Parkinson's Disease Reviews: 2002
(363 References)
(2002). "Speech therapy in Parkinson's disease." Mov Disord 17 Suppl 4: S163-6.
(2002). "Psychosocial counseling in Parkinson's disease." Mov Disord 17 Suppl 4: S160-2.
(2002). "Physical and occupational therapy in Parkinson's disease." Mov Disord 17 Suppl 4: S156-9.
(2002). "Surgical treatment for Parkinson's disease: neural transplantation." Mov Disord 17 Suppl 4: S148-55.
(2002). "Surgical treatment for Parkinson's disease: deep brain surgery." Mov Disord 17 Suppl 4: S128-47.
(2002). "Drugs to treat dementia and psychosis: management of Parkinson's disease." Mov Disord 17 Suppl 4: S120-7.
(2002). "Treatment of depression in idiopathic Parkinson's disease." Mov Disord 17 Suppl 4: S112-9.
(2002). "Drugs to treat autonomic dysfunction in Parkinson's disease." Mov Disord 17 Suppl 4: S103-11.
(2002). "DA agonists -- non-ergot derivatives: ropinirole: management of Parkinson's disease." Mov Disord 17 Suppl 4: S98-102.
(2002). "DA agonists -- non-ergot derivatives: pramipexole: management of Parkinson's disease." Mov Disord 17 Suppl 4: S93-7.
(2002). "DA agonists -- non-ergot derivatives: piribedil: management of Parkinson's disease." Mov Disord 17 Suppl 4: S90-2.
(2002). "DA agonists -- non-ergot derivatives: apomorphine: management of Parkinson's disease." Mov Disord 17 Suppl 4: S83-9.
(2002). "DA agonists -- ergot derivatives: pergolide: management of Parkinson's disease." Mov Disord 17 Suppl 4: S79-82.
(2002). "DA agonists -- ergot derivatives: lisuride: management of Parkinson's disease." Mov Disord 17 Suppl 4: S74-8.
(2002). "DA agonists -- ergot derivatives: dihydroergocryptine (DHEC): management of Parkinson's disease." Mov Disord 17 Suppl 4: S72-3.
(2002). "DA agonists -- ergot derivatives: cabergoline: management of Parkinson's disease." Mov Disord 17 Suppl 4: S68-71.
(2002). "DA agonists -- ergot derivatives: bromocriptine: management of Parkinson's disease." Mov Disord 17 Suppl 4: S53-67.
(2002). "COMT inhibitors: management of Parkinson's disease." Mov Disord 17 Suppl 4: S45-51.
(2002). "MAO-B inhibitors for the treatment of Parkinson's disease." Mov Disord 17 Suppl 4: S38-44.
(2002). "Levodopa: management of Parkinson's disease." Mov Disord 17 Suppl 4: S23-37.
(2002). "Amantadine and other antiglutamate agents: management of Parkinson's disease." Mov Disord 17 Suppl 4: S13-22.
(2002). "Anticholinergic therapies in the treatment of Parkinson's disease." Mov Disord 17 Suppl 4: S7-12.
(2002). "Altropane. O 587." Drugs R D 3(3): 188-9.
(2002). "MS, Parkinson's disease and physiotherapy." Drug Ther Bull 40(5): 38-40.
In the UK, around 10-12 in every 10,000 people have multiple sclerosis, typical features of which include weakness, ataxia, spasticity and sensory loss. By comparison, around 16-18 in every 10,000 have Parkinson's disease, a condition typified by rigidity, bradykinesia, tremor and postural instability. Both conditions can limit function with, for example, nearly 25% of patients with multiple sclerosis and about 10% of those with Parkinson's disease being dependent on a wheelchair. Physiotherapy is widely used as part of a multidisciplinary approach to the management of multiple sclerosis, while 7-38% of people with Parkinson's disease are referred for physiotherapy. Here, we review the evidence for physiotherapy in the management of patients with either condition.
(2002). "Understanding changes in cholinergic function: implications for treating dementia." J Clin Psychiatry 63(3): 259-69.
Akaike, A., H. Katsuki, et al. (2002). "[Role of nitric oxide in survival and death of neurons]." Nippon Yakurigaku Zasshi 119(1): 15-20.
The prominent pathological feature of the brain in Parkinson's disease is selective degeneration of dopaminergic neurons in the substantia nigra of the midbrain. Glutamate and nitric oxide (NO) are the major effectors of the radical stress that may induce selective loss of dopaminergic neurons. It has been postulated that neurotoxicity induced by glutamate and NO in dopaminergic neurons is regulated by certain endogenous factors. We have reported that estradiol protects dopaminergic neurons against NO-mediated glutamate neurotoxicity by reducing intracellular reactive oxygen species (ROS) levels. We further searched for a candidate for neuroprotective substances with unique structure. From the ether extract of fetal calf serum (FCS), we isolated a novel substance possessing protective activity against neurotoxicity induced by glutamate NO. The compound was a sulfur-containing diterpenoid and showed hydroxyl radical scavenging activity. We further analyzed the change of resistance to excitotoxicity in midbrain dopaminergic neurons in co-culture with the striatum by using a slice culture technique. The results suggested that the generation of NO is involved in NMDA cytotoxicity on dopaminergic neurons and that increased activity of SOD in co-culture renders dopaminergic neurons resistant to NMDA cytotoxicity by preventing peroxynitrite formation. Those findings suggest that regulation of intracellular ROS levels plays a critical role in protecting neurons against NO-mediated radical stress in neurodegenerative disorders.
Albers, D. S. and M. F. Beal (2002). "Mitochondrial dysfunction in progressive supranuclear palsy." Neurochem Int 40(6): 559-64.
A progressive impairment of mitochondrial function has been suggested to play a critical role in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Huntington's disease. Mitochondrial dysfunction can lead to number of deleterious consequences including impaired calcium buffering, generation of free radicals, activation of the mitochondrial permeability transition pore and secondary excitotoxicity. Progressive supranuclear palsy (PSP) is a rare neurological disorder characterized by the appearance of supranuclear gaze palsy and extrapyramidal symptoms [Arch. Neurol. 10 (1964) 333]. Although the etiological basis of PSP is unknown, compelling evidence from spectroscopy studies in PSP patients, biochemical studies in post-mortem PSP brain tissue and PSP cybrids has emerged that supports a contributory role of bio-energetic defects in the pathogenesis of PSP.
Albin, R. L. (2002). "Sham surgery controls: intracerebral grafting of fetal tissue for Parkinson's disease and proposed criteria for use of sham surgery controls." J Med Ethics 28(5): 322-5.
Sham surgery is a controversial and rarely used component of randomised clinical trials evaluating surgical interventions. The recent use of sham surgery in trials evaluating efficacy of intracerebral fetal tissue grafts in Parkinson's disease has highlighted the ethical concerns associated with sham surgery controls. Macklin, and Dekkers and Boer argue vigorously against use of sham surgery controls. Macklin presents a broad argument against sham surgery controls while Dekkers and Boer present a narrower argument that sham surgery is unnecessary in the specific setting of fetal tissue engraftment for Parkinson's disease. I defend sham surgery controls against both these criticisms. Appropriate clinical trial design, sometimes including sham surgery, is needed to ensure that false positive trial results do not occur and endanger public safety. Results of a completed trial of fetal tissue grafting for Parkinson's disease are used to illustrate the potential benefits of, and problems associated with, sham surgery controls. Sham surgery controls, however, should be employed only when absolutely necessary. I suggest criteria for appropriate use of sham surgery controls.
Allam, M. F., A. Serrano del Castillo, et al. (2002). "Smoking and Parkinson's disease: explanatory hypothesis." Int J Neurosci 112(7): 851-4.
A systematic review was conducted to estimate the pooled risk of smoking for Parkinson's disease in Chinese populations. The four identified case-control studies had odds ratios with 95% confidence intervals nearly or overlapping unity. Pooled odds ratio of these studies was 0.77 with 95% confidence interval 0.60 to 0.97. It was suggested that smoking induces debrisoquine 4-hydroxylase, which is responsible for the metabolism of antipsychotic drugs and the detoxification of certain environmental toxins known to cause dopaminergic neural damage. This could be the explanation of these contradictory results as cytochrome P-450 CYP2D6 debrisoquine hydroxylase gene polymorphism is known to be much lower in Chinese than in Caucasian people. This systematic review raises concerns about generalization of the conclusion previously settled by many cohort and case-control studies.
Allam, M. F., M. J. Campbell, et al. (2002). "[Parkinson's disease and smoking: coherence and plausibility]." Rev Neurol 34(7): 686-9.
INTRODUCTION. Many studies have shown that smoking is lower in patients with Parkinson s disease. However, in other investigations this was not observed. The various studies involved showed wide variation with regard to methodology, criteria for diagnosis and periods of observation and hence it is difficult to compare them. DEVELOPMENT. The first studies published were designed to examine the effects of smoking in general and information was obtained regarding the possible disorders related to tobacco smoking according to the records of mortality, which may contain errors due to selective mortality and mistaken diagnosis. Most of the studies of cases and controls included prevalent cases which accepted the study, mainly hospital cases. Also it is probable that the prevalent cases of Parkinson s disease do not smoke because of their disorders of movement. CONCLUSIONS. Many researchers have found important information about the pathophysiology of Parkinson s disease and its association with smoking. However, the hypothesis regarding the association between smoking and low risk of Parkinson s disease are various and independent, apart from the hypothesis of a truly biological mechanisms. Since the subject is still controversial, systematic reviews together with epidemiological and experimental studies are necessary.
Anderson, K. E. and W. J. Weiner (2002). "Psychiatric symptoms in Parkinson's disease." Curr Neurol Neurosci Rep 2(4): 303-9.
Aside from the well-known triad of resting tremor, postural instability, and bradykinesia, Parkinson's disease (PD) patients may also develop psychiatric illness as a part of their disease. The psychiatric symptoms may be as disabling as the movement disorder, but are often amenable to treatment. We review the most recent investigations of mood disorders, anxiety disorders, and hallucinations/ psychosis in PD. We then highlight new treatment studies for hallucinations/psychosis in PD.
Andrade, C. and S. Kurinji (2002). "Continuation and maintenance ECT: a review of recent research." J Ect 18(3): 149-58.
Continuation and maintenance electroconvulsive therapy (ECT) is used to reduce the risk for relapse and recurrence of illness in patients who fare poorly with continuation and maintenance medication regimens. Despite the potential value of these ECT schedules, both are relatively neglected in clinical practice. This article therefore reviews the last decade of research on the subject. Although the research comprises mostly single and multiple case reports and small open studies, continuation and maintenance ECT does emerge as a safe and effective treatment for relapse- and recurrence-prone patients who have responded to a course of ECT.
Arenas, E. (2002). "Stem cells in the treatment of Parkinson's disease." Brain Res Bull 57(6): 795-808.
Stem cells have been suggested as candidate therapeutic tools for neurodegenerative disorders, given their ability to give rise to the appropriate cell types after grafting in vivo. In this review I summarize some of the evidence currently available concerning two approaches for the treatment of Parkinson's disease: (1) The generation of dopaminergic neurons from embryonic stem cells, multipotent stem cells, and neuronal progenitor cells for cell replacement therapy. (2) The engineering of multipotent stem cells to release glial cell-line derived neurotrophic factor, a potent neurotrophic factor for dopaminergic neurons, in a neuroprotective and neuroregenerative approach to the treatment of Parkinson's disease.
Arsland, D. (2002). "[Dementia with Lewy bodies]." Tidsskr Nor Laegeforen 122(5): 525-9.
BACKGROUND: Some 10%-15% of patients with dementia are diagnosed as dementia with Lewy bodies (DLB), a disorder characterised by the presence of Lewy bodies in the brainstem and cortex. MATERIAL AND METHODS: Review of pathology, clinical symptoms, pharmacological and nonpharmacological treatment, based on the literature and on personal experience. RESULTS: Neurochemical findings are marked cortical reduction of acetylcholine and nigrostriatal dopamine deficiency. Key features of the clinical syndrome are dementia, fluctuating consciousness, visual hallucinations and parkinsonism. There are pathological and clinical overlaps between DLB and Alzheimer's disease on the one hand, and between DLB and Parkinson's disease on the other; the relationship between these diseases awaits further elucidation. Clinical consensus criteria for DLB have been published and shown to have high sensitivity and specificity. Fluctuating consciousness may be difficult to detect, but diagnostic instruments exist that may help in the evaluation. Drug treatment of DLB is difficult. Cholinesterase inhibitors have been shown to improve cognition and psychiatric symptoms. Atypical antipsychotics may improve psychosis, but some patients develop severe sensitivity reactions. The effect of antiparkinson agents is unknown.
Assal, F. and J. L. Cummings (2002). "Neuropsychiatric symptoms in the dementias." Curr Opin Neurol 15(4): 445-50.
PURPOSE OF REVIEW: Neuropsychiatric, or non-cognitive symptoms are increasingly recognized as manifestations of dementias. RECENT FINDINGS: In Alzheimer's disease, recent advances have included the identification of behavioral profiles, differentiation of apathy and depression, characterization of risk factors for psychosis and its links to agitation and aggression, and an analysis of depressive symptoms in the absence of major depression. Functional neuroimaging data mainly supported the role of the anterior cingulate in apathy. The orbitofrontal and anterior cingulate tangle burden were associated with agitation, and increased orbitofrontal and mid-temporal muscarinic M2 receptors with psychosis and hallucinations. Selected genetic polymorphisms of dopamine and serotonin receptors or transporters were linked with aggression, hallucinations or psychosis. When compared with other dementias, individuals with frontotemporal dementia disclosed, as expected, different behaviors and particularly aberrant social behavior. The frequency of delusions and visual hallucinations was increased in Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies, suggesting common mechanisms such as Lewy body pathology and cholinergic deficiency. The latter was supported by an improvement of these symptoms by cholinesterase inhibitors. SUMMARY: Future research directions include both clinical and basic neuroscience investigations. The detection of early neuropsychiatric symptoms might be a marker for dementia, and the possible existence of a mild neuropsychiatric impairment syndrome should be explored. More longitudinal studies with pathological confirmation will facilitate correlations with neuropsychiatric symptoms. Functional neuroimaging and behavioral neurogenetics will permit in-vivo correlations and consequently help patient management and care.
Bahr, B. A. and J. Bendiske (2002). "The neuropathogenic contributions of lysosomal dysfunction." J Neurochem 83(3): 481-9.
Multiple lines of evidence implicate lysosomes in a variety of pathogenic events that produce neurodegeneration. Genetic mutations that cause specific enzyme deficiencies account for more than 40 lysosomal storage disorders. These mostly pre-adult diseases are associated with abnormal brain development and mental retardation. Such disorders are characterized by intracellular deposition and protein aggregation, events also found in age-related neurodegenerative diseases including (i) Alzheimer's disease and related tauopathies (ii) Lewy body disorders and synucleinopathies such as Parkinson's disease, and (iii) Huntington's disease and other polyglutamine expansion disorders. Of particular interest for this review is evidence that alterations to the lysosomal system contribute to protein deposits associated with different types of age-related neurodegeneration. Lysosomes are in fact highly susceptible to free radical oxidative stress in the aging brain, leading to the gradual loss of their processing capacity over the lifespan of an individual. Several studies point to this lysosomal disturbance as being involved in amyloidogenic processing, formation of paired helical filaments, and the aggregation of alpha-synuclein and mutant huntingtin proteins. Most notably, experimentally induced lysosomal dysfunction, both in vitro and in vivo, recapitulates important pathological features of age-related diseases including the link between protein deposition and synaptic loss.
Balachandran, K. P., D. Stewart, et al. (2002). "Chronic pericardial constriction linked to the antiparkinsonian dopamine agonist pergolide." Postgrad Med J 78(915): 49-50.
Constrictive pericarditis is present when a fibrotic, thickened, and adherent pericardium restricts diastolic filling of the heart. Several drugs can cause pericarditis, which can lead to chronic pericardial constriction. A case of constrictive pericarditis in a patient receiving the antiparkinsonian drug pergolide is reported.
Barker, R. A. (2002). "Repairing the brain in Parkinson's disease: where next?" Mov Disord 17(2): 233-41.
Baronti, F. (2002). "[Psychological and cognitive problems in Parkinson disease--therapeutic possibilities]." Schweiz Rundsch Med Prax 91(10): 411-7.
Depression, hallucinations, psychosis and cognitive deficits may often complicate advanced Parkinson's disease. Their detection and treatment have extraordinary importance, as they may cause significant invalidity and even an increase in mortality. Optimization of antiparkinsonian therapy may exert a positive influence on depressive symptoms, and should therefore be performed before antidepressant drugs are started. On the other hand, hallucinations and dementia do usually benefit from a discontinuation or dosage reduction of anticholinergic drugs, selegiline, DA-agonists and amantadine. When a levodopa monotherapy is indicated, slow-release formulations should be avoided. When a neuroleptic treatment is needed, clozapine and maybe quetiapine should be preferred. Preliminary evidence suggests that cholinesterase inhibitors might partially improve cognitive deficits in Parkinson's disease.
Beal, M. F. (2002). "Coenzyme Q10 as a possible treatment for neurodegenerative diseases." Free Radic Res 36(4): 455-60.
Coenzyme Q10 (CoQ10) is an essential cofactor of the electron transport gene as well as an important antioxidant, which is particularly effective within mitochondria. A number of prior studies have shown that it can exert efficacy in treating patients with known mitochondrial disorders. We investigated the potential usefulness of coenzyme Q10 in animal models of Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). It has been demonstrated that CoQ10 can protect against striatal lesions produced by the mitochondrial toxins malonate and 3-nitropropionic acid. These toxins have been utilized to model the striatal pathology, which occurs in HD. It also protects against 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice. CoQ10 significantly extended survival in a transgenic mouse model of ALS. CoQ10 can significantly extend survival, delay motor deficits and delay weight loss and attenuate the development of striatal atrophy in a transgenic mouse model of HD. In this mouse model, it showed additive efficacy when combined with the N-methyl-D-aspartate (NMDA) receptor antagonist, remacemide. CoQ10 is presently being studied as a potential treatment for early PD as well as in combination with remacemide as a potential treatment for HD.
Beal, M. F. (2002). "Oxidatively modified proteins in aging and disease." Free Radic Biol Med 32(9): 797-803.
There is a large body of evidence implicating oxidative damage in the pathogenesis of both normal aging and neurodegenerative diseases. Oxidative damage to proteins has been well established. Although there are a large number of potential oxidative modifications only a few have been systematically studied. The most frequently studied marker of oxidative damage to proteins is protein carbonyl groups. 3-Nitrotyrosine is thought to be a relatively specific marker of oxidative damage mediated by peroxynitrite. Increased concentrations of both protein carbonyls and 3-nitrotyrosine have been documented in both normal aging as well as in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). These findings help to provide a rationale for trials of antioxidants in neurodegenerative diseases.
Benarroch, E. E. (2002). "New findings on the neuropathology of multiple system atrophy." Auton Neurosci 96(1): 59-62.
Multiple system atrophy (MSA) provides a typical example of the integrative role of the central autonomic network in controlling cardiovascular, respiratory, bladder and gastrointestinal functions. There is increasing evidence that neurochemically defined neuronal groups of the brainstem are selectively affected in MSA to a much greater degree than in Parkinson's disease. These include the catecholaminergic neurons of the rostral ventrolateral medulla (C1 group) which project to the intermediolateral cell column and are involved in modulation of sympathetic vasomotor outflow, and noradrenergic neurons of the caudal ventrolateral medulla (A1 group) projecting to the magnocellular nuclei of the hypothalamus and regulating vasopressin (AVP) release. Loss of these groups of neurons may, at least in part, explain the development of orthostatic hypotension, baroreflex dysfunction, and impaired reflex AVP release in response to hypotension. There is preliminary evidence that cardiovagal neurons of the ventrolateral portion of the nucleus ambiguus, distinct from the branchimotor neurons of the compact region, may also be affected in MSA. Loss of cholinergic neurons in the medullary arcuate nucleus, considered by some to be the homologous to the central chemosensitive region of the ventral medullary surface, may contribute to disturbances in automatic ventilation, particularly during sleep, in patients with MSA.
Berg, D. and G. Becker (2002). "Perspectives of B-mode transcranial ultrasound." Neuroimage 15(3): 463-73.
Transcranial color coded sonography has proved valuable in the diagnostic work-up of cerebrovascular disorders in adults. More recently, evidences have converged that transcranial sonography is also useful in the diagnosis of brain parenchymal disorders. Here, a new field of application is the visualization of signal intensity shift in specific brain areas in some neurodegenerative disorders (Parkinson's disease, idiopathic dystonia, and depression). Findings obtained by transcranial ultrasound complement information from other neuroimaging data in these disorders and have led to the generation of new pathophysiological concepts. In this review we summarize the application fields of transcranial sonography with special emphasis on recent findings in neurodegenerative disorders and their implications for future research. As new application and processing techniques are being developed transcranial color coded sonography will gain increasing impact on both diagnosis and research of neurological disorders.
Bergman, H. and G. Deuschl (2002). "Pathophysiology of Parkinson's disease: from clinical neurology to basic neuroscience and back." Mov Disord 17 Suppl 3: S28-40.
Parkinson's disease (PD) is characterized by motor and nonmotor (cognitive and limbic) deficits. The motor signs of PD include hypokinetic signs such as akinesia/bradykinesia, rigidity and loss of normal postural reflexes, and hyperkinetic signs such as tremor. Dopamine depletion in the striatum is the hallmark of PD and of its animal models, still the pathophysiology of the parkinsonian symptoms and especially of parkinsonian tremor are under debate. The most extreme hypotheses argue about peripheral versus central nervous system origin, intrinsic cellular oscillator versus network oscillators, and basal ganglia-based pathophysiology versus cerebellar-thalamic based pathophysiology. Recent studies support the view that parkinsonian symptoms are most likely due to abnormal synchronous oscillating neuronal activity within the basal ganglia. Peripheral factors do only play a minor role for the generation, maintenance, and modulation of PD tremor and other signs. The most likely candidates producing these neuronal oscillations are the weakly coupled neural networks of the basal ganglia-thalamo-cortical loops. However, the present evidence supports the view that the basal ganglia loops are influenced by other neuronal structures and systems and that the tuning of these loops by cerebello-thalamic mechanisms and by other modulator neurotransmitter systems entrain the abnormal synchronized oscillations. Neurosurgical procedures, such as lesions or high-frequency stimulation of different parts of the loop, might resume the normal unsynchronized activity of the basal ganglia circuitry, and, therefore, ameliorate the clinical symptoms of Parkinson's disease.
Betarbet, R., T. B. Sherer, et al. (2002). "Animal models of Parkinson's disease." Bioessays 24(4): 308-18.
Animal models are important tools in experimental medical science to better understand pathogenesis of human diseases. Once developed, these models can be exploited to test therapeutic approaches for treating functional disturbances observed in the disease of interest. On the basis of experimental and clinical findings, Parkinson's disease (PD) was the first neurological disease to be modeled and, subsequently, to be treated by neurotransmitter replacement therapy. Agents that selectively disrupt or destroy catecholaminergic systems, such as reserpine, methamphetamine, 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine have been used to develop PD models. Recently, it has been found that agricultural chemicals, such as rotenone and paraquat, when administered systemically, can reproduce specific features of PD in rodents, apparently via oxidative damage. Transgenic animals that over-express alpha-synuclein are used to study the role of this protein in dopaminergic degeneration. This review critically discusses animal models of PD and compares them with characteristics of the human disease.
Bevan, M. D., P. J. Magill, et al. (2002). "Move to the rhythm: oscillations in the subthalamic nucleus-external globus pallidus network." Trends Neurosci 25(10): 525-31.
Recent anatomical, physiological and computer modeling studies have revealed that oscillatory processes at the levels of single neurons and neuronal networks in the subthalamic nucleus (STN) and external globus pallidus (GPe) are associated with the operation of the basal ganglia in health and in Parkinson's disease (PD). Autonomous oscillation of STN and GPe neurons underlies tonic activity and is important for synaptic integration, whereas abnormal low-frequency rhythmic bursting in the STN and GPe is characteristic of PD. These recent findings provide further support for the view that the basal ganglia use both the pattern and the rate of neuronal activity to encode information.
Bharath, S., M. Hsu, et al. (2002). "Glutathione, iron and Parkinson's disease." Biochem Pharmacol 64(5-6): 1037-48.
Parkinson's disease (PD) is a progressive neurodegenerative disease involving neurodegeneration of dopaminergic neurons of the substantia nigra (SN), a part of the midbrain. Oxidative stress has been implicated to play a major role in the neuronal cell death associated with PD. Importantly, there is a drastic depletion in cytoplasmic levels of the thiol tripeptide glutathione within the SN of PD patients. Glutathione (GSH) exhibits several functions in the brain chiefly acting as an antioxidant and a redox regulator. GSH depletion has been shown to affect mitochondrial function probably via selective inhibition of mitochondrial complex I activity. An important biochemical feature of neurodegeneration during PD is the presence of abnormal protein aggregates present as intracytoplasmic inclusions called Lewy bodies. Oxidative damage via GSH depletion might also accelerate the build-up of defective proteins leading to cell death of SN dopaminergic neurons by impairing the ubiquitin-proteasome pathway of protein degradation. Replenishment of normal glutathione levels within the brain may hold an important key to therapeutics for PD. Several reports have suggested that iron accumulation in the SN patients might also contribute to oxidative stress during PD.
Bialecka, M., M. Drozdzik, et al. (2002). "[Role of gene polymorphism of catechol-O-methyltransferase (COMT), monoamine oxidase B (MAOB), cytochrome P450 2D6 (CYP2D6) and N-acetyltransferase 2 (NAT2) in pathogenesis of Parkinson's disease]." Neurol Neurochir Pol 36(1): 113-21.
Factors underlying pathogenesis of diseases are currently being searched. In recent years increasing number of reports on genetic background of central nervous system diseases have appeared. In the search of factors that can precipitate degeneration of dopaminergic neurons the role of enzymes catabolising xenobiotics (CYP2D6, NAT2) and enzymes metabolising catecholamines (COMT, MAO B) has been postulated. Polymorphism of genes coding for isotypes characterised by different biological activity could be responsible for the propensity for Parkinson's disease, progression and efficacy of pharmacotherapy of the disease.
Biglan, K. M. and R. G. Holloway (2002). "A review of pramipexole and its clinical utility in Parkinson's disease." Expert Opin Pharmacother 3(2): 197-210.
Parkinson's disease (PD) is a common neurodegenerative disorder characterised by selective loss of dopaminergic neurones in the substantia nigra and resulting in progressive disability. Therapy has focused on replacing depleted dopamine (DA) via supplementation with levodopa or DA agonists. Pramipexole (Mirapex), Pharmacia Corp.) has recently been approved for the treatment of PD. Evidence from preclinical studies and clinical trials have proven the effectiveness of this agent in ameliorating the symptoms of PD. There is also non-human evidence that pramipexole may be neuroprotective and could therefore possibly slow disease progression; however, this has yet to be proven in humans. The use of pramipexole may be limited by its side effect profile compared to standard therapies and its relatively higher cost compared to levodopa. Despite these concerns, pramipexole does have a role in the treatment of PD in all stages of the illness and may arguably be the treatment of choice in early disease. In addition to its use in PD, pramipexole has shown some utility in the treatment of restless legs syndrome (RLS), depression and schizophrenia.
Bilbao Garay, J., N. Mesa Plaza, et al. (2002). "[Serotonin syndrome: report of a fatal case and review of the literature]." Rev Clin Esp 202(4): 209-11.
We report here the case of a patient with fluoxetine and selegiline induced serotonin syndrome, which presented as encephalopathy, generalized myoclonias, fever, stiffness and sweating, complicated with acute renal failure, rhabdomyolysis and disseminated intravascular coagulation findings. The patient died 6 days after admission. This syndrome is discussed, with an analysis of its causes, pathophysiology and therapy. A special emphasis is placed on the clinical issues and differential diagnosis with the malignant neuroleptic syndrome and other clinical entities with which it could be mistaken. General recommendations are provided to avoid this poorly characterized syndrome that, as in our patient, may have a fatal outcome.
Bjorklund, L. M. and O. Isacson (2002). "Regulation of dopamine cell type and transmitter function in fetal and stem cell transplantation for Parkinson's disease." Prog Brain Res 138: 411-20.
Blakeley, J. and J. Jankovic (2002). "Secondary causes of paroxysmal dyskinesia." Adv Neurol 89: 401-20.
PxD are sudden, episodic, involuntary movement disorders that may include any combination of dystonia, chorea, athetosis, or ballism. The majority of reported cases are familial or idiopathic; however, there have been several reports of secondary PxD. We report 20 new cases of secondary, non-psychogenic PxD, and review 130 cases reported in the literature. The results suggest that although PxD is a rare disorder, secondary forms may be more common than previously recognized, accounting for 26% of all cases in our series. Secondary cases are notable for their variability in age of onset, the presence of both kinesigenic and non-kinesigenic symptoms in some patients, the prevalence of sensory precipitants, and most importantly, the reversal of symptoms when the underlying etiology is treated in some patients. In addition to MS, other causes to be considered in patients presenting with PxD include cerebral vascular insufficiency and stroke, trauma, metabolic abnormalities, and CNS infections. Awareness of the association of these etiologies with secondary PxD will permit prompt diagnoses and appropriate interventions. Potential pathophysiologic mechanisms including loss of inhibition or primary neuronal hyperactivity are discussed. In addition, recent hypotheses regarding channelopathies in relation to PxD are presented.
Boer, G. J. and H. Widner (2002). "Clinical neurotransplantation: core assessment protocol rather than sham surgery as control." Brain Res Bull 58(6): 547-53.
Basic neurotransplantation research evoked clinical trials of restorative brain surgery. Parkinson's disease was the first and primary test bed for this putative new therapeutic method. Various centers performed the grafting surgery and the behavioral evaluations in different ways, and observed a varying degree of symptomatic relief. This led to a plea for double blind placebo-controlled clinical trials, which have since been performed and of which the first outcomes were recently published. In the present paper this approach of experimental neurotransplantation in brain diseases is discussed and rejected. Neural grafting in the central nervous system is irreversible and is therefore not suitable for experimental approaches originally designed for and best suited to drug studies. For Parkinson's disease in particular, the technique is far from optimized to perform large-scale studies at this stage. Moreover, previous negative results of adrenal medulla tissue implantation in the brain of patients make placebo effects rather unlikely. Moral arguments concerning the validity of the informed consent, therapeutic misconception, and the risk/benefit ratio can be added in the plea against this control surgery. Finally, a recommendation is made for study designs that apply a disease-dedicated core assessment protocol (CAP) that can evaluate the period from pre-operative to post-convalescent stages quantitatively, and therefore, unbiased. The strength of these CAPs is that they allow comparisons of different grafting techniques, of results between centers and of other types of interventions and invasive treatments such as deep brain stimulation. On ethical grounds, it is unacceptable not to use a study design that circumvents sham or imitation surgery. It is a challenge for the neuroscience community to develop CAPs for brain diseases that are eligible for neurotransplantation in the future.
Bonini, N. M. (2002). "Chaperoning brain degeneration." Proc Natl Acad Sci U S A 99 Suppl 4: 16407-11.
Drosophila has emerged as a premiere model system for the study of human neurodegenerative disease. Genes associated with neurodegeneration can be expressed in flies, causing phenotypes remarkably similar to those of the counterpart human diseases. Because human neurodegenerative diseases, including Huntington's and Parkinson's diseases, are disorders for which few cures or treatments are available, Drosophila brings to bear powerful genetics to the problem of these diseases. The molecular chaperones were the first modifiers defined that interfere in the progression of such disease phenotypes in Drosophila. Hsp70 is a potent suppressor of both polyglutamine disease and Parkinson's disease in Drosophila. These studies provide the promise of treatments for human neurodegeneration through the up-regulation of stress and chaperone pathways.
Bonnefoy, M., J. Drai, et al. (2002). "[Antioxidants to slow aging, facts and perspectives]." Presse Med 31(25): 1174-84.
FREE RADICALS AND THE THEORY OF AGING: Severe oxidative stress progressively leads to cell dysfunction and ultimately cell death. Oxidative stress is defined as an imbalance between pro-oxidants and/or free radicals on the one hand, and anti-oxidizing systems on the other. The oxygen required for living may indirectly be responsible for negative effects; these deleterious effects are due to the production of free radicals, which are toxic for the cells (superoxide anions, hydroxyl radicals, peroxyl radicals, hydrogen peroxide, hydroperoxides and peroxinitrite anions). Free radical attacks are responsible for cell damage and the targeted cells are represented by the cell membranes, which are particularly rich in unsaturated fatty acids, sensitive to oxidation reactions; DNA is also the target of severe attacks by these reactive oxygen species (ROS). THE DEFENCE SYSTEMS: These are represented by the enzymes and free radical captors. The latter are readily oxidizable composites. The free radical captor or neutralization systems of these ROS use a collection of mechanisms, vitamins (E and C), enzymes [superoxide dismutase (SOD), glutathion peroxidase (GPx) and others], and glutathion reductase (GSH), capable of neutralizing peroxinitrite. The efficacy of this system is dependent on the genome for the enzymatic defence systems, and on nutrition for the vitamins. Some strategies aimed at reducing oxidative stress-related alterations have been performed in animals. However, only a few can be used and are efficient in humans, such as avoidance of unfavourable environmental conditions (radiation, dietary carcinogens, smoking...) and antioxidant dietary supplementation. DIETARY SUPPLEMENTATION: Epidemiological data suggest that antioxidants may have a beneficial effect on many age-related diseases: atherosclerosis, cancer, some neurodegenerative and ocular diseases. However, the widespread use of supplements is hampered by several factors: the lack of prospective and controlled studies; insufficient knowledge on the pro-oxidant, oxidant and ant-oxidant properties of the various supplements; growing evidence that free radicals are not only by-products, but also play an important role in cell signal transduction, apoptosis and infection control. RECOMMENDATIONS: Although current data indicate that antioxidants cannot prolong maximal life span, the beneficial impact of antioxidants on various age-related degenerative diseases may forecast an improvement in life span and enhance quality of life. The current lack of sufficient data does not permit the systematic recommendation of anti-oxidants. Nevertheless, antioxidant-rich diets with fruit and vegetables should be recommended.
Bonnet, A. M. (2002). "[Alpha-2 adrenergic receptors and Parkinson's disease]." Presse Med 31(25): 1193-5.
Bonuccelli, U., A. Colzi, et al. (2002). "Pergolide in the treatment of patients with early and advanced Parkinson's disease." Clin Neuropharmacol 25(1): 1-10.
Introduced on the market in 1989, pergolide, a D1/D2 dopamine receptor agonist, is still widely prescribed for the treatment of patients with early and advanced Parkinson's disease (PD). Initially, pergolide was introduced as an adjunct therapy to levodopa treatment in patients exhibiting fluctuating motor responses and dyskinesias. Results of recent randomized controlled clinical trials in de novo patients with PD show that pergolide is able to improve parkinsonian symptoms when used as monotherapy. Moreover, preliminary results of a long-term monotherapy study in early PD suggest that pergolide is as effective as levodopa, and that a significant delay in the time of the onset of levodopa-induced motor complications can be obtained. A number of randomized studies have shown that pergolide is more effective than bromocriptine as adjunct therapy to levodopa in patients with advanced PD; the greater benefit found with pergolide could be ascribed to its action on both D1 and D2 dopamine receptors. However, controlled comparative studies with new dopamine agonists, such as ropinirole, cabergoline, and pramipexole, have not been performed yet. Interestingly, few open studies in patients with complicated PD have shown that high doses of pergolide (> 6 mg/d) are able to improve motor fluctuations and dyskinesias through a dramatic reduction of levodopa dosage. The side-effect profile of pergolide is similar to that of other dopamine agonists, and complications such as sleep attack and serosal fibrosis have been rarely reported.
Boraud, T., E. Bezard, et al. (2002). "From single extracellular unit recording in experimental and human Parkinsonism to the development of a functional concept of the role played by the basal ganglia in motor control." Prog Neurobiol 66(4): 265-83.
Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects the whole basal ganglia (BG). Various techniques have been used to study BG physiology and pathophysiology. Among these, extracellular single unit recording remains of particular importance. An impressive number of studies of BG electrophysiological activity have been carried out, both in non-human and in human primates, but the data collected show many omissions and disparities. BG activity has been well defined in the physiological situation, but remains far from clear in the Parkinsonian and virtually unexplored in the dopamine (DA)-replacement situation. This paper provides a brief synopsis of (i) recording techniques and (ii) BG electrophysiological activity in normal, Parkinsonian, and dopamine-replacement situations. We have restricted the data used to those obtained in BG structures of human and non-human primates. Only single unit recordings have been reported and four electrophysiological characteristics retained: mean firing frequency, firing pattern, periodic oscillation, and response to both passive and active movement. We have attempted to summarize (i) the commonly accepted characteristics of each BG structure in the three situations, (ii) discrepancies that exist, and (iii) missing elements. Then, the main successive theories aimed to explain the role played by BG in motor control are presented and discussed in the light of the most recently obtained results using the latest technological advances.
Braune, S. (2002). "[Autonomic disorders in idiopathic Parkinson syndrome: diagnostic relevance and therapeutic possibilities]." Schweiz Rundsch Med Prax 91(10): 402-6.
Involvement of the autonomic nervous system in Parkinson's disease (PD) demonstrates the multiple system character of this disease exceeding the extrapyramidal system. Forty to sixty percent of patients with PD suffer from symptoms of autonomic failure impairing their quality of life. Autonomic failure in PD is caused by damage to the postganglionic part of the autonomic nervous system. Scintigraphy with radiolabeled metaiodobenzylguanidin (MIBG) provides evidence of autonomic involvement at an early stage of the disease and enables an early differential diagnosis of PD versus other neurodegenerative disorders. Sensitivity to identify PD versus multiple system atrophy is 89.7%, specificity in 94.6%. Orthostatic hypotension is a frequently overlooked symptom in PD. Diagnosis and cause of orthostatic hypotension can be identified with clinical methods. There are effective physical and pharmacological treatments to improve symptoms.
Bruguerolle, B. and N. Simon (2002). "Biologic rhythms and Parkinson's disease: a chronopharmacologic approach to considering fluctuations in function." Clin Neuropharmacol 25(4): 194-201.
The existence of circadian rhythms and their implication in many pathologic processes have been underlined in several diseases but have not been evaluated in Parkinson's disease. The aim of this paper is to review diurnal variations of clinical, biologic, or experimental factors described with Parkinson's disease. Clinical data often report daily fluctuations of motor activity pattern, but the effect of the stage of the disease and the respective roles of drugs are difficult to evaluate. Sleep disturbances in Parkinson's disease patients also reveal alterations of circadian rhythms. Autonomic dysfunction, described in Parkinson's disease, reveals numerous alterations in circadian regulations including loss of circadian rhythm of blood pressure, increased diurnal blood pressure variability, and postprandial hypotension. Many biologic indices such as cortisol, catecholamines, and melatonin are also altered. Circadian rhythms in dopaminergic systems as well as possible daily fluctuations in kinetics of drug treatments are likely involved in such variations. Few clinical studies have been devoted to circadian patterns of drug response. As for other diseases where biologic rhythms are concerned Parkinson's disease therapy may be influenced by further understanding of circadian influence.
Brundin, P. (2002). "GDNF treatment in Parkinson's disease: time for controlled clinical trials?" Brain 125(Pt 10): 2149-51.
Brydak, L. B. (2002). "[Neurological complication of influenza infections]." Przegl Epidemiol 56 Suppl 1: 16-30.
The aim of this study was to present neurological complications of influenza infections. Infections caused by influenza viruses can be very serious and may lead even to death resulted from the post-infectious complications. The most often occurring complications are pneumonia, bronchitis, bronchiolitis, myocarditis and otitis media. The other group is neurological post-influenza complications, including dementia, epileptic disorders, cerebrovascular disease, febrile convulsions, toxic encephalopathy, encephalitis, meningitis, subarachnoid hemorrhages, lethargic encephalitis, psychosis or increase in the number of cases of Parkinson's disease. The first way of prevention of influenza is vaccination that results in healthy, social and economic benefits.
Bullock, R. and A. Saharan (2002). "Atypical antipsychotics: experience and use in the elderly." Int J Clin Pract 56(7): 515-25.
The use of antipsychotics is common in the elderly Typical antipsychotics are not without risk, especially in tardive dyskinesia, which, when balanced against relatively low efficacy, make their use debatable. Atypical antipsychotics have much less in the way of side-effects and are much less likely to induce tardive dyskinesia. However, there is much less in the published literature about the efficacy of these drugs in the elderly and how best to use them in primary psychosis, Parkinson's disease and the behavioural and psychological symptoms of dementia. This review attempts to summarise the current literature and make some tentative recommendations for each of the commonest atypicals, based on the current evidence.
Burn, D. J. (2002). "Beyond the iron mask: towards better recognition and treatment of depression associated with Parkinson's disease." Mov Disord 17(3): 445-54.
This review examines the frequency of depression complicating Parkinson's disease (PD), its aetiology and clinical features, and also how it may be recognised and treated. Studies investigating the frequency of depression in PD have yielded figures ranging between 2.7% and 70%. Methodological differences account for much of the disparity. The aetiology of depression in PD is complex, and probably relates to both biological and exogenous factors. Dysfunction of multiple neurotransmitter systems, including the serotonergic system, may be involved. Mood disturbances resulting from deep brain stimulation of the subthalamic nucleus may provide a fruitful area for future research, and assist our understanding of the neural networks involved in mediating depression. Several recent studies have confirmed that depression in the PD patient is a major determinant of quality of life and that this is closely related to dysfunction in other clinically important health areas. The validity for many existing scales in the screening, diagnosis, and monitoring of depression in the PD patient has not been established. The Montgomery-Asberg Depression Rating Scale and the Hamilton Rating Scale for Depression appear to have good diagnostic sensitivity and specificity when compared with DSM-IV criteria. Recommendations for the optimal drug treatment of depression in PD are difficult to give, due to an inexplicable dearth of sizeable, placebo-controlled studies. A majority of physicians would probably now opt for a selective serotonin reuptake inhibitor in the depressed PD patient. There is no good evidence that these drugs are associated with a worsening of motor features, but they should probably not be coprescribed with selegiline, because of the risk of causing a potentially serious serotonin syndrome. Several studies have suggested that depression in the PD patient is associated with a more rapid deterioration in cognitive and motor functions, perhaps as a surrogate marker for more extensive brainstem cell loss.
Butterfield, D. A., A. Castegna, et al. (2002). "Vitamin E and neurodegenerative disorders associated with oxidative stress." Nutr Neurosci 5(4): 229-39.
Several neurodegenerative disorders are associated with oxidative stress that is manifested by lipid peroxidation, protein oxidation and other markers. Included in these disorders in which oxidative stress is thought to play an important role in their pathogenesis are Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), tardive dyskinesia, Huntington's disease (HD), and multiple sclerosis. This review presents some of the chemistry of vitamin E as an antioxidant and summarizes studies in which vitamin E has been employed in these disorders and models thereof.
Cantello, R. (2002). "Applications of transcranial magnetic stimulation in movement disorders." J Clin Neurophysiol 19(4): 272-93.
The author reviews the applications of transcranial magnetic stimulation (TMS) in a series of movement disorders--namely, Parkinson's disease, corticobasal degeneration, multiple system atrophy, progressive supranuclear palsy, essential tremor, dystonia, Huntington's chorea, myoclonus, the ataxias, Tourette's syndrome, restless legs syndrome, Wilson's disease, Rett syndrome, and stiff-person syndrome. Single- and paired-pulse TMS studies have been done mainly for pathophysiologic purposes. Repetitive TMS has been used largely for therapy. Many TMS abnormalities are seen in the different diseases. They concur to show that motor cortical areas and their projections are the main target of the basal ganglia dysfunction typical of movement disorders. Interpretation has not always been clear, and sometimes there were discrepancies and contradictions. Largely, this may be the result of the extreme heterogeneity of the methods used and of the patients studied. It is premature to give repetitive TMS a role in treatment. Overall, however, TMS gives rise to a new, outstanding enthusiasm in the neurophysiology of movement disorders. There is reason to predict that TMS, with its continuous technical refinement, will prove even more helpful in the near future. Then, research achievements are reasonably expected to spill over into clinical practice.
Cantello, R., R. Tarletti, et al. (2002). "Transcranial magnetic stimulation and Parkinson's disease." Brain Res Brain Res Rev 38(3): 309-27.
While motor cortical areas are the main targets of the integrative activity of basal ganglia, their main output consists of the corticospinal system. Transcranial magnetic stimulation (TMS), a relatively new method to investigate corticospinal physiology, has been widely used to assess possible changes secondary to Parkinson's disease (PD). The use of single- and paired-pulse TMS, two varieties of the original technique, disclosed multiple functional alterations of the corticospinal pathway. For instance, when the latter was tested at 'rest', or in response to somesthetic afferents, it showed excess excitability or reduced inhibition. In turn, during production of a voluntary output, its activation was defective, or inadequately modulated. One major mechanism may be a dysfunction of the interneurons mediating the level of excitation within cortical area 4. For instance, there is a shortening of the so-termed 'central silent period', which is a complex, TMS-induced, inhibitory phenomenon possibly mediated by activation of GABA(B) receptors. The so-called 'short-interval intracortical inhibition', which is possibly mediated by GABA(A) receptors, is also diminished. Levodopa restores these and other TMS alterations, thus demonstrating that cortical area 4 is sensitive to dopamine modulation. Overall, TMS has provided substantial new pathophysiological insights, which point to a central role of the primary motor cortex in the movement disorder typical of PD. Repetitive (r-)TMS, another form of TMS, has been studied as a treatment for PD motor signs. Although some reports are favorable, others are not, and have raised the problem of appropriate control experiments. Although extremely interesting, the potential therapeutic role of r-TMS in PD needs further evaluation.
Carbon, M. and D. Eidelberg (2002). "Modulation of regional brain function by deep brain stimulation: studies with positron emission tomography." Curr Opin Neurol 15(4): 451-5.
Carlsson, A. (2002). "Treatment of Parkinson's with L-DOPA. The early discovery phase, and a comment on current problems." J Neural Transm 109(5-6): 777-87.
Caroff, S. N., S. C. Mann, et al. (2002). "Movement disorders associated with atypical antipsychotic drugs." J Clin Psychiatry 63 Suppl 4: 12-9.
Data from clinical trials reviewed in this article fulfill predictions based on preclinical findings that atypical antipsychotic drugs are associated with a reduced potential for inducing extrapyramidal symptoms (EPS) and other movement disorders. Atypical drugs have been shown to reduce all subtypes of acute EPS, the frequency of EPS-related patient dropouts, and the need for concomitant antiparkinsonian drug use. Clozapine remains superior to other atypicals in treating psychosis without worsening motor symptoms in patients with Parkinson's disease. Atypicals may be selectively advantageous in treating schizophrenic patients with a predisposition to catatonia. Although the risk of developing lethal neuroleptic malignant syndrome may be diminished with atypical drugs, clinicians must remain alert to the signs of this disorder. Atypicals have reduced liability for inducing tardive dyskinesia (TD) and show antidyskinetic properties in patients with preexisting TD. Passive resolution of TD may be facilitated in some patients by the use of these agents. Thus, the risk of movement disorders has become only one of several considerations in choosing among antipsychotic drugs.
Carr, J. (2002). "Tremor in Parkinson's disease." Parkinsonism Relat Disord 8(4): 223-34.
Rest tremor is a common feature of Parkinson's disease, but its underlying pathophysiology remains unknown. This review hypothesizes that tremor is related to selective loss of components of the substantia nigra. The relative scarcity of tremor in related Parkinsonian conditions may indicate a dissociation associated with different pathological involvement of the substantia nigra and its connections. Connections of the subthalamic nucleus with the pallidum, modified by cortical and nigral inputs, allow for the transfer of tremorogenic activity to the thalamus. Thalamo-cortical interactions, tempered by cerebellar input, generate the final common pathway for tremor production.
Cartier, L. (2002). "[Falls and gait alterations in elderly]." Rev Med Chil 130(3): 332-7.
There is a higher frequency of falls in the elderly than in young people, due to age related physiological changes in gait. There is a lower amplitude of pelvic movements that affects gait efficiency. Equilibrium is also disturbed since the trunk assumes the leadership of gait, displacing the pelvis. Many diseases of elderly individuals, such as Parkinson disease, spastic paraparesis, cerebrovascular accidents or neuropathies, further impair the gait. Therefore, after the age of 65, all falls must be considered symptomatic.
Cavalieri, E. L., E. G. Rogan, et al. (2002). "Initiation of cancer and other diseases by catechol ortho-quinones: a unifying mechanism." Cell Mol Life Sci 59(4): 665-81.
Exposure to estrogens is a risk factor for breast and other human cancers. Initiation of breast, prostate and other cancers has been hypothesized to result from reaction of specific estrogen metabolites, catechol estrogen-3,4-quinones, with DNA to form depurinating adducts at the N-7 of guanine and N-3 of adenine by 1,4-Michael addition. The catechol of the carcinogenic synthetic estrogen hexestrol, a hydrogenated derivative of diethylstilbestrol, is metabolized to its quinone, which reacts with DNA to form depurinating adducts at the N-7 of guanine and N-3 of adenine. The catecholamine dopamine and the metabolite catechol (1,2-dihydroxybenzene) of the leukemogen benzene can also be oxidized to their quinones, which react with DNA to form predominantly analogous depurinating adducts. Apurinic sites formed by depurinating adducts are converted into tumor-initiating mutations by error-prone repair. These mutations could initiate cancer by estrogens and benzene, and Parkinson's disease by the neurotransmitter dopamine. These data suggest a unifying molecular mechanism of initiation for many cancers and neurodegenerative diseases and lay the groundwork for designing strategies to assess risk and prevent these diseases.
Cenci, M. A., I. Q. Whishaw, et al. (2002). "Animal models of neurological deficits: how relevant is the rat?" Nat Rev Neurosci 3(7): 574-9.
Animal models of neurological deficits are essential for the assessment of new therapeutic options. It has been suggested that rats are not as appropriate as primates for the symptomatic modelling of disease, but a large body of data argues against this view. Comparative analyses of movements in rats and primates show homology of many motor patterns across species. Advances have been made in identifying rat equivalents of akinesia, tremor, postural deficits and dyskinesia, which are relevant to Parkinson's disease. Rat models of hemiplegia, neglect and tactile extinction are useful in assessing the outcome of ischaemic or traumatic brain injury, and in monitoring the effects of therapeutic interventions. Studies in rodents that emphasize careful behavioural analysis should continue to be developed as effective and inexpensive models that complement studies in primates.
Chaudhuri, K. R., S. Pal, et al. (2002). "'Sleep attacks' or 'unintended sleep episodes' occur with dopamine agonists: is this a class effect?" Drug Saf 25(7): 473-83.
Controversial reports of sudden onset 'sleep attacks' resulting in road traffic accidents have recently been reported in patients with Parkinson's disease (PD) taking the non-ergot dopamine D(2 )/D(3) receptor agonists pramipexole and ropinirole. These reports have generated considerable debate as the concept of 'sleep attacks' is disputed amongst sleep specialists and most believe that isolated 'sleep attacks' not preceded by warning on the background of chronic sleepiness or 'unintended sleepiness' do not exist. A series of case reports suggested that this phenomenon may not be exclusive to the non-ergot dopamine agonists such as pramipexole or ropinirole and indeed may occur with most dopaminergic agents. Recent evidence suggest that a 'sleepiness' or 'hypoactivity' reaction to dopaminergic therapy may be related to underlying dopamine deficiency of PD rather than a drug effect. In this report we provide the evidence for the phenomenon being a class effect attributable to all dopamine agonists currently employed in the management of PD. Controversy surrounding excessive daytime sleepiness (EDS) in PD and the use of the Epworth Sleepiness Scale (ESS) in relation to PD is also discussed. In spite of variable reports, EDS is recognised to be common in PD and is likely to be related to both the disease process and drug therapy. Studies using multiple sleep latency tests have also reported differing results in PD although a recent study indicated that a subset of 'sleepy' patients with PD may experience pathological somnolence with resultant detrimental consequence on daytime and cognitive functions. We recommend that the issue of 'sleepiness' or 'sleep attacks' in PD should be routinely checked in all patients with PD and indirectly assessed by using either the ESS or the recently introduced Parkinson's Disease Sleep Scale. Those with reported 'sleep attacks' or 'unintended sleep episodes' and excessive daytime sleepiness while taking dopamine agonists or dopaminergic agents such as levodopa should have a review of their medication, should not be driving a car on their own and some may merit formal sleep architecture studies. The latter may identify sleep disorders such as secondary narcolepsy which may benefit from the use of a wakefulness promoting agent.
Christen, Y. (2002). "[Proteins and mutations: a new vision (molecular) of neurodegenerative diseases]." J Soc Biol 196(1): 85-94.
Neurodegenerative diseases have long been considered to be poorly defined, misunderstood, and inadequately treated. In recent years, research on Alzheimer's disease has led to numerous advances that have improved our understanding of this form of dementia and also of the entire category of neurodegenerative diseases. It now appears that numerous neurodegenerative diseases of the central nervous system correspond to the aggregation of specific proteins: beta-amyloid in Alzheimer disease, tau protein in Alzheimer disease, fronto-temporal dementia, progressive supranuclear palsy and corticobasal degeneration, alpha-synuclein in Parkinson disease and Lewy body dementia, PrP protein in prion diseases, SOD in amyotrophic lateral sclerosis, polyglutamine expansions in Huntington's disease and other diseases, etc. It is remarkable that in all these cases mutations have been identified for genes coding for these proteins and able to cause the disease and, moreover, that the introduction of the corresponding gene into transgenic mice (or other transgenic animals) has made it possible to create animal models of these conditions. This suggests that the proteins in question play a determinative role in the pathogenesis of these diseases and are not simply consequences of it. Neurodegenerative diseases are proteinopathies. But they are also networkopathies because the neuronal proteins are organized in functional networks. We must also note that all these diseases are associated with the process of aging, for they do not appear in the young. This fact suggests that the anomaly (genetic or otherwise) concerning a given protein does not suffice by itself to induce the disease process. Many observations suggest that the additional event involved, common to all neurodegenerative conditions, may be the intervention of free radicals. We thus propose here the theory that the diversity of neurodegenerative diseases is explained by the combination of two pathogenic events: one specific and associated with the aggregation of a particular protein in the nervous system, the other, non-specific and associated with aging and with the production and harmful actions of free radicals. This unified interpretation leads directly to treatment hypotheses: the development of drugs capable either of inhibiting the production or aggregation of proteins specifically implicated in diverse diseases (or promoting their elimination) or of inhibiting the production or action of free radicals in the nervous system. The former should target one of these various diseases, and the latter should act on a wide range of diseases. The two approaches may conceivably be combined.
Clarke, C. E. and M. Guttman (2002). "Dopamine agonist monotherapy in Parkinson's disease." Lancet 360(9347): 1767-9.
CONTEXT: Levodopa is the gold-standard therapy for Parkinson's disease. However, long-term treatment leads to involuntary movements and response fluctuations which add to the complexities of later disease-management. In addition, preclinical evidence suggests that levodopa is toxic to dopaminergic neurons. These problems have led to a move away from levodopa towards initial monotherapy with a dopamine agonist. STARTING POINT: Positron-emission tomography (PET) and single-photon emission computed tomography (SPECT) tracers have been developed which may be considered surrogate markers for remaining dopaminergic neurons. In a randomised controlled trial in patients with early Parkinson's disease, the Parkinson Study Group used 123I-beta-CIT SPECT (JAMA 2002; 287: 1653-61). Those patients given pramipexole had significantly reduced loss of striatal uptake at 46 months compared with those given levodopa (16.0% vs 25.5%). In a similar trial, Alan Whone and colleagues used 18F-DOPA PET (Neurology 2002; 58 [suppl 3]: A82-83). Patients given ropinirole had significantly reduced loss of striatal uptake at 24 months compared with those given levodopa (13% vs 20%). These studies suggest that agonist monotherapy may be neuroprotective and/or that levodopa is toxic. This work has been criticised as the SPECT results may have resulted from a differential effect of the agonist and levodopa on the regulation of the dopamine transporter, thereby influencing the imaging outcome measure. Other criticisms include insufficient data on the use of the potential neuroprotectant selegiline and patients on pramipexole in the SPECT study appear to have been clinically slow progressors. Single clinical trials with each of the four modern agonists compared with levodopa show that as monotherapy the agonists delay the onset of involuntary movements, although at the expense of poorer treatment of motor impairments and disability and more dopaminergic adverse events. The only health-related quality of life data show no difference between pramipexole and levodopa after 4 years. No information on health-economics measures is available but agonists cost two to three times as much as levodopa. WHERE NEXT? Young patients should be treated with agonist monotherapy since the trials included predominantly younger patients who have a higher incidence of motor complications. Those with significant co-morbidity, dementia, or a short life-expectancy should be treated with the lowest dose of levodopa required to maintain motor function. For the vast majority though, no clear guidance can be given. Further large-scale pragmatic trials in large numbers of patients over prolonged periods are urgently required.
Cole, N. B. and D. D. Murphy (2002). "The cell biology of alpha-synuclein: a sticky problem?" Neuromolecular Med 1(2): 95-109.
Parkinson's disease (PD) is the most common neurodegenerative motor disorder, marked by chronic progressive loss of neurons in the substantia nigra, thereby damaging purposeful control of movement. For decades, it was believed that PD was caused solely by environmental causes. However, the discovery of genetic factors involved in PD has revolutionized our attempts to understand the disease's pathology. PD now appears to be more polygenetic than previously thought and is most likely caused by a complex interaction of genetic risks and environmental exposures. The first gene found to be mutated in PD encodes for the presynaptic protein alpha-synuclein, which is also a major component of Lewy bodies and Lewy neurites, the neuropathological hallmarks of the disease. While these findings provide a classic example of how rare genetic mutations in disease can point to important pathways in idiopathic disease pathologies, much of the study of alpha-synuclein has focused on understanding how this protein undergoes the transition from an unfolded monomer to amorphous aggregates or Lewy body-like filaments rather than addressing what its fundamental function might be. Since alterations in synuclein function may predispose to the disease pathology of PD, regardless of the presence of genetic mutations, a more thorough understanding of the cellular regulation and function of alpha-synuclein may be of crucial importance to our understanding of this degenerating disorder.
Collins, M. A. and E. J. Neafsey (2002). "Potential neurotoxic "agents provocateurs" in Parkinson's disease." Neurotoxicol Teratol 24(5): 571-7.
Idiopathic Parkinson's disease (PD), one of the most common neurodegenerative disorders associated with aging, is characterized neurochemically by abnormal and profound loss of nigrostriatal dopamine (DA) neurons. A prominent current view is that the excessive degeneration of the dopaminergic system is the outcome of extended insults by environmental neurotoxins or endogenous neurotoxic factors in genetically vulnerable or susceptible individuals. Recent insights into the identities and mechanisms of potential neurotoxic species, which span pesticides, environmental contaminants including heterocyclic amines with beta-carboline (betaC) and isoquinoline (IQ) structures, endogenous DA metabolites or intermediates, neuromelanin, metals, and infectious agents, are presented.
Corti, O. and A. Brice (2002). "[Parkin, alpha-synuclein and other molecular aspects of Parkinson's disease]." J Soc Biol 196(1): 95-10.
Parkinson's disease is a neurodegenerative disorder characterized by the progressive degeneration of the dopaminergic nigrostriatal pathway, and the presence of Lewy bodies. Over the past few years, several genes involved in inherited forms of the disease have been uncovered. In a small number of families with autosomal dominant inheritance, mutations have been identified in the genes encoding a-synuclein and ubiquitin carboxy-terminal hydrolase L1. Mutations in the parkin gene are a common cause of autosomal recessive parkinsonism with early onset, and also account for more than 15% of isolated cases with onset before age 45. The function of Parkin, a ubiquitin ligase involved in the degradation of protein substrates by the ubiquitin-proteasome pathway, highlights that ubiquitin-mediated proteolysis may play an important role in the pathophysiology of idiopathic Parkinson's disease.
Cox, P. A. and O. W. Sacks (2002). "Cycad neurotoxins, consumption of flying foxes, and ALS-PDC disease in Guam." Neurology 58(6): 956-9.
The Chamorro people of Guam have been afflicted with a complex of neurodegenerative diseases (now known as ALS-PDC) with similarities to ALS, AD, and PD at a far higher rate than other populations throughout the world. Chamorro consumption of flying foxes may have generated sufficiently high cumulative doses of plant neurotoxins to result in ALS-PDC neuropathologies, since the flying foxes forage on neurotoxic cycad seeds.
Crawford, T. J., D. Bennett, et al. (2002). "Cognition and the inhibitory control of saccades in schizophrenia and Parkinson's disease." Prog Brain Res 140: 449-66.
Historically, various lines of evidence have converged on the view that the brain expends much of its neural resources on inhibiting its own activity in a critical step towards the cognitive control of behaviour. The loss of inhibitory control is widely reported in neurological and psychiatric disorders; however, the consequences of reduced inhibition in terms of wider cognitive effects on cognitive control operations such as planning, abstract thought, working memory and the ability to appreciate the perspective of others ('theory of mind') has been widely overlooked. The antisaccade paradigm examines the conflict between a prepotent stimulus that produces a powerful urge to fixate the target, and the overriding goal to 'look' in the opposite direction. In this chapter we illustrate how this paradigm is increasingly used to explore the relationship of inhibitory control and cognition in Parkinson's disease, schizophrenia and healthy participants. Evidence is presented that is consistent with the theory of cognitive inhibition as a distinct process that can be dissociated from working memory. We conclude that the inhibitory control of saccadic eye movement should be studied in the wider context of cognitive operations.
Crowther, D. C. (2002). "Familial conformational diseases and dementias." Hum Mutat 20(1): 1-14.
Familial conformational diseases occur when a mutation alters the conformation of a protein resulting in abnormal intermolecular interactions, protein aggregation, and consequent tissue damage. The molecular mechanisms of conformational disease are best understood for the serine protease inhibitor (serpin) superfamily of proteins. The serpinopathies include alpha(1)-antitrypsin (SERPINA1) deficiency and the newly characterized familial encephalopathy with neuroserpin inclusion bodies (FENIB) resulting from mutations in the neuroserpin (SERPINI1) gene. This review discusses how insights gained from the study of the serpins may be used to guide our research into other common diseases such as Alzheimer disease, Huntington disease, and Parkinson disease.
Cushing, M. L., K. A. Traviss, et al. (2002). "Parkinson's disease: implications for nutritional care." Can J Diet Pract Res 63(2): 81-7.
Parkinson's Disease (PD) is a chronic, progressive, neurodegenerative disease. People with PD are particularly susceptible to weight loss and malnutrition. Involuntary movements associated with PD result in increased energy expenditure, while both disease symptoms and medication side-effects can limit food intake. In addition, patients with the disease may choose to follow unconventional nutritional therapies that exacerbate malnutrition. Dietitians play a key role in helping patients with PD to optimize their nutritional status and manage various nutrition-related symptoms and medication side-effects. To assume this role, dietitians need to have current knowledge about PD and its nutritional consequences, as well as strategies for managing a variety of nutrition-related symptoms.
Cyr, M., F. Calon, et al. (2002). "Estrogenic modulation of brain activity: implications for schizophrenia and Parkinson's disease." J Psychiatry Neurosci 27(1): 12-27.
Evidence suggests the estrogens may play a role in various mental and neurodegenerative diseases. We review the evidence implicating estradiol in schizophrenia and Parkinson's disease. Epidemiologic and clinical studies on the effects of estrogens in schizophrenia are surveyed, and animal studies and in vitro models of the modulatory effects of estrogens on neurotransmitters associated with schizophrenia (i.e., dopamine, serotonin, glutamate) are reviewed. Epidemiologic and clinical data suggesting a role for estrogens in Parkinson's disease and in vivo and in vitro models demonstrating neuroprotective effects of estrogens are then examined. Despite the numerous animal studies on the effects of estrogens in the brain, clinical data are sparse and often contradictory. Compounds with more specific and potent estrogenic activity in the brain are required to further research efforts in this area. Possible candidates are the selective estrogen receptor modulators (SERMs), whose agonist or antagonist properties depend on the target tissue. The effects of various SERMs in the brain are reviewed, and our novel findings on the effects of SERMs on 5-HT2A receptors in the rat cortex and nucleus accumbens are presented. We suggest that drugs with estrogenic activity in the brain may have therapeutic potential, either by modulating brain neurotransmission or through neuroprotective activity.
Da Cunha, C., M. E. Angelucci, et al. (2002). "The lesion of the rat substantia nigra pars compacta dopaminergic neurons as a model for Parkinson's disease memory disabilities." Cell Mol Neurobiol 22(3): 227-37.
1. In this article we review the studies of memory disabilities in a rat model of Parkinson's disease (PD). 2. Intranigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to rats causes a partial lesion in the substantia nigra, compact part (SNc) and a specific loss of dopamine and its metabolites in the striatum of rats. 3. These animals present learning and memory deficits but no sensorimotor impairments, thus modeling the early phase of PD when cognitive impairments are observed but the motor symptoms of the disease are barely present. 4. The cognitive deficits observed in these animals affect memory tasks proposed to model habit learning (the cued version of the water maze task and the two-way active avoidance task) and working memory (a working memory version of the water maze), but spare long-term spatial memory (the spatial reference version of the Morris water maze). 5. The treatment of these animals with levodopa in a dose that restores the striatal level of dopamine does not reverse these memory impairments, probably because this treatment promotes a high level of dopamine in extrastriatal brain regions, such as the prefrontal cortex and the hippocampus. 6. On the other hand, the adenosine receptor antagonist, caffeine, partly reverse the memory impairment effect of SNc lesion in these rats. This effect may be due to caffeine action on nigrostriatal neurons, since it induces dopamine release and modulates the interaction between adenosine and dopamine receptor activity. 7. These results suggest that the MPTP SNc-lesioned rats are a good model to study memory disabilities related to PD and that caffeine and other selective A(2A) adenosine receptor antagonists are promising drugs to treat this symptoms in PD patients.
Dajas, F., G. Costa, et al. (2002). "Antioxidant and cholinergic neuroprotective mechanisms in experimental parkinsonism." Funct Neurol 17(1): 37-44.
Danisi, F. (2002). "Parkinson's disease. Therapeutic strategies to improve patient function and quality of life." Geriatrics 57(3): 46-50; quiz 52.
Idiopathic Parkinson's disease (PD) is an age-related neuro-degenerative disorder characterized by slowness, stiffness, resting tremor, gait impairment, and postural instability. Levodopa is the most potent pharmacologic agent for symptom management and is associated with an increase in quality of life and longevity for patients with PD, but chronic use causes motor complications. The availability of several newer types of agents--dopamine agonists, monoamine oxidase inhibitors, and catechol-O-methyltransferase inhibitors--gives physicians increased flexibility with regard to first-line therapy, adjunct therapy, and managing or reducing the frequency of motor complications and other side effects associated with chronic levodopa therapy.
Dawson, T. M. and V. L. Dawson (2002). "Neuroprotective and neurorestorative strategies for Parkinson's disease." Nat Neurosci 5 Suppl: 1058-61.
Advances in understanding the molecular mechanisms of cell death and the pathogenesis of sporadic and familial Parkinson's disease are creating new opportunities for the development of neuroprotective and/or neurorestorative therapies. Here we review many of these advances, highlighting areas and strategies that might be particularly suited to the development of innovative approaches that prevent degeneration and/or restore function in Parkinson's disease.
Dawson, T., A. Mandir, et al. (2002). "Animal models of PD: pieces of the same puzzle?" Neuron 35(2): 219-22.
Parkinson's disease (PD) is a common neurodegenerative disorder with no known cure. The etiology of PD is likely due, in part, to combinations of genetic susceptibilities and environmental factors. In rare familial cases, PD is due to genetic mutations. A number of new genetic and toxin models of PD and advances in older models are yielding important new information about the pathogenesis of PD. This has prompted us to critically review the current animal models for PD and discuss how these models may yield fresh insights into the pathogenesis of PD, as well as new therapeutic opportunities.
de la Fuente-Fernandez, R. and A. J. Stoessl (2002). "Parkinson's disease: imaging update." Curr Opin Neurol 15(4): 477-82.
PURPOSE OF REVIEW: We aim to review recent neuroimaging contributions to our understanding of the cause and pathogenesis of Parkinson's disease, as well as treatment-related complications of disease, with a focus on functional anatomy and neurochemistry. RECENT FINDINGS: Recent reports describe altered dopaminergic activity in extrastriatal regions, as well as changes in other monoaminergic systems, such as serotonin. Attempts to correlate altered dopaminergic function with personality traits have also been described in the last year. The role of different markers of presynaptic dopaminergic integrity in the assessment of disease progression is discussed, as is the role of biomarkers in detection of preclinical disease. Cerebral activation studies not only confirm altered function of cortico-striatal-thalamo-cortical loops in Parkinson's, but also emphasize the importance of networks involving the cerebellum. The ability to detect changes in synaptic availability of dopamine using positron emission tomography with [(11)C]raclopride is reviewed, including the application to detect altered levels of dopamine in response to pharmacological, mechanical and behavioral stimuli. Such studies have been used to identify altered patterns associated with the development of motor fluctuations, as well as a biochemical substrate underlying the placebo effect in Parkinson's. SUMMARY: Functional imaging studies can provide novel insights into the etiopathogenesis of Parkinson's disease, as well as the mechanisms that contribute to complications of long-term therapy. They also shed light on the mechanisms that may underly behavioral changes and benefit derived from surgical interventions.
de la Fuente-Fernandez, R. and A. J. Stoessl (2002). "The placebo effect in Parkinson's disease." Trends Neurosci 25(6): 302-6.
The biochemical bases of the placebo effect are still incompletely known. We show here that the placebo effect in Parkinson's disease is due, at least in part, to the release of dopamine in the striatum. We propose that the placebo effect might be related to reward mechanisms. The expectation of reward (i.e. clinical benefit) seems to be particularly relevant. According to this theory, brain dopamine release could be a common biochemical substrate for the placebo effect encountered in other medical conditions, such as pain and depression. Other neurotransmitters or neuropeptides, however, are also likely to be involved in mediating the placebo effect (e.g. opioids in pain disorders, serotonin in depression).
Deane, K. H., C. Ellis-Hill, et al. (2002). "Systematic review of paramedical therapies for Parkinson's disease." Mov Disord 17(5): 984-91.
We evaluated the efficacy of physiotherapy, occupational therapy, and speech and language therapy in Parkinson's disease by synthesizing six Cochrane systematic reviews. All randomised, controlled trials examining the efficacy of a paramedical therapy versus control intervention and all those comparing the efficacy of two forms of active therapy in Parkinson's disease were included. Trials were identified by searching biomedical databases, reference lists, hand searching, and contacting investigators. The main outcome measures were quality of life, speech intelligibility, activities of daily living, and individual measures of motor and speech impairment. We identified 16 physiotherapy randomised controlled trials (399 patients), two occupational therapy trials (84 patients), and five speech and language therapy for dysarthria trials (154 patients). None of these studies examined nonpharmacological swallowing therapy for dysphagia. We were unable to perform meta-analysis of the results because the trials used heterogeneous therapy methods and outcome measures. The trials also had marked methodological flaws that could have introduced bias. In summary, we failed to find conclusive evidence of benefit for any form of paramedical therapy sufficient to recommend them in routine clinical practice. However, this lack of evidence is not proof of a lack of effect. Further large pragmatic randomised controlled trials are required to determine the effectiveness of paramedical therapies in Parkinson's disease.
Deglon, N. and P. Aebischer (2002). "Lentiviruses as vectors for CNS diseases." Curr Top Microbiol Immunol 261: 191-209.
Deleu, D., M. G. Northway, et al. (2002). "Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson's disease." Clin Pharmacokinet 41(4): 261-309.
Current research in Parkinson's disease (PD) focuses on symptomatic therapy and neuroprotective interventions. Drugs that have been used for symptomatic therapy are levodopa, usually combined with a peripheral decarboxylase inhibitor, synthetic dopamine receptor agonists, centrally-acting antimuscarinic drugs, amantadine, monoamine oxidase-B (MAO-B) inhibitors and catechol-O-methyltransferase (COMT) inhibitors. Drugs for which there is at least some evidence for neuroprotective effect are certain dopamine agonists, amantadine and MAO-B inhibitors (selegiline). Levodopa remains the most effective drug for the treatment of PD. Several factors contribute to the complex clinical pharmacokinetics of levodopa: erratic absorption, short half-life, peripheral O-methylation and facilitated transport across the blood-brain barrier. In patients with response fluctuations to levodopa, the concentration-effect curve becomes steeper and shifts to the right compared with patients with stable response. Pharmacokinetic-pharmacodynamic modelling can affect decisions regarding therapeutic strategies. The dopamine agonists include ergot derivatives (bromocriptine, pergolide, lisuride and cabergoline), non-ergoline derivatives (pramipexole, ropinirole and piribedil) and apomorphine. Most dopamine agonists have their specific pharmacological profile. They are used in monotherapy and as an adjunct to levodopa in early and advanced PD. Few pharmacokinetic and pharmacodynamic data are available regarding centrally acting antimuscarinic drugs. They are characterised by rapid absorption after oral intake, large volume of distribution and low clearance relative to hepatic blood flow, with extensive metabolism. The mechanism of action of amantadine remains elusive. It is well absorbed and widely distributed. Since elimination is primarily by renal clearance, accumulation of the drug can occur in patients with renal dysfunction and dosage reduction must be envisaged. The COMT inhibitors entacapone and tolcapone dose-dependently inhibit the formation of the major metabolite of levodopa, 3-O-methyldopa, and improve the bioavailability and reduce the clearance of levodopa without significantly affecting its absorption. They are useful adjuncts to levodopa in patients with end-of-dose fluctuations. The MAO-B inhibitor selegiline may have a dual effect: reducing the catabolism of dopamine and limiting the formation of neurotoxic free radicals. The