[show abstract][hide abstract] 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.
Movement Disorders 10/2008; 23 Suppl 3:S599-612. · 4.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: There is an urgent need for therapies that slow or reverse the progression of Parkinson's disease (PD). Neurotrophic factors can improve the function of degenerating neurons and protect against further neurodegeneration, and gene transfer might be a means to deliver effectively these factors to the brain. The aim of this study was to assess the safety, tolerability, and potential efficacy of gene delivery of the neurotrophic factor neurturin.
In this phase I, open-label clinical trial, 12 patients aged 35-75 years with a diagnosis of PD for at least 5 years in accordance with the UK Brain Bank Criteria received bilateral, stereotactic, intraputaminal injections of adeno-associated virus serotype 2-neurturin (CERE-120). The first six patients received doses of 1.3x10(11) vector genomes (vg)/patient, and the next six patients received 5.4x10(11) vg/patient. This trial is registered with ClinicalTrials.gov, number NCT00252850.
The procedure was well tolerated. Extensive safety monitoring in all patients revealed no clinically significant adverse events at 1 year. Several secondary measures of motor function showed improvement at 1 year; for example, a mean improvement in the off-medication motor subscore of the Unified Parkinson's Disease Rating Scale (UPDRS) of 14 points (SD 8; p=0.000121 [36% mean increase; p=0.000123]) and a mean increase of 2.3 h (2; 25% group mean increase; p=0.0250) in on time without troublesome dyskinesia were seen. Improvements in several secondary measures were not significant, including the timed walking test in the off condition (p=0.053), the Purdue pegboard test of hand dexterity (p=0.318), the reduction in off time (p=0.105), and the activities of daily living subscore (part II) of the UPDRS (p=0.080). (18)F-levodopa-uptake PET did not change after treatment with either dose of CERE-120.
The initial data support the safety, tolerability, and potential efficacy of CERE-120 as a possible treatment for PD; however, these results must be viewed as preliminary until data from blinded, controlled clinical trials are available.
Ceregene; Michael J Fox Foundation for Parkinson's Research.
The Lancet Neurology 06/2008; 7(5):400-8. · 23.92 Impact Factor
[show abstract][hide abstract] ABSTRACT: We have previously reported that specific dopamine agonists mediate protection against apoptosis induced by oxidative stress by activating the D2 receptor-coupled phosphoinositide 3-kinase (PI-3K)/Akt pathway. In the present study we examined the downstream effectors of PI-3K/Akt signaling and their role in cell death after oxidative stress and protection provided by ropinirole, a D2 receptor agonist in PC12 cells and primary cultures of dopamine neurons. Ropinirole treatment was associated with rapid translocation and phosphorylation of the PI-3K substrate Akt and phosphorylation of Akt substrates. One of these Akt downstream substrates was identified as the pro-apoptotic factor glycogen synthase kinase-3beta (GSK-3beta). Ropinirole-induced protection was associated with phosphorylation of GSK-3beta (inactivation). In contrast, inhibition of PI-3K blocked the phosphorylation of Akt and GSK-3beta (activation) and prevented the protection mediated by ropinirole. Suppression of Akt with specific short hairpin RNA in normal PC12 cells caused cell death, which was associated with reduced phosphorylation of GSK-3beta and reduced levels of beta-catenin, a transcriptional activator that is regulated by GSK-3beta. Knock-out of GSK-3beta expression with a short hairpin RNA alone was itself sufficient to cause cell death. We further demonstrated that oxidative stress induced by hydrogen peroxide (H2O2) dephosphorylates Akt and GSK-3beta, increases GSK-3beta activity, and promotes an interaction with beta-catenin and its degradation. Inhibition of GSK-3beta activity by inhibitor VIII protects cells from H2O2 similar to ropinirole. These results indicate that GSK-3beta downstream of Akt plays a critical role in cell death and survival in these models.
Journal of Biological Chemistry 06/2008; 283(22):15469-78. · 4.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Fourteen years after transplantation into the striatum of an individual with Parkinson's disease, grafted nigral neurons were found to have Lewy body-like inclusions that stained positively for alpha-synuclein and ubiquitin and to have reduced immunostaining for dopamine transporter. These pathological changes suggest that Parkinson's disease is an ongoing process that can affect grafted cells in the striatum in a manner similar to host dopamine neurons in the substantia nigra. These findings have implications for cell-based therapies and for understanding the cause of Parkinson's disease.
Nature medicine 06/2008; 14(5):504-6. · 27.14 Impact Factor
[show abstract][hide abstract] ABSTRACT: Clinical features that are prognostic indicators of placebo response among dyskinetic Parkinson's disease patients were determined. Placebo-associated improvements occur in Parkinsonism, but responses in dyskinesia have not been studied. Placebo data from two multicenter studies with identical design comparing sarizotan to placebo for treating dyskinesia were accessed. Sarizotan (2 mg/day) failed to improve dyskinesia compared with placebo, but both treatments improved dyskinesia compared with baseline. Stepwise regression identified baseline characteristics that influenced dyskinesia response to placebo, and these factors were entered into a logistic regression model to quantify their influence on placebo-related dyskinesia improvements and worsening. Because placebo-associated improvements in Parkinsonism have been attributed to heightened dopaminergic activity, we also examined the association between changes in Parkinsonism and dyskinesia. Four hundred eighty-four subjects received placebo treatment; 178 met criteria for placebo-associated dyskinesia improvement and 37 for dyskinesia worsening. Older age, lower baseline Parkinsonism score, and lower total daily levodopa doses were associated with placebo-associated improvement, whereas lower baseline dyskinesia score was associated with placebo-associated worsening. Placebo-associated dyskinesia changes were not correlated with Parkinsonism changes, and all effects in the sarizotan group were statistically explained by the placebo-effect regression model. Dyskinesias are affected by placebo treatment. The absence of correlation between placebo-induced changes in dyskinesia and Parkinsonism argues against a dopaminergic activation mechanism to explain placebo-associated improvements in dyskinesia. The magnitude and variance of placebo-related changes and the factors that influence them can be helpful in the design of future clinical trials of antidyskinetic agents.
Movement Disorders 05/2008; 23(5):700-7. · 4.56 Impact Factor
[show abstract][hide abstract] 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.
[show abstract][hide abstract] 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.
Movement Disorders 01/2008; 22(16):2314-24. · 4.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: We studied the prevalence of movement disorders in a large nursing home population (397 patients, mean age 86 years) in New York City. Patients were first evaluated by specially trained research coordinators and final clinical diagnoses were confirmed by a movement disorder specialist. A movement disorder was identified in 21% of patients (83/397). The most frequent movement disorders were essential tremor (ET) (8.8%) and parkinsonism (7.1%). Only half of those admitted with a diagnosis of parkinsonism were confirmed in their diagnosis by the movement disorder specialists. Three percent of patients exhibited drug-induced tremor, 1.3% had dystonia, 0.5% had myoclonus and 0.3% had generalized dyskinesias. Overall, our findings underline the high frequency of movement disorders in a nursing home population. The discrepancy between our findings and the prevalence rates for parkinsonism reported on the initial transfer diagnosis emphasizes the difficulty of accurate diagnosis of movement disorders and in particular parkinsonism.
Archives of Gerontology and Geriatrics 01/2008; 46(3):359-66. · 1.70 Impact Factor
[show abstract][hide abstract] ABSTRACT: Mutations in Leucine-rich repeat kinase 2 (LRRK2) are linked to the most common familial forms and some sporadic forms of Parkinson's disease (PD). The LRRK2 protein contains two well-known functional domains, MAPKKK-like kinase and Rab-like GTPase domains. Emerging evidence shows that LRRK2 contains kinase activity which is enhanced in several PD-associated mutants of LRRK2. However, the GTPase activity of LRRK2 has yet to be formally demonstrated. Here, we produced and purified the epitope-tagged LRRK2 protein from transgenic mouse brain, and showed that purified brain LRRK2 possesses both kinase and GTPase activity as assayed by GTP binding and hydrolysis. The brain LRRK2 is associated with elevated kinase activity in comparison to that from transgenic lung or transfected cultured cells. In transfected cell cultures, we detected GTP hydrolysis activity in full-length as well as in GTPase domain of LRRK2. This result indicates that LRRK2 GTPase can be active independent of LRRK2 kinase activity (while LRRK2 kinase activity requires the presence of LRRK2 GTPase as previously shown). We further found that PD mutation R1441C/G in the GTPase domain causes reduced GTP hydrolysis activity, consistent with the altered enzymatic activity in the mutant LRRK2 carrying PD familial mutations. Therefore, our study shows the biochemical characteristics of brain-specific LRRK2 which is associated with robust kinase and GTPase activity. The distinctive levels of kinase/GTPase activity in brain LRRK2 may help explain LRRK2-associated neuronal functions or dysfunctions in the pathogenesis of PD.
Journal of Neurochemistry 11/2007; 103(1):238-47. · 3.97 Impact Factor
[show abstract][hide abstract] 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.
Movement Disorders 10/2007; 22 Suppl 17:S335-42. · 4.56 Impact Factor
[show abstract][hide abstract] 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.
Journal of Neuropathology and Experimental Neurology 09/2007; 66(8):675-82. · 4.35 Impact Factor
[show abstract][hide abstract] ABSTRACT: 2006, there was, no single instrument (questionnaire or scale) for attempting a comprehensive assessment of the wide range of nonmotor symptoms (NMS) of Parkinson's disease (PD). The PD nonmotor group, a multidisciplinary group of experts including patient group representatives developed and validated the NMS screening questionnaire (NMSQuest) comprising 30 items. The NMSQuest is a self completed screening tool designed to draw attention to the presence of NMS. In this paper, we present the results gathered from 545 patients using the definitive version of the NMSQuest highlighting the prevalence of the wide range of NMS flagged in the NMSQuest from consecutive PD patients in an international setting.
Movement Disorders 09/2007; 22(11):1623-9. · 4.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: In the past decade, there has been an increasing emphasis on laboratory-based translational research. This has led to significant scientific advances in our understanding of disease mechanisms and in the development of novel approaches to therapy such as gene therapy, RNA interference, and stem cells. However, the translation of these remarkable scientific achievements into new and effective disease-modifying therapies has lagged behind these scientific accomplishments. We use the term "translational experimental therapeutics" to describe the pathway between the discovery of a basic disease mechanism or novel therapeutic approach and its translation into an effective treatment for patients with a specific disease. In this article, we review the components of this pathway, and discuss issues that might impede this process. Only by optimizing this pathway can we realize the full therapeutic potential of current scientific discoveries and translate the astounding advances that have been accomplished in the laboratory into effective treatments for our patients.
Mount Sinai Journal of Medicine A Journal of Translational and Personalized Medicine 05/2007; 74(1):7-14. · 1.99 Impact Factor
[show abstract][hide abstract] 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.
[show abstract][hide abstract] ABSTRACT: The objective of this study is to conduct a dose-finding study of sarizotan in Parkinson's disease (PD) patients with dyskinesia to identify a safe dose and to identify a sensitive dyskinesia rating measure. Sarizotan is a novel compound with full 5-HT(1A) agonist properties and additional high affinity for D(3) and D(4) receptors. An open label study documented improvements in PD patients with levodopa-induced dyskinesia. There is no precedent for study designs or outcome measures in pivotal trials of antidyskinesia therapies. The approach used here was a multicenter, randomized, placebo-controlled, double-blind, parallel study. Included were PD patients optimized to levodopa and dopaminergic drugs with moderately disabling dyskinesias present greater than or equal to 25% of the waking day. Interventions included sarizotan 2, 4, or 10 mg/day or matching placebo, given in two doses. There were two outcome measures: the primary measure was change from baseline in diary-based on time without dyskinesia; the secondary measures were change from baseline in scores on the Abnormal Involuntary Movement Scale (AIMS), the composite score of Unified Parkinson's Disease Rating Scale (UPDRS) Items 32+33 (dyskinesia duration and disability) and total UPDRS. A total of 398 subjects were randomized, with 381 included in the intention-to-treat population. No significant changes occurred on sarizotan compared to placebo on any diary-based measure of dyskinesia or the AIMS score. The composite score of UPDRS Items 32+33 was significantly improved with 2 mg/day sarizotan, with a trend at 10 mg/day. Adverse events were not significantly different in sarizotan- and placebo-treated patients, but off time significantly increased with sarizotan 10 mg/day. Sarizotan 2 mg/day is a safe agent in PD patients with dyskinesia. To test its role in abating dyskinesia, future studies should focus on this dose and will use the composite score of UPDRS Items 32+33 as the primary outcome.
Movement Disorders 02/2007; 22(2):179-86. · 4.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: This article presents the revision process, major innovations, and clinimetric testing program for the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (UPDRS), known as the MDS-UPDRS. The UPDRS is the most widely used scale for the clinical study of Parkinson's disease (PD). The MDS previously organized a critique of the UPDRS, which cited many strengths, but recommended revision of the scale to accommodate new advances and to resolve problematic areas. An MDS-UPDRS committee prepared the revision using the recommendations of the published critique of the scale. Subcommittees developed new material that was reviewed by the entire committee. A 1-day face-to-face committee meeting was organized to resolve areas of debate and to arrive at a working draft ready for clinimetric testing. The MDS-UPDRS retains the UPDRS structure of four parts with a total summed score, but the parts have been modified to provide a section that integrates nonmotor elements of PD: I, Nonmotor Experiences of Daily Living; II, Motor Experiences of Daily Living; III, Motor Examination; and IV, Motor Complications. All items have five response options with uniform anchors of 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Several questions in Part I and all of Part II are written as a patient/caregiver questionnaire, so that the total rater time should remain approximately 30 minutes. Detailed instructions for testing and data acquisition accompany the MDS-UPDRS in order to increase uniform usage. Multiple language editions are planned. A three-part clinimetric program will provide testing of reliability, validity, and responsiveness to interventions. Although the MDS-UPDRS will not be published until it has successfully passed clinimetric testing, explanation of the process, key changes, and clinimetric programs allow clinicians and researchers to understand and participate in the revision process.
Movement Disorders 02/2007; 22(1):41-7. · 4.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: There is an important unmet medical need in Parkinson's disease for a neuroprotective treatment that slows or stops disease progression. TCH346 is a potent anti-apoptotic drug that protects against loss of dopaminergic neurons in laboratory models. Our aim was to assess TCH346 as a neuroprotective drug in patients with Parkinson's disease.
Patients presenting at 45 international movement disorder clinics with early untreated Parkinson's disease were assessed as part of this parallel-group, double-blind, randomised controlled trial. 301 eligible patients were randomly assigned 12-18 months' treatment with TCH346 at a daily dose of 0.5 mg (n=78), 2.5 mg (n=79), or 10 mg (n=73), or placebo (n=71), followed by a 4 week washout period. The primary outcome measure was time to development of a disability requiring dopaminergic treatment. Secondary outcome measures were the annual rate of change in the unified Parkinson's disease rating scale (UPDRS) and the PDQ-39, a measure of quality of life. Analyses were by intention-to-treat. This study is pending registration with .
255 patients completed the study. TCH346 did not differ from placebo for any of the study outcomes. Treatment was needed in 26 (34%) patients in the TCH346 0.5 mg group, 30 (38%) in the TCH346 2.5 mg group, 24 (33%) in the TCH346 10 mg group, and 23 (32%) in the placebo group. There were no significant differences between groups. There were no differences between groups in the annual change in the UPDRS or PDQ-39 either. Few patients withdrew because of adverse events and none was judged to be related to the study intervention.
TCH346 did not show evidence of a neuroprotective effect. The discrepancy between the preclinical promise of TCH346 and the clinical outcome could have arisen because of the use of laboratory models that do not accurately reflect the pathogenesis of Parkinson's disease, the doses of study drug used, insensitive clinical endpoints, and the patient population selected for study.
The Lancet Neurology 01/2007; 5(12):1013-20. · 23.92 Impact Factor