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.

Objective-PREDICT-HD is a large-scale international study of people with the Huntington Disease CAG-repeat expansion who are not yet diagnosed with HD. The objective of this study was to determine at what stage in the HD prodrome cognitive differences from CAG-normal controls can be reliably detected.Method-For each of 738 HD CAG-expanded participants, we computed estimated years to clinical diagnosis and probability of diagnosis in five years, based on age and CAG repeat expansion number (Langbehn, Brinkman, Falush, Paulsen, & Hayden, 2004). We then stratified the sample into groups: "NEAR," estimated to be ≤ 9 years, "MID," between 9 and 15 years, and "FAR," ≥ 15 years. The control sample included 168 CAG-normal participants. Nineteen cognitive tasks were used to assess attention, working memory, psychomotor functions, episodic memory, language, recognition of facial emotion, sensory-perceptual functions, and executive functions.Results-Compared to the controls, the NEAR group showed significantly poorer performance on nearly all, and the MID group on about half of the cognitive tests (p = 0.05, Cohen's d Near as large as −1.17, Mid as large as −0.61). One test even revealed significantly poorer performance in the FAR group (Cohen's d = −0.26). Individual tasks accounted for 0.2% to 9.7% of the variance in estimated proximity to diagnosis. Overall, the cognitive battery accounted for 34% of the variance; in comparison, the UHDRS Motor Score accounted for 11.7%. Conclusions-Neurocognitive tests are robust clinical indicators of the disease process prior to reaching criteria for motor diagnosis of HD.Keywords cognitive assessment; presymptomatic; neuropsychology; psychomotor; prediagnosis Huntington disease (HD) is a progressive, fatal, autosomal dominant neurodegenerative disease that primarily affects movement, cognition, and psychiatric functions. Diagnosis of HD is based on the presence of unequivocal motor signs of HD, in conjunction with a positive genetic test for the HD CAG expansion or a confirmed family history of HD. Most people with the HD gene appear healthy throughout their youth and early adulthood, and then gradually develop signs and symptoms of HD, often leading to a diagnosis in middle age. The age of diagnosis varies in accordance with the number of CAG repeats on the expanded allele, although there is also substantial individual variability not accounted for by this genetic factor (Andrew et al., 1993;Gusella, MacDonald, Ambrose, & Duyao, 1993). A growing community of researchers is directing efforts at finding treatments to delay onset or slow the progression of early pathological changes in an attempt to reduce the tremendous personal and social costs of HD. Finding effective therapeutic or preventive treatments for HD depends critically on the ability to reliably and sensitively measure clinical signs of disease.Cognitive measures have excellent potential both for identifying individuals beginning to show subtle signs prior to the diagnosis of HD who might be suitable for clinical trials,...

No abstract

Accurate understanding of practice characteristics, performance stability, and error on neuropsychological tests is essential to both valid clinical assessment and maximization of signal detection for clinical trials of cognitive enhancing drugs. We examined practice effects in 28 healthy adults. As part of a larger study using donepezil and simulating a Phase I trial, participants were randomized into: placebo, no-treatment and donepezil. Donepezil results are presented elsewhere. Neuropsychological tests were administered in a fixed order for 6 weeks, with alternate forms available for most tests. Despite alternate forms, ANOVAs revealed significant improvements for the pooled control group (placebo and no-treatment) on all tests except Letter Number Sequencing and Trails B. Learning occurred principally in the first three to four sessions. PASAT and Stroop interference showed the greatest learning. Thus, serial assessment with alternate forms may attenuate retest effects on some tests, but continued learning occurs on novel tests or those in which an advantageous test-taking strategy can be identified. Alternate forms and baseline practice sessions may help control early, rapid improvements in clinical trials.

Practice effects, defined as improvements in cognitive test performance due to repeated exposure to the test materials, have traditionally been viewed as sources of error. However, they might provide useful information for predicting cognitive outcome. The current study used three separate patient samples (older adults with mild cognitive impairments, individuals who were HIV+, individuals with Huntington's disease) to examine the relationship between practice effects and cognitive functioning at a later point. Across all three samples, practice effects accounted for as much as 31-83% of the variance in the follow-up cognitive scores, after controlling for baseline cognitive functioning. If these findings can be replicated in other patients with neurodegenerative disorders, clinicians and researchers may be able to develop predictive models to identify the individuals who are most likely to demonstrate continued cognitive decline across time. The ability to utilize practice effects data would add a simple, convenient, and non-invasive marker for monitoring an individual patient's cognitive status. Additionally, this prognostic index could be used to offer interventions to patients who are in the earliest stages of progressive neurodegenerative disorders.