Parkinson's Disease References: 2003
(570 References)
(2003). "[In Process Citation]." Genetika 39(2): 223-8.
A method for analysis of deletions and duplications of individual exons and groups of exons in the parkin gene (PARK2) in both homozygous and heterozygous states has been developed. The method is based on semiquantitative polymerase chain reaction (PCR). The method has been used for analysis of the frequency of deletions in gene PARK2 in patients with idiopathic Parkinson's disease from Bashkortostan. Two unrelated patients have been found to carry a deletion of the 12th (last) exon of gene PARK2. Possibly, this deletion has caused the disease in the given patients.
(2003). "[Parkinson disease: effective treatment of sleep disturbances]." Fortschr Neurol Psychiatr 71(1): 2 p following 54.
Aarsland, D., K. Andersen, et al. (2003). "Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study." Arch Neurol 60(3): 387-92.
BACKGROUND: Few longitudinal studies of dementia in Parkinson disease (PD) have been reported, and the proportion of patients with PD who eventually develop dementia is unknown. OBJECTIVE: To examine the 8-year prevalence, characteristics, and risk factors of dementia in patients with PD. METHODS: Patients were recruited from an epidemiological study of PD in the county of Rogaland, Norway, using explicit criteria for PD. Subjects with cognitive impairment at disease onset were excluded. A semistructured caregiver-based interview, cognitive rating scales, and neuropsychological tests were used to diagnose dementia according to criteria from the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition at baseline and 4 and 8 years later. A population-based sample of 3295 subjects in the municipality of Odense, Denmark, was used as a comparison group and examined at baseline and after 2 and 5 years. RESULTS: We included 224 patients with PD (116 women). At baseline, 51 patients (26%) had dementia. Fifty-five patients died, and 10 refused follow-up without their dementia status known. Forty-three and 28 new cases of dementia were identified at the 4- and 8-year evaluations, respectively. The 4-year prevalence of dementia in PD was nearly 3 times higher than in the non-PD group. The 8-year prevalence in PD was 78.2% (95% confidence interval [CI], 71.1-84.0). Risk factors for dementia were hallucinations before baseline (odds ratio [OR] = 3.1; 95% CI, 1.6-6.2) and akinetic-dominant or mixed tremor/akinetic PD (OR = 3.3; 95% CI, 1.2-8.5). CONCLUSIONS: More than three quarters of this representative PD cohort developed dementia during the 8-year study period. Early hallucinations and akinetic-dominant PD were associated with an increased risk of dementia.
Abbruzzese, G. and A. Berardelli (2003). "Sensorimotor integration in movement disorders." Mov Disord 18(3): 231-40.
Although current knowledge attributes movement disorders to a dysfunction of the basal ganglia-motor cortex circuits, abnormalities in the peripheral afferent inputs or in their central processing may interfere with motor program execution. We review the abnormalities of sensorimotor integration described in the various types of movement disorders. Several observations, including those of parkinsonian patients' excessive reliance on ongoing visual information during movement tasks, suggest that proprioception is defective in Parkinson's disease (PD). The disturbance of proprioceptive regulation, possibly related to the occurrence of abnormal muscle-stretch reflexes, might be important for generating hypometric or bradykinetic movements. Studies with somatosensory evoked potentials (SEPs), prepulse inhibition, and event-related potentials support the hypothesis of central abnormalities of sensorimotor integration in PD. In Huntington's disease (HD), changes in SEPs and long-latency stretch reflexes suggest that a defective gating of peripheral afferent input to the brain might impair sensorimotor integration in cortical motor areas, thus interfering with the processing of motor programs. Defective motor programming might contribute to some features of motor impairment in HD. Sensory symptoms are frequent in focal dystonia and sensory manipulation can modify the dystonic movements. In addition, specific sensory functions (kinaesthesia, spatial-temporal discrimination) can be impaired in patients with focal hand dystonia, thus leading to a "sensory overflow." Sensory input may be abnormal and trigger focal dystonia, or defective "gating" may cause an input-output mismatch in specific motor programs. Altogether, several observations strongly support the idea that sensorimotor integration is impaired in focal dystonia. Although elemental sensation is normal in patients with tics, tics can be associated with sensory phenomena. Some neurophysiological studies suggest that an altered "gating" mechanism also underlies the development of tics. This review underlines the importance of abnormal sensorimotor integration in the pathophysiology of movement disorders. Although the physiological mechanism remains unclear, the defect is of special clinical relevance in determining the development of focal dystonia.
Abe, Y., T. Kachi, et al. (2003). "Occipital hypoperfusion in Parkinson's disease without dementia: correlation to impaired cortical visual processing." J Neurol Neurosurg Psychiatry 74(4): 419-22.
OBJECTIVE: The purpose of this study was to analyse changes in regional cerebral blood flow (rCBF) in Parkinson's disease (PD) without dementia. METHODS: Twenty eight non-demented patients with PD and 17 age matched normal subjects underwent single photon emission computed tomography with N-isopropyl-p-[(123)I]iodoamphetamine to measure rCBF. The statistical parametric mapping 96 programme was used for statistical analysis. RESULTS: The PD patients showed significantly reduced rCBF in the bilateral occipital and posterior parietal cortices (p<0.01, corrected for multiple comparison p<0.05), when compared with the control subjects. There was a strong positive correlation between the score of Raven's coloured progressive matrices (RCPM) and the rCBF in the right visual association area (p<0.01, corrected for multiple comparison p<0.05) among the PD patients. CONCLUSIONS: This study showed occipital and posterior parietal hypoperfusion in PD patients without dementia. Furthermore, it was demonstrated that occipital hypoperfusion is likely to underlie impairment of visual cognition according to the RCPM test, which is not related to motor impairment.
Abe, T., C. Isobe, et al. (2003). "Alteration of 8-hydroxyguanosine concentrations in the cerebrospinal fluid and serum from patients with Parkinson's disease." Neurosci Lett 336(2): 105-8.
In order to investigate the possible role of oxidative RNA damage in the pathogenesis of Parkinson's disease (PD), the concentrations of the oxidative stress marker 8-hydroxyguanosine (8-OHG) were measured in the cerebrospinal fluid (CSF) and the serum of patients with PD and control subjects. The concentration of 8-OHG in CSF in PD patients was approximately three-fold that in controls (P < 0.001). The concentration of 8-OHG in CSF decreased significantly with the duration of disease (r(s) = -0.46, P < 0.05). However, the concentration of 8-OHG in serum was not significantly altered in PD patients compared to that in controls. In addition, the concentration of 8-OHG in CSF showed no correlation with that in serum in both the controls and PD patients suggesting that the 8-OHG concentrations in the CSF do not reflect those in serum and may be probably reflect those in brain tissue. These in vivo findings suggest a possible role of 8-OHG and increased oxidative RNA damage in the early stage of the development of PD.
Adler, C. H., J. N. Caviness, et al. (2003). "Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson's disease." Mov Disord 18(3): 287-93.
We assessed the safety and efficacy of modafinil for the treatment of excessive daytime sleepiness in patients with Parkinson's disease (PD). This was a single-site, randomized, double-blind, placebo-controlled crossover study of 21 PD patients having an Epworth Sleepiness Scale (ESS) score >/=10. They received either placebo or modafinil 200 mg/day for 3 weeks, followed by a washout week, then the alternate treatment for 3 weeks. The ESS data demonstrated a carryover effect, so the changes from baseline ESS scores were compared between the two treatments for period 1 only. The ESS scores for the placebo group went from 16.0 +/- 4.2 (mean +/- SD) to 17.0 +/- 5.1 and for the modafinil group went from 17.8 +/- 4.2 to 14.4 +/- 5.7 (P = 0.039). There was no significant carryover effect for any other measure. The patient Clinical Global Impression of Change (+3 to -3) improved by 0.75 on modafinil compared with 0.15 for placebo (P = 0.07). A total of 7 of 20 (35%) of the patients reported some improvement on modafinil but not placebo. There was no significant improvement or worsening of the UPDRS subscores I-III, Timed Tap test, or time on. Vital signs, electrocardiograms, and lab tests were unchanged. Modafinil was very well tolerated. Our data demonstrate that, in a small sample size, administration of 200 mg/day of modafinil was associated with few side effects and was modestly effective for the treatment of excessive daytime sleepiness in patients with PD.
Agid, Y., I. Arnulf, et al. (2003). "Parkinson's disease is a neuropsychiatric disorder." Adv Neurol 91: 365-70.
Ahlskog, J. E. (2003). "Slowing Parkinson's disease progression: recent dopamine agonist trials." Neurology 60(3): 381-9.
In recent clinical trials, chronic treatment of patients with PD with pramipexole or ropinirole was associated with a slower decline of imaged striatal dopaminergic signal, compared to levodopa monotherapy. Although this could reflect slowed progression of PD, equally plausible is a pharmacologic effect on proteins that interact with the imaging radioligands. To date, there is no compelling evidence favoring dopamine agonists over levodopa; either is an appropriate choice for initial treatment of PD.
Akincioglu, C., M. Unlu, et al. (2003). "Cardiac innervation and clinical correlates in idiopathic Parkinson's disease." Nucl Med Commun 24(3): 267-71.
SUMMARY We evaluated the cardiac innervation status of patients with idiopathic Parkinson's disease (IPD), in order to recognize cardiac dysautonomia at an early clinical stage, using I- -iodobenzylguanidine ( I-MIBG) scintigraphy and its relation to other clinical and laboratory parameters. Fourteen patients with IPD at Hoehn-Yahr stage I and 11 age-matched controls were studied. Patients were scored according to the Unified Parkinson's Disease Rating Scale (UPDRS) in aspects of daily life activities, cognitive and emotional status and motor examination. All patients underwent 5 min electrocardiographic recordings in order to assess the heart rate variability. Planar I-MIBG studies at 15 min and 3 h after intravenous injection of 185 MBq were performed. Heart-to-mediastinum (H/M) ratios were calculated. Plasma catecholamine levels were also evaluated. The mean H/M ratios in patients and controls were 1.84+/-0.40 and 2.35+/-0.29, respectively ( <0.05). Although the mean plasma adrenaline and noradrenaline levels were in the normal range, a weak inverse correlation existed between the noradrenaline levels and late I-MIBG H/M ratios ( =-0.442), which was not statistically significant. There were no correlations between the other parameters. Eight patients had normal electrocardiography, whereas four had findings of autonomic imbalance. In conclusion, cardiac dysautonomia is common and seems to occur independent of the clinical stage and symptoms in patients with IPD. I-MIBG scintigraphy is a powerful tool in its assessment.
Al-Chalabi, A. and C. C. Miller (2003). "Neurofilaments and neurological disease." Bioessays 25(4): 346-55.
Neurofilaments are one of the major components of the neuronal cytoskeleton and are responsible for maintaining the calibre of axons. They are modified by post-translational changes that are regulated in complex fashions including by the interaction with neighbouring glial cells. Neurofilament accumulations are seen in several neurological diseases and neurofilament mutations have now been associated with Charcot-Marie-Tooth disease, Parkinson's disease and amyotrophic lateral sclerosis. In this review, we discuss the structure, normal function and molecular pathology of neurofilaments. BioEssays 25:346-355, 2003.
Al-Hayk, K. and M. S. LeDoux (2003). "Epilepsia partialis continua mistaken for Parkinson's disease." Mov Disord 18(1): 107.
Albanese, A. (2003). "Review: several drugs are efficacious for symptomatic treatment of Parkinson disease." ACP J Club 138(1): 14.
Albin, R. L. and K. A. Frey (2003). "Initial agonist treatment of Parkinson disease: a critique." Neurology 60(3): 390-4.
The evidence supporting initial dopamine agonist treatment of PD is reviewed. The two rationales for initial agonist treatment are reduced frequency of motor complications and possible relative neuroprotection by dopamine agonists. The basic science supporting these rationales is equivocal. The clinical evidence for advantages of initial agonist treatment is incomplete. More data are required to determine the optimal initial treatment for PD.
Alegret, M., F. Valldeoriola, et al. (2003). "Cognitive effects of unilateral posteroventral pallidotomy: A 4-year follow-up study." Mov Disord 18(3): 323-8.
We assessed the long-term neuropsychological effects of unilateral posteroventral pallidotomy in Parkinson's disease. Eleven Parkinson's disease patients, from an original cohort of 15 consecutive patients who underwent pallidotomy, were evaluated. A neuropsychological battery was administered to each patient before (3 days) and after (3 months and 4 years) surgery during the effects of levodopa. The following tests were administered: Rey's Auditory-Verbal Learning Test, Visual Associative Learning test from the Wechsler Memory Scale-Revised, Luria's motor alternation, Benton's Judgment of Line Orientation, Trail Making, phonetic verbal fluency, Stroop test, Petrides' working memory tasks, Beck's depression questionnaire and the Maudsley obsessional-compulsive inventory. In the 3-month postoperative assessment, there was a significant worsening in phonetic verbal fluency and an improvement in Benton's Judgment of Line Orientation test. In the 4-year follow-up assessment, phonetic verbal fluency and Benton's Judgment of Line Orientation test returned to baseline scores. Although there was no significant difference between pre- and postsurgical scores for long-term visual associative memory, there was a significant deterioration between 3-month and 4-year follow-up performances. Our results suggest that unilateral posteroventral pallidotomy may produce transient changes in prefrontal and visuospatial functions, but there is no evidence of permanent neuropsychological effects.
Allam, M. F., A. S. Del Castillo, et al. (2003). "[Parkinson s disease, tobacco and age: meta analysis]." Rev Neurol 36(6): 510-3.
INTRODUCTION. Epidemiological studies have demonstrated contradictory results about the association between smoking and the risk of Parkinson s disease (PD). OBJECTIVE. Examine the hypothesis of the EUROPARKINSON group that smoking protects against PD only in patients below 75 years of age. MATERIAL AND METHODS. We conducted a meta analysis including all observational studies that were published about this association before January 2001. All languages were included with no restriction for year of publication. Risk estimate and its 95% confidence interval (95% CI) were extracted or calculated for all localized studies in patients below or above 75 years of age. RESULTS. Seventeen studies investigated the association between PD risk and smoking in patients below 75 years of age. Meanwhile, only seven studies investigated the association in patients above 75 years of age. The fixed effect pooled analysis in patients below 75 years of age was 0.59 (95% CI: 0.52 0.67), with insignificant homogeneity test. Patients above 75 years of age had fixed effect pooled analysis of 0.76 (95% CI: 0.59 0.99), with insignificant homogeneity test. CONCLUSIONS. The pooled analysis in patients below 75years of age clearly demonstrates that smoking is inversely associated with PD risk. The 95% CI of the pooled analysis in patients above 75 years of age is nearly overlapping unity. This result is not in favor for the negative association in old patients, and confirms the hypothesis of the EUROPARKINSON group.
Allam, M. F., A. S. Del Castillo, et al. (2003). "Parkinson's disease, smoking and family history: meta-analysis." Eur J Neurol 10(1): 59-62.
To estimate the pooled risk of tobacco smoking for Parkinson's disease (PD) in patients with and without PD family history. We conducted systematic searches of Medline, PsycLIT, Embase, Current contents, Best Evidence, Nisc Mexico Biblioline, previous reviews, examination of cited reference sources and personal contact and discussion with several investigators expert in the field. Studies in all languages were considered. Published observational studies on PD and cigarette smoking stratified by PD family history were reviewed. When two or more papers were based on an identical study, the paper that principally investigated the relationship between PD, smoking stratified by PD family history or the paper that was published last was used. Three case-control studies were carried out between 1996 and 2000, of which one reported risk estimates. The risk of ever smoker in patients with positive PD family history was 0.82 (95% confidence interval 0.44-1.53). There was an obvious protective effect in the pooled estimate in patients with negative PD family history [odds ratio 0.77 (95% confidence interval 0.59-1.01)]. Although our pooled estimates show that smoking is inversely associated with the risk of PD only in patients with negative PD family history, further studies evaluating the interaction between smoking and PD family history are strongly needed.
Almeida, Q. J., L. R. Wishart, et al. (2003). "Disruptive influences of a cued voluntary shift on coordinated movement in Parkinson's disease." Neuropsychologia 41(4): 442-52.
A temporary and/or involuntary stoppage of movement is identifiable in the execution phase of writing, walking, and turning movements in individuals with Parkinson's disease (PD) and may be referred to as freezing. However, the unpredictability of such akinetic impairments has made it difficult to study experimentally. The present study compared PD and age-matched control groups in their ability to coordinate continuous and simultaneous upper limb movements in trials involving two parts. In the first part of each trial, participants performed either in-phase movements (symmetric, simultaneous movement toward and away from the midline of the body), or anti-phase movements (isodirectional). At the midpoint of the trial, they were signaled by an auditory metronome to execute an intentional and voluntarily switch from the coordination currently being performed to the opposite coordination pattern. In the second half of the trial participants were required to maintain performance in the other coordination mode. All trials were paced by an auditory metronome at one of three different speeds (0.75, 1.25, 1.75 Hz). Measures of temporal coordination (relative phase) indicated that overall, participants with PD required significantly longer periods of time to achieve a switch between coordination patterns compared to healthy controls, and experienced greater difficulty changing from the in-phase to anti-phase mode of coordination. As well, movement stoppage was observed in 53.9% of the in-phase to anti-phase switch trials, but in only 15.5% of the anti-phase to in-phase trials. We conclude that interruptions to movement execution are most common when switching to coordinated movements that impose greater motor demands in individuals with PD.
Alves da Costa, C. (2003). "Recent advances on alpha-synuclein cell biology: functions and dysfunctions." Curr Mol Med 3(1): 17-24.
Alpha-synuclein is a recently discovered protein that was first identified as the major non amyloid component of senile plaques, the cerebral lesion likely responsible for Alzheimer's disease. The role of alpha-synuclein in another brain disease namely Parkinson's disease, has been more deeply documented. It appears that alpha-synuclein fills up the intracytoplasmic inclusions called Lewy bodies that likely contribute to the etiology of Parkinson's disease. Furthermore, rare familial forms of Parkinson's disease have been shown to be linked to autosomal dominant mutations of alpha-synucleins. Is alpha-synuclein a bridge between Alzheimer's and Parkinson's diseases? Could it be seen as a common denominator for these two neurodegenerative diseases? These issues could be better addressed by further delineating the physiological function of alpha-synuclein and, as a corollary, the dysfunction taking place along with the diseases. Here, I will review the recent advances concerning the physiology of alpha-synuclein and will particularly focus on the post-traductional events leading to drastic biophysical transformations. I will describe recent works suggesting that these modifications directly modulate the normal function of alpha-synuclein, likely accounting for the dysfunction associated with Parkinson's disease and perhaps contributing to Alzheimer's pathology.
Anderson, M. E., N. Postupna, et al. (2003). "Effects of high-frequency stimulation in the internal globus pallidus on the activity of thalamic neurons in the awake monkey." J Neurophysiol 89(2): 1150-60.
The reduction in symptoms of Parkinson's disease produced by high-frequency stimulation (HFS) in the internal globus pallidus (GPi) has been proposed to be due to stimulus-induced inactivation of pallidal neurons and resulting disinhibition of thalamic neurons. We tested this in awake Macaca fascicularis by stimulating between pairs of electrodes inserted into GPi under electrophysiological control and recording the responses evoked in thalamic neurons. HFS produced a reduction, not an increase, in discharge frequency during the stimulus train in 77% of the responsive thalamic neurons. Only 16% of the responsive cells showed an increase in discharge during stimulation and, for some of these, stimulation at a similar intensity produced contralateral muscle contraction, a probable sign of current spread to the internal capsule. The few thalamic neurons studied during bursting had a reduction in burst frequency and duration during HFS. We conclude that high-frequency stimulation within GPi does not necessarily facilitate thalamic discharge, and it may act, instead, to interrupt abnormal patterns of thalamic discharge associated with parkinsonian symptoms.
Antony, T., W. Hoyer, et al. (2003). "Cellular polyamines promote the aggregation of alpha-synuclein." J Biol Chem 278(5): 3235-40.
The cellular polyamines putrescine, spermidine, and spermine accelerate the aggregation and fibrillization of alpha-synuclein, the major protein component of Lewy bodies associated with Parkinson's disease. Circular dichroism and fluorometric thioflavin T kinetic studies showed a transition of alpha-synuclein from unaggregated to highly aggregated states, characterized by lag and transition phases. In the presence of polyamines, both the lag and transition times were significantly shorter. All three polyamines accelerated the aggregation and fibrillization of alpha-synuclein to a degree that increased with the total charge, length, and concentration of the polyamine. Electron and scanning force microscopy of the reaction products after the lag phase revealed the presence of aggregated particles (protofibrils) and small fibrils. At the end of the transition phase, alpha-synuclein formed long fibrils in all cases, although some morphological variations were apparent. In the presence of polyamines, fibrils formed large networks leading ultimately to condensed aggregates. In the absence of polyamines, fibrils were mostly isolated. We conclude that the polyamines at physiological concentrations can modulate the propensity of alpha-synuclein to form fibrils and may hence play a role in the formation of cytosolic alpha-synuclein aggregates.
Arakawa, K., H. Tomi, et al. (2003). "Middle latency auditory-evoked potentials in myotonic dystrophy: relation to the size of the CTG trinucleotide repeat and intelligent quotient." J Neurol Sci 207(1-2): 31-6.
OBJECTIVE: Major components of MLAEPs are thought to originate in the temporal lobe. Absence of the Pb potential has been demonstrated in MLAEPs in Alzheimer's disease and demented Parkinson's disease patients. To validate usefulness of middle latency auditory-evoked potentials (MLAEPs) in evaluating the central nervous system (CNS) involvement of myotonic dystrophy (MyD). METHODS: MLAEPs were recorded in eight patients with MyD and nine normal control subjects. In the patient group, the size of the CTG triplet repeat expansion within the dystrophia myotonica protein kinase (DMPK) gene and the revised Wechsler Adult Intelligence Scale (WAIS-R) were also assessed. RESULTS: The latency of the Nb potential showed a significant correlation with the size of the CTG repeat expansion (r=0.734, P=0.036). The Pb latency also tended to prolong according to CTG amplification (r=0.644, P=0.087). The amplitudes of Na and Pa significantly increased compared with those of normal control subjects (P=0.024 and 0.016, respectively). However, they did not correlate with IQ or CTG amplification. CONCLUSIONS: Abnormal MLAEPs may indicate CNS involvement in MyD. Although the precise generating mechanisms of Nb are unclear, the correlation of Nb latency with CTG amplification suggests that MLAEPs can reflect the extent of genetic abnormality.
Arima, H., K. Sobue, et al. (2003). "Transient and reversible parkinsonism after acute organophosphate poisoning." J Toxicol Clin Toxicol 41(1): 67-70.
Parkinsonism is a rare complication in patients with organophosphate poisoning. To date there have been two cases of transient parkinsonism after acute and severe cholinergic crisis, both of which were successfully treated using amantadine, an anti-parkinsonism drug. We report on an 81-year-old woman who was admitted for the treatment of acute severe organophosphate poisoning. Although acute cholinergic crisis was treated successfully with large doses of atropine and 2-pyridine aldoxime methiodide (PAM), extrapyramidal manifestations were noticed on hospital day 6. The neurological symptoms worsened, and the diagnosis of parkinsonism was made by a neurologist on hospital day 9. Immediately, biperiden (5mg), an anti-parkinsonism drug, was administered intravenously, and her symptoms markedly improved. From the following day, biperiden (5 mg/day) was given intramuscularly for eight days. Subsequently, neurological symptoms did not relapse, and no drugs were required. Our patient is the third case of parkinsonism developing after an acute severe cholinergic crisis and the first case successfully treated with biperiden. Patients should be carefully observed for the presence of neurological signs in this kind of poisoning. If present, an anti-parkinsonism drug should be considered.
Aruoma, O. I. (2003). "Methodological considerations for characterizing potential antioxidant actions of bioactive components in plant foods." Mutat Res 523-524: 9-20.
The study of free radicals and antioxidants in biology is producing medical revolution that promises a new age of health and disease management. From prevention of the oxidative reactions in foods, pharmaceuticals and cosmetics to the role of reactive oxygen species (ROS) in chronic degenerative diseases including cancer, autoimmune, inflammatory, cardiovascular and neurodegenerative (e.g. Alzheimer's disease, Parkinson's disease, multiple sclerosis, Downs syndrome) and aging challenges continue to emerge from difficulties associated with methods used in evaluating antioxidant actions in vivo. Our interest presently is focused on development of neurodegeneration models based on the integrity of neuronal cells in the central nervous system and how they are protected by antioxidants when challenged by neurotoxins as well as Fenton chemistry models based on the profile of polyunsaturated fatty acids (PUFAs) for the assessment of antioxidant actions in vivo. Use continues to be made of several in vitro analytical tools to characterise the antioxidant propensity of bioactive compounds in plant foods and supplements. For example, the oxygen radical absorbance capacity (ORAC), ferric reducing antioxidant power (FRAP), total oxidant scavenging capacity (TOSC), the deoxyribose assay, assays involving oxidative DNA damage, assays involving reactive nitrogen intermediates (e.g. ONOO(-)), Trolox equivalent antioxidant capacity (TEAC) and the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. There is need to agree governance on in vitro antioxidant methods based on an understanding of the mechanisms involved. Because some of the assays are done in non-physiological pH values, it is impossible to extrapolate the results to physiological environment. The consensus of opinion is that a mix of these tools should be used in assessing the antioxidant activities in vitro. The proof of bio-efficacy must emanate from application of reliable in vivo models where markers of baseline oxidative damage are examined from the standpoint of how they are affected by changes in diet or by antioxidant supplements.
Asai, Y., T. Nomura, et al. (2003). "A coupled oscillator model of disordered interlimb coordination in patients with Parkinson's disease." Biol Cybern 88(2): 152-62.
Coordination between the left and right limbs during cyclic movements, which can be characterized by the amplitude of each limb's oscillatory movement and relative phase, is impaired in patients with Parkinson's disease (PD). A pedaling exercise on an ergometer in a recent clinical study revealed several types of coordination disorder in PD patients. These include an irregular and burst-like amplitude modulation with intermittent changes in its relative phase, a typical sign of chaotic behavior in nonlinear dynamical systems. This clinical observation leads us to hypothesize that emergence of the rhythmic motor behaviors might be concerned with nonlinearity of an underlying dynamical system. In order to gain insight into this hypothesis, we consider a simple hard-wired central pattern generator model consisting of two identical oscillators connected by reciprocal inhibition. In the model, each oscillator acts as a neural half-center controlling movement of a single limb, either left or right, and receives a control input modeling a flow of descending signals from higher motor centers. When these two control inputs are tonic-constant and identical, the model has left-right symmetry and basically exhibits ordered coordination with an alternating periodic oscillation. We show that, depending on the intensities of these two control inputs and on the difference between them that introduces asymmetry into the model, the model can reproduce several behaviors observed in the clinical study. Bifurcation analysis of the model clarifies two possible mechanisms for the generation of disordered coordination in the model: one is the spontaneous symmetry-breaking bifurcation in the model with the left-right symmetry. The other is related to the degree of asymmetry reflecting the difference between the two control inputs. Finally, clinical implications by the model's dynamics are briefly discussed.
Ascherio, A., H. Chen, et al. (2003). "Caffeine, postmenopausal estrogen, and risk of Parkinson's disease." Neurology 60(5): 790-5.
BACKGROUND: Men who regularly consume caffeinated drinks have a lower risk of PD than do nondrinkers, but this relation has not been found in women. Because this sex difference could be due to hormonal effects, the authors examined prospectively the risk of PD according to use of postmenopausal hormones and caffeine intake among participants in the Nurses' Health Study. METHODS: The study population comprised 77,713 women free of PD, stroke, or cancer at baseline, who were postmenopausal at baseline or reached menopause before the end of the study. During 18 years of follow-up the authors documented 154 cases of PD. RESULTS: Overall, the risk of PD was similar in women using hormones and women who never used hormones (relative risk 1.02, 95% CI 0.69 to 1.52). Use of hormones, however, was associated with a reduced risk of PD among women with low caffeine consumption (RR 0.39, 95% CI 0.13 to 1.17), and with increased risk among women with high caffeine consumption (RR 2.44, 95% CI 0.75 to 7.86; p for interaction = 0.01). Among hormone users, women consuming six or more cups of coffee per day had a fourfold higher risk of PD (RR 3.92, 95% CI 1.49 to 10.34; p = 0.006) than did women who never drink coffee. CONCLUSION: These results suggest that caffeine reduces the risk of PD among women who do not use postmenopausal hormones, but increases risk among hormone users. Clinical trials of caffeine or estrogens in women should avoid the combined use of these agents.
Ashby, F. G., S. Noble, et al. (2003). "Category learning deficits in Parkinson's disease." Neuropsychology 17(1): 115-24.
Sixteen patients with Parkinson's disease (PD), 15 older controls (OCs), and 109 younger controls (YCs) were compared in 2 category-learning tasks. Participants attempted to assign colored geometric figures to 1 of 2 categories. In rule-based tasks, category membership was defined by an explicit rule that was easy to verbalize, whereas in information-integration tasks, there was no salient verbal rule and accuracy was maximized only if information from 3 stimulus components was integrated at some predecisional stage. The YCs performed the best on both tasks. The PD patients were highly impaired compared with the OCs, in the rule-based categorization task but were not different from the OCs in the information-integration task. These results support the hypothesis that learning in these 2 tasks is mediated by functionally separate systems.
Askenasy, J. J. (2003). "Sleep disturbances in Parkinsonism." J Neural Transm 110(2): 125-50.
The present article is meant to suggest an approach to the guidelines for the therapy of sleep disturbances in Parkinson's Disease (PD) patients.The factors affecting the quality of life in PD patients are depression, sleep disturbances and dependence. A large review of the literature on sleep disturbances in PD patients, provided the basis for the following classification of the sleep-arousal disturbances in PD patients.We suggest a model based on 3 steps in the treatment of sleep disturbances in PD patients. This model allowing the patient, the spouse or the caregiver a quiet sleep at night, may postpone the retirement and the institutionalization of the PD patient.I.Correct diagnosis of sleep disorders based on detailed anamnesis of the patient and of the spouse or of the caregiver. One week recording on a symptom diary (log) by the patient or the caregiver. Correct diagnosis of sleep disorders co morbidities. Selection of the most appropriate sleep test among: polysomnography (PSG), multiple sleep latency test (MSLT), multiple wake latency test (MWLT), Epworth Sleepiness Scale, actigraphy or video-PSG. II. The nonspecific therapeutic approach consists in: a) Checking the sleep effect on motor performance, is it beneficial, worse or neutral. b) Psycho-physical assistance. c) Dopaminergic adjustment is necessary owing to the progression of the nigrostriatal degeneration and the increased sensitivity of the terminals, which alter the normal modulator mechanisms of the motor centers in PD patients. Among the many neurotransmitters of the nigro-striatal pathway one can distinguish two with a major influence on REM and NonREM 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 PD motor symptoms. L-Dopa and its agonists by suppressing cholinergic receptors suppress REM sleep. The permanent adjustment according to the progression of the degenerative process of the disease will diminishe aggravation.The following types of sleep-arousal disturbances have to be considered in PD patients: - Sleep DisturbancesLight Fragmented Sleep (LFS)Abnormal Motor Activity During Sleep (AMADS)REM Behavior Disorders (RBD)Sleep Related Breathing Disorders (SRBD)Sleep Related Hallucinations (SRH)Sleep Related Psychotic Behavior (SRPB) - Arousal DisturbancesSleep Attacks (SA)Excessive Daytime Sleepiness (EDS)Each syndrome has to receive a score according to its severity III. The specific therapy consists in: LFS: Benzodiazepines & Nondiazepines.AMADS: Clonazepam, Opioid, Apomorphine infusion; RBD: Clonazepam and dopaminergic agonists; SRBD: CPAP, UPPP, nasal interventions, losing weight; SRH: Clozapine, Risperidone; SRPD: Nortriptyline, Clozapine, Olanzepine; SA-adjustment; EDS-arousing drugs. Each therapeutic approach must be tailored to the individual PD patient.
Auricchio, A., P. D. Acton, et al. (2003). "In vivo quantitative noninvasive imaging of gene transfer by single-photon emission computerized tomography." Hum Gene Ther 14(3): 255-61.
Systems aimed at detecting gene expression noninvasively in vivo are desirable for evaluating the outcome of gene transfer in clinical trials. Several approaches have been exploited using magnetic resonance imaging and spectroscopy ((31)P MRS), positron emission tomography (PET), single-photon emission tomography (SPECT), and detection of bioluminescent signals. An ideal system is based on transfer of a marker gene, the activity of which can be detected against a background from the target tissue without interfering with normal physiology or eliciting an immune response. The majority of approaches described to date use genes encoding a nonmammalian protein that can elicit immune responses or a transmembrane receptor as a marker gene whose ectopic expression may cause aberrant signaling in the target cell through binding to endogenous ligands. The dopamine transporter (DAT) is normally expressed at high levels, mainly in the dopaminergic neurons of the central nervous system. We previously synthesized a radioactive ligand, [(99m)Tc]TRODAT-1, that binds with high affinity to the dopamine transporter, allowing for SPECT imaging of the striatum in normal control subjects and individuals affected with Parkinson's disease. Here we describe a strategy to monitor gene transfer based on adeno-associated viral vector (AAV)-mediated transduction of DAT in murine muscle followed by [(99m)Tc]TRODAT-1 imaging by SPECT of cells expressing the transgene. We show that quantitative, noninvasive imaging of gene transfer is successfully achieved in vivo, using a single-photon computed tomography camera. This system employs a reporter gene encoding a mammalian protein that is absent in most tissues, has no enzymatic activity, and does not activate intracellular pathways. This should be useful to monitor gene transfer in the settings of gene therapy.
Avshalumov, M. V., B. T. Chen, et al. (2003). "Glutamate-Dependent Inhibition of Dopamine Release in Striatum Is Mediated by a New Diffusible Messenger, H2O2." J Neurosci 23(7): 2744-50.
How glutamate regulates dopamine (DA) release in striatum has been a controversial issue. Here, we resolve this by showing that glutamate, acting at AMPA receptors, inhibits DA release by a nonclassic mechanism mediated by hydrogen peroxide (H(2)O(2)). Moreover, we show that GABA(A)-receptor activation opposes this process, thereby enhancing DA release. The influence of glutamate and GABA on DA release was assessed in striatal slices using carbon-fiber microelectrodes and fast-scan cyclic voltammetry. Modulation by both transmitters was prevented by H(2)O(2)-metabolizing enzymes. In addition, the influence of GABA(A)-receptor activation was lost when AMPA receptors were blocked with GYKI-52466. Together, these data show that modulation of DA release by glutamate and GABA depends on H(2)O(2) generated downstream from AMPA receptors. This is the first evidence that endogenous glutamate can lead to the generation of reactive oxygen species under physiological conditions. We also show that inhibition of DA release by H(2)O(2) is mediated by sulfonylurea-sensitive K(+) channels: tolbutamide blocked DA modulation by glutamate and by GABA. The absence of ionotropic glutamate or GABA receptors on DA terminals indicates that modulatory H(2)O(2) is generated in non-DA cells. Thus, in addition to its known excitatory actions in striatum, glutamate mediates inhibition by generating H(2)O(2) that must diffuse from postsynaptic sites to inhibit presynaptic DA release via K(+)-channel opening. These findings have significant implications not only for normal striatal function but also for understanding disease states that involve DA and oxidative stress, including disorders as diverse as Parkinson's disease and schizophrenia.
Bal, S., A. Akiotanciota, et al. (2003). "Upper extremity contractures heralding Parkinson's disease." Joint Bone Spine 70(1): 86.
Baldi, I., P. Lebailly, et al. (2003). "Neurodegenerative diseases and exposure to pesticides in the elderly." Am J Epidemiol 157(5): 409-14.
The authors investigated the hypothesis that exposure to pesticides could be related to central nervous system disorders in a prospective cohort study of 1,507 French elderly (1992-1998). Lower cognitive performance was observed in subjects who had been occupationally exposed to pesticides. In men, the relative risks of developing Parkinson's disease and Alzheimer's disease for occupational exposure assessed by a job exposure matrix were 5.63 (95% confidence interval: 1.47, 21.58) and 2.39 (95% confidence interval: 1.02, 5.63), respectively, after confounding factors were taken into account. No association was found with having a primary job in agriculture or with environmental pesticide exposure, nor was an association found in women. These results suggest the presence of neurologic impairments in elderly persons who were exposed occupationally to pesticides.
Bares, M., P. Kanovsky, et al. (2003). "Excessive daytime sleepiness and 'sleep attacks' induced by entacapone." Fundam Clin Pharmacol 17(1): 113-6.
Three patients with advanced Parkinson's disease, all of whom developed excessive daytime sleepiness and 'sleep attacks' after the administration of entacapone, are described. This is another demonstration that inappropriate daytime sleep episodes are not exclusive to dopamine agonists.
Bares, M., M. Brazdil, et al. (2003). "The effect of apomorphine administration on smooth pursuit ocular movements in early Parkinsonian patients." Parkinsonism Relat Disord 9(3): 139-44.
Electrooculography (EOG) recordings in 21 L-DOPA-naive patients suffering from Parkinson's disease (PD) were made before and after apomorphine subcutaneous administration (ASA). The effect of apomorphine on smooth pursuit eye movements (SPEM) was studied. Age-matched healthy subjects, who underwent SPEM recordings without the ASA procedure, were examined in order to compare baseline SPEM. EOG recordings were used to compare the patient group and the control group, and to compare the SPEM before and after ASA within the patient group. Significant differences in SPEM were found between both groups, as well as in the SPEM before and after ASA. The theory that SPEM is disturbed in early PD patients was confirmed. The dopaminergic control of horizontal SPEM is supposed.
Barnes, J., L. Boubert, et al. (2003). "Reality monitoring and visual hallucinations in Parkinson's disease." Neuropsychologia 41(5): 565-74.
Between 8 and 40% of Parkinson disease (PD) patients will have visual hallucinations (VHs) during the course of their illness. Although cognitive impairment has been identified as a risk factor for hallucinations, more specific neuropsychological deficits underlying such phenomena have not been established. Research in psychopathology has converged to suggest that hallucinations are associated with confusion between internal representations of events and real events (i.e. impaired-source monitoring). We evaluated three groups: 17 Parkinson's patients with visual hallucinations, 20 Parkinson's patients without hallucinations and 20 age-matched controls, using tests of visual imagery, visual perception and memory, including tests of source monitoring and recollective experience. The study revealed that Parkinson's patients with hallucinations appear to have intact visual imagery processes and spatial perception. However, there were impairments in object perception and recognition memory, and poor recollection of the encoding episode in comparison to both non-hallucinating Parkinson's patients and healthy controls. Errors were especially likely to occur when encoding and retrieval cues were in different modalities. The findings raise the possibility that visual hallucinations in Parkinson's patients could stem from a combination of faulty perceptual processing of environmental stimuli, and less detailed recollection of experience combined with intact image generation.
Bartolome, F., S. Fanjul, et al. (2003). "[Primary focal dystonia: descriptive study of 205 patients]." Neurologia 18(2): 59-65.
Objetives: To describe the clinical and epidemiologic aspects of different types of focal dystonia. Patients and methods: A total of 205 patients with primary focal dystonia were studied retrospectively and the following variables were analyzed: gender, age of onset, age at examination, evolution time, history of trauma, association with other movement disorders, fluctuations of dystonic symptoms as well as a family history of dystonia, Parkinson's disease, tremor, and lefthandedness or stuttering. We compared these variables among the different clinical categories of focal dystonia. Results: Those patients with cranial and laryngeal dystonia were significantly older at the onset of symptoms compared with patients with writer's cramp. Males were more prevalent than females in all categories of focal dystonia except for cranial dystonia. Prior history of trauma and association with tremor were more frequent in patients with cervical dystonia than in those with others dystonic categories. Most patients with cranial, cervical and laryngeal dystonia had fluctuations in the intensity of dystonic symptoms, unlike the patients with writer's cramp. Conclusions: There is a caudo-cranial gradient in age of onset and the age of onset increases as the cranial presentation becomes greater. Females are more prevalent in cranial dystonia and there is a preponderance of males in the dystonias with a lower location. The dystonias with cranial distribution frequently present fluctuations of symptoms during the day. Association with other movement disorders, such as tremor, and prior history of trauma, is common in patients with cervical dystonia. Neurologia 2003;18(2):59-65
Barzilai, A. and E. Melamed (2003). "Molecular mechanisms of selective dopaminergic neuronal death in Parkinson's disease." Trends Mol Med 9(3): 126-32.
Parkinson's disease (PD) is a progressive neurological disease caused by selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Although PD has been heavily researched, the precise etiology of nigral cell loss is still unknown and, consequently, treatment is largely symptomatic rather than preventive. There are conflicting data regarding the mode of dopaminergic cell death in PD and, hence, this remains controversial. Several mutations in specific genes have recently been linked with hereditary forms of PD. Although none of these mutations are seen in idiopathic disease cases, the elucidation of these genetic defects sheds light on the nature of idiopathic PD. It is possible that dopaminergic neurogenesis also contributes to the etiology of idiopathic PD. In addition, intracellular as well as extracellular substances found in the SNc are believed to function as damaging pathogenetic factors. These factors, and the interactions among them, might hold the secret to the underlying causes of the selective death of dopaminergic neurons in PD.
Barzilai, A., D. Daily, et al. (2003). "The molecular mechanisms of dopamine toxicity." Adv Neurol 91: 73-82.
Bauer, A. K., B. Faiola, et al. (2003). "Genetic susceptibility to benzene-induced toxicity: role of NADPH: quinone oxidoreductase-1." Cancer Res 63(5): 929-35.
Enzymes that activate and detoxify benzene are likely genetic determinants of benzene-induced toxicity.NAD(P)H: quinone oxidoreductase-1 (NQO1) detoxifies benzoquinones, proposed toxic metabolites of benzene. NQO1 deficiency in humans is associated with an increased risk of leukemia, specifically acute myelogenous leukemia, and benzene poisoning. We examined the importance of NQO1 in benzene-induced toxicity by hypothesizing that NQO1-deficient (NQO1-/-) mice are more sensitive to benzene than mice with wild-type NQO1 (NQO1+/+; 129/Sv background strain). Male and female NQO1-/- and NQO1+/+ mice were exposed to inhaled benzene (0, 10, 50, or 100 ppm) for 2 weeks, 6 h/day, 5 days/week. Micronucleated peripheral blood cells were counted to assess genotoxicity. Peripheral blood counts and bone marrow histology were used to assess hematotoxicity and myelotoxicity. p21 mRNA levels in bone marrow cells were used as determinants of DNA damage response. Female NQO1-/- mice were more sensitive (6-fold) to benzene-induced genotoxicity than the female NQO1+/+ mice. Female NQO1-/- mice had a 9-fold increase (100 versus 0 ppm) in micronucleated reticulocytes compared with a 3-fold increase in the female NQO1+/+ mice. However, the induced genotoxic response in male mice was similar between the two genotypes (> or = 10-fold increase at 100 ppm versus 0 ppm). Male and female NQO1-/- mice exhibited greater hematotoxicity than NQO1+/+ mice. p21 mRNA levels were induced significantly in male mice (>10-fold) from both strains and female NQO1-/- mice (> 8-fold), which indicates an activated DNA damage response. These results indicate that NQO1 deficiency results in substantially greater benzene-induced toxicity. However, the specific patterns of toxicity differed between the male and female mice.
Bauer, S., E. Moyse, et al. (2003). "Effects of the alpha(2)-adrenoreceptor antagonist dexefaroxan on neurogenesis in the olfactory bulb of the adult rat in vivo: selective protection against neuronal death." Neuroscience 117(2): 281-91.
A dysfunction of noradrenergic mechanisms originating in the locus coeruleus has been hypothesised to be the critical factor underlying the evolution of central neurodegenerative diseases [Colpaert FC (1994) Noradrenergic mechanism Parkinson's disease: a theory. In: Noradrenergic mechanisms in Parkinson's disease (Briley M, Marien M, eds) pp 225-254. Boca Raton, FL, USA: CRC Press Inc.]. alpha(2)-Adrenoceptor antagonists, presumably in part by facilitating central noradrenergic transmission, afford neuroprotection in vivo in models of cerebral ischaemia, excitotoxicity and devascularization-induced neurodegeneration. The present study utilised the rat olfactory bulb as a model system for examining the effects of the selective alpha(2)-adrenoceptor antagonist dexefaroxan upon determinants of neurogenesis (proliferation, survival and death) in the adult brain in vivo. Cell proliferation (5-bromo-2'-deoxyuridine labelling) and cell death associated with DNA fragmentation (terminal dideoxynucleotidyl transferase-catalysed 2'-deoxyuridine-5'-triphosphate nick end-labelling assay) were quantified following a 7-day treatment with either vehicle or dexefaroxan (0.63 mg/kg i.p., three times daily), followed by a 3-day washout period. The number of terminal dideoxynucleotidyl transferase-catalysed 2'-deoxyuridine-5'-triphosphate nick end-labelling-positive nuclei in the olfactory bulb was lower in dexefaroxan-treated rats, this difference being greatest and significant in the subependymal layer (-52%). In contrast, 5-bromo-2'-deoxyuridine-immunoreactive nuclei were more numerous (+68%) in the bulbs of dexefaroxan-treated rats whilst no differences were detected in the proliferating region of the subventricular zone. Terminal dideoxynucleotidyl transferase-catalysed 2'-deoxyuridine-5'-triphosphate nick end-labelling combination with glial fibrillary acidic protein or neuronal-specific antigen immunohistochemistry revealed that terminal dideoxynucleotidyl transferase-catalysed 2'-deoxyuridine-5'-triphosphate nick end-labelling-positive nuclei were associated primarily with a neuronal cell phenotype. These findings suggest that dexefaroxan increases neuron survival in the olfactory bulb of the adult rat in vivo, putatively as a result of reducing the apoptotic fate of telencephalic stem cell progenies.
Baufreton, J., M. Garret, et al. (2003). "D5 (not D1) dopamine receptors potentiate burst-firing in neurons of the subthalamic nucleus by modulating an L-type calcium conductance." J Neurosci 23(3): 816-25.
Dopamine is a crucial factor in basal ganglia functioning. In current models of basal ganglia, dopamine is postulated to act on striatal neurons. However, it may also act on the subthalamic nucleus (STN), a key nucleus in the basal ganglia circuit. The data presented here were obtained in brain slices using whole-cell patch clamp. They reveal that D5 dopamine receptors strengthen electrical activity in the subset of subthalamic neurons endowed with burst-firing capacity, resulting in longer discharges of spontaneous or evoked bursts. To distinguish between D1 and D5 subtypes, the action of agonists in the D1/D5 receptor family was first investigated on rat subthalamic neurons. Single-cell reverse transcription-PCR profiling showed that burst-competent neurons only expressed D5 receptors. Accordingly, receptors localized in postsynaptic membranes within the STN were labeled by a D5-specific antibody. Second, agonists in the D1/D5 family were tested in mouse brain slices. It was found that these agonists were active in D1 receptor knock-out mice in a similar way to wild-type mice or rats. This proved that D5 rather than D1 receptors were involved. Pharmacological tools (dihydropyridines, omega-conotoxins, and calciseptine) were used to identify the target of D5 receptors as an L-type channel. This was reached via G-protein and protein kinase A. The action of dopamine on D5 receptors therefore shapes neuronal activity. It contributes to normal information processing in basal ganglia outside striatum. This finding may be useful in drug therapy for various disorders involving changes in STN activity, such as Parkinson's disease and related disorders.
Beal, M. F. (2003). "Bioenergetic approaches for neuroprotection in Parkinson's disease." Ann Neurol 53(3 Suppl 1): S39-48.
There is considerable evidence suggesting that mitochondrial dysfunction and oxidative damage may play a role in the pathogenesis of Parkinson's disease (PD). This possibility has been strengthened by recent studies in animal models, which have shown that a selective inhibitor of complex I of the electron transport gene can produce an animal model that closely mimics both the biochemical and histopathological findings of PD. Several agents are available that can modulate cellular energy metabolism and that may exert antioxidative effects. There is substantial evidence that mitochondria are a major source of free radicals within the cell. These appear to be produced at both the iron-sulfur clusters of complex I as well as the ubiquinone site. Agents that have shown to be beneficial in animal models of PD include creatine, coenzyme Q(10), Ginkgo biloba, nicotinamide, and acetyl-L-carnitine. Creatine has been shown to be effective in several animal models of neurodegenerative diseases and currently is being evaluated in early stage trials in PD. Similarly, coenzyme Q(10) is also effective in animal models and has shown promising effects both in clinical trials of PD as well as in clinical trials in Huntington's disease and Friedreich's ataxia. Many other agents show good human tolerability. These agents therefore are promising candidates for further study as neuroprotective agents in PD. Ann Neurol 2003;53 (suppl 3):S39-S48
Beatty, W. W. (2003). "Psychiatric and Cognitive Disorders in Parkinson's Disease." Am J Psychiatry 160(4): 804.
Becker, G. (2003). "[Methods for the early diagnosis of Parkinson's disease]." Nervenarzt 74 Suppl 1: S7-S11.
Patients with idiopathic Parkinson's disease display a 60% degeneration of the nigrostriatal neurons before motor symptoms have progressed enough to allow clinical diagnosis. It is clear that any neuroprotective therapy starting at such a late stage can have no substantial effect on the disease progression.Therefore, earlier diagnosis must be the goal of future research,when at most mild motor or nonmotor symptoms are present or when only risk factors can be identified.Evidence of various gene mutations associated with idiopathic Parkinsonism raise the hope that these or other biological markers will allow earlier identification of patients at risk. A possibly significant vulnerability factor for developing Parkinson's disease can also be demonstrated by means of transcranial sonography. Since the individual tests are not sufficiently specific or sensitive, a gradual, precise, and inexpensive battery of tests needs to be developed for the successful identification of a risk group for this disease. The extent of damage to the dopaminergic system in these patients can be quantified using nuclear techniques.
Behrens, S. and K. Sommerville (2003). "Non-oral drug delivery in Parkinson's disease: a summary from the symposium at the 7th International Congress of Parkinson's Disease and Movement Disorders." Expert Opin Pharmacother 4(4): 595-9.
This symposium reviewed the issues of non-oral therapy in the late stage Parkinson's disease (PD). The accepted standard treatment of PD is oral levodopa or oral dopamine agonists. However, the long-term complications and limitations of this treatment might be improved by changing therapy from the present pulsatile stimulation to a more constant stimulation of central dopamine receptors. Stimulation of these receptors may be possible with non-oral drug delivery treatments. Many of these non-oral options have been evaluated during the last few decades to find a more continuous drug delivery. The non-oral treatment options include invasive measures such as intraduodenal levodopa, subcutaneous apomorphin and most recently, the non-invasive transdermal (patch) delivery system, with the novel dopamine agonist rotigotine (Aderis Pharmaceuticals Inc.). The benefits of the non-oral, more continuous dopaminergic treatment of PD needs to be demonstrated in clinical trials and long-term clinical practice, before they can be considered as potential replacements of the standard oral therapy.
Belluscio, M. A., F. Kasanetz, et al. (2003). "Spreading of slow cortical rhythms to the basal ganglia output nuclei in rats with nigrostriatal lesions." Eur J Neurosci 17(5): 1046-52.
A high proportion of neurons in the basal ganglia display rhythmic burst firing after chronic nigrostriatal lesions. For instance, the periodic bursts exhibited by certain striatal and subthalamic nucleus neurons in 6-hydroxydopamine-lesioned rats seem to be driven by the approximately 1 Hz high-amplitude rhythm that is prevalent in the cerebral cortex of anaesthetized animals. Because the striatum and subthalamic nucleus are the main afferent structures of the substantia nigra pars reticulata, we examined the possibility that the low-frequency modulations (periodic bursts) that are evident in approximately 50% nigral pars reticulata neurons in the parkinsonian condition were also coupled to this slow cortical rhythm. By recording the frontal cortex field potential simultaneously with single-unit activity in the substantia nigra pars reticulata of anaesthetized rats, we proved the following. (i) The firing of nigral pars reticulata units from sham-lesioned rats is not coupled to the approximately 1 Hz frontal cortex slow oscillation. (ii) Approximately 50% nigral pars reticulata units from 6-hydroxydopamine-lesioned rats oscillate synchronously with the approximately 1 Hz cortical rhythm, with the cortex leading the substantia nigra by approximately 55 ms; the remaining approximately 50% nigral pars reticulata units behave as the units recorded from sham-lesioned rats. (iii) Periodic bursting in nigral pars reticulata units from 6-hydroxydopamine-lesioned rats is disrupted by episodes of desynchronization of cortical field potential activity. Our results strongly support that nigrostriatal lesions promote the spreading of low-frequency cortical rhythms to the substantia nigra pars reticulata and may be of outstanding relevance for understanding the pathophysiology of Parkinson's disease.
Benabid, A. L., L. Vercucil, et al. (2003). "Deep brain stimulation: what does it offer?" Adv Neurol 91: 293-302.
Benarroch, E. E., A. M. Schmeichel, et al. (2003). "Preservation of branchimotor neurons of the nucleus ambiguus in multiple system atrophy." Neurology 60(1): 115-7.
Cholinergic neurons in the nucleus ambiguus (NA) were counted in autopsy tissue obtained from five patients with multiple system atrophy (MSA), four patients with PD, and five controls. The number of neurons in the dorsal NA was not significantly different among the three groups. Neurons in the ventrolateral portion of the NA were depleted in MSA. Laryngeal stridor cannot be explained solely by neuronal loss in the NA.
Benito-Leon, J., F. Bermejo-Pareja, et al. (2003). "Prevalence of PD and other types of parkinsonism in three elderly populations of central Spain." Mov Disord 18(3): 267-74.
The prevalence of Parkinson's disease (PD) and other types of parkinsonism in three elderly populations of central Spain was investigated using a door-to-door, two-phase approach. This design called for the administration of a brief questionnaire to subjects 65 years of age or older taken from the census of one urban municipality of Greater Madrid (Margaritas, Getafe), one rural site (Arevalo County, Avila), and one urban district of Madrid (Lista) in Spain (N = 5,278). Study neurologists extensively investigated those subjects who screened positively. The diagnoses, based on specified criteria, were reviewed to increase reliability across neurologists. We found 118 subjects with parkinsonism: 81 affected by PD (68.6%), 26 drug-induced parkinsonism (22.0%), 6 parkinsonism in dementia (5.1%), 3 vascular parkinsonism (2.5%), and 2 unspecified parkinsonism (1.7%). The prevalence was 2.2% (95% confidence interval [CI], 1.8-2.6) for all types of parkinsonism and 1.5% (95% CI, 1.2-1.8) for PD. The prevalence estimates of parkinsonism and PD increased with age, declining at 85 years and over. Age prevalence ratios were higher for men. Twenty-three subjects (28.4%) of the subjects with PD were detected through the screening and had not been diagnosed previously. Overall prevalence estimates of PD and other types of parkinsonism in central Spain rank at levels similar to those recently reported for other European and non-European elderly populations. Despite improvement in access to health services, an important proportion of PD patients may never seek neurological attention. Copyright 2002 Movement Disorder Society
Bensadoun, J. C., L. Pereira de Almeida, et al. (2003). "Comparative study of GDNF delivery systems for the CNS: polymer rods, encapsulated cells, and lentiviral vectors." J Control Release 87(1-3): 107-15.
Glial cell line-derived neurotrophic factor (GDNF) holds great promise for the treatment of Parkinson's disease. In humans, its intracerebroventricular administration leads to limiting side effects. Direct parenchymal delivery using mechanical means, or cell and gene therapy represent potential alternatives. In the present study, a representative of each of these three approaches, i.e. polymer rods, genetically modified encapsulated cells and lentiviral vectors was analyzed for its ability to release GDNF in the striatum of rats. One week post-surgery, GDNF was detected over a distance of 4 mm with all three methods. At 4 weeks GDNF staining diminished with rods and to a lesser extent with encapsulated cells, whereas it increased with lentiviral vectors. Nanogram range of GDNF was measured with all methods at 1 week. At 4 weeks, GDNF levels decreased significantly with rods, whereas they remained stable with encapsulated cells and lentiviral vectors. We conclude that all three methods investigated allow striatal delivery of GDNF, but the time during which it needs to be released will determine the approach chosen for clinical application.
Berding, G., T. Brucke, et al. (2003). "[[(123)I]beta-CIT SPECT imaging of dopamine and serotonin transporters in Parkinson's disease and multiple system atrophy]." Nuklearmedizin 42(1): 31-8.
AIMS: Definition of the regional pattern of dopamine transporter (DAT) dysfunction in advanced Parkinson's disease (PD) and evaluation of a potential correlation between DAT binding and symptoms; elucidation of the role of DAT imaging in the differential diagnosis of PD and multiple system atrophy (MSA); assessment and comparison of serotonin transporter (SERT) binding in PD and MSA. METHODS: [(123)I]ss-CIT SPECT was performed in 14 patients with advanced PD, 10 with moderate MSA and 20 healthy persons. Specific to nonspecific tracer binding ratios (V(3)") were calculated via ROI analysis of uptake images at 4 h (SERT binding) and 24 h (DAT binding) p. i. RESULTS: In PD bilateral reduction of striatal DAT binding (63-70%) was seen. The caudate ipsilateral to the clinically predominantly affected side showed relatively the least impairment. Significant correlations (r = -0.54 to -0.64) between DAT binding and Hoehn and Yahr stage, UPDRS-scores and duration of disease were found. In MSA DAT binding was less reduced (40-48%) targeting the putamen contralateral to the side of clinical predominance. Significantly lower SERT binding was observed in PD midbrain and MSA hypothalamus compared to controls - and in MSA relative to PD mesial frontal cortex. CONCLUSIONS: In advanced PD striatal DAT binding is markedly reduced with the least reduction in caudate ipsilateral to the clinically predominantly affected side. In moderate MSA with asymmetrical symptoms DAT dysfunction is predominant in the contralateral putamen, a pattern seen in early PD. The reduction of SERT in the midbrain area of PD patients suggests additional tegmental degeneration while in MSA the serotonergic system seems to be more generally affected.
Berding, G., C. H. Schrader, et al. (2003). "[ N-methyl (11)C]meta-Hydroxyephedrine positron emission tomography in Parkinson's disease and multiple system atrophy." Eur J Nucl Med Mol Imaging 30(1): 127-31.
Orthostatic hypotension (OH) can be present in idiopathic Parkinson's disease (IPD) as well as in atypical parkinsonian syndromes such as multiple system atrophy (MSA). According to clinical tests of sympathetic nerve function and histopathological data, OH is caused by primarily postganglionic sympathetic dysfunction in IPD and by predominantly central and preganglionic degeneration in MSA. It has been proposed that this concept of a different underlying pathogenesis for OH should be applied in the differential diagnosis of parkinsonian disorders, in the form of measurements of sympathetic myocardial innervation. In this pilot study, myocardial imaging with [ N-methyl (11)C]meta-hydroxyephedrine ((11)C-HED) and positron emission tomography (PET) was used as a quantitative tool to evaluate the feasibility of such an approach. Seven patients were included in the study. Two had MSA and OH, three had probable IPD and OH (duration of disease, >3 years), one had probable IPD without OH (disease duration, 3 years) and one had possible IPD without OH (disease duration, 2 years). Ratios of maximal (11)C-HED uptake in the myocardium to that in the liver at 5 and 40 min post injection (p.i.) and - based on kinetic modelling - tracer influx rates K(1) were calculated. Compared with MSA patients ( n=2), IPD patients with OH ( n=3) showed definitely lower uptake ratios at both 5 min p.i. (0.39-0.57 vs 0.78-0.79) and 40 min p.i. (0.21-0.60 vs 0.89-1.06), as well as lower K(1) values (0.198-0.359 vs 0.384-0.450 min(-1)). The patient with probable IPD without OH showed intermediate values (uptake ratio at 5 min: 0.65; uptake ratio at 40 min: 0.87; K(1)=0.363). In the patient with possible IPD, values (uptake ratio at 5 min: 0.96; uptake ratio at 40 min: 1.04; K(1)=0.400) did not differ from those observed in MSA. These results support the hypothesis that measurement of myocardial innervation may contribute to the differential diagnosis of parkinsonian disorders and suggest a need for quantitative pathophysiological imaging, particularly at early stages of disease.
Bergman, J., I. Brettholz, et al. (2003). "Donepezil as Add-on Treatment of Psychotic Symptoms in Patients with Dementia of the Alzheimer's Type." Clin Neuropharmacol 26(2): 88-92.
Traditionally, the neuropsychiatric symptoms of Alzheimer's disease (AD) have been managed with neuroleptics or benzodiazepines, which have serious side effects. Preliminary observations suggest the possible value of cholinesterase inhibitors in the amelioration of psychotic symptoms in patients with dementia of the Alzheimer's type, dementia with Lewy bodies, and in patients with Parkinson's disease. Twelve inpatients with AD with psychotic symptoms and lack of improvement of their delusions/hallucinations during perphenazine treatment (8 mg/day) for 3 weeks received random open-label donepezil 5 mg daily in addition to an ongoing treatment of 8 mg/day perphenazine or 16 mg/day perphenazine. Assessments conducted at baseline and after weeks 2 and 4 included the Mini-Mental State Examination, the Global Deterioration Scale, the Positive and Negative Symptoms Scale, and the Clinical Global Impressions scale. Frequency of extrapyramidal symptoms was measured according to the Abnormal Involuntary Movement Scale. The donepezil-perphenazine group exhibited substantially greater and clinical improvements in mental state. At the end of the trial (4 weeks), Positive and Negative Symptoms Scale scores revealed significant differences between both groups (p = 0.006). The Clinical Global Impressions scale and the Mini-Mental State Examination scores also showed significant differences between the donepezil-perphenazine group and the perphenazine group (p = 0.028 and p = 0.027 respectively). No significant differences were found in the Global Deterioration Scale scores. Abnormal Involuntary Movement Scale scores showed a significant deterioration in extrapyramidal symptoms in the perphenazine group compared with the donepezil-perphenazine group (p = 0.016). Donepezil augmentation of neuroleptics may be appropriate for those patients for whom neuroleptic monotherapy either does not lead to symptom remission or is associated with intolerable adverse effects. This was an open-label study and there is need for larger studies with double-blind control and a long-term study design to define the efficacy of donepezil for patients with AD and psychotic symptoms.
Bezard, E., C. E. Gross, et al. (2003). "Presymptomatic compensation in Parkinson's disease is not dopamine-mediated." Trends Neurosci 26(4): 215-21.
The symptoms of Parkinson's disease (PD) appear only after substantial degeneration of the dopaminergic neuron system (e.g. an 80% depletion of striatal dopamine) - that is, there is a substantive presymptomatic period of the disease. It is widely believed that dopamine-related compensatory mechanisms are responsible for delaying the appearance of symptoms. Recent advances in understanding the presymptomatic phase of PD have increased our understanding of these dopamine-related compensatory mechanisms and have highlighted the role of non-dopamine-mediated mechanisms both within and outside the basal ganglia. This increased knowledge of plasticity within cortical-basal-ganglia-thalamocortical circuitry as dopaminergic neuron degeneration progresses has implications for understanding plasticity in neural circuits generally and, more specifically, for developing novel therapeutics or presymptomatic diagnostics for PD.
Bhattacharya, K. F., S. Nouri, et al. (2003). "Selegiline in the treatment of Parkinson's disease: its impact on orthostatic hypotension." Parkinsonism Relat Disord 9(4): 221-4.
Less than a consensus exists as to whether chronic treatment with selegiline in combination with levodopa/carbidopa in patients with Parkinson's disease, is associated with more pronounced orthostatic hypotension than treatment with levodopa/carbidopa alone. To resolve this issue, we compared orthostatic tolerance and autonomic reflexes in 95 patients with Parkinson's disease treated chronically with either selegiline alone (n=10), levodopa/carbidopa alone (n=49) or both agents combined (n=36). Supine heart rate and blood pressure, autonomic cardiovascular reflexes and the frequency and magnitude of orthostatic hypotension were similar in all three treatment groups.
Birks, J. and L. Flicker (2003). "Selegiline for Alzheimer's disease." Cochrane Database Syst Rev(1): CD000442.
BACKGROUND: Alzheimer's disease is the most common cause of dementia in older people accounting for some 60% of cases with late-onset cognitive deterioration. It is now thought that several neurotransmitter dysfunctions are involved from an early stage in the pathogenesis of Alzheimer's disease-associated cognitive decline. The efficacy of selegiline for symptoms of Alzheimer's disease remains controversial and is reflected by its low rate of prescription and the lack of approval by several regulatory authorities in Europe and elsewhere. Reasons for this uncertainty involve the modest overall effects observed in some trials, the lack of benefit observed in several trials, the use of cross-over designs which harbour methodological problems in a disease like dementia and the difficulty in interpreting results from trials when a variety of measurement scales are used to assess outcomes. OBJECTIVES: The objective of this review is to assess whether or not selegiline improves the well-being of patients with Alzheimer's disease. SEARCH STRATEGY: The Cochrane Dementia and Cognitive Impairment Group Register of Clinical Trials, was searched using the terms 'selegiline', 'l-deprenyl', "eldepryl" and "monamine oxidase inhibitor-B". MEDLINE, PsycLIT and EMBASE electronic databases were searched with the above terms in addition to using the group strategy (see group details) to limit the searches to randomised controlled trials. SELECTION CRITERIA: All unconfounded, double-blind, randomised controlled trials in which treatment with selegiline was administered for more than a day and compared to placebo in patients with dementia. DATA COLLECTION AND ANALYSIS: An individual patient data meta-analysis of selegiline, Wilcock 2002 provides much of the data that are available for this review. Seven studies provided individual patient data and this was pooled with summary statistics from the published papers of the other nine studies. Where possible, intention-to-treat data were used but usually the meta analyses were restricted to completers' data (data on people who completed the study). MAIN RESULTS: There are 17 included trials. There were very few significant treatment effects and these were all in favour of selegiline; cognition at 4-6 weeks and 8-17 weeks, and activities of daily living at 4-6 weeks. There is little evidence of adverse effects caused by selegiline, and few withdrew from trials, apart from the Sano trial. The analyses were conducted on data available. There was no attempt to correct for missing patients because there were so few and withdrawal was probably unconnected with treatment. All trials examined the cognitive effects of selegiline, and in addition 12 trials examined the behavioural and mood effects. The meta-analysis revealed benefits on memory function, shown by improvement in the memory tests from several cognitive tests (the Randt Memory Index from Agnoli 1990 and Agnoli 1992, the BSRT from Sunderland 1992, prose recall from Filip 1991, ADAS-cog from Lawlor 1997, the Wechsler Memory Scale from Loeb 1990 and Mangoni 1991, the Rey -AVL from Piccinin 1990, and the MMSE from Sano 1995, Tariot 1998, Filip 1991, Freedman 1996, Burke 1993 and Riekkinen 1993). The combined memory tests, and overall the combined cognitive tests, analysed using standardised mean differences, showed an improvement due to selegiline compared with placebo at 4-6 weeks (SMD 0.39, 95%CI 0.07 to 0.72, P = 0.02, random effects model ) and 8-17 weeks, ( SMD 0.44, 95%CI 0.04 to 0.84, P = 0.03, random effects model). The meta-analyses of emotional state show no treatment effects. Several studies assessed activities of daily living using several different scales, the GBS-motor function from Agnoli 1990, the NOSIE-daily living from Filip 1991, the BDS-daily living from Loeb 1990 and Mangoni 1991, the DS from Sano 1995 and PIADL from Tariot 1998. The combined tests, analysed using the standardised mean difference, showed an improvement due to selegiline at 4-6 weeks (SMD -0.27, 95% CIs -0.41 to -0.13, P = <.001). The global rating scales, the BDS used by Burke 1993 and Tariot 1998, and the GBS used by Agnoli 1990 and Agnoli 1992, and the GDS used by Freedman 1996 and the CGI by Filip 1991, analysed using standardised mean differences showed no effect of selegiline. A variety of adverse effects were recorded, but very few patients left a trial as a direct result. Four studies reported no side effects. Mangoni 1991 reported poor tolerability for 3 patients out of 68 on treatment and 1 out of 51 on placebo, resulting in dropouts. Small numbers found equally in both groups reported anxiety, agitation, dizziness, nausea and dyspepsia. Piccinin 1990 reported that selegiline was well tolerated with few adverse reactions (dizziness and orthostatic hypotension) and no resulting drop outs. Burke 1993 and Loeb 1990 both reported that selegiline was very well tolerated with no serious side effects. Sano 1995 reported 49 categories of adverse events but found no differences between the 4 arms of the factorial trial. Freedman 1996 reported unequal numbers of dropouts in the trial with 7 subjects withdrawing from the selegiline group and only 1 subject from the placebo group. The meta-analyses of the numbers suffering adverse effects, and of the numbers of withdrawals before the end of the trial show no difference between control and selegiline. REVIEWER'S CONCLUSIONS: Despite its initial promise, ie the potential neuroprotective properties, and its role in the treatment of Parkinson's disease sufferers, selegiline for Alzheimer's disease has proved disappointing. Although there is no evidence of a significant adverse event profile, there is also no evidence of a clinically meaningful benefit for Alzheimer's disease sufferers. This is true irrespective of the outcome measure evaluated, ie cognition, emotional state, activities of daily living, and global assessment, whether in the short, or longer term (up to 69 weeks), where this has been assessed. There would seem to be no justification, therefore, to use it in the treatment of people with Alzheimer's disease, nor for any further studies of its efficacy in Alzheimer's disease.
Blackburn, T. P. and R. S. Sloviter (2003). "Epilepsy, Parkinson's disease, migraine and brain plasticity - the next paradigm shift?" Curr Opin Pharmacol 3(1): 3-5.
Blanchet, P. J., L. V. Metman, et al. (2003). "Renaissance of amantadine in the treatment of Parkinson's disease." Adv Neurol 91: 251-7.
Bonifati, V., P. Rizzu, et al. (2003). "Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism." Science 299(5604): 256-9.
The DJ-1 gene encodes a ubiquitous, highly conserved protein. Here, we show that DJ-1 mutations are associated with PARK7, a monogenic form of human parkinsonism. The function of the DJ-1 protein remains unknown, but evidence suggests its involvement in the oxidative stress response. Our findings indicate that loss of DJ-1 function leads to neurodegeneration. Elucidating the physiological role of DJ-1 protein may promote understanding of the mechanisms of brain neuronal maintenance and pathogenesis of Parkinson's disease.
Bordet, R., D. Devos, et al. (2003). "Study of Circadian Melatonin Secretion Pattern at Different Stages of Parkinson's Disease." Clin Neuropharmacol 26(2): 65-72.
To explore changes in melatonin secretion patterns and biologic rhythms in Parkinson's disease patients with or without levodopa-related motor complications (LDRMCs), the authors investigated, in an observational study, circadian rhythms of central temperature, motor activity, plasma cortisol, and melatonin in three groups: de novo untreated patients (group I), patients treated with levodopa + dopamine agonist and without LDRMCs (group II), and patients treated with levodopa + dopamine agonist and with LDRMCs (group III). There were no differences among the three groups for the rhythm of temperature, motor activity, or plasma cortisol. There was a significant (p < 0.05) phase advance in plasma melatonin secretion in patients receiving a dopaminergic treatment compared with untreated patients. The daytime area under the curve (AUC) was increased significantly in group III, and the nighttime AUC-to-daytime AUC ratio of melatonin secretion decreased significantly in group III, suggesting that the nychthemeral pattern of melatonin secretion was changed in patients with LDRMCs. Comparison of the three groups suggests a slight but insignificant phase advance and amplitude decrease of circadian melatonin secretion related to both evolution and treatment of Parkinson's disease. Despite the lack of a global desynchronization in other circadian biologic rhythms, the circadian secretion pattern of melatonin is modified in patients with LDRMCs.
Bosman, T., K. Van Laere, et al. (2003). "Anatomically standardised (99m)Tc-ECD brain perfusion SPET allows accurate differentiation between healthy volunteers, multiple system atrophy and idiopathic Parkinson's disease." Eur J Nucl Med Mol Imaging 30(1): 16-24.
The clinical differentiation between typical idiopathic Parkinson's disease (IPD) and atypical parkinsonian disorders such as multiple system atrophy (MSA) is complicated by the presence of signs and symptoms common to both forms. The goal of this study was to re-evaluate the contribution of brain perfusion single-photon emission tomography (SPET) with anatomical standardisation and automated analysis in the differentiation of IPD and MSA. This was achieved by discriminant analysis in comparison with a large set of age- and gender-matched healthy volunteers. Technetium-99m ethyl cysteinate dimer SPET was performed on 140 subjects: 81 IPD patients (age 62.6+/-10.2 years; disease duration 11.0+/-6.4 years; 50 males/31 females), 15 MSA patients (61.5+/-9.2 years; disease duration 3.0+/-2.2 years; 9 males/6 females) and 44 age- and gender-matched healthy volunteers (age 59.2+/-11.9 years; 27 males/17 females). Patients were matched for severity (Hoehn and Yahr stage). Automated predefined volume of interest (VOI) analysis was carried out after anatomical standardisation. Stepwise discriminant analysis with cross-validation using the leave-one-out method was used to determine the subgroup of variables giving the highest accuracy for this differential diagnosis. Between MSA and IPD, the only regions with highly significant differences in uptake after Bonferroni correction were the putamen VOIs. Comparing MSA versus normals and IPD, with putamen VOI values as discriminating variables, cross-validated performance showed correct classification of MSA patients with a sensitivity of 73.3%, a specificity of 84% and an accuracy of 83.6%. Additional input from the right caudate head and the left prefrontal and left mesial temporal cortex allowed 100% discrimination even after cross-validation. Discrimination between the IPD group alone and healthy volunteers was accurate in 94% of the cases after cross-validation, with a sensitivity of 91.4% and a specificity of 100%. The three-group classification (MSA, IPD and healthy volunteers) resulted in an overall accuracy of 86% post hoc, with 98% of normals, 78% of IPD and 93% of MSA correctly classified. These values were slightly lower after cross-validation: 96% for healthy volunteers, 77% for IPD and 67% for MSA. In conclusion, using age- and gender-matched healthy volunteer data and anatomical standardisation, it is possible to differentiate between IPD and MSA with high discriminating power in clinically relevant circumstances.
Braak, H., K. Del Tredici, et al. (2003). "Staging of brain pathology related to sporadic Parkinson's disease." Neurobiol Aging 24(2): 197-211.
Sporadic Parkinson's disease involves multiple neuronal systems and results from changes developing in a few susceptible types of nerve cells. Essential for neuropathological diagnosis are alpha-synuclein-immunopositive Lewy neurites and Lewy bodies. The pathological process targets specific induction sites: lesions initially occur in the dorsal motor nucleus of the glossopharyngeal and vagal nerves and anterior olfactory nucleus. Thereafter, less vulnerable nuclear grays and cortical areas gradually become affected. The disease process in the brain stem pursues an ascending course with little interindividual variation. The pathology in the anterior olfactory nucleus makes fewer incursions into related areas than that developing in the brain stem. Cortical involvement ensues, beginning with the anteromedial temporal mesocortex. From there, the neocortex succumbs, commencing with high order sensory association and prefrontal areas. First order sensory association/premotor areas and primary sensory/motor fields then follow suit. This study traces the course of the pathology in incidental and symptomatic Parkinson cases proposing a staging procedure based upon the readily recognizable topographical extent of the lesions.
Branchek, T. A. and T. P. Blackburn (2003). "Trace amine receptors as targets for novel therapeutics: legend, myth and fact." Curr Opin Pharmacol 3(1): 90-7.
Trace amines are attracting attention as neurotransmitters because they are believed to play a role in human disorders such as schizophrenia, depression, attention deficit disorder and Parkinson's disease. Research to date is promising and confirms the need for continuing work to forge the way for new drug discovery.
Brandstadter, D. and W. H. Oertel (2003). "Depression in Parkinson's disease." Adv Neurol 91: 371-81.
Bronte-Stewart, H. (2003). "Parkinson's Disease: Surgical Options." Curr Treat Options Neurol 5(2): 131-147.
Surgical therapy for Parkinson's disease (PD) has been a treatment option for over 100 years. Advances in the knowledge of basal ganglia physiology and in techniques of stereotactic neurosurgery and neuroimaging have allowed more accurate placement of lesions or "brain pacemakers" in the sensorimotor regions of target nuclei. This, in turn, has led to improved efficacy with fewer complications than in the past. Currently, bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) is the preferred option (and is approved by the US Food and Drug Administration) for the surgical treatment of PD. The most important predictors for outcome for DBS for PD are patient selection and electrode location. Patients should have a documented preoperative improvement from dopaminergic medication of at least 30% in the patient's Unified Parkinson's Disease Rating Scale motor disability scores. A levodopa challenge may be needed to document the best "on" state. Dementia or active cognitive decline must be excluded. Active psychiatric disease should be treated preoperatively. Patients should be motivated, with good support systems, and committed to the postoperative management of DBS therapy. Deep brain stimulation should be considered when the patient begins to experience dyskinesia and on-off fluctuations despite optimal medical therapy. Deep brain stimulation is not a good option at the final stages of the disease because of the increased incidence of dementia and severe comorbidity. The DBS electrode should be placed in the sensorimotor region of the GPi or STN. Subthalamic nucleus and GPi DBS can improve all motor aspects of PD, as well as predictable "on" time, without dyskinesia or fluctuations. On average, STN DBS results in a greater reduction of dopaminergic medication compared with GPi DBS. Because of the smaller size of the target region, the pulse generator battery life is longer with STN then with GPi DBS. Deep brain stimulation programming is a skill that is readily learned and may be required of all neurologists in the future. Emerging surgical therapies are restorative, and they aim to replace or regenerate degenerating dopaminergic neurons. These include embryonic mesencephalic tissue transplantation, human embryonic stem cell transplantation, and gene-derived methods of intracerebral implantation of growth factors and dopamine- producing cell lines. It will be important to determine whether DBS, if performed before the onset of motor response complications to medical therapy, may prevent this stage of disease altogether or delay it for a significant period of time. The same question applies to the future with restorative therapy.
Brooks, D. J. (2003). "Imaging end points for monitoring neuroprotection in Parkinson's disease." Ann Neurol 53(3 Suppl 1): S110-9.
In this review, the potential role of positron emission tomography and single-photon emission computed tomography as biological markers for following the progression of Parkinson's disease (PD) is discussed, and their value for assessing the efficacy of putative neuroprotective agents in PD is considered. It is concluded that functional imaging provides a valuable adjunct to clinical assessment when judging the efficacy of neuroprotective approaches to PD. Ann Neurol 2003;53: (suppl 3)S110-S119
Brotchie, J. M. (2003). "CB(1) cannabinoid receptor signalling in Parkinson's disease." Curr Opin Pharmacol 3(1): 54-61.
Signalling at CB(1) cannabinoid receptors plays a key role in the control of movement in health and disease. In recent years, an increased understanding of the physiological role of transmission at CB(1) receptors throughout the basal ganglia circuitry has led to the identification of novel therapeutic approaches to both the symptoms of Parkinson's disease and the side effects of current anti-parkinsonian therapies, especially L(3,4) dihydroxyphenylalamine (levodopa)-induced dyskinesia. Thus, because activation of basal ganglia CB(1) receptors can modulate neurotransmission and contribute to synaptic plasticity in a manner similar to that described in other brain regions, it also appears that endocannabinoids might modulate cell-cell signalling via effects on neurotransmitter re-uptake and postsynaptic actions mediating cross talk between multiple receptor types. Recent studies in animal models and in the clinic suggest that CB(1) receptor antagonists could prove useful in the treatment of parkinsonian symptoms and levodopa-induced dyskinesia, whereas CB(1) receptor agonists could have value in reducing levodopa-induced dyskinesia.
Brown, P. (2003). "Oscillatory nature of human basal ganglia activity: Relationship to the pathophysiology of Parkinson's disease." Mov Disord 18(4): 357-63.
Alterations of basal ganglia physiology in parkinsonism may consist of two elements, an increase in the firing rate of neurones and a change in the pattern of synchronisation of discharges between neurones. Recent findings suggest the presence of two principal modes of synchronised activity within the human subthalamo-pallidal-thalamo-cortical circuit, at <30 Hz and >60 Hz. These oscillations are dynamically and systematically modulated by task, thereby suggesting a functional role in movement. More importantly, the two frequency modes are inversely affected by movement, consistent with opposing actions, and differentially expressed according to the prevailing level of dopaminergic activity. It is argued that the balance between these modes determines the effects of basal ganglia-thalamocortical projections on the motor areas of the cortex. The lower frequency oscillations facilitate slow idling rhythms in the motor areas of the cortex, whereas synchronisation at high frequency restores dynamic task-related cortical ensemble activity in the gamma band.Copyright 2002 Movement Disorder Society
Brown, R. G., M. Jahanshahi, et al. (2003). "Pallidotomy and incidental sequence learning in Parkinson's disease." Neuroreport 14(1): 21-4.
Converging evidence from animal research and human brain imaging studies, points to an important role of cortical-striatal motor circuitry in the incidental learning of serial order information. To date, attempts to address this role through the study of patients with striatal disorder have proved inconclusive. The present study examined the impact of a therapeutic lesion of the globus pallidus in patients with Parkinson's disease. The lesion, which blocks a primary output of the putamen to the motor cortices, eliminated incidental learning relative both to controls and unoperated patients. The finding offers support for models proposing that context detection within the striatum is a central process in serial order learning. An unexpected effect of the lesion was to significantly reduce the response time to random stimuli relative to an ordered series, the opposite of the normal pattern. It is speculated that this may reflect an unconscious alerting response to novelty, a process suggested to involve the ventral striatum and its cortical targets. Research on Parkinson's disease patients undergoing functional basal ganglia surgery may shed further light on the mechanisms and neuronal substrate of serial order learning in humans.
Brusa, L., A. Bassi, et al. (2003). "Pramipexole in comparison to l-dopa: a neuropsychological study." J Neural Transm 110(4): 373-80.
Twenty right-handed patients affected by early/mild Parkinson's disease were evaluated in a randomised study using neuropsychological and clinical assessements during three treatment modalities: when in the off treatment condition, when on pramipexole, and when on l-dopa. In comparison to the off treatment condition, the DA-agonist pramipexole produced a significant impairment of short term verbal memory, attentional-executive functions and verbal fluency, while l-dopa did not. Moreover, pramipexole opposite to l-dopa, failed to improve FAS and Stroop tests. Present findings indicate that pramipexole may worsen cognitive functions although not exceeding normative values.
Buhmann, C., A. Bussopulos, et al. (2003). "Dopaminergic response in Parkinsonian phenotype of Machado-Joseph disease." Mov Disord 18(2): 219-21.
We report on a patient with genetically proven Machado-Joseph Disease (MJD) presenting with signs indistin