECTIVES: 1. To compare the efficacy and effectiveness of novel physiotherapy techniques versus 'standard' physiotherapy in patients with Parkinson's disease. Standard physiotherapy is defined as the type of therapy that the physiotherapist would usually use to treat Parkinson's disease. 2. To compare the efficacy and effectiveness of one physiotherapy technique versus a second form of physiotherapy. SEARCH STRATEGY: Relevant trials were identified by electronic searches of MEDLINE, EMBASE, CINAHL, ISI-SCI, AMED, MANTIS, REHABDATA, REHADAT, GEROLIT, Pascal, LILACS, MedCarib, JICST-EPlus, AIM, IMEMR, SIGLE, ISI-ISTP, DISSABS, Conference Papers Index, Aslib Index to Theses, the Cochrane Controlled Trials Register, the CentreWatch Clinical Trials listing service, the metaRegister of Controlled Trials, ClinicalTrials.gov, CRISP, PEDro, NIDRR and NRR; and examination of the reference lists of identified studies and other reviews. SELECTION CRITERIA: Only randomised controlled trials (RCT) were included. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by KD and CEH and differences settled by discussion. MAIN RESULTS: Seven trials were identified with 142 patients. All used small numbers of patients and the method of randomisation and concealment of allocation was poor or not statedin all of the trials. These methodological problems could potentially lead to bias from a number of sources. The methods of physiotherapy varied so widely that the data could not be combined. REVIEWER'S CONCLUSIONS: Considering the small number of patients examined, the methodological flaws in many of the studies and the possibility of publication bias, there is insufficient evidence to support or refute the efficacy of any given form of physiotherapy over another in Parkinson's disease. Another Cochrane review, Physiotherapy for patients with Parkinson's Disease, found that there was insufficient evidence to support or refute the efficacy of physiotherapy compared to no physiotherapy in Parkinson's disease. A wide range of physiotherapy approaches were used in these studies and a survey of UK physiotherapists confirmed that they also use an eclectic combination of techniques in the treatment of Parkinson's disease (Plant 1999). Therefore a consensus must be found as to 'best practice' physiotherapy for Parkinson's disease. The efficacy of 'standard' physiotherapy should be proved first before examining variations in physiotherapy methods. Therefore large well designed randomised controlled trials are needed to judge the effect of physiotherapy in Parkinson's disease. After this large RCTs are needed to demonstrate the most effective form of physiotherapy in Parkinson's disease. Outcome measures with particular relevance to patients, carers, physiotherapists and physicians should be chosen and the patients monitored for at least 6 months to determine the duration of any effect. The trials should be reported according to CONSORT guidelines (CONSORT 1996). Deane, K. H., D. Jones, et al. (2001). "Physiotherapy for patients with Parkinson s Disease (Cochrane Review)." Cochrane Database Syst Rev 3: CD002817. BACKGROUND: Despite optimal medical and surgical therapies for Parkinson's disease, patients develop progressive disability. The role of the physiotherapist is to maximise functional ability and minimise secondary complications through movement rehabilitation within a context of education and support for the whole person. OBJECTIVES: To compare the efficacy and effectiveness of physiotherapy with placebo or no interventions in patients with Parkinson's disease. SEARCH STRATEGY: Relevant trials were identified by electronic searches of MEDLINE, EMBASE, CINAHL, ISI-SCI, AMED, MANTIS, REHABDATA, REHADAT, GEROLIT, Pascal, LILACS, MedCarib, JICST-EPlus, AIM, IMEMR, SIGLE, ISI-ISTP, DISSABS, Conference Papers Index, Aslib Index to Theses, the Cochrane Controlled Trials Register, the CentreWatch Clinical Trials listing service, the metaRegister of Controlled Trials, ClinicalTrials.gov, CRISP, PEDro, NIDRR and NRR; and examination of the reference lists of identified studies and other reviews. SELECTION CRITERIA: Only randomised controlled trials (RCT) were included, however those trials that allowed quasi-random methods of allocation were allowed. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by KD and DJ and differences settled by discussion. MAIN RESULTS: Eleven trials were identified with 280 patients. Eight trials did not have adequate placebo treatments, all used small numbers of patients and the method of randomisation and concealment of allocation was good in only four trials. These methodological problems could potentially lead to bias from a number of sources. Although ten of the trials claimed a positive effect from physiotherapy, few outcomes measured were statistically significant. Walking velocity was measured in four trials and increased significantly in two of them. Stride length was the only other outcome measured in more than one trial, it was significantly improved in two trials. Five other outcomes improved significantly in individual studies, but eight other outcomes did not improve significantly. REVIEWER'S CONCLUSIONS: Considering the methodological flaws in many of the studies, the small number of patients examined, and the possibility of publication bias, there is insufficient evidence to support or refute the efficacy of physiotherapy in Parkinson's disease. The studies illustrate that a wide range of approaches are being employed by physiotherapists to treat Parkinson's disease. This was confirmed by the UK survey of physiotherapists. There is a need to develop a consensus as to 'best-practice'. Large well designed placebo-controlled RCTs are then needed to demonstrate the efficacy and effectiveness of 'best practice' physiotherapy in Parkinson's disease. The stage of the disease at which the physiotherapy is given should be specified at the outset. Outcome measures with particular relevance to patients, carers, physiotherapists and physicians should be chosen and the patients monitored for at least six months to determine the duration of any beneficial effects. The trials should be reported according to CONSORT guidelines. Deane, K. H., R. Whurr, et al. (2001). "Non-pharmacological therapies for dysphagia in Parkinson's disease." Cochrane Database Syst Rev 1: CD002816. BACKGROUND: Dysphagia occurs frequently in Parkinson's disease although patients themselves may be unaware of swallowing difficulties. Speech and language therapists in conjunction with nurses and dietitians use techniques that aim to improve swallowing and reduce the risk of choking, aspiration and chest infections. OBJECTIVES: ~Bullet~To compare the efficacy and effectiveness of non-pharmacological swallowing therapy for dysphagia versus placebo or no intervention in patients with Parkinson's disease. ~Bullet~To compare one form of non-pharmacological swallowing therapy for dysphagia with another in patients with Parkinson's disease. SEARCH STRATEGY: Relevant trials were identified by electronic searches of MEDLINE, EMBASE, CINAHL, ISI-SCI, AMED, MANTIS, REHABDATA, REHADAT, GEROLIT, Pascal, LILACS, MedCarib, JICST-EPlus, AIM, IMEMR, SIGLE, ISI-ISTP, DISSABS, Conference Papers Index, Aslib Index to Theses, the Cochrane Controlled Trials Register, the CentreWatch Clinical Trials listing service, the metaRegister of Controlled Trials, ClinicalTrials.gov, CRISP, PEDro, NIDRR and NRR; and examination of the reference lists of identified studies and other reviews. SELECTION CRITERIA: Only randomised controlled trials (RCT) were included. We did not examine any trials using drugs or surgery to treat the dysphagia. We did not examine any trials where part of the therapist's advice was to insert a nasogastric or percutaneous gastrostomy tube. DATA COLLECTION AND ANALYSIS: Not applicable. MAIN RESULTS: No randomised controlled trials or controlled trials were found that examined the efficacy of non-pharmacological swallowing therapy for the treatment of dysphagia in Parkinson's disease. However there is one large RCT currently recruiting patients that will compare 'chin down' posture with thickened liquids in the treatment of dysphagia. The main outcomes will be the rates of aspiration and pneumonia. REVIEWER'S CONCLUSIONS: There is currently no evidence to support or refute the efficacy of non-pharmacological swallowing therapy for dysphagia in Parkinson's disease. Large well designed placebo-controlled RCTs are required to assess the effectiveness of swallowing therapy for dysphagia in Parkinson's disease and reported according to CONSORT guidelines. Suitable outcome measures should be chosen so that the efficacy and effectiveness of non-pharmacological swallowing therapy can be assessed and an economic analysis performed. Outcomes which have meaning to patients and carers should be used wherever possible since they need to know the value of this therapy in practical terms. The patients should be followed for at least 6 months to determine the duration of any improvement. Deane, K. H., R. Whurr, et al. (2001). "A comparison of speech and language therapy techniques for dysarthria in Parkinson s Disease (Cochrane Review)." Cochrane Database Syst Rev 2: CD002814. BACKGROUND: Dysarthria is a common manifestation of Parkinson's disease that increases in frequency and intensity with the progress of the disease (~~ Streifler 1984~~). Up to 20% of Parkinsonian patients are referred for speech and language therapy (S&LT), its aim being to improve the intelligibility of the patient's speech. OBJECTIVES: ~Bullet~To compare the efficacy and effectiveness of novel S&LT techniques versus standard S&LT to treat dysarthria in patients with Parkinson's disease. ~Bullet~To compare the efficacy and effectiveness of one S&LT technique versus a second form of S&LT to treat Parkinsonian dysarthria. SEARCH STRATEGY: Relevant trials were identified by electronic searches of MEDLINE, EMBASE, CINAHL, ISI-SCI, AMED, MANTIS, REHABDATA, REHADAT, GEROLIT, Pascal, LILACS, MedCarib, JICST-EPlus, AIM, IMEMR, SIGLE, ISI-ISTP, DISSABS, Conference Papers Index, Aslib Index to Theses, the Cochrane Controlled Trials Register, the CentreWatch Clinical Trials listing service, the metaRegister of Controlled Trials, ClinicalTrials.gov, CRISP, PEDro, NIDRR and NRR; and examination of the reference lists of identified studies and other reviews. SELECTION CRITERIA: Only randomised controlled trials (RCT) were included. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by KD and RW and differences settled by discussion. MAIN RESULTS: Only two trials were identified with only 71 patients. The method of randomisation was good in only one trial and the concealment of allocation was inadequate in both trials. These methodological problems could potentially lead to bias from a number of sources. The methods used in the two studies varied so much that meta-analysis of the results was not possible. ~~ Scott 83~~ compared prosodic exercises with visual cues with prosodic exercises alone (See Glossary: ~~ Table 01~~). The authors examined prosody and intelligibility as outcome measures immediately after therapy. ~~ Ramig 95~~ compared the Lee Silverman Voice Therapy (LSVT) which emphasises increased vocal effort, with respiratory therapy which aimed to increase respiratory muscle activity. ~~ Ramig 95~~ examined a wide range of vocal characteristics, activities of daily living affected by speech, depression and the carer's impressions of the patient's speech quality. Some of these outcomes were measured up to 24 months after the end of the therapy. However, in neither study were changes in outcomes due to 'Therapy A' compared with the changes due to 'Therapy B' statistically. Therefore no comment on the comparative efficacy of these types of speech and language therapy can be made. REVIEWER'S CONCLUSIONS: Considering the methodological flaws in both of these studies, the small number of patients examined, and the possibility of publication bias, there is insufficient evidence to support or refute the efficacy of any given form of S&LT over another to treat dysarthria in Parkinson's disease. Given the lack of evidence from RCTs to support or refute the efficacy of S&LT in Parkinson's disease (see Cochrane review 'Speech and Language therapy for Dysarthria in Patients with Parkinson's Disease'), the consensus as to what is considered 'best-practice' S&LT must be proved first through a large well-designed placebo-controlled randomised trial before examining variations in S&LT methodology. The design of these trials should minimise bias and be reported fully using CONSORT guidelines (~~ CONSORT 1996~~). Outcome measures with particular relevance to patients, their carers, physicians and speech and language therapists should be chosen and the patients followed for at least 6 months to determine the duration of any improvement. Deane, K. H., R. Whurr, et al. (2001). "Speech and Language Therapy for Dysarthria in Parkinson s Disease (Cochrane Review)." Cochrane Database Syst Rev 2: CD002812. BACKGROUND: Dysarthria is a common manifestation of Parkinson's disease which increases in frequency and intensity with the progress of the disease (~~ Streifler 1984~~). Up to 20% of Parkinsonian patients are referred for speech and language therapy (S&LT), its aim being to improve the intelligibility of the patient's speech. OBJECTIVES: To compare the efficacy of speech and language therapy versus placebo or no interventions in patients with Parkinson's disease. SEARCH STRATEGY: Relevant trials were identified by electronic searches of MEDLINE, EMBASE, CINAHL, ISI-SCI, AMED, MANTIS, REHABDATA, REHADAT, GEROLIT, Pascal, LILACS, MedCarib, JICST-EPlus, AIM, IMEMR, SIGLE, ISI-ISTP, DISSABS, Conference Papers Index, Aslib Index to Theses, the Cochrane Controlled Trials Register, the CentreWatch Clinical Trials listing service, the metaRegister of Controlled Trials, ClinicalTrials.gov, CRISP, PEDro, NIDRR and NRR; and examination of the reference lists of identified studies and other reviews. SELECTION CRITERIA: Only randomised controlled trials (RCT) were included. DATA COLLECTION AND ANALYSIS: Data were abstracted independently by KD and RW and differences settled by discussion. MAIN RESULTS: Three randomised controlled trials were found comparing speech and language therapy with placebo for speech disorders in Parkinson's disease. A total of 63 patients were examined. The loudness of the patients' voices were increased by between 7-18%, depending on the speaking task being performed. It is likely that this is a clinically significant improvement. After six months the degree of improvement was reduced but was still statistically significant. Overall measures of dysarthria were measured in two trials and also improved. The clinical significance of these improvements was less clear cut as intelligibility of speech was not measured in any of these studies. REVIEWER'S CONCLUSIONS: Considering the small number of patients examined, the methodological flaws in many of the studies, and the possibility of publication bias, there is insufficient evidence to support or refute the efficacy of speech and language therapy for dysarthria in Parkinson's disease. A Delphi-style survey is needed to develop a consensus as to what is 'standard' S&LT for dysarthria in Parkinson's disease. Then a large well designed placebo-controlled RCT is needed to demonstrate speech and language therapy's effectiveness for dysarthria in Parkinson's disease. The trial should conform to CONSORT guidelines. Outcome measures with particular relevance to patients should be chosen and the patients followed for at least 6 months to determine the duration of any improvement. Deecke, L. (2001). "Clinical neurophysiology of Parkinson's disease. Bereitschaftspotential and contingent negative variation." Adv Neurol 86: 257-71. Defebvre, L. and G. Kemoun (2001). "[Gait disorders in Parkinson disease. Neuroanatomic and physiologic organization of gait]." Presse Med 30(9): 445-51. GAIT IS A VOLUNTARY, AUTOMATIC AND REFLEX RHYTHMIC ACTIVITY: It is generated by a central pattern generator identified from animal models. This spinal gait generator (SGG) is controlled by various parts of the central nervous system: the descending tracts and locomotor regions of the brainstem, the cerebellum, the basal ganglia, the motor and parietal cortex and the hippocampus. Kinesthetic inputs which project to the SGG and the cerebellum, play an important role in the production of postural reflex responses; vestibular and visual inputs mainly control balance. GAIT MAINLY DEPENDS ON THE RELATIONSHIP BETWEEN POSTURE BALANCE AND MOVEMENT: As concerns posture each segment is under the control of both peripheral and central nervous systems and is used as a system of reference to organize movements of adjacent segments. Balance is maintained by sensory inputs which provide corrective mechanisms: anticipatory postural responses, reflex postural responses and voluntary responses. DIFFERENT DESCRIPTIVE PARAMETERS MAY BE PROPOSED: Analysis of kinematic (displacement, speed and acceleration of segments) and kinetic parameters during the four successive stages of gait (posture, initiation, rhythmic gait and return to the initial posture) provides an understanding of neurological gait disorders. In particular the relationship between the center of pressure and the center of gravity is used to analyze infraclinical gait abnormalities. NEW AND SOPHISTICATED INVESTIGATIONS METHODS ARE AVAILABLE: The optoelectronic system provides a tridimensional analysis of movement and can be combined with forceplate and electromyographic recordings. These methods constitute an interesting contribution to the clinical analysis of gait. CLASSIFICATION: This is established according to clinical data and the positionment of the lesion among the structures of the nervous system. The physiopathological approach is then specified taking into account the lesions of the muscular, skeletal and nervous structures. Degos, J. D., D. Malapert, et al. (2001). "[Toe phasic posture reflex: description and distribution among patients with neurological disease and in the general population]." Rev Neurol (Paris) 157(3): 284-8. A clinical sign is described consisting of a brief extension of the toes after upward tapping of the plantar surface of their terminal phalanges. Electrological data support the hypothesis of a long loop reflex, which we call the "toe phasic posture reflex" (TPPR). In a preliminary study, this sign was observed in patients with central nervous system disease, especially in subcortical brain disorders regardless of etiology. In Parkinson's disease, it was seen mostly in severe and postural forms. Among 237 healthy subjects, it was observed in none of those under 70 years old (n=116), and in 10p. cent of those over 69 years and doing no sport (n=132), but in none of those doing regularly gymnastics or swimming (n=29). TPPR could thus be a sign of motor and especially postural aging. Dekkers, W. and G. Boer (2001). "Sham neurosurgery in patients with Parkinson's disease: is it morally acceptable?" J Med Ethics 27(3): 151-6. For a few decades, patients with Parkinson's disease (PD) have been treated with intracerebral transplantations of fetal mesencephalic tissue. The results of open trials have been variable. Double blind, placebo-controlled studies have recently been started in order to further investigate the efficacy of this new medical technique. In this paper we challenge the need for sham surgery in neurotransplantation research on PD patients. Considerations regarding the research subjects' informed consent, therapeutic misconception, the integrity of the human body, and the assessment of risks and benefits argue against sham surgery for patients with PD. Moreover, there is an alternative, less harmful mode of research that can provide the same or comparable scientific evidence. A plea is made for intrapatient research based on quantitative measurements of the patient's pre- and post-operative condition combined with similar research on a reference group of patients who have received the standard treatment. Del Dotto, P., N. Pavese, et al. (2001). "Intravenous amantadine improves levadopa-induced dyskinesias: an acute double-blind placebo-controlled study." Mov Disord 16(3): 515-20. Experimental evidence suggests that glutamatergic receptor blockade may improve the motor response complications associated with long-term levodopa treatment in Parkinson's disease (PD) patients. Our objective was to evaluate the acute effect of amantadine, a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, on levodopa-induced dyskinesias, and to gain further insights into the antidyskinetic mechanism of this drug. Nine PD patients with motor fluctuations and severely disabling peak of dose dyskinesias received their first morning levodopa dose, followed by a 2-hour intravenous amantadine (200 mg) or placebo infusion, on two different days. Parkinsonian symptoms and dyskinesias were assessed every 15 minutes during the infusion and for 3 hours thereafter, while patients were taking their usual oral antiparkinsonian therapy, by means of Unified Parkinson's Disease Rating Scale (UPDRS, motor examination), tapping test, and a modified Abnormal Involuntary Movement Scale (AIMS). Intravenous amantadine acutely improved levodopa-induced dyskinesias by 50%without any loss of the anti-parkinsonian benefit from levodopa. This study confirms the antidyskinetic effect of amantadine and strengthens the rationale for using antiglutamatergic drugs in the treatment of parkinsonian motor fluctuations. Delacourte, A. (2001). "The molecular parameters of tau pathology. Tau as a killer and a witness." Adv Exp Med Biol 487: 5-19. Deleu, D. (2001). "Smoking, alcohol, and coffee consumption preceding Parkinson's disease." Neurology 56(7): 984-5. Deleu, D., Y. Hanssens, et al. (2001). "Levodopa, ayurveda and Parkinson's disease." J Neurol Sci 184(1): 89-92. Dell'Agnello, G., R. Ceravolo, et al. (2001). "SSRIs do not worsen Parkinson's disease: evidence from an open-label, prospective study." Clin Neuropharmacol 24(4): 221-7. Selective serotonin reuptake inhibitors (SSRIs) have been reported to be useful in the treatment of depression in patients with Parkinson's disease (PD). However, a few reports have suggested that SSRIs may worsen parkinsonian motor symptomatology and extrapyramidal side effects have been reported in depressed patients treated with SSRIs. So far, no prospective trial comparing the effects of different SSRIs in depressed patients with PD has been performed. The aim of the present study was to assess the effects of four SSRIs (citalopram, fluoxetine, fluvoxamine, and sertraline) on motor performance and their efficacy on depression in a group of patients with PD. Sixty-two consecutive nondemented, nonfluctuating, depressed patients with PD were included in four treatment groups (15 patiens received citalopram, 16 fluoxetine, 16 fluvoxamine, and 15 sertraline). The evaluation of extrapyramidal and depressive symptomatology was performed with use of the Unified Parkinson's Disease Rating Scale (UPDRS), Beck Depression Inventory, and Hamilton Depression Rating Scale at baseline and after 1, 3, and 6 months. Fifty-two patients completed the study. UPDRS scores were not significantly modified by the add-on therapy with each of the SSRIs studied. A significant improvement in depressive symptoms from baseline to the end of the trial was obtained with all SSRIs (Beck and Hamilton scores improving; p < 0.05 according to an analysis of variance). Our findings suggest that SSRIs do not significantly worsen extrapyramidal symptomatology and may ameliorate depression in patients with PD. DeLong, M. R. and T. Wichmann (2001). "Deep brain stimulation for Parkinson's disease." Ann Neurol 49(2): 142-3. Delwaide, P. J. (2001). "Parkinsonian rigidity." Funct Neurol 16(2): 147-56. Demakis, G. J., T. P. Sawyer, et al. (2001). "Incidental recall on WAIS-R digit symbol discriminates Alzheimer's and Parkinson's diseases." J Clin Psychol 57(3): 387-94. The purpose of this study was to examine how Alzheimer's (n = 37) and Parkinson's (n = 21) patients perform on the incidental recall adaptation to the Digit Symbol of the Wechsler Adult Intelligence Scale-Revised (WAIS-R) and how such performance is related to established cognitive efficiency and memory measures. This adaptation requires the examinee to complete the entire subtest and then, without warning, to immediately recall the symbols associated with each number. Groups did not differ significantly on standard Digit Symbol administration (90 seconds), but on recall Parkinson's patients recalled significantly more symbols and symbol-number pairs than Alzheimer's patients. Using only the number of symbols recalled, discriminate function analysis correctly classified 76% of these patients. Correlations between age-corrected scaled score, symbols incidentally recalled, and established measures of cognitive efficiency and memory provided evidence of convergent and divergent validity. Age-corrected scaled scores were more consistently and strongly related to cognitive efficiency, whereas symbols recalled were more consistently and strongly related to memory measures. These findings suggest that the Digit Symbol recall adaptation is actually assessing memory and that it can be another useful way to detect memory impairment. Demirel, M., Y. Yazan, et al. (2001). "Formulation and in vitro-in vivo evaluation of piribedil solid lipid micro- and nanoparticles." J Microencapsul 18(3): 359-71. Modification of the dissolution rate and, thus, the enhancement of the bioavailability of a dopaminergic drug, piribedil, which has a low aqueous solubility and short elimination half-life have been the aim in this study. Preparations of micron and submicron particles using solid lipid carriers have been performed for this purpose. For the avoidance of solvent residues resulting from the preparation technique, cold and hot homogenization methods have been used to prepare solid lipid particles. After obtaining an appropriate particle size, piribedil loading and preparation yield by the use of those two methods, various formulations have been prepared with different lipid, drug and surfactant materials. The factors mentioned were found to affect properties of the particles, and the release rate was found to be the fastest in acidic medium. Suspensions of pure piribedil and a formulation, selected according to the results obtained from in vitro dissolution and particle size experiments, were compared using tremor tests in mice. The same suspensions were applied perorally to rabbits and bioavailability of the solid lipid particle was found to be higher than the pure piribedil. After an in vitro-in vivo evaluation of piribedil solid lipid particles developed for Parkinson's disease therapy, it has been determined that release rate could be controlled and piribedil bioavailability could be improved. Demirkiran, M., H. Bozdemir, et al. (2001). "Vascular parkinsonism: a distinct, heterogeneous clinical entity." Acta Neurol Scand 104(2): 63-7. OBJECTIVES: The aim of this study was to define the symptoms and signs of suspected vascular parkinsonism (VP) which is still a debatable concept. MATERIAL AND METHODS: Patients with parkinsonism were grouped into patients with suspected VP and Parkinson's disease (PD) after other causes for secondary parkinsonism, and parkinsonism-plus syndromes were excluded. The clinical features of 16 patients with suspected VP to those of 50 diagnosed with PD were compared. All patients were assessed using unified Parkinson's disease rating scale (UPDRS) and all had cerebral MRIs. RESULTS: Patients with VP had significantly older onset age and shorter duration of disease with gait disorder as the most frequent initial symptom. All PD patients had satisfactory response to levodopa treatment, whereas only 38% VP patients had satisfactory response to levodopa treatment. Vascular risk factors were more common in VP (81%) than PD (32%). Postural instability, freezing, gait disturbance, pyramidal signs, and postural tremor were significantly more prevalent in patients with VP than in PD. In VP patients these features were more prominent in the lower limbs. Twenty-five percent had acute onset VP. All patients with VP had ischemic lesions, mainly in subcortical white matter, to a lesser extent basal ganglia and brainstem, in their cerebral MRIs, while 70% of PD patients had normal MRIs. CONCLUSION: The differences in the clinical features support the concept that VP is a distinct clinical entity with heterogeneous clinical, MRI, and possibly pathophysiological features. Depatie, L. and S. Lal (2001). "Apomorphine and the dopamine hypothesis of schizophrenia: a dilemma?" J Psychiatry Neurosci 26(3): 203-20. The dopamine (DA) hypothesis of schizophrenia implicates an enhancement of DA function in the pathophysiology of the disorder, at least in the genesis of positive symptoms. Accordingly, apomorphine, a directly acting DA receptor agonist, should display psychotomimetic properties. A review of the literature shows little or no evidence that apomorphine, in doses that stimulate postsynaptic DA receptors, induces psychosis in non-schizophrenic subjects or a relapse or exacerbation of psychotic symptoms in patients with schizophrenia. After a detailed review of the literature reporting psychotogenic effects of apomorphine in patients with Parkinson's disease, an interpretation of these data is difficult, in part because of several confounding factors, such as the concomitant use of drugs known to induce psychosis and the advanced state of the progressive neurological disorder. In the context of the DA hypothesis of schizophrenia, the limited ability of apomorphine to induce psychosis, in contrast to indirectly acting DA agonists that increase synaptic DA, may be explained by the relatively weak affinity of apomorphine for the D3 receptor compared with DA. Alternatively, enhancement of DA function, though necessary, may be insufficient by itself to induce psychosis. Descombes, S., A. M. Bonnet, et al. (2001). "Dual-release formulation, a novel principle in L-dopa treatment of Parkinson's disease." Neurology 56(9): 1239-42. A single morning dose of dual-release formulation was compared with a slow-release formulation of L-dopa plus benserazide in a randomized, double-blind, cross-over study in 16 fluctuating patients with PD. The mean time to "on" was shorter with the dual-release formulation (43 +/- 31 minutes) than with the slow-release formulation (81 +/- 39 minutes) (p < 0.001), whereas the mean time to relapse to "off" was similar for both formulations. The dual-release formulation had a significantly shorter time to reach peak concentration (t(max)) and greater maximum concentration (C(max)) and area under the plasma concentration time curve (AUC(0--5 h)) than the slow-release formulation, whereas apparent elimination half-life (t(1/2)) was similar for both formulations. DeStefano, A. L., L. I. Golbe, et al. (2001). "Genome-wide scan for Parkinson's disease: the GenePD Study." Neurology 57(6): 1124-6. A genome-wide scan for idiopathic PD in a sample of 113 PD-affected sibling pairs is reported. Suggestive evidence for linkage was found for chromosomes 1 (214 cM, lod = 1.20), 9 (136 cM, lod = 1.30), 10 (88 cM, lod = 1.07), and 16 (114 cM, lod = 0.93). The chromosome 9 region overlaps the genes for dopamine beta-hydroxylase and torsion dystonia. Although no strong evidence for linkage was found for any locus, these results may be of value in comparison with similar studies by others. Deterding, T. A., J. R. Votaw, et al. (2001). "Biodistribution and radiation dosimetry of the dopamine transporter ligand." J Nucl Med 42(2): 376-81. 18F-labeled 2 beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(-2-fluoroethyl)nortropane ([18F]FECNT) is a recently developed dopamine transporter ligand with potential applications in patients with Parkinson's disease and cocaine addiction. METHODS: Estimates of the effective dose equivalent and doses for specific organs were made using biodistribution data from 16 Sprague-Dawley rats and nine rhesus monkeys. PET images from two rhesus monkeys were used to calculate the residence time for the basal ganglia. The computer program MIRDOSE3 was used to calculate the dosimetry according to the methodology recommended by MIRD. RESULTS: The basal ganglia were the targeted tissues receiving the highest dose, 0.11 mGy/MBq (0.39 rad/mCi). The effective dose equivalent was 0.018 mSv/MBq (0.065 rem/mCi), and the effective dose was 0.016 mSv/MBq (0.058 rem/mCi). CONCLUSION: Our data show that a 185-MBq (5-mCi) injection of [18F]FECNT leads to an estimated effective dose of 3 mSv (0.3 rem) and an estimated dose to the target organ or tissue of 19.4 mGy (1.93 rad). Deuschl, G., J. Raethjen, et al. (2001). "The pathophysiology of tremor." Muscle Nerve 24(6): 716-35. Tremor is defined as rhythmic oscillatory activity of body parts. Four physiological basic mechanisms for such oscillatory activity have been described: mechanical oscillations; oscillations based on reflexes; oscillations due to central neuronal pacemakers; and oscillations because of disturbed feedforward or feedback loops. New methodological approaches with animal models, positron emission tomography, and mathematical analysis of electromyographic and electroencephalographic signals have provided new insights into the mechanisms underlying specific forms of tremor. Physiological tremor is due to mechanical and central components. Psychogenic tremor is considered to depend on a clonus mechanism and is thus believed to be mediated by reflex mechanisms. Symptomatic palatal tremor is most likely due to rhythmic activity of the inferior olive, and there is much evidence that essential tremor is also generated within the olivocerebellar circuits. Orthostatic tremor is likely to originate in hitherto unidentified brainstem nuclei. Rest tremor of Parkinson's disease is probably generated in the basal ganglia loop, and dystonic tremor may also originate within the basal ganglia. Cerebellar tremor is at least in part caused by a disturbance of the cerebellar feedforward control of voluntary movements, and Holmes' tremor is due to the combination of the mechanisms producing parkinsonian and cerebellar tremor. Neuropathic tremor is believed to be caused by abnormally functioning reflex pathways and a wide variety of causes underlies toxic and drug-induced tremors. The understanding of the pathophysiology of tremor has made significant progress but many hypotheses are not yet based on sufficient data. Modern neurology needs to develop and test such hypotheses, because this is the only way to develop rational medical and surgical therapies. Dewey, R. B., Jr., J. T. Hutton, et al. (2001). "A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events." Arch Neurol 58(9): 1385-92. OBJECTIVE: To assess the safety and efficacy of subcutaneous apomorphine hydrochloride administration for off-state (poor motor function) periods in patients with Parkinson disease with motor fluctuations under both inpatient titration and outpatient therapeutic conditions. PATIENTS AND METHODS: Twenty-nine patients had advanced Parkinson disease with 2 hours or more off time despite aggressive oral therapy. Patients randomly received titrated doses of subcutaneous apomorphine hydrochloride (2-10 mg, n = 20) or pH-matched vehicle placebo (n = 9) during an inpatient and 1-month outpatient phase. A change in the United Parkinson Disease Rating Scale motor score 20 minutes after inpatient dosing during a practically defined off-state event and the percentage of injections successfully aborting off-state events were the primary inpatient and outpatient efficacy factors. RESULTS: The average (SEM) levodopa equivalent dose of apomorphine hydrochloride was 5.4 +/- 0.5 mg and the mean placebo dose was 1.0 mL. Mean inpatient United Parkinson Disease Rating Scale motor scores were reduced by 23.9 and 0.1 points (62% and 1%) by apomorphine treatment and placebo, respectively (P<.001). The mean percentage of outpatient injections resulting in successful abortion of off-state events was 95% for apomorphine and 23% for placebo (P<.001). Inpatient response was significantly correlated with and predictive of outpatient efficacy (P<.001). The levodopa dose was not predictive of the apomorphine dose requirement. Frequent adverse events included dyskinesia, yawning, and injection site reactions. CONCLUSION: Apomorphine by intermittent subcutaneous injection is effective and safe for outpatient use to reverse off-state events that occur despite optimized oral therapy. Dhawan, V. and D. Eidelberg (2001). "SPECT imaging in Parkinson's disease." Adv Neurol 86: 205-13. Diaz-Cabiale, Z., Y. Hurd, et al. (2001). "Adenosine A2A agonist CGS 21680 decreases the affinity of dopamine D2 receptors for dopamine in human striatum." Neuroreport 12(9): 1831-4. Adenosine A2A receptors (A2AR) and dopamine D2 receptors (D2R) are highly concentrated in the striatum, where they are co-localized and exert reciprocal antagonistic interactions. It has been suggested that the A2R/D2R interactions might provide a therapeutic approach for basal ganglia disorders, such as Parkinson's disease, and schizophrenia. In the present work evidence is presented for the existence of an A2AR/D2R interaction in human brain by using quantitative autoradi- ography. The areas analyzed were the dorsal caudate nucleus and putamen. Parallel studies were performed in rat striatal sections. The A2AR agonist CGS 21680 was found to significantly increase IC50 values of competitive inhibition curves of the D2R/D3R antagonist [125I]iodosulpiride vs dopamine both in rat striatal and human striatal brain sections. Dickman, M. S. (2001). "von Economo encephalitis." Arch Neurol 58(10): 1696-8. In April 1917, Dr Constantin von Economo presented his clinical and pathologic findings of a new disease--soon to be part of a worldwide epidemic--before the Vienna Psychiatric Society. He named it encephalitis lethargica. After years of careful observation, he collected and analyzed thousands of cases and classified them into 3 clinical syndromes: somnolent-ophthalmoplegic, hyperkinetic, and amyostatic-akinetic forms. He described the now legendary postencephalitic Parkinsonism, noting that symptoms could emerge years after the original infection, often without signs of prodromal "flu." He emphasized the neuropathologic findings: inflammatory changes in the tegmentum of the midbrain accounting for the sleep disturbance and ocular signs. After encountering sporadic cases following the epidemic, he concluded that the somnolent-ophthalmoplegic syndrome was the primary expression of encephalitis lethargica. This article outlines the observations and conclusions of Dr von Economo during and after the epidemic through seminal quotations primarily from his published works, as well as from more recent reports. Dickson, D., M. Farrer, et al. (2001). "Pathology of PD in monozygotic twins with a 20-year discordance interval." Neurology 56(7): 981-2. Dietz, M., S. Harder, et al. (2001). "Levodopa pharmacokinetic-pharmacodynamic modeling and 6-[18F]levodopa positron emission tomography in patients with Parkinson's disease." Clin Pharmacol Ther 70(1): 33-41. OBJECTIVE: Parameters of a pharmacokinetic-pharmacodynamic (PK-PD) model of levodopa have been claimed to reflect the magnitude of the dopaminergic deficit in patients with Parkinson's disease. The aim of this study was to correlate such parameters with positron emission tomography (PET) with levodopa tagged with 6-fluorine 18, an established imaging method for striatal dopaminergic neurons. METHODS: Twenty-three patients in different disease stages (Hoehm and Yahr stage 2.5-5 [Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967;4:427-42]; median duration, 12 years) were studied. PK-PD modeling followed a single oral dose of levodopa/benserazide. The sum score of the Columbia Rating Scale (CURSSigma) was used for clinical assessments. A nonparametric effect compartment approach assuming a sigmoidal E(max) model was applied to the PK-PD analysis of plasma levodopa concentrations and corresponding CURSSigma. Thereafter 6-[18F]levodopa PET was performed, and the influx rate constants (k(c)) for the putamen and the caudatus region were correlated with the median effective concentration (EC(50)) and the equilibrium half-life (T(eq)) of the PK-PD model. RESULTS: (1) A significant correlation was observed between PK-PD parameters or with k(c) putamen as the dependent variable and the duration of the disease as the independent variable, which explains 33% of the variability of the EC(50), 42% of the variability of T(eq), and 36% of the variability of k(c). (2) Significant correlations were observed between k(c) and either EC(50) or T(eq), yielding the closest correlation for the putamen region (r = -0.47, P <.05; and r = 0.55, P <.01; respectively). CONCLUSIONS: Our findings show that key parameters of a PK-PD model of levodopa were in fairly close agreement with imaging of dopaminergic neurons by 6-[18F]levodopa PET. However, although PK-PD modeling of levodopa has been proven as a useful investigation of approaches aimed to restore dopaminergic deficits or to monitor disease progression, this modeling cannot serve as a pathomorphologic surrogate for the loss of striatal dopaminergic neurons. Dietz, V. (2001). "Gait disorder in spasticity and Parkinson's disease." Adv Neurol 87: 143-54. The central programming, timing, and reciprocal mode of leg muscle activation during gait are basically intact in patients with spastic paresis. Exaggerated monosynaptic reflexes are associated with a loss of the functionally essential polysynaptic reflex mechanisms, both being dependent on supraspinal control. When this control is either not yet matured (small children) or impaired (spastic paresis), inhibition of monosynaptic stretch reflexes is missing in combination with a reduced facilitation of polysynaptic reflexes. A spinal or cerebral lesion associated with paresis is followed by a transformation of motor units (and most probably shortening of muscle fibers leading to muscle contracture), such that tension development in the muscle occurs in a simpler fashion. Calf muscle tension during gait is normally determined by modulated gastrocnemius or soleus EMG activity. In the spastic leg, calf muscle tension is associated with the stretching of the tonically activated muscle. This regulation of muscle tension at a lower level is efficient insofar as it enables the patient to support body weight during gait. Consequently, physiotherapeutic approaches should be applied primarily and antispastic drug therapy secondarily in mobile patients; whereas antispastic drugs may relieve muscle spasms and improve nursing care in immobilized patients. Djaldetti, R. and E. Melamed (2001). "New therapies for Parkinson's disease." J Neurol 248(5): 357-62. In the last decade there has been a surge of new therapeutic strategies for the treatment of Parkinson's disease along with a change of concepts about how the disease should be treated. The gold standard remains levodopa preparations, which have a rapid and dramatic symptomatic effect by replenishing the reduced dopamine levels in caudate and putamen nuclei. However, keeping in mind the complications that may emerge following long-term treatment, its initiation should possibly be delayed to the more advanced stages of the illness, especially in younger patients, in favour of dopamine agonists monotherapy. The adverse reactions that become prominent and disabling in late stages of the disease, i. e., dyskinesias, response fluctuations, and psychiatric side effects, can currently be managed by novel pharmacological as well as surgical strategies. Future therapies will focus on transplantation of dopaminergic embryonic tissue, gene therapy, and neuroprotective treatments. Djaldetti, R., E. Melamed, et al. (2001). "Abnormal skin wrinkling in the less affected side in hemiparkinsonism-a possible test for sympathetic dysfunction in Parkinson's disease." Biomed Pharmacother 55(8): 475-8. Some patients with Parkinson's disease (PD) suffer from autonomic dysfunction, even in the early stage of the disease. We examined the skin wrinkling response following immersion of the hands in warm water in 18 patients with hemiparkinsonism. This test evaluates the function of the sympathetic autonomic system. Mean age of the patients was 61 +/- 10 and mean disease duration 5.5 +/- 3.5 years. Both hands of each patient were immersed in warm water for 30 minutes and the number of skin ridges of the fingertip of each finger was counted. The results of each hand were compared to those of nine healthy controls. The mean number of the ridges of the less affected hand was significantly decreased as compared to the affected hand and controls (6.1 +/- 6.8 vs 13.1 +/- 6.8 and 15.3 +/- 8.5, respectively; P < 0.01). These results suggest that autonomic dysfunction is prevalent in the less affected side of patients with PD and can be simply tested by the skin response test. Djaldetti, R., V. Rosmarin, et al. (2001). "The pharmacokinetic profile of the "first ever" oral dose of levodopa in de novo patients with Parkinson's disease." Clin Neuropharmacol 24(2): 95-8. To understand the delay in the clinical benefit that commonly occurs after initiation of levodopa (L-Dopa) treatment, we examined the pharmacokinetic profile of L-Dopa after the first oral dose ever taken of L-Dopa/carbidopa in untreated patients with Parkinson's disease and followed these parameters after 1 month of treatment. This was performed in correlation with the clinical therapeutic effect. Plasma levels of L-Dopa were measured with use of high-performance liquid chromatography with electrochemical detection after administration of the "first ever" 125 mg L-Dopa/12.5 mg carbidopa tablet in 15 patients with de novo Parkinson's disease (mean age, 69 +/- 11 y, mean disease duration, 1.5 +/- 0.8 years). Blood samples were drawn before administration and thereafter at various intervals for a period of 4 hours. Repeated measurements after the same oral dose were performed after 1 month of continued therapy with L-Dopa/carbidopa 125/12.5 mg three times daily. Patients were clinically evaluated by unified Parkinson's disease rating scale motor scores. There was a modest clinical improvement after 1 month of continuous L-Dopa treatment (motor scores, 13.1 +/- 11.6 vs. 17.6 +/- 11.7; p < 0.01). Peak plasma L-Dopa levels and area under the curve did not differ significantly between the first-ever dose and after 1 month of continuous treatment (0.9 +/- 0.1 vs. 1.0 +/- 0.1 microg/mL and 66.0 +/- 30.9 vs. 86.2 +/- 34.9 microg/mL, respectively; p < 0.1. There was also no change in time to peak levels between measurements. Results indicate that the first-ever dose of oral L-Dopa is well absorbed and that pharmacokinetic mechanisms such as reduced absorption of L-Dopa probably do not play a major role in the initial delay in clinical response to oral L-Dopa/carbidopa in patients with Parkinson's disease. The latter phenomena may be linked to central pharmacodynamic mechanisms. Dodel, R. C., K. Berger, et al. (2001). "Health-related quality of life and healthcare utilisation in patients with Parkinson's disease: impact of motor fluctuations and dyskinesias." Pharmacoeconomics 19(10): 1013-38. Idiopathic Parkinson's disease (PD) is a common chronic progressive neuro-degenerative disorder associated with the progressive loss of dopaminergic neurons in the substantia nigra. The natural course of the disease may lead to severe disability despite a variety of pharmacological and surgical treatment options. Levodopa is still the most effective symptomatic treatment for PD; however, long term use can cause a number of adverse effects including motor complications, nausea and vomiting, postural hypotension and changes in mental status. The onset of motor complications marks a crucial point in the management of PD. They may present as changes between akinetic and mobile phases (motor fluctuations) or as abnormal involuntary movements (dyskinesias). After levodopa treatment for 3 to 5 years, motor complications occur in approximately 50% of patients, and after 10 years in >80% of patients. Treatment options have recently expanded as new drugs have been licensed and surgical procedures refined. Patients with motor complications present a demanding task in disease management, and often multiple drugs and high dosages are necessary to achieve only suboptimal control, resulting in increased healthcare utilisation. Costs increase considerably in patients with motor fluctuations and dyskinesias compared with patients without these symptoms. In a French study, 6-month direct medical costs per patient increased from 1648 euros (EUR) to EUR3028 in patients without and with motor fluctuations, respectively. In a recent French study a significant difference in monthly direct medical costs was found in patients with and without dyskinesias (EUR560 vs 170). Unfortunately, no data are available on the effect of motor complications on indirect costs. Several studies have shown that health-related quality of life (HR-QOL) is reduced when motor fluctuations occur. This may also be true of dyskinesias, but because of the limited number of studies a definite conclusion is not yet possible. Recently, surgical treatment options have been used to deal with advanced PD and late stage complications. Although their effect on motor complications and HR-QOL is well documented, they result in increased costs (total medical cost: EUR28920) compared with drug treatment alone and are increasingly restricted by healthcare providers. The purpose of this article is to review the available data from pharmacotherapeutic. surgical and economic studies on HR-QOL and healthcare expenditure in patients with PD, with a major focus on the impact of motor fluctuations and dyskinesias. Dodel, R. C., F. Lohmuller, et al. (2001). "A polymorphism in the intronic region of the IL-1alpha gene and the risk for Parkinson's disease." Neurology 56(7): 982-3. Doevendans, P. A. and H. J. Wellens (2001). "Wolff-Parkinson-white syndrome: a genetic disease?" Circulation 104(25): 3014-6. Doty, R. L. (2001). "Olfactory deficit in Alzheimer's disease?" Am J Psychiatry 158(9): 1533-4; discussion 1534-5. Doty, R. L. (2001). "Olfaction." Annu Rev Psychol 52: 423-52. The main and accessory olfactory systems have received considerable attention on the part of scientists and clinicians during the last decade, largely because of (a) quantum advances in understanding their genetically expressed receptor mechanisms, (b) evidence that their receptor cells undergo neurogenesis and both programmed and induced cell death, and (c) important technical and practical developments in psychophysical measurement. The latter developments have led to the proliferation of standardized olfactory testing in laboratories and clinics, and to the discovery that smell loss is among the first signs of a number of neurodeg