Ira Shoulson

Variable expression of Parkinson's disease: A base‐line analysis of the DAT ATOP cohort

The DATATOP database, which includes clinical information on 800 patients with early untreated Parkinsons disease (PD), is well suited to explore clinical heterogeneity in PD. Patients with early-onset PD (≤40 years, N = 33) reached the same level of disability as the late-onset PD (≥70 years, N = 85) group at a significantly slower rate (2.9 vs. 1.7 years). Early-onset PD patients functioned cognitively better than late-onset PD patients. Bradykinesia, and postural instability and gait difficulty (PIGD), were more common at onset in patients with a rapid rate of disease progression (“malignant PD”; duration of symptoms <1 year and Hoehnflahr stage of 2.5, N = 11) as compared with those with a relatively slow rate of progression (“benign PD”; duration of symptoms >4 years, N = 65). Comparisons of tremor-dominant PD (mean tremor score/ mean PIGD score ≤1.5, N = 441) with the PIGD-dominant type (mean tremor score/mean PIGD score ≥1.0, N = 233) provided support for the existence of clinical subtypes. The PIGD group reported significantly greater subjective intellectual, motor, and occupational impairment than the tremor group. Stage II patients had higher depression scores than stage I patients. Among the patients participating in the DATATOP, older age at onset with bradykinesia, or with the PIGD form of PD, is associated with more functional disability than when the symptoms are dominated by tremor or begin at a younger age.

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.

Dopamine transporter imaging is associated with long-term outcomes in Parkinson's disease†‡

Dopamine (DA) transporter (DAT) imaging has been studied as a diagnostic tool for degenerative parkinsonism. Our aim was to measure the prognostic value of imaging for motor and nonmotor outcomes in Parkinsons disease (PD). We prospectively evaluated a Parkinsons cohort after enrollment in a de novo clinical trial with a battery of motor (UPDRS), cognitive (Montreal Cognitive Assessment), and behavioral measures. DAT imaging with [123I][β]‐CIT and single‐photon emission computerized tomography (SPECT) was performed at baseline and after 22 months. In total, 491 (91%) of the 537 subjects had evidence of DA deficiency on their baseline scan, consistent with PD, and were included in the analyses. The cohort was followed for 5.5 (0.8) years, with a mean duration of diagnosis of 6.3 (1.2). Lower striatal binding at baseline was independently associated with higher risk for clinical milestones and measures of disease severity, including motor‐related disability, falling and postural instability, cognitive impairment, psychosis, and clinically important depressive symptoms. Subjects in the bottom quartile for striatal binding, compared to the top quartile, had an odds ratio (95% confidence interval) of 3.3 (1.7, 6.7) for cognitive impairment and 12.9 (2.6, 62.4) for psychosis. Change from baseline in imaging after 22 months was also independently associated with motor, cognitive, and behavioral outcomes. DAT imaging with [123I][β]‐CIT and SPECT, shortly after the diagnosis of PD, was independently associated with clinically important long‐term motor and nonmotor outcomes. These results should be treated as hypothesis generating and require confirmation.

A randomized clinical trial of CPI-1189 for HIV-associated cognitive-motor impairment.

Background: CPI-1189 is a compound with antioxidant properties that blocks tumor necrosis factor-α (TNFα) effects in animal models. It has neuroprotective properties in model systems for HIV-associated neurotoxicity and thus is a candidate for neuroprotective therapy in humans with HIV-associated CNS disease. Objective: To assess the tolerability and safety of CPI-1189 in treating HIV-associated cognitive–motor impairment. Methods: Sixty-four subjects with mild to moderate HIV-associated cognitive–motor impairment were randomized to receive either placebo or 50 or 100 mg daily of CPI-1189 in addition to optimal HIV therapy. Subjects were followed prospectively in a double-masked study for 10 weeks. The primary assessment was tolerability and safety of the compound. Secondary objectives examined neuropsychological and functional change associated with this treatment. Results: The study compound was well tolerated, with 91% of CPI-1189-treated subjects and 76% of placebo-treated subjects completing the trial. Skin rash was seen equally in placebo and active arms, but the only study withdrawals due to skin rash occurred in CPI-1189-treated subjects (n = 2). One subject developed a cataract on drug (100 mg/day). CD4 lymphocyte counts and plasma HIV viral load remained stable in all groups throughout the trial. No significant treatment effects were observed on the change in composite Z-scores for eight neuropsychologic measures (NPZ-8). The Grooved Pegboard Test (nondominant) showed improved performance with CPI-1189 at 100 mg/day (p = 0.01), but no other neuropsychometric or functional measures demonstrated significant improvement. Conclusions: CPI-1189 was well tolerated in HIV subjects with cognitive–motor disorder. This study was not powered to conclusively determine efficacy and showed no consistent treatment-associated improvement in cognitive or functional measures.

Safety and tolerability of high-dosage coenzyme Q10 in Huntington's disease and healthy subjects.

Coenzyme Q10 (CoQ10), a potential neuroprotective compound, was previously investigated at a dosage of 600 mg/day in Huntingtons disease (HD) patients and demonstrated a trend toward slowing disease progression. Higher CoQ10 dosages may prove beneficial. We investigated the tolerability and blood levels associated with 1,200, 2,400, and 3,600 mg/day of CoQ10 in HD and healthy subjects. Twenty‐eight subjects (20 HD, 8 healthy) enrolled in a 20‐week open‐label trial. Subjects started on 1,200 mg/day of CoQ10, increasing every 4 weeks by 1,200 mg to a maximum dosage of 3,600 mg/day. Monthly evaluations included review of adverse events and CoQ10 blood levels. Twenty‐three subjects (82%) achieved the target dosage of 3,600 mg/day. Six subjects (2 healthy, 4 HD) withdrew prematurely (gastrointestinal (GI) symptoms in 3, worsening HD in 2, and 1 because of a fall). All three serious adverse events occurred in a single subject, and were deemed unrelated to CoQ10. The most common adverse events seen were GI symptoms. Mean (± SD) CoQ10 blood levels achieved over the course of the trial were as follows: 1.26 ± 1.27 μg/mL (baseline, n = 28), 5.59 ± 2.24 μg/mL (1,200 mg/day, week 4, n = 26), 6.38 ± 3.25 μg/mL (2,400 mg/day, week 8, n = 25), 7.49 ± 4.09 μg/mL (3,600 mg/day, week 12, n = 23), and 6.78 ± 3.36μg/mL (3,600 mg/day, week 20, n = 20). CoQ10 was well tolerated with over 80% of subjects achieving the target dosage. Dosages of 2,400 mg/day may provide the best balance between tolerability and blood level achieved. Further studies examining the efficacy of 2,400 mg/day are planned.

Milestones in Huntington Disease

There have been extraordinary advances in our knowledge of the underlying gene, the protein it encodes, various models of disease, and potential targets for effective therapies for Huntington disease. Huntington disease research has increased exponentially in the past 25 years, and we now understand many of the molecular mechanisms underlying the disease. Still, more work needs to be done before we have a full understanding of the pathophysiology of the disease. Clinical research on biomarkers and clinical trials on potential neuroprotective agents are underway. Here we review our progress in these areas over the last 25 years and speculate on what the next 25 years may hold.

Natural history of Huntington disease.

IMPORTANCE Understanding the natural history of Huntington disease will inform patients and clinicians on the disease course and researchers on the design of clinical trials. OBJECTIVE To determine the longitudinal change in clinical features among individuals with Huntington disease compared with controls. DESIGN, SETTING, AND PARTICIPANTS Prospective, longitudinal cohort study at 44 research sites in Australia (n = 2), Canada (n =4), and the United States (n = 38). Three hundred thirty-four individuals with clinically manifest Huntington disease who had at least 3 years of annually accrued longitudinal data and 142 controls consisting of caregivers and spouses who had no genetic risk of Huntington disease. MAIN OUTCOMES AND MEASURES Change in movement, cognition, behavior, and function as measured by the Unified Huntingtons Disease Rating Scale, the Mini-Mental State Examination, and vital signs. RESULTS Total motor score worsened by 3.0 points (95% CI, 2.5-3.4) per year and chorea worsened by 0.3 point per year (95% CI, 0.1-0.5). Cognition declined by 0.7 point (95% CI, 0.6-0.8) per year on the Mini-Mental State Examination. Behavior, as measured by the product of frequency and severity score on the Unified Huntingtons Disease Rating Scale, worsened by 0.6 point per year (95% CI, 0.0-1.2). Total functional capacity declined by 0.6 point per year (95% CI, 0.5-0.7). Compared with controls, baseline body mass index was lower in those with Huntington disease (25.8 vs 28.8; P < .001), and average pulse was higher (74.2 vs 69.6 beats/min; P < .001). CONCLUSIONS AND RELEVANCE Over 3 years, the cardinal features of Huntington disease all declined in a monotonic manner. These data quantify the natural history of the disease and may inform the design of trials aimed at reducing its burden. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00313495.

Dietary intake in adults at risk for Huntington disease: analysis of PHAROS research participants.

Objective: To examine caloric intake, dietary composition, and body mass index (BMI) in participants in the Prospective Huntington At Risk Observational Study (PHAROS). Methods: Caloric intake and macronutrient composition were measured using the National Cancer Institute Food Frequency Questionnaire (FFQ) in 652 participants at risk for Huntington disease (HD) who did not meet clinical criteria for HD. Logistic regression was used to examine the relationship between macronutrients, BMI, caloric intake, and genetic status (CAG <37 vs CAG ≥37), adjusting for age, gender, and education. Linear regression was used to determine the relationship between caloric intake, BMI, and CAG repeat length. Results: A total of 435 participants with CAG <37 and 217 with CAG ≥37 completed the FFQ. Individuals in the CAG ≥37 group had a twofold odds of being represented in the second, third, or fourth quartile of caloric intake compared to the lowest quartile adjusted for age, gender, education, and BMI. This relationship was attenuated in the highest quartile when additionally adjusted for total motor score. In subjects with CAG ≥37, higher caloric intake, but not BMI, was associated with both higher CAG repeat length (adjusted regression coefficient = 0.26, p = 0.032) and 5-year probability of onset of HD (adjusted regression coefficient = 0.024; p = 0.013). Adjusted analyses showed no differences in macronutrient composition between groups. Conclusions: Increased caloric intake may be necessary to maintain body mass index in clinically unaffected individuals with CAG repeat length ≥37. This may be related to increased energy expenditure due to subtle motor impairment or a hypermetabolic state.

Mendelian randomization of serum urate and parkinson disease progression

Higher serum urate concentrations predict more favorable prognosis in individuals with Parkinson disease (PD). The purpose of this study was to test the causality of this association using a Mendelian randomization approach.

Safety of rasagiline in elderly patients with Parkinson disease

The authors examined age effects on adverse events from two randomized, controlled trials of rasagiline, comparing younger (younger than70 years) and older (70 years and older) subjects. Older patients were more prone to serious adverse effects than younger patients, but there was no statistical interaction between age and rasagiline exposure. This absence of an age-rasagiline interaction suggests that rasagiline does not require special safety precautions for elderly subjects with Parkinson disease.