Detection of Huntington's disease decades before diagnosis: the Predict-HD study.

OBJECTIVE: The objective of the Predict-HD study is to use genetic, neurobiological and refined clinical markers to understand the early progression of Huntington's disease (HD), prior to the point of traditional diagnosis, in persons with a known gene mutation. Here we estimate the approximate onset and initial course of various measurable aspects of HD relative to the time of eventual diagnosis. METHODS: We studied 438 participants who were positive for the HD gene mutation, but did not yet meet the diagnostic criteria for HD and had no functional decline. Predictability of baseline cognitive, motor, psychiatric and imaging measures was modelled non-linearly using estimated time until diagnosis (based on CAG repeat length and current age) as the predictor. RESULTS: Estimated time to diagnosis was related to most clinical and neuroimaging markers. The patterns of association suggested the commencement of detectable changes one to two decades prior to the predicted time of clinical diagnosis. The patterns were highly robust and consistent, despite the varied types of markers and diverse measurement methodologies. CONCLUSIONS: These findings from the Predict-HD study suggest the approximate time scale of measurable disease development, and suggest candidate disease markers for use in preventive HD trials.

Predictors of nursing home placement in Huntington disease.

OBJECTIVE: To determine whether motor, behavioral, or psychiatric symptoms in Huntington disease (HD) predict skilled nursing facility (SNF) placement. METHODS: Subjects were participants in the Huntington Study Group's Unified Huntington Disease Rating Scale Database (Rochester, NY) between January 1994 and September 1999. Specific motor, psychiatric, and behavioral variables in subjects residing at home and in SNF were analyzed using chi2 and Student's t-tests. For a subset of subjects for whom longitudinal data existed, a Cox proportional hazards model controlling for age, sex, and disease duration was used. RESULTS: Among 4,809 subjects enrolled, 3,070 had clinically definite HD. Of these, 228 (7.4%) resided in SNF. The SNF residents' average age was 52 years, average disease duration was 8.6 years, and they were predominantly women (63%). The SNF residents had worse motor function (chorea, bradykinesia, gait abnormality, and imbalance, p < 0.0001); were more likely to have obsessions, compulsions, delusions, and auditory hallucinations; and had more aggressive, disruptive (p < 0.0001), and irritable behaviors (p = 0.0012). For 1,559 subjects, longitudinal data existed (average length of follow-up, 1.9 years), and 87 (5%) moved from home to SNF. In the Cox model, bradykinesia (HR 1.965, 95% CI 1.083 to 3.564), impaired gait (HR 3.004, 95% CI 1.353 to 6.668), and impaired tandem walking (HR 2.546, 95% CI 1.460 to 4.439) were predictive of SNF placement. CONCLUSIONS: Institutionalized patients with HD are more motorically, psychiatrically, and behaviorally impaired than their counterparts living at home. However, motor variables alone predicted institutionalization. Treatment strategies that delay the progression of motor dysfunction in HD may postpone the need for institutionalization.

A randomized, controlled trial of remacemide for motor fluctuations in Parkinson's disease.

BACKGROUND: Preclinical studies suggest that glutamate antagonists help ameliorate motor fluctuations in patients with PD treated with levodopa. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study, the authors assessed the safety, tolerability, and efficacy of the glutamate receptor blocker remacemide hydrochloride in 279 patients with motor fluctuations treated with levodopa. The primary objective was to assess the short-term tolerability and safety of four dosage levels of remacemide during 7 weeks of treatment. Patients were also monitored with home diaries and the Unified PD Rating Scale (UPDRS) to collect preliminary data on treatment efficacy. RESULTS: Remacemide was well tolerated up to a dosage of 300 mg/d on a twice daily schedule and 600 mg/d on a four times daily schedule. The most common dosage-related adverse events were dizziness and nausea, as observed in previous studies of remacemide. The percent "on" time and motor UPDRS scores showed trends toward improvement in the patients treated with 150 and 300 mg/d remacemide compared with placebo-treated patients, although these improvements were not significant. CONCLUSION: Remacemide is a safe and tolerable adjunct to dopaminergic therapy for patients with PD and motor fluctuations. Although this study had limited power to detect therapeutic effects, the observed improvement is consistent with studies of non-human primates with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian signs and symptoms. Additional studies are warranted to confirm these results over an extended period of observation, and to explore the potential neuroprotective effects of remacemide in slowing the progression of PD.

Rate of functional decline in Huntington's disease. Huntington Study Group.

OBJECTIVE: To determine the rate of functional decline in a large cohort of patients with Huntington's disease (HD) followed at 43 sites by the Huntington Study Group (HSG). METHODS: The annual rate of functional decline was measured using the Total Functional Capacity Scale (TFC) and the Independence Scale (IS) in 960 patients with definite HD followed prospectively for a mean of 18.3 months. All patients were rated with the Unified Huntington's Disease Rating Scale (UHDRS). Sample size calculations for hypothetical clinical trials were calculated. RESULTS: A factor analysis of the UHDRS at baseline yielded 15 factors accounting for 77% of the variance. The TFC score declined at a rate of 0.72 units/year (standard error [SE] 0.04) and the IS score declined at a rate of 4.52 units/year (SE 0.23). Lower TFC score at baseline, indicating more severe impairment, was associated with less rapid annual decline in TFC score, perhaps reflecting the floor effect of the scale. The annual rate of decline for 575 patients with baseline TFC scores of 7 to 13 was 0.97 (SE 0.06), was 0.38 (SE 0.08) for 270 patients with baseline TFC scores of 3 to 6, and was 0.06 (SE 0.1) for 101 patients with TFC scores of 0 to 2. In multivariate analysis (n = 960), longer disease duration and better cognitive status at baseline were associated with a less rapid rate of decline in TFC score, whereas depressive symptomatology was the only factor associated with more rapid decline on the IS score. Age at onset of HD, sex, weight, and education did not affect decline on either score. CONCLUSIONS: The comparable rates of decline on the TFC and the IS scores with other published studies suggest that these estimates of functional decline are representative of HD patients who are evaluated at HSG research sites. In longitudinal analysis, longer disease duration and better neuropsychological performance at baseline were associated with a less rapid rate of decline in TFC score, whereas depressive symptomatology at baseline was associated with a more rapid decline in the IS score. These rates of functional decline and the covariates that modify them should be considered in estimating statistical power and designing future therapeutic trials involving HD patients with early or moderately severe disease.