A potential biomarker in sports-related concussion: brain functional connectivity alteration of the default-mode network measured with longitudinal resting-state fMRI over thirty days.

Current diagnosis and monitoring of sports-related concussion rely on clinical signs and symptoms, and balance, vestibular, and neuropsychological examinations. Conventional brain imaging often does not reveal abnormalities. We sought to assess if the longitudinal change of functional and structural connectivity of the default-mode network (DMN) can serve as a potential biomarker. Eight concussed Division I collegiate football student-athletes in season (one participated twice) and 11 control subjects participated in this study. ImPACT (Immediate Post-Concussion Assessment and Cognitive Testing) was administered over the course of recovery. High-resolution three dimensional T1-weighted, T2*-weighted diffusion-tensor images and resting-state functional magnetic resonance imaging (rs-fMRI) scans were collected from each subject within 24 h, 7±1 d and 30±1 d after concussion. Both network based and whole-brain based functional correlation analyses on DMN were performed. ImPACT findings demonstrated significant cognitive impairment across multiple categories and a significant increase of symptom severity on Day 1 following a concussion but full recovery by 6.0±2.4 d. While the structural connectivity within DMN and gross anatomy appeared unchanged, a significantly reduced functional connectivity within DMN from Day 1 to Day 7 was found in the concussed group in this small pilot study. This reduction was seen in eight of our nine concussion cases. Compared with the control group, there appears a general trend of increased DMN functional connectivity on Day 1, a significant drop on Day 7, and partial recovery on Day 30. The results of this pilot study suggest that the functional connectivity of DMN measured with longitudinal rs-fMRI can serve as a potential biomarker to monitor the dynamically changing brain function after sports-related concussion, even in patients who have shown clinical improvement.

Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial.

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.