Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces "off" time in Parkinson's disease: a double-blind, randomized, multicenter clinical trial (6002-US-005).

OBJECTIVE: Based on new understanding of nondopaminergic pathways involved in Parkinson's disease (PD) pathophysiology, a selective adenosine A(2A) receptor antagonist, istradefylline, shows promise for the treatment of PD. METHODS: Istradefylline (40mg/day) was studied in levodopa-treated PD subjects experiencing prominent wearing-off motor fluctuations. At 23 North American sites, 196 subjects were randomized in a double-blind, 12-week outpatient clinical trial of istradefylline (114 completing the trial) or placebo (58 completing the trial). The primary efficacy measure was change from baseline to end point in the percentage of daily awake "off" time, recorded by subjects using a patient PD diary. Secondary end points evaluated "on" time (including "on time with dyskinesia"), the Unified Parkinson's Disease Rating Scale, and a Clinical Global Impression-Improvement of Illness score. Clinical laboratory, electrocardiograms, vital signs, and adverse event monitoring comprised the safety monitoring. RESULTS: After randomization, approximately 88% of subjects completed the double-blind period. Compared with baseline, the decrease of daily awake "off" time for istradefylline was a mean (+/- standard deviation) of -10.8 +/- 16.6% (95% confidence interval, -13.46 to -7.52) and for placebo, -4.0 +/- 15.7% (95% confidence interval, -7.73-0.31; p = 0.007 using two-way analysis of variance). This effect corresponded to changes from baseline in total daily awake "off" time of -1.8 +/- 2.8 hours for istradefylline and -0.6 +/- 2.7 hours for placebo (p = 0.005). Treatment-emergent adverse effects with istradefylline were generally mild. INTERPRETATION: Istradefylline was safe, well tolerated, and offered a clinically meaningful reduction in "off" time without increased troublesome dyskinesia.

LRRK2 p.Ile1371Val Mutation in a Case with Neuropathologically Confirmed Multi-System Atrophy.

BACKGROUND: Mutations in the leucine rich repeat kinase 2 (LRRK2) gene are among the most common genetic causes of Lewy body Parkinson's disease (PD). However, LRRK2 mutations can also lead to a variety of pathological phenotypes other than typical PD, including relatively pure nigrostriatal cell loss without alpha-synuclein-positive Lewy bodies or Lewy neurites, progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). The mechanisms behind this remarkable pleomorphic pathology are currently unclear. OBJECTIVE: To genetically and pathologically characterize a case with a LRRK2, p.Ile1371Val rare variant and pathologically proven MSA. METHODS: From the brain donation program at the Parkinson's Institute and Clinical Center, we selected 26 brains with family history and a with clinicopathological diagnosis of PD (n = 20), MSA (n = 4), or PSP (n = 2). We performed neuropathological evaluation, including alpha-synuclein and tau immunohistochemistry and sequenced 188 genes that have been reported as causative for or associated with neurodegenerative diseases. RESULTS: We identified a known LRRK2, p.Ile1371Val genetic variant in a case with clinically diagnosed and pathologically proven MSA. Neuropathology revealed that the olivopontocerebellar system was more affected than the striatonigral system. CONCLUSIONS: Our data suggest that genetic variants in the LRRK2 gene can present clinically and neuropathologically as MSA. One other LRRK2 genetic variant (LRRK2, p.Ile2020Thr) has been reported with a neuropathological diagnosis of MSA. Interestingly, the LRRK2 variant (LRRK2, p.Ile1371Val) identified here has been reported previously in a postmortem case with Lewy body PD.Future studies are critical to discover the mechanisms leading to different neurodegenerative trajectories both in neuronal and glial cell populations.

Genetic fine-mapping of the Iowan SNCA gene triplication in a patient with Parkinson's disease.

The "Iowa kindred," a large Iowan family with autosomal-dominant Parkinson's disease, has been followed clinically since the 1920s at the Mayo Clinic. In 2003, the genetic cause was determined to be a 1.7 Mb triplication of the alpha-synuclein genomic locus. Affected individuals present with an early-onset, severe parkinsonism-dementia syndrome. Here, we present a descendant of the Iowa kindred with novel, disease-associated non-motor findings of reduced heart rate variability, complete anosmia, and a rare skin condition called colloid milium. At autopsy, key neuropathological findings were compatible with diffuse Lewy body disease. Using high-resolution comparative genomic hybridization (CGH) array analysis to fine-map the genomic breakpoints, we observed two independent recombination events of the SNCA locus that resulted in a genomic triplication of twelve genes, including SNCA, and the disruption of two genes, HERC6 and CCSER1, at the genomic breakpoints. In conclusion, we provide further evidence that the mere two-fold overexpression of alpha-synuclein leads to a fulminant alpha-synucleinopathy with rapid progression and severe clinical and neuropathological features.

Balancing short-term symptom control and long-term functional outcomes in patients with Parkinson's disease.

Levodopa has played a central role in the treatment of Parkinson's disease for nearly 40 years and remains the single most effective symptomatic treatment for the disease. However, the response to levodopa therapy changes over time, and its long-term use is commonly associated with disabling motor complications. For this reason, the appropriate role of levodopa in the treatment of Parkinson's disease-in particular, the question of when to initiate therapy with the drug-has been a matter of controversy. Because levodopa is the most effective treatment for Parkinson's disease, the management of this disease becomes a matter of balancing short-term symptom control with long-term functional outcomes. This article provides an overview of the basis for levodopa-associated motor complications and their impact on patients' clinical function and quality of life, followed by a discussion of strategies for managing these complications to achieve optimum symptom control while minimizing the adverse effects of long-term therapy.

Neurodegenerative disorders mimicking progressive supranuclear palsy: a report of three cases.

Progressive supranuclear palsy (PSP) is rarely confused with other parkinsonian disorders once the vertical gaze palsy appears. Corticobasal degeneration is the most common differential diagnostic entity. We describe three cases diagnosed during life as PSP but found to have another neurologic disorder at autopsy. No explanation for the gaze palsies was found in any case.

Rest tremor in rhesus monkeys with MPTP-induced parkinsonism.

Rest tremor (RTr) is a typical feature of Parkinson's diseases (PD). Animal models of PD presenting with RTr are indispensable for understanding the pathophysiology of human RTr and the development of new therapeutic agents. In this report we studied the occurrence of tremor on rhesus monkeys rendered parkinsonian by an intracarotid (ICA) infusion followed by 2-4 iv. doses of n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The animals' parkinsonism was assessed using a rating scale, activity monitors and a novel tremor monitor. The animals manifested bilateral parkinsonism with more severe clinical signs on the side of the body contralateral to the ICA infusion. The RTr in these animals had a mean peak frequency of 7.9 Hz (S.E.: 0.12), and a mean amplitude of 5.1/d/s/rtz (S.E.: 0.69). Substantial reduction in RTr amplitude (80.4%) was observed after oral L-DOPA administration. Our results suggest that: 1) RTr is present after the combined administration of ICA and iv. MPTP. 2) The mean RTr frequency in rhesus monkeys may be higher than in parkinsonian patients. However, as in PD, RTr frequency in the monkey was maintained within a narrow band width. 3) As in PD, L-DOPA administration to MPTP-treated monkeys reduced the amplitude of RTr and improved the parkinsonian features. Monitoring and quantifying the RTr in the MPTP-parkinsonian monkeys provide an objective, non invasive way to measure the outcome of therapeutic interventions and, further support the concept that loss of dopaminergic innervation contributes to the occurrence of RTr.

Voluntarily simulated tremor in normal subjects.

Based on the hypothesis that rhythmical, tremor-like movements produced by normal subjects might be influenced by similar central oscillatory neuronal networks believed to determine the features of the pathologic tremors of Parkinson's disease (PD) or Essential Tremor (ET) patients, we examined the neurophysiological characteristics of a tremor mimicked by normal volunteers and compare this data with those from PD or ET tremors. Voluntarily simulated tremor (VST) was studied in 47 neurologically intact subjects, resting tremor in 10 patients with PD and postural tremor in 10 patients with ET. Using a tremor analysis system based on a solid state gyroscopic sensor sensitive to angular rate, the following parameters were determined: frequency, amplitude (angular displacement) and regularity (Q coefficient of constancy). We also performed an inertial loading test and a test-retest analysis. Nearly all normal subjects were able to simulate a tremor that was indistinguishable, in frequency and regularity, from that of PD or ET, although the amplitude was significantly higher in normal subjects. As in pathological tremors, the VST frequency was significantly influenced by age, but not by gender, handedness or previous knowledge of tremor. Inertial load did not modify the tremor frequency, suggesting that mechanical factors were minor. We also found a logarithmic inverse relationship between frequency and amplitude of the VST. We concluded that VST shares many similarities with pathological tremors. It is therefore possible that all tremors are somehow influenced by the same central oscillators which may become disinhibited and clinically apparent in pathological conditions such as PD or ET.

Mitochondrial dysfunction in skin fibroblasts from a Parkinson's disease patient with an alpha-synuclein triplication.

Mitochondrial dysfunction has been frequently implicated in the neurodegenerative process that underlies Parkinson's disease (PD), but the basis for this impairment is not fully understood. The goal of this study was to investigate the effects of α-synuclein (α-syn) gene multiplication on mitochondrial function in human tissue. To investigate this question, human fibroblasts were taken from a patient with parkinsonism carrying a triplication in the α-syn gene. Unexpectedly, the cells showed a significant decrease in cell growth compared to matched healthy controls. With regard to mitochondrial function, α-syn triplication fibroblasts exhibited a 39% decrease in ATP production, a 40% reduction in mitochondrial membrane potential, and a 49% reduction in complex I activity. Furthermore, they proved to be more sensitive to the effects of the nigrostrial toxicant paraquat compared to controls. Finally, siRNA knockdown of α-syn resulted in a partial rescue of mitochondrial impairment and reduction of paraquat-induced cell toxicity, suggesting that α-syn plays a causative role for mitochondrial dysfunction in these patient-derived peripheral skin fibroblasts.

Tolerability and efficacy of switching from oral selegiline to Zydis selegiline in patients with Parkinson's disease.

Selegiline is a monoamine-B specific inhibitor used to treat Parkinson's disease. A Zydis sublingual preparation has more efficient absorption and less first pass amphetamine metabolites. We conducted an open label oral to Zydis switch study to evaluate tolerability of rapid switch, and relative efficacy, in 48 subjects from 5 sites. Overall patients preferred the Zydis preparation. Per clinician global impressions, fluctuations improved and the "on" UPDRS part II scores improved. Total UPDRS and measures of fatigue and sleep were unchanged. Adverse events were mild. Patients generally preferred the Zydis selegiline preparation but the modest difference is of unclear clinical significance given the open label nature of the trial.

Orally disintegrating selegiline in Parkinson patients with dopamine agonist-related adverse effects.

OBJECTIVE: To determine whether adding orally disintegrating selegiline (ODS) while decreasing dopamine agonist (DA) dosages would reduce DA-related adverse effects (AEs) of excessive daytime sleepiness (EDS), pedal edema, hallucinations, and impulse control disorders (ICDs) without compromising efficacy in Parkinson disease (PD) patients. METHODS: This was a 12-week open-label study of 60 PD patients with motor fluctuations and DA-related AEs of EDS, pedal edema, hallucinations, and ICDs. Orally disintegrating selegiline was initiated at 1.25 mg once daily, and down titration of the DA was started with a goal of a 50% reduction by 1 week. At week 6, ODS was increased to 2.5 mg, and further reductions of the DA were allowed if the AEs were not resolved. RESULTS: The addition of ODS allowed a reduction in the mean daily dose of pramipexole from 2.3 to 0.5 mg and immediate-release ropinirole from 11.2 to 2.9 mg. Most subjects reported a reduction or resolution of DA-related AEs; 94% with EDS (n = 50), 73% with pedal edema (n = 26), 86% with hallucinations (n = 15), and 84% with ICDs (n = 25). Mean activities of daily living and motor scores from the Unified Parkinson's Disease Rating Scale as well as quality-of-life scores were significantly improved without an increase in daily "off" time. The most common AEs, most of which resolved after titration, were worsening of PD, nausea/vomiting, dyskinesia, increased off time, body aches, insomnia, orthostatic hypotension, and increased anxiety and depression. CONCLUSIONS: In most subjects, the addition of ODS with decreasing dosages of DAs substantially reduced EDS, pedal edema, hallucinations, and ICDs without compromising efficacy.