[Show abstract][Hide abstract] ABSTRACT: In an open-label phase 1 trial, gene delivery of the trophic factor neurturin via an adeno-associated type-2 vector (AAV2) was well tolerated and seemed to improve motor function in patients with advanced Parkinson's disease. We aimed to assess the safety and efficacy of AAV2-neurturin in a double-blind, phase 2 randomised trial.
We did a multicentre, double-blind, sham-surgery controlled trial in patients with advanced Parkinson's disease. Patients were randomly assigned (2:1) by a central, computer generated, randomisation code to receive either AAV2-neurturin (5·4 × 10¹¹ vector genomes) injected bilaterally into the putamen or sham surgery. All patients and study personnel with the exception of the neurosurgical team were masked to treatment assignment. The primary endpoint was change from baseline to 12 months in the motor subscore of the unified Parkinson's disease rating scale in the practically-defined off state. All randomly assigned patients who had at least one assessment after baseline were included in the primary analyses. This trial is registered at ClinicalTrials.gov, NCT00400634.
Between December, 2006, and November, 2008, 58 patients from nine sites in the USA participated in the trial. There was no significant difference in the primary endpoint in patients treated with AAV2-neurturin compared with control individuals (difference -0·31 [SE 2·63], 95% CI -5·58 to 4·97; p=0·91). Serious adverse events occurred in 13 of 38 patients treated with AAV2-neurturin and four of 20 control individuals. Three patients in the AAV2-neurturin group and two in the sham surgery group developed tumours.
Intraputaminal AAV2-neurturin is not superior to sham surgery when assessed using the UPDRS motor score at 12 months. However, the possibility of a benefit with additional targeting of the substantia nigra and longer term follow-up should be investigated in further studies.
Ceregene and Michael J Fox Foundation for Parkinson's Research.
Full-text · Article · Oct 2010 · The Lancet Neurology
[Show abstract][Hide abstract] ABSTRACT: A disease-modifying therapy that slows or stops disease progression is one of the major unmet needs in the management of Parkinson's disease. To date, no therapy has been approved for disease modification despite promising laboratory data and positive results in clinical trials. This is because confounding symptomatic or pharmacologic effects cannot be excluded. The delayed start study provides an opportunity to define therapies that provide benefit that cannot be explained by an early symptomatic effect alone. However, this trial design does not necessarily provide a meaningful measure of the effect of the intervention on cumulative disability. In contrast, the long-term simple study provides a measure of the effect of the drug on cumulative disability but does not address mechanism of action. Together these two trials provide a road map for defining a disease modifying drug and determining the long term cumulative effect of the drug on the disease.
No preview · Article · Sep 2010 · Movement Disorders
[Show abstract][Hide abstract] ABSTRACT: L-dopa is the most widely used and most effective therapy for Parkinson disease (PD), but chronic treatment is associated with motor complications in the majority of patients. It has been hypothesized that providing more continuous delivery of L-dopa to the brain would reduce the risk of motor complications, and that this might be accomplished by combining L-dopa with entacapone, an inhibitor of catechol-O-methyltransferase, to extend its elimination half-life.
We performed a prospective 134-week double-blind trial comparing the risk of developing dyskinesia in 747 PD patients randomized to initiate L-dopa therapy with L-dopa/carbidopa (LC) or L-dopa/carbidopa/entacapone (LCE), administered 4x daily at 3.5-hour intervals. The primary endpoint was time to onset of dyskinesia.
In comparison to LC, patients receiving LCE had a shorter time to onset of dyskinesia (hazard ratio, 1.29; p = 0.04) and increased frequency at week 134 (42% vs 32%; p = 0.02). These effects were more pronounced in patients receiving dopamine agonists at baseline. Time to wearing off and motor scores were not significantly different, but trended in favor of LCE treatment. Patients in the LCE group received greater L-dopa dose equivalents than LC-treated patients (p < 0.001).
Initiating L-dopa therapy with LCE failed to delay the time of onset or reduce the frequency of dyskinesia compared to LC. In fact, LCE was associated with a shorter time to onset and increased frequency of dyskinesia compared to LC. These results may reflect that the treatment protocol employed did not provide continuous L-dopa availability and the higher L-dopa dose equivalents in the LCE group.
No preview · Article · Jul 2010 · Annals of Neurology
[Show abstract][Hide abstract] ABSTRACT: Gait dysfunction and falling are major sources of disability for patients with advanced Parkinson's disease (PD). It is presently thought that the fundamental defect is an inability to generate normal stride length. Our data suggest, however, that the basic problem in PD gait is an impaired ability to match step frequency to walking velocity. In this study, foot movements of PD and normal subjects were monitored with an OPTOTRAK motion-detection system while they walked on a treadmill at different velocities. PD subjects were also paced with auditory stimuli at different frequencies. PD gait was characterized by step frequencies that were faster and stride lengths that were shorter than those of normal controls. At low walking velocities, PD stepping had a reduced or absent terminal toe lift, which truncated swing phases, producing shortened steps. Auditory pacing was not able to normalize step frequency at these lower velocities. Peak forward toe velocities increased with walking velocity and PD subjects could initiate appropriate foot dynamics during initial phases of the swing. They could not control the foot appropriately in terminal phases, however. Increased treadmill velocity, which matched the natural PD step frequency, generated a second toe lift, normalizing step size. Levodopa increased the bandwidth of step frequencies, but was not as effective as increases in walking velocity in normalizing gait. We postulate that the inability to control step frequency and adjust swing phase dynamics to slower walking velocities are major causes for the gait impairment in PD.
Preview · Article · Mar 2010 · Journal of Neurophysiology
[Show abstract][Hide abstract] ABSTRACT: Reduced expression of dyskinesia is observed in levodopa-primed MPTP-treated common marmosets when dopamine agonists are used to replace levodopa. We now investigate whether a combination of the D-2/D-3 agonist pramipexole and levodopa also reduces dyskinesia intensity while maintaining the reversal of motor disability. Drug naïve, non-dyskinetic MPTP-treated common marmosets were treated daily for up to 62 days with levodopa (12.5 mg/kg plus carbidopa 12.5 mg/kg p.o. BID) or pramipexole (0.04-0.3 mg/kg BID) producing equivalent reversal of motor disability and increases in locomotor activity. Levodopa alone resulted in marked dyskinesia induction but little or no dyskinesia resulted from the administration of pramipexole. From day 36, some animals were treated with a combination of levodopa (3.125-6.25 mg/kg plus carbidopa 12.5 mg/kg p.o. BID) and pramipexole (0.1-0.2 mg/kg p.o. SID). This improved motor disability to a greater extent than occurred with levodopa alone. Importantly, while dyskinesia was greater than that produced by pramipexole alone, the combination resulted in less intense dyskinesia than produced by levodopa alone. These results suggest that pramipexole could be administered with a reduced dose of levodopa to minimize dyskinesia in Parkinson's disease while maintaining therapeutic efficacy.
No preview · Article · Feb 2010 · Movement Disorders
[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.
Full-text · Article · Dec 2009 · Annals of Neurology
[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.
No preview · Article · Dec 2009 · Annals of Neurology
[Show abstract][Hide abstract] ABSTRACT: Cell-based therapies that involve transplantation into the striatum of dopaminergic cells have attracted considerable interest as possible treatments for Parkinson's disease (PD). However, all double-blind, sham-controlled, studies have failed to meet their primary endpoints, and transplantation of dopamine cells derived from the fetal mesencephalon is associated with a potentially disabling form of dyskinesia that persists even after withdrawal of levodopa (off-medication dyskinesia). In addition, disability in advanced patients primarily results from features such as gait dysfunction, freezing, falling, and dementia, which are likely due to nondopaminergic pathology. These features are not adequately controlled with dopaminergic therapies and are thus unlikely to respond to dopaminergic grafts. More recently, implanted dopamine neurons have been found to contain Lewy bodies, suggesting that they are dysfunctional and may have been affected by the PD pathological process. Collectively, these findings do not bode well for the short-term future of cell-based dopaminergic therapies in PD.
No preview · Article · Nov 2009 · Annals of Neurology
[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.)
Full-text · Article · Sep 2009 · New England Journal of Medicine
[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.
No preview · Article · Jul 2009 · Neurobiology of Disease
[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.