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. Neuropathological examination revealed moderate to severe depletion of pigmented nerve cells in the substantia nigra in each case. Lewy bodies were not present. In Patients 1 and 2, there was gliosis and clustering of microglia around nerve cells. Patient 3 had a similar picture and also showed large amounts of extraneuronal melanin. These findings are indicative of active, ongoing nerve cell loss, suggesting that a time‐limited insult to the nigrostriatal system can set in motion a self‐perpetuating process of neurodegeneration. Although the mechanism by which this occurs is far from clear, the precedent set by the cases could have broad implications for human neurodegenerative disease.

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 (Ϯ standard deviation) of Ϫ10.8 Ϯ 16.6% (95% confidence interval, Ϫ13.46 to Ϫ7.52) and for placebo, Ϫ4.0 Ϯ 15.7% (95% confidence interval, Ϫ7.73-0.31; p ϭ 0.007 using two-way analysis of variance). This effect corresponded to changes from baseline in total daily awake "off" time of Ϫ1.8 Ϯ 2.8 hours for istradefylline and Ϫ0.6 Ϯ 2.7 hours for placebo ( p ϭ 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. Neurol 2008;63:295-302 Although Parkinson's disease (PD) has several treatment options that initially can provide excellent symptomatic relief, 1 control of its disabilities typically declines over time. Because PD is characterized by loss of dopaminergic neurons projecting from substantia nigra to striatal nuclei, the most rational and effective therapy for restoring dopaminergic neurotransmission has been the dopamine precursor L-dopa. Ann2 Two years after starting L-dopa therapy, however, many patients start to experience fluctuations that interrupt control of parkinsonism, sometimes for up to several hours per day. 3,4 Adjusting the effects of L-dopa (by dosing changes or extenders such as catechol-Omethyltransferase or monoamine oxidase B inhibitors) or adding other dopaminergic drugs can improve "off" (undermedicated) states. Despite these options, inadequate control of motor fluctuations is a major source of disability for chronically treated PD.Beyond restoring dopaminergic input to striatal neurons, other pharmacological interventions can influence From the

A Randomized Clinical Trial of High-Dosage Coenzyme Q10 in Early Parkinson Disease No Evidence of Benefit The Parkinson Study Group QE3 Investigators 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. DESIGN, SETTING, AND PARTICIPANTS A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson's Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation. INTERVENTIONS The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E. MAIN OUTCOMES AND MEASURES Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo. RESULTS The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo). CONCLUSIONS AND RELEVANCE Coenzyme Q10 was safe and well tolerated in this population, bu...

This pattern is consistent with a genetic cause of essential tremor. Because monozygotic concordance is not 100%, environmental factors may also play a role in the cause of the 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. An additional experiment tested the effect of intentionally increasing sniff vigor on olfactory performance in 20 additional patients. PD patients were significantly impaired in olfactory identification (P < 0.0001) and detection (P < 0.007). As predicted, PD patients were also significantly impaired at sniffing, demonstrating significantly reduced sniff airflow rate (P < 0.01) and volume (P < 0.002). Furthermore, a patient's ability to sniff predicted his or her performance on olfactory tasks, i.e., the more poorly patients sniffed, the worse their performance on olfaction tests (P < 0.009). Finally, increasing sniff vigor improved olfactory performance in those patients whose baseline performance had been poorest (P < 0.05). These findings implicate a sniffing impairment as a component of the olfactory impairment in PD and further depict sniffing as an important component of human olfaction.