ABSTRACT
IMPORTANCE: Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD). OBJECTIVE: To determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial. DESIGN, SETTING, AND PARTICIPANTS: The Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled. INTERVENTIONS: Participants were randomized to 1 of 3 treatment arms: placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 500-mg capsules taken orally up to 2 capsules 3 times per day. They were followed for up to 24 months (median, 18 months) while receiving the study drug plus 1 washout month. MAIN OUTCOMES AND MEASURES: The prespecified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid. RESULTS Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in the inosine groups relative to placebo. No participant developed gout and 3 receiving inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 inosine groups (P < .001 for each) vs placebo, and cerebrospinal fluid urate level was greater in both inosine groups (P = .006 and <.001, respectively). Secondary analyses demonstrated nonfutility of inosine treatment for slowing disability. CONCLUSIONS AND RELEVANCE: Inosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early PD. The findings support advancing to more definitive development of inosine as a potential disease-modifying therapy for PD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00833690.
Subject(s)
Inosine/therapeutic use , Parkinson Disease/blood , Parkinson Disease/cerebrospinal fluid , Uric Acid/blood , Uric Acid/cerebrospinal fluid , Aged , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Double-Blind Method , Female , Follow-Up Studies , Humans , Male , Middle Aged , Parkinson Disease/drug therapy , Treatment OutcomeABSTRACT
Cognitive dysfunction is one of the hallmarks of Huntington's disease (HD) and may precede the onset of motor symptoms. The Montreal Cognitive Assessment (MoCA), a brief cognitive screening instrument with high specificity and sensitivity for detecting early cognitive impairments, has not been studied in the HD population. In this study, we compare the MoCA with the mini-mental state examination (MMSE) as a screening tool for cognitive dysfunction among 53 patients with HD. The mean MMSE score was 26 +/- 2.4, and mean MoCA score was 21 +/- 4.4. Twenty-one patients (81%) of those who scored >or=26 on the MMSE had the MoCA score <26. Thirty-two patients (78%) of those who scored >or=24 on the MMSE had the MoCA score <24. The MoCA may be a more sensitive screening tool for cognitive impairments in HD relative to the MMSE.
Subject(s)
Cognition Disorders/diagnosis , Cognition Disorders/etiology , Huntington Disease/complications , Neuropsychological Tests , Adult , Aged , Disability Evaluation , Female , Humans , Male , Mass Screening/methods , Mental Status Schedule , Middle AgedABSTRACT
Sleep disorders and daytime somnolence have not been systematically studied in the Huntington disease (HD) population. In this study we have assessed nocturnal sleep and daytime somnolence in 30 patients recruited from a subspecialty HD clinic. Disturbed nocturnal sleep and excessive daytime somnolence were common in this cohort. Further studies employing objective measures of sleep/daytime somnolence in the HD population are needed.