Parkinson Disease: Olanow CW

Olanow CW. · No affiliation provided · Arch Neurol. · Pubmed #16157740 links to  free full text

This publication has no abstract.

Olanow CW, Stern MB, Sethi K. · Department of Neurology, Mount Sinai School of Medicine, 1 Gustave Levy Place, Annenberg 14-94, New York, NY 10029, USA. · Neurology. · Pubmed #19470958 No free full text.

Abstract: Parkinson disease (PD) is an age-related neurodegenerative disorder that affects as many as 1-2% of persons aged 60 years and older. With the aging of the population, the frequency of PD is expected to increase dramatically in the coming decades. Current therapy is largely based on a dopamine replacement strategy, primarily using the dopamine precursor levodopa. However, chronic treatment is associated with the development of motor complications, and the disease is inexorably progressive. Further, advancing disease is associated with the emergence of features such as freezing, falling, and dementia which are not adequately controlled with dopaminergic therapies. Indeed, it is now appreciated that these nondopaminergic features are common and the major source of disability for patients with advanced disease. Many different therapeutic agents and treatment strategies have been evaluated over the past several years to try and address these unmet medical needs, and many promising approaches are currently being tested in the laboratory and in the clinic. As a result, there are now many new therapies and strategic approaches available for the treatment of the different stages of PD, with which the treating physician must be familiar in order to provide patients with optimal care. This monograph provides an overview of the management of PD patients, with an emphasis on pathophysiology, and the results of recent clinical trials. It is intended to provide physicians with an understanding of the different treatment options that are available for managing the different stages of the disease and the scientific rationale of the different approaches.

Olanow CW. · Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA. · Neurology. · Pubmed #19221316 No free full text.

Abstract: A disease-modifying therapy is the most important unmet medical need in the treatment of Parkinson disease (PD). Laboratory studies have identified many promising candidate agents, but none has been proven to be neuroprotective in PD. A major limitation has been the development of an endpoint that accurately reflects the underlying disease state. This dramatically limits the potential for a new drug being approved as a disease-modifying agent in PD. For the present, the best opportunity to provide patients with PD with a disease-modifying effect is with agents that have been approved for their symptomatic effects. This article reviews currently available drugs for PD and considers the evidence that they might have neuroprotective effects in PD.

Obeso JA, Marin C, Rodriguez-Oroz C, Blesa J, Benitez-Temiño B, Mena-Segovia J, Rodríguez M, Olanow CW. · Departments of Neurology, Neurophysiology and Neurosurgery, Clinica Universitaria and Medical School, Neuroscience Centre, Center for Applied Medical Research, University of Navarra, Pamplona, Spain. · Ann Neurol. · Pubmed #19127584 No free full text.

Abstract: The pathophysiology of Parkinson's disease is reviewed in light of recent advances in the understanding of the functional organization of the basal ganglia (BG). Current emphasis is placed on the parallel interactions between corticostriatal and corticosubthalamic afferents on the one hand, and internal feedback circuits modulating BG output through the globus pallidus pars interna and substantia nigra pars reticulata on the other. In the normal BG network, the globus pallidus pars externa emerges as a main regulatory station of output activity. In the parkinsonian state, dopamine depletion shifts the BG toward inhibiting cortically generated movements by increasing the gain in the globus pallidus pars externa-subthalamic nucleus-globus pallidus pars interna network and reducing activity in "direct" cortico-putaminal-globus pallidus pars interna projections. Standard pharmacological treatments do not mimic the normal physiology of the dopaminergic system and, therefore, fail to restore a functional balance between corticostriatal afferents in the so-called direct and indirect pathways, leading to the development of motor complications. This review emphasizes the concept that the BG can no longer be understood as a "go-through" station in the control of movement, behavior, and emotions. The growing understanding of the complexity of the normal BG and the changes induced by DA depletion should guide the development of more efficacious therapies for Parkinson's disease.

Olanow CW, Kieburtz K, Schapira AH. · Department of Neurology, Mount Sinai School of Medicine, New York, USA. · Ann Neurol. · Pubmed #19127580 No free full text.

Abstract: The development of a neuroprotective therapy that slows, stops, or reverses neurodegeneration in Parkinson's disease (PD) is the single most important unresolved issue in the management of this disorder. Current therapies provide effective control of symptoms, particularly in the early stages of the disease, but disease progression is associated with the development of "nondopaminergic" features such as postural instability, falling, and dementia that are not adequately controlled with existing medications. There are many promising candidate neuroprotective agents based on pathological and laboratory studies, but to date, it has not been possible to determine that any drug has a disease-modifying effect in PD. Obstacles to the development of a neuroprotective therapy in PD include: (1) uncertainty as to the precise cause of cell death in PD and what to target; (2) the lack of an animal model of PD that precisely reflects the etiopathogenesis of the disease, the pattern of dopaminergic and nondopaminergic pathology, and its chronic, progressive nature; (3) determination of the correct dose to use in clinical trials; and (4) delineation of a clinical end point that is an accurate measure of the underlying disease and is not confounded by potential symptomatic effects of a study intervention. New developments in understanding the cause of the disease, in the development of animal models of PD, and in clinical trial methodology will hopefully hasten the resolution of these problems.

Stocchi F, Tagliati M, Olanow CW. · IRCCS San Raffaele, Via della Pisana 235, Roma, Italy. · Mov Disord. · Pubmed #18781681 No free full text.

Abstract: Chronic levodopa treatment for Parkinson's disease patients is frequently associated with the development of motor complications such as end-of-dose wearing-off and dyskinesias. In this review, we provide an overview of the strategies available for dealing with these problems. Medical management includes manipulation of levodopa dosing to establish the optimum treatment schedule, improving levodopa absorption, catechol-O-methyl transferase-inhibition (COMT), Monoamine oxidase-B (MAO-B) inhibition, dopaminergic agonists, amantadine, and continuous dopaminergic infusions. Surgical procedures and particularly deep brain stimulation are also reviewed. It should be noted that none of these treatments has been shown to provide anti-parkinsonian efficacy that is greater than what can be achieved with levodopa. We highlight the importance of initiating therapy with a treatment strategy that reduces the risk that a Parkinson's disease patient will develop motor complications in the first place. Key Words: Advanced PD, dyskinesias, motor fluctuations, levodopa, dopamine agonists, COMT inhibitors, MAO-B inhibitors.

Olanow CW. · Department of Neurology, Mount Sinai School of Medicine, New York, New York, USA. · Mov Disord. · Pubmed #18781663 No free full text.

Abstract: After 40 years, levodopa remains the most effective therapy for the treatment of PD. However, long-term therapy is complicated by motor fluctuations and dyskinesia that can represent a source of significant disability for some patients. Other medical therapies that are currently available for the treatment of PD primarily represent an attempt to prevent or treat motor complications. Surgical therapies improve motor complications in appropriate candidates, but do not provide antiparkinsonian benefits that are superior to levodopa, and are themselves associated with potentially serious side effects. Increasing information suggests that levodopa-induced motor complications relate to pulsatile, nonphysiologic dopamine replacement. A therapeutic strategy that could deliver levodopa/dopamine to the brain in a more continuous and physiologic manner might be expected to provide all of the benefits of standard levodopa with reduced motor complications. Such a levodopa formulation might replace all current dopaminergic antiparkinsonian medications and avoid the need for surgery in most PD patients. However, problems of continuous dopaminergic stimulation must be addressed and avoided, and the issue of nondopaminergic features remains to be addressed.

Olanow CW. · Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA. · Mov Disord. · Pubmed #18175394 No free full text.

Abstract: A number of factors have been implicated in the pathogenesis of cell death in Parkinson's disease (PD). These include oxidative stress, mitochondrial dysfunction, inflammation, excitotoxicity, and apoptosis. While the precise pathogenic mechanism leading to neurodegeneration in PD is not known, there is considerable evidence suggesting that cell death occurs by way of a signal-mediated apoptotic process. PD is also characterized by intracellular proteinaceous inclusions or Lewy bodies. Proteolytic stress arises as a consequence of the excessive production of misfolded proteins, which exceed the capacity of the ubiquitin-proteasome system to degrade them. Recent genetic and laboratory studies support the possible relevance of proteolytic stress to both familial and sporadic forms of PD. Postmortem studies have shown that in the SNc of sporadic PD patients there are reduced levels of the alpha subunit of the 20S proteasome and reduced proteolytic enzyme activities. A determination as to the precise cause of cell death in PD, and the identification of specific targets for the development of drugs that might modify disease progression is one of the most critical goals in PD research. It is anticipated that over the next few years there will be a flurry of scientific activity examining the mechanism of cell death and putative neuroprotective interventions.

Dubois B, Burn D, Goetz C, Aarsland D, Brown RG, Broe GA, Dickson D, Duyckaerts C, Cummings J, Gauthier S, Korczyn A, Lees A, Levy R, Litvan I, Mizuno Y, McKeith IG, Olanow CW, Poewe W, Sampaio C, Tolosa E, Emre M. · INSERM-UPMC UMRS 610, Federation of Neurology, AP-HP, Salpêtrière Hospital; Université Paris6, Paris, France. · Mov Disord. · Pubmed #18098298 links to  free full text

Abstract: A preceding article described the clinical features of Parkinson's disease dementia (PD-D) and proposed clinical diagnostic criteria for "probable" and "possible" PD-D. The main focus of this article is to operationalize the diagnosis of PD-D and to propose practical guidelines based on a two level process depending upon the clinical scenario and the expertise of the evaluator involved in the assessment. Level I is aimed primarily at the clinician with no particular expertise in neuropsychological methods, but who requires a simple, pragmatic set of tests that are not excessively time-consuming. Level I can be used alone or in concert with Level II, which is more suitable when there is the need to specify the pattern and the severity on the dementia of PD-D for clinical monitoring, research studies or pharmacological trials. Level II tests can also be proposed when the diagnosis of PD-D remains uncertain or equivocal at the end of a Level I evaluation. Given the lack of evidence-based standards for some tests when applied in this clinical context, we have tried to make practical and unambiguous recommendations, based upon the available literature and the collective experience of the Task Force. We accept, however, that further validation of certain tests and modifications in the recommended cut off values will be required through future studies.

Olanow CW, Watkins PB. · Department of Neurology, Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, NY 10029, USA. · Clin Neuropharmacol. · Pubmed #17909307 No free full text.

Abstract: Tolcapone (Tasmar), an inhibitor of catechol-O-methyltransferase, is an effective antiparkinsonian agent when used as an adjunct to levodopa in patients with Parkinson disease who have end-of-dose motor fluctuations. In clinical trials, tolcapone significantly reduced "off" time and levodopa requirements. The drug is generally well tolerated, with the most common adverse events being dopaminergic related. However, clinical trials demonstrated dose-related increases in liver enzymes, and postmarketing surveillance noted 4 cases of acute hepatotoxicity with 3 fatalities that were attributed to tolcapone. For this reason, the drug was withdrawn from the market in some countries, and its use was severely restricted in the United States. An analysis of safety data indicates that, since the labeling restrictions in 1998, there have been more than 40,000 patient-years of tolcapone treatment worldwide, with only 3 reports of severe, but reversible, liver injury and no reports of hepatic fatality. It can be concluded that severe liver injury due to tolcapone is a rare event. Based on these data, the drug has been reintroduced to the market in several European countries, and the Food and Drug Administration in the United States has modified monitoring requirements. The new labeling recommends monitoring of liver function every 2 to 4 weeks for 6 months and at the physician's discretion thereafter. In addition, patients must be taken off the drug if blood tests show enzyme elevation of greater than twice the upper limit of normal. This article reviews the data pertaining to the safety and efficacy of tolcapone.

Kordower JH, Olanow CW. · Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA. · Exp Neurol. · Pubmed #17888424 No free full text.

Abstract: Gene therapy for Parkinson's disease has become a clinical reality with three different approaches currently being tested in patients. All three trials employ an adeno-associated virus with a type two serotype (AAV2). To date, no serious adverse events related to the injections of therapeutic vectors have been reported in any patient. This safety profile was predicted based upon, in some cases, exhaustive preclinical testing in both rodent and primate species. Still some argue that regulatable promoters are required so that expression of the transgene can be halted should untoward side effects arise. We argue that given the current empirical data base of AAV2, the lack of regulatable promoters that have been proven to be safe and effective, and the pressing clinical needs of PD patients, the mandatory use of regulatable vectors is not only unnecessary but, in some instances, misguided and potentially dangerous. This commentary will outline the issues related to the use of regulatable promoters for gene therapy for PD and express our opinion as to why mandating the use of such promoters might result in outcomes that are unsafe, unproductive, and counter to the progress of scientifically sound, clinical research.

Perl DP, Olanow CW. · Department of Pathology, Mount Sinai School of Medicine, New York, NY 10029-6574, USA. · J Neuropathol Exp Neurol. · Pubmed #17882011 No free full text.

Abstract: Manganese is an essential trace metal that is widely used in industry, particularly in the manufacture of steel. Exposure to high levels of manganese can cause neurotoxicity with the development of a form of parkinsonism known as manganism. It has recently been hypothesized that manganese exposure might also cause or accelerate the development of Parkinson disease (PD). This article is a review of the pathologic studies that have been reported in patients with manganism and in primates experimentally intoxicated with manganese. They demonstrate a consistent pattern characterized by damage to the globus pallidus (particularly the internal segment) with sparing of the substantia nigra pars compacta and the absence of Lewy bodies. This finding contrasts with what is seen in PD, in which there is preferential degeneration of dopamine neurons in the substantia nigra pars compacta coupled with Lewy bodies and preservation of the pallidum. These pathologic findings do not support the notion that manganese causes PD but rather argues that manganese-induced parkinsonism and PD are distinct and separate disease entities.

Lippa CF, Duda JE, Grossman M, Hurtig HI, Aarsland D, Boeve BF, Brooks DJ, Dickson DW, Dubois B, Emre M, Fahn S, Farmer JM, Galasko D, Galvin JE, Goetz CG, Growdon JH, Gwinn-Hardy KA, Hardy J, Heutink P, Iwatsubo T, Kosaka K, Lee VM, Leverenz JB, Masliah E, McKeith IG, Nussbaum RL, Olanow CW, Ravina BM, Singleton AB, Tanner CM, Trojanowski JQ, Wszolek ZK, Anonymous00243. · Department of Neurology, Drexel University College of Medicine, Philadelphia, PA 19102, USA. · Neurology. · Pubmed #17353469 No free full text.

Abstract: For more than a decade, researchers have refined criteria for the diagnosis of dementia with Lewy bodies (DLB) and at the same time have recognized that cognitive impairment and dementia occur commonly in patients with Parkinson disease (PD). This article addresses the relationship between DLB, PD, and PD with dementia (PDD). The authors agreed to endorse "Lewy body disorders" as the umbrella term for PD, PDD, and DLB, to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of alpha-synuclein metabolism. We concluded that the differing temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, a single Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal alpha-synuclein inclusions are the defining pathologic process common to both PDD and DLB. There was consensus that improved understanding of the pathobiology of alpha-synuclein should be a major focus of efforts to develop new disease-modifying therapies for these disorders. The group agreed on four important priorities: 1) continued communication between experts who specialize in PDD or DLB; 2) initiation of prospective validation studies with autopsy confirmation of DLB and PDD; 3) development of practical biomarkers for alpha-synuclein pathologies; 4) accelerated efforts to find more effective treatments for these diseases.

Olanow CW, McNaught KS. · Department of Neurology, Mount Sinai School of Medicine, New York, New York10029, USA. · Mov Disord. · Pubmed #16972273 No free full text.

Abstract: Increasing genetic, pathological, and experimental evidence suggest that neurodegeneration in both familial and sporadic forms of Parkinson's disease (PD) may be related to a defect in the capacity of the ubiquitin-proteasome system (UPS) to clear unwanted proteins, resulting in protein accumulation, aggregation, and cytotoxicity. This concept is supported by in vitro and in vivo laboratory experiments which show that inhibition of UPS function can cause neurodegeneration coupled with the formation of Lewy body-like inclusions. This hypothesis could account for the presence of protein aggregates and Lewy bodies in PD, the other biochemical features seen in the disorder, and the age-related vulnerability of the substantia nigra pars compacta. It also suggests novel targets for putative neuroprotective therapies for PD.

Olanow CW, Obeso JA, Stocchi F. · Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA. · Nat Clin Pract Neurol. · Pubmed #16932589 No free full text.

Abstract: Continuous dopaminergic stimulation is a therapeutic strategy for the management of Parkinson's disease, which proposes that dopaminergic agents that provide continuous stimulation of striatal dopamine receptors will delay or prevent the onset of levodopa-related motor complications. Dopaminergic neurons in the basal ganglia normally fire in a random but continuous manner, so that striatal dopamine concentrations are maintained at a relatively constant level. In the dopamine-depleted state, however, intermittent oral doses of levodopa induce discontinuous stimulation of striatal dopamine receptors. This pulsatile stimulation leads to molecular and physiologic changes in basal ganglia neurons and the development of motor complications. These effects are reduced or avoided when dopaminergic therapies are delivered in a more continuous and physiologic manner. Studies in primate models and patients with Parkinson's disease have shown that continuous or long-acting dopaminergic agents are associated with a decreased risk of motor complications compared with short-acting dopamine agonists or levodopa formulations. Continuous dopaminergic stimulation can be achieved with a continuous infusion, but infusion therapies are cumbersome and not likely to be acceptable to patients with early disease. The current challenge is to develop a long-acting oral formulation of levodopa that provides comparable anti-parkinsonian benefits without motor complications.

Olanow CW, Obeso JA, Stocchi F. · Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA. · Lancet Neurol. · Pubmed #16857573 No free full text.

Abstract: Levodopa-induced motor complications are a common source of disability for patients with Parkinson's disease. Evidence suggests that motor complications are associated with non-physiological, pulsatile stimulation of dopamine receptors. In healthy brains, dopamine neurons fire continuously, striatal dopamine concentrations are relatively constant, and there is continuous activation of dopamine receptors. In the dopamine-depleted state, standard levodopa therapy does not normalise the basal ganglia. Rather, levodopa or other short-acting dopaminergic drugs induce molecular changes and altered neuronal firing patterns in basal ganglia neurons leading to motor complications. The concept of continuous dopaminergic stimulation proposes that continuous delivery of a dopaminergic drug will prevent pulsatile stimulation and avoid motor complications. In monkeys treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and patients with Parkinson's disease, long-acting or continuous infusion of a dopaminergic drug reduces the risk of motor complications. The current challenge is to develop a long-acting oral formulation of levodopa that provides clinical benefits but avoids motor complications.

Lang AE, Miyasaki J, Olanow CW, Stoessl AJ, Suchowersky O. · Division of Neurology, Department of Medicine, University of Toronto, Toronto Western Hospital, Canada. · Can J Neurol Sci. · Pubmed #16225167 No free full text.

Abstract: There are numerous concerns related to treatment choices involving early dopaminergic therapy in Parkinson's disease. These include the effect on the underlying progression of the neurodegenerative process as well as the development of motor complications such as fluctuations and dyskinesias. A number of recent basic and clinical studies have provided new insights but have also added confusion and controversy. This report summarizes presentations and discussion dealing with these issues from a one-day symposium involving Canadian Movement Disorders neurologists.

McNaught KS, Olanow CW. · Department of Neurology, Mount Sinai School of Medicine, Annenberg 14-73, One Gustave L. Levy Place, New York, NY 10029, USA. · Neurobiol Aging. · Pubmed #16207501 No free full text.

Abstract: Parkinson's disease (PD) is a slowly progressive, age-related, neurodegenerative disorder. The cause and mechanism of neuronal death have been elusive. However, recent genetic, postmortem and experimental evidence show that protein accumulation and aggregation are prominent occurrences in both sporadic and familial PD. The relevance of these events to other cellular and biochemical changes, and to the neurodegenerative process, is being unraveled. It is increasingly evident that one or a combination of defects, including mutations, oxidative stress, mitochondrial impairment and dysfunction of the ubiquitin-proteasome system, lead to an excess production and aggregation of abnormal proteins in PD. In this respect, altered protein handling appears to be a central factor in the pathogenic process occurring in the various hereditary and sporadic forms of PD. This suggests that manipulation of proteolytic systems is a rational approach in the development of neuroprotective therapies that could modify the pathological course of PD.

Snyder BJ, Olanow CW. · Department of Neurosurgery, Mount Sinai School of Medicine, New York, NY 10029, USA. · Curr Opin Neurol. · Pubmed #16003112 No free full text.

Abstract: PURPOSE OF REVIEW: The hallmark pathologic feature of Parkinson's disease is loss of melanized dopaminergic neurons within the substantia nigra pars compacta coupled with depletion of striatal dopamine. This is responsible for the major motor features of the disease. Whereas dopaminergic replacement therapy is effective in the early stages of the illness, chronic treatment is associated with motor complications and development of features that do not respond to levodopa therapy. Development of cellular therapies offers the potential to provide more effective treatment for the disease without motor complications. RECENT FINDINGS: Two clinical trials of fetal nigral transplantation failed to meet their primary endpoint and were complicated by the development of dyskinesia that persisted after withdrawal of levodopa ('off-medication' dyskinesia). However, recent studies suggest that both the limited clinical response and off-medication dyskinesia may be related to partial, but incomplete, dopaminergic reinnervation of the striatum and that both might be improved by transplantation of more dopamine neurons. Stem cells offer the potential to provide a virtually unlimited supply of optimized dopaminergic neurons that can provide enhanced benefits in comparison to fetal mesencephalic transplants. Stem cells have now been shown to be capable of differentiating into dopamine neurons that provide benefits following transplantation in animal models of Parkinson's disease. However, cell survival and behavioral responses are limited. There have been numerous advances in enhancing the yield of dopamine neurons from stem cells, and promoting their survival and consequent clinical effects. SUMMARY: Stem cells offer great promise as a therapy for Parkinson's disease, but numerous hurdles remain to be overcome with stem cell therapy. The adverse event profile of transplantation must be determined, and societal and ethical issues addressed. As Parkinson's disease involves degeneration of both dopaminergic and non-dopaminergic neurons, it also remains to be determined if transplantation of even the ideal dopamine neuron will improve non-dopaminergic features of the disease or provide benefits superior to existing therapies.

Olanow CW, Jankovic J. · Department of Neurology, Mount Sinai School of Medicine, Annenberg 14-94, One Gustave L. Levy Place, New York, NY 10029, USA. · Mov Disord. · Pubmed #15822111 No free full text.

Abstract: The introduction of levodopa in the late 1960s represented a landmark in the therapy of Parkinson's disease (PD). However, motor complications of chronic levodopa therapy have emerged as a major limitation of this otherwise effective therapy. Advancing medical and surgical treatment of these complications has been the main objective of clinical trials during the past few decades. In addition, basic research has focused on better understanding of the mechanisms of motor complications and how to prevent them. Slowing or delaying the progression of the disease delays the need for levodopa therapy; therefore, neuroprotective strategies may play an important role in preventing the onset and reducing the severity of levodopa-related adverse effects. In this introductory review, we present the rationale for current and experimental therapies designed to favorably modify the progression of PD. If implemented early in the course of the disease, such treatments, if found effective, may not only alter the natural progression of the disease but may also delay or minimize motor and nonmotor complications associated with levodopa.

Hälbig TD, Tse W, Olanow CW. · Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. · Neurol Clin. · Pubmed #15501359 No free full text.

This publication has no abstract.

Olanow CW, Agid Y, Mizuno Y, Albanese A, Bonuccelli U, Bonucelli U, Damier P, De Yebenes J, Gershanik O, Guttman M, Grandas F, Hallett M, Hornykiewicz O, Jenner P, Katzenschlager R, Langston WJ, LeWitt P, Melamed E, Mena MA, Michel PP, Mytilineou C, Obeso JA, Poewe W, Quinn N, Raisman-Vozari R, Rajput AH, Rascol O, Sampaio C, Stocchi F. · Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA. · Mov Disord. · Pubmed #15372588 No free full text.

Abstract: Levodopa is the most effective symptomatic agent in the treatment of Parkinson's disease (PD) and the "gold standard" against which new agents must be compared. However, there remain two areas of controversy: (1) whether levodopa is toxic, and (2) whether levodopa directly causes motor complications. Levodopa is toxic to cultured dopamine neurons, and this may be a problem in PD where there is evidence of oxidative stress in the nigra. However, there is little firm evidence to suggest that levodopa is toxic in vivo or in PD. Clinical trials have not clarified this situation. Levodopa is also associated with motor complications. Increasing evidence suggests that they are related, at least in part, to the short half-life of the drug (and its potential to induce pulsatile stimulation of dopamine receptors) rather than to specific properties of the molecule. Treatment strategies that provide more continuous stimulation of dopamine receptors provide reduced motor complications in MPTP monkeys and PD patients. These studies raise the possibility that more continuous and physiological delivery of levodopa might reduce the risk of motor complications. Clinical trials to test this hypothesis are underway. We review current evidence relating to these areas of controversy.

Olanow CW, Perl DP, DeMartino GN, McNaught KS. · Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA. · Lancet Neurol. · Pubmed #15261611 No free full text.

Abstract: Parkinson's disease (PD) is an age-related neurodegenerative disorder that is associated with the formation of intracytoplasmic protein aggregates (Lewy-body inclusions) in neurons of the substantia nigra pars compacta and other brain areas. These inclusions were discovered over 90 years ago, but the mechanism underlying their formation and their relevance to the neurodegenerative process are unknown. Recent studies have begun to shed light on the biogenesis of Lewy bodies and suggest that they are related to aggresomes. Aggresomes are cytoprotective proteinaceous inclusions formed at the centrosome that segregate and facilitate the degradation of excess amounts of unwanted and possibly cytotoxic proteins. The concept of Lewy bodies as aggresome-related inclusions fits well with ongoing discoveries suggesting that altered protein handling might contribute to the neurodegenerative process in familial and sporadic forms of PD.

Olanow CW. · Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA. · Ann N Y Acad Sci. · Pubmed #15105268 No free full text.

Abstract: It has long been appreciated that manganese exposure can cause neurotoxicity and a neurologic syndrome that resembles Parkinson's disease (PD). Current evidence indicates that manganese-induced parkinsonism can be differentiated from PD because of its predilection to accumulate in and damage the pallidum and striatum rather than the SNc. The clinical syndrome, response to levodopa, imaging studies with MRI and PET, and pathologic features all help to distinguish these two conditions and permit the correct diagnosis to be established. This is of particular relevance in differentiating patients with parkinsonism due to manganese intoxication from patients with idiopathic PD who have incidental manganese exposure.

Olanow CW. · Department of Neurology, Mount Sinai School of Medicine, Annenberg 14-94, One Gustave L. Levy Place, Box 1137, New York, New York 10029, USA. · Annu Rev Med. · Pubmed #14746509 No free full text.

Abstract: Parkinson's disease (PD) is an age-related neurodegenerative disease that affects approximately one million people in the United States. The introduction of levodopa revolutionized the treatment for this disorder, but the long-term utility of the drug is limited by motor complications, the development of features such as postural instability and dementia that do not respond to treatment, and continued disease progression. Insights into the organization of the basal ganglia in the normal and PD conditions has permitted the design of new treatment strategies that reduce the risk of developing motor complications. Additionally, increased knowledge of the mechanisms responsible for cell death in PD has permitted the development of putative neuroprotective drugs that might slow or stop disease progression. No drug has yet been established to alter the rate of disease progression, but the rapid pace of research offers reason for optimism.