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.

Conversion to carbidopa and levodopa extended-release (IPX066) followed by its extended use in patients previously taking controlled-release carbidopa-levodopa for advanced Parkinson's disease.

Background: IPX066 (Rytary®; carbidopa and levodopa [CD-LD] extended-release capsules) was designed to achieve therapeutic LD plasma concentrations within 1h of dosing and maintain LD concentrations for a prolonged duration in early or advanced Parkinson's disease (PD).

Methods: In this open-label study, patients underwent 6weeks of conversion to IPX066 from their prior controlled-release (CR)±immediate-release (IR) CD-LD therapy and 6months of maintenance (with an additional 6months of IPX066 at some sites). Clinical utility was assessed at both the end of conversion and maintenance.

A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit.

Importance: Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit.

Objective: To examine whether CoQ10 could slow disease progression in early PD.

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.

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.

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.

Single-dose administration of MK-0657, an NR2B-selective NMDA antagonist, does not result in clinically meaningful improvement in motor function in patients with moderate Parkinson's disease.

The glutamatergic system is thought to contribute to the motor disturbances observed in Parkinson's disease. Blockade of glutamatergic activity by a selective antagonist of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor is associated with improvement in motor symptoms in a preclinical model of Parkinson's disease. A randomized, double-blind, double-dummy, placebo-controlled, 3-period crossover study was conducted in patients with moderate Parkinson's disease to evaluate the pharmacologic activity of MK-0657, an NR2B-selective NMDA receptor antagonist.

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).

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.

Novel features in a patient homozygous for the L347P mutation in the PINK1 gene.

The purpose of this study was to assess the genotype-phenotype of PINK1 mutations. We genotyped eight known mutations in three clinic-based cohorts with Parkinsonism and found one homozygous p.L347P mutation in PINK1.

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.

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.

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).

Essential tremor in twins: an assessment of genetic vs environmental determinants of etiology.

Objective: To determine the relative contribution of genetics and environment to essential tremor using a twin study method.

Methods: Twins with postural or kinetic tremor were identified by movement disorders specialists during the conduct of a study investigating PD in members of the National Academy of Sciences and National Research Council World War II Veteran Twins Registry. The diagnosis of essential tremor was made by consensus using established diagnostic criteria.

An impairment in sniffing contributes to the olfactory impairment in Parkinson's disease.

Although the presence of an olfactory impairment in Parkinson's disease (PD) has been recognized for 25 years, its cause remains unclear. Here we suggest a contributing factor to this impairment, namely, that PD impairs active sniffing of odorants. We tested 10 men and 10 women with clinically typical PD, and 20 age- and gender-matched healthy controls, in four olfactory tasks: (i) the University of Pennsylvania smell identification test; (ii and iii) detection threshold tests for the odorants vanillin and propionic acid; and (iv) a two-alternative forced-choice detection paradigm during which sniff parameters (airflow peak rate, mean rate, volume, and duration) were recorded with a pneomatotachograph-coupled spirometer.

The long-term safety and efficacy of pramipexole in advanced Parkinson's disease.

Objective: To assess the long-term safety and efficacy of pramipexole in advanced Parkinson's disease over a four year time period.Methods: This study is an open-label extension trial of pramipexole for Parkinson's disease open to patients completing a double-blind placebo controlled safety and efficacy trial of this drug. Three hundred and six patients entered the trial.

A randomized, controlled trial of remacemide for motor fluctuations in Parkinson's disease.

Background: Preclinical studies suggest that glutamate antagonists help ameliorate motor fluctuations in patients with PD treated with levodopa.

Methods: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study, the authors assessed the safety, tolerability, and efficacy of the glutamate receptor blocker remacemide hydrochloride in 279 patients with motor fluctuations treated with levodopa. The primary objective was to assess the short-term tolerability and safety of four dosage levels of remacemide during 7 weeks of treatment.

Pattern of dopaminergic loss in the striatum of humans with MPTP induced parkinsonism.

Objectives: To examine the distribution of striatal dopaminergic function in humans with parkinsonism induced by 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP) to determine if there is a caudate-putamen gradient as is seen in idiopathic Parkinson's disease.

Methods: We scanned nine humans exposed to MPTP with parkinsonism ranging from minimal to severe using [(18)F]fluorodopa (FD) and high resolution PET. The results were compared with those of 10 patients with Parkinson's disease and six normal subjects.

Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure.

This report provides the first detailed neuropathological study of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in humans. All 3 subjects self-administered the drug under the impression it was "synthetic heroin" and subsequently developed severe and unremitting parkinsonism, which was L-dopa responsive, at least in the earlier stages of illness. Survival times ranged from 3 to 16 years.

Quantification of dyskinesia in Parkinson's disease: validation of a novel instrumental method.

We used a rotation-sensitive movement monitor (RoMM) to quantify and characterize dyskinesia in Parkinson's disease (PD). Both upper limbs of 22 patients with dyskinetic PD were recorded and videotaped simultaneously. Three neurologists reviewed the video segments and rated severity of dyskinesia on a four-point scale; they also assessed any asymmetry of dyskinesia between the right and left side as well as the dyskinesia type (choreic, dystonic, or mixed).

Autopsy-proven progressive supranuclear palsy in two siblings.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder that is generally considered to be nonfamilial. We report a brother and sister with clinical and pathologic findings characteristic of PSP. Both developed parkinsonism in the eighth decade of life and within 5 years exhibited severe postural instability, bradykinesia, rigidity, dystonia, dysarthria, dysphagia, urinary incontinence, pseudobulbar palsy, and supranuclear oculomotor dysfunction but no tremor.