Baseline Hemodynamic Impairment and Future Stroke Risk in Adult Idiopathic Moyamoya Phenomenon: Results of a Prospective Natural History Study.

BACKGROUND AND PURPOSE: The purpose was to test the hypothesis that increased oxygen extraction fraction (OEF), a marker of severe hemodynamic impairment measured by positron emission tomography, is an independent risk factor for subsequent ischemic stroke in this population. METHODS: Adults with idiopathic moyamoya phenomena were recruited between 2005 and 2012 for a prospective, multicenter, blindly adjudicated, longitudinal cohort study. Measurements of OEF were obtained on enrollment. Subjects were followed up for the occurrence of ipsilateral ischemic stroke at 6-month intervals. Patients were censored at the time of surgical revascularization or at last follow-up. The primary analysis was time to ischemic stroke in the territory of the occlusive vasculopathy. RESULTS: Forty-nine subjects were followed up during a median of 3.7 years. One of 16 patients with increased OEF on enrollment had an ischemic stroke and another had an intraparenchymal hemorrhage. Three of 33 patients with normal OEF had an ischemic stroke. On a per-hemisphere basis, 21 of 79 hemispheres with moyamoya vasculopathy had increased OEF at baseline. No ischemic strokes and one hemorrhage occurred in a hemisphere with increased OEF (n=21). Sixteen patients (20 hemispheres), including 5 with increased OEF at enrollment, were censored at a mean of 5.3 months after enrollment for revascularization surgery. CONCLUSIONS: The risk of new or recurrent stroke was lower than expected. The low event rate, low prevalence of increased OEF, and potential selection bias introduced by revascularization surgery limit strong conclusions about the association of increased OEF and future stroke risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00629915.

Memantine for non-motor features of Parkinson's disease: a double-blind placebo controlled exploratory pilot trial.

OBJECT: To perform an exploratory study evaluating memantine for several common non-motor problems in Parkinson's disease. METHODS: We conducted a single center, double-blind, placebo controlled pilot trial of memantine, titrated to 20 mg/day, in PD subjects. Inclusion criteria were intentionally broad and included both fluctuating and non-fluctuating patients. After baseline assessments, subjects (N = 40) were randomized to drug and placebo groups. They received a battery of traditional and non-motor assessments. After a safety call (2 weeks after baseline) they returned for identical assessments at week 8. An 8-week open label extension was started if desired. RESULTS: Subject demographics (age 69.1 ± 7.8; 24 males), were similar in the drug and placebo groups. Four dropped from the study while on drug vs. none on placebo. Two of 36 remaining dropped out over the 8-week open label section. Of the 34 who completed the final open label visit, 24 elected to be prescribed memantine after the study. During the controlled trial, there was no significant change in UPDRS section I or II, Epworth sleepiness scale, fatigue severity scale, Hamilton depression scale, Conner adult inventory, PD Quality of Life-39, or clinical global impressions. UPDRS "on" motor scores tended to improved, p = 0.19. CONCLUSION: Memantine was well tolerated in PD; however, specific measures of sleepiness, fatigue, depression, and attention did not significantly improve. The majority of subjects elected to stay on the drug after the open label extension suggesting some unassessed benefit.

Comparison of orally dissolving carbidopa/levodopa (Parcopa) to conventional oral carbidopa/levodopa: A single-dose, double-blind, double-dummy, placebo-controlled, crossover trial.

Levodopa use in fluctuating Parkinson's disease (PD) is complicated by an inconsistent and prolonged onset to clinical improvement. An orally dissolved carbidopa/levodopa (OD C/L) preparation (Parcopa UCB Pharma) is available in the United States. This offers potential advantages to shorten the duration from ingestion to clinical improvement. Surprisingly, this has never been clinically assessed. We tested 20 patients with fluctuating PD and a Unified Parkinson's Disease Rating Scale (UPDRS) "off" motor score of ≥ 25 in a 2-day, single-dose, double-blind, double-dummy, crossover study. Patients arrived in the morning in the practically defined "off" state and were randomly assigned to receive identical doses of either oral C/L and OD placebo or OD C/L and oral C/L placebo on 1st day and the reverse combination on a 2nd day. After training, patients underwent bilateral hand tapping at baseline and every 5 minutes for 60 minutes after dose ingestion. Stride length (SL) was recorded at 5-minute intervals with an ambulatory gait monitor. Patients identified their subjective latency to "on" and noted drug preferences and adverse events. They also underwent a UPDRS motor examination at baseline and 60 minutes after dose. Twenty subjects [15 male, age 68.7 (9.7), PD duration 13.4 (6.8)] completed. There were no significant group differences in tapping speed, subjective time to "on," latency of increased SL, or overall preference. However, all trends did favor OD C/L. Adverse events were similar. This small pilot study did not show significant group differences favoring OD C/L; however, larger studies may be justified, and individual patients may benefit.

Double-blind therapeutic trial in Angelman syndrome using betaine and folic acid.

Angelman syndrome (AS) is caused by reduced or absent expression of the maternally inherited ubiquitin protein ligase 3A gene (UBE3A), which maps to chromosome 15q11-q13. UBE3A is subject to genomic imprinting in neurons in most regions of the brain. Expression of UBE3A from the maternal chromosome is essential to prevent AS, because the paternally inherited gene is not expressed, probably mediated by antisense UBE3A RNA. We hypothesized that increasing methylation might reduce expression of the antisense UBE3A RNA, thereby increasing UBE3A expression from the paternal gene and ameliorating the clinical phenotype. We conducted a trial using two dietary supplements, betaine and folic acid to promote global levels of methylation and attempt to activate the paternally inherited UBE3A gene. We performed a number of investigations at regular intervals including general clinical and developmental evaluations, biochemical determinations on blood and urine, and electroencephalographic studies. We report herein the data on 48 children with AS who were enrolled in a double-blind placebo-controlled protocol using betaine and folic acid for 1 year. There were no statistically significant changes between treated and untreated children; however, in a small subset of patients we observed some positive trends.

Efficacy and tolerability of pregabalin in essential tremor: a randomized, double-blind, placebo-controlled, crossover trial.

We performed a double-blind, crossover-design study to assess the tolerability and efficacy of pregabalin (PGB) in patients with essential tremor (ET). Twenty patients (11 women; mean age of 62.2+/-12.7 years, mean ET duration of 25.5+/-14.9 years) with ET were randomized for treatment with PGB (150-600 mg/day) or placebo, titrated over 6 weeks. Identical assessments of the Fahn-Tolosa-Marin Tremor Rating Scale (TRS) (primary endpoint), Clinical Global Impression of Change (CGI-C), Quality of Life in Essential Tremor Questionnaire (QUEST), Hamilton Anxiety Scale (HAM-A), and a sleep hygiene questionnaire (HD-16) were made at the baseline, at the end of treatment periods for both drug and placebo, and following the 2-week washout period preceding crossover. We found no improvement in any of the TRS measures and a statistically significant worsening of QUEST scores while patients were taking PGB. Adverse events were similar in frequency to previously published studies of PGB, the most common being drowsiness and dizziness.

Comparing knowledge and attitudes towards genetic testing in Parkinson's disease in an American and Asian population.

INTRODUCTION: Recent discoveries of disease-causing genes in Parkinson's disease (PD) have generated considerable interest regarding genetic testing in PD. The attitudes toward genetic testing are largely influenced by knowledge and preconceived notions. OBJECTIVE: We investigated the relationship between knowledge of and attitude towards predictive genetic testing of PD in two independent centers in America and Asia involving PD patients and caregivers. METHODS: In a prospective study involving 515 subjects comprising of PD patients and their caregivers in two independent centers in America and Asia, the level of knowledge about genetic testing and patients' attitudes towards such testing were evaluated using a standardized questionnaire. RESULTS: American PD patients had a higher level of knowledge of PD genetics than Asian PD (31.1% vs. 12.3%, p=0.0002). A greater number of American PD patients and caregivers reported a positive attitude towards the potential medical benefits of genetic testing compared to their Asian counterparts (85.4% vs. 42.2%, 92.2% vs. 32.1%, p<0.00005), but a more negative attitude towards potential compromise in getting health and life insurance (43.7% vs. 25.8%, p=0.0002). However, in the Asian cohort, multivariate analysis revealed that a high level of genetics knowledge was associated with a positive attitude response regarding the potential medical benefits of testing (p<0.0005), but a negative attitude towards compromises in healthcare and life insurance, getting a job and starting a family (p<0.0005). These associations were not observed amongst American subjects. CONCLUSIONS: The relationship between level of genetic knowledge and attitude towards potential risks and benefits of predictive genetic testing in PD was distinctly different in two independent, racially and culturally different PD populations and caregivers. These observations have clinical implications in the development of PD genetic counseling programs.