[Show abstract][Hide abstract] ABSTRACT: A therapy that slows disease progression is the major unmet need in Parkinson's disease.
In this double-blind trial, we examined the possibility that rasagiline has disease-modifying effects in Parkinson's disease. A total of 1176 subjects with untreated Parkinson's disease were randomly assigned to receive rasagiline (at a dose of either 1 mg or 2 mg per day) for 72 weeks (the early-start group) or placebo for 36 weeks followed by rasagiline (at a dose of either 1 mg or 2 mg per day) for 36 weeks (the delayed-start group). To determine a positive result with either dose, the early-start treatment group had to meet each of three hierarchical end points of the primary analysis based on the Unified Parkinson's Disease Rating Scale (UPDRS, a 176-point scale, with higher numbers indicating more severe disease): superiority to placebo in the rate of change in the UPDRS score between weeks 12 and 36, superiority to delayed-start treatment in the change in the score between baseline and week 72, and noninferiority to delayed-start treatment in the rate of change in the score between weeks 48 and 72.
Early-start treatment with rasagiline at a dose of 1 mg per day met all end points in the primary analysis: a smaller mean (+/-SE) increase (rate of worsening) in the UPDRS score between weeks 12 and 36 (0.09+/-0.02 points per week in the early-start group vs. 0.14+/-0.01 points per week in the placebo group, P=0.01), less worsening in the score between baseline and week 72 (2.82+/-0.53 points in the early-start group vs. 4.52+/-0.56 points in the delayed-start group, P=0.02), and noninferiority between the two groups with respect to the rate of change in the UPDRS score between weeks 48 and 72 (0.085+/-0.02 points per week in the early-start group vs. 0.085+/-0.02 points per week in the delayed-start group, P<0.001). All three end points were not met with rasagiline at a dose of 2 mg per day, since the change in the UPDRS score between baseline and week 72 was not significantly different in the two groups (3.47+/-0.50 points in the early-start group and 3.11+/-0.50 points in the delayed-start group, P=0.60).
Early treatment with rasagiline at a dose of 1 mg per day provided benefits that were consistent with a possible disease-modifying effect, but early treatment with rasagiline at a dose of 2 mg per day did not. Because the two doses were associated with different outcomes, the study results must be interpreted with caution. (ClinicalTrials.gov number, NCT00256204.)
New England Journal of Medicine 09/2009; 361(13):1268-78. · 54.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rotigotine is a novel, non-ergoline dopamine D(3)/D(2)/D(1)-receptor agonist for the treatment of Parkinson's disease that can be continuously delivered by the transdermal route to provide stable plasma levels. Continuous drug delivery should reduce the risk of dyskinesia induction in comparison to pulsatile dopaminergic treatment. Thus the aim of the study was to compare the reversal of motor disability and induction of dyskinesia produced by continuous compared to pulsatile rotigotine administration in MPTP-treated common marmosets. The study also investigated whether pulsatile or continuous rotigotine administration in combination with l-DOPA prevented l-DOPA-induced dyskinesia. Animals were treated for 28 days with vehicle or pulsatile (twice daily) or continuous delivery of rotigotine (via an osmotic minipump). Subsequently, l-DOPA was then co-administered for a further 28 days. Animals were assessed for locomotor activity, motor disability and dyskinesia induction. The study showed that both continuous and pulsatile administration of rotigotine improved motor deficits and normalized motor function in MPTP-treated monkeys. However, continuous rotigotine delivery reduced dyskinesia expression compared to pulsatile treatment. Both pulsatile and continuous rotigotine administration produced less dyskinesia than administration of l-DOPA alone. The addition of l-DOPA to either pulsatile or continuous rotigotine treatment resulted in the induction of marked dyskinesia similar to that produced by treatment with l-DOPA alone. These data further support the hypothesis that continuous delivery of a dopaminergic agent reduces the risk of dyskinesia induction. However, continuous rotigotine administration did not prevent l-DOPA from inducing dyskinesia suggesting that l-DOPA may induce dyskinesia by mechanisms different from dopamine agonist drugs.
[Show abstract][Hide abstract] ABSTRACT: We explored the relationship between ubiquitin proteasome system (UPS) and lysosomal markers and the formation of alpha-synuclein (alpha-syn) inclusions in nigral neurons in Parkinson disease (PD). Lysosome Associated Membrane Protein 1(LAMP1), Cathepsin D (CatD), and Heat Shock Protein73 (HSP73) immunoreactivity were significantly decreased within PD nigral neurons when compared to age-matched controls. This decrease was significantly greater in nigral neurons that contained alpha-syn inclusions. Immunoreactivity for 20S proteasome was similarly reduced in PD nigral neurons, but only in cells that contained inclusions. In aged control brains, there is staining for alpha-syn protein, but it is non-aggregated and there is no difference in LAMP1, CatD, HSP73 or 20S proteasome immunoreactivity between alpha-syn positive or negative neuromelanin-laden nigral neurons. Targeting over-expression of mutant human alpha-syn in the rat substantia nigra using viral vectors revealed that lysosomal and proteasomal markers were significantly decreased in the neurons that displayed alpha-syn-ir inclusions. These findings suggest that alpha-syn aggregation is a key feature associated with decline of proteasome and lysosome and support the hypothesis that cell degeneration in PD involves proteosomal and lysosomal dysfunction, impaired protein clearance, and protein accumulation and aggregation leading to cell death.
Neurobiology of Disease 07/2009; 35(3):385-98. · 5.62 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Experimental studies suggest that deep brain stimulation (DBS) of the subthalamic nucleus (STN) induces impulsivity in patients with Parkinson's disease (PD). The purpose of this study was to assess various measures of impulse control in PD patients with STN DBS in comparison to patients receiving medical therapy.
In a cross-sectional evaluation, 53 consecutively eligible patients were assessed for impulsivity with the Barratt Impulsiveness Scale, for impulse control disorders (ICDs) using the Minnesota Impulsive Disorders Interview, and for obsessive-compulsive symptoms using the Maudsley Obsessional-Compulsive Inventory.
Independent samples t-tests revealed that compulsivity scores were not different between DBS patients and patients without DBS. However, impulsivity scores were significantly higher in DBS patients. Additionally, ICDs were observed in 3 of 16 (19%) DBS patients and in 3 of 37 (8%) medically treated patients. No association was found between the use of dopamine agonists and impulsivity in DBS patients.
Our data suggest that screening for impulsivity and ICDs should be performed prior to DBS, and that patients should be monitored for these problems during follow-up. Prospective trials are needed to confirm the findings of this exploratory study and to elucidate the reasons of a possible induction of impulsivity by STN DBS.
European Journal of Neurology 03/2009; 16(4):493-7. · 4.16 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: This report describes pathological changes within the grafted neurons of another patient with Parkinson's disease (PD) who died 14 years posttransplantation. Although numerous healthy appearing grafted neurons were present at this long-term time point, some displayed Lewy bodies as evidenced by alpha-synuclein, ubiquitin, and thioflavin-S staining. Additionally, there was a general loss of dopamine transporter-immunoreactivity in grafted neurons. Some grafted cell displayed a loss of tyrosine hydroxylase. These data support the emerging concept that PD-like pathology is seen in young grafted neurons when they survive long term.
Movement Disorders 12/2008; 23(16):2303-6. · 5.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We present a clinimetric assessment of the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). The MDS-UDPRS Task Force revised and expanded the UPDRS using recommendations from a published critique. The MDS-UPDRS has four parts, namely, I: Non-motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. Twenty questions are completed by the patient/caregiver. Item-specific instructions and an appendix of complementary additional scales are provided. Movement disorder specialists and study coordinators administered the UPDRS (55 items) and MDS-UPDRS (65 items) to 877 English speaking (78% non-Latino Caucasian) patients with Parkinson's disease from 39 sites. We compared the two scales using correlative techniques and factor analysis. The MDS-UPDRS showed high internal consistency (Cronbach's alpha = 0.79-0.93 across parts) and correlated with the original UPDRS (rho = 0.96). MDS-UPDRS across-part correlations ranged from 0.22 to 0.66. Reliable factor structures for each part were obtained (comparative fit index > 0.90 for each part), which support the use of sum scores for each part in preference to a total score of all parts. The combined clinimetric results of this study support the validity of the MDS-UPDRS for rating PD.
Movement Disorders 12/2008; 23(15):2129-70. · 5.63 Impact Factor
[Show abstract][Hide abstract] 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.
Movement Disorders 10/2008; 23 Suppl 3:S613-22. · 5.63 Impact Factor
[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. · 5.63 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