Seven-year clinical follow-up of premanifest carriers of Huntington's disease

Abstract

Detecting subtle clinical abnormalities in the ‘premanifest’ phase of Huntington’s disease (HD) is of importance in the development of instruments to monitor early therapeutic intervention trials. The current study examined changes in motor function, cognition and behaviour over a period of seven years in premanifest carriers of the HD gene mutation. Twenty-nine carriers without unequivocal motor signs of HD and 43 non-carrier controls were prospectively examined four times. The assessments consisted of the Unified Huntington’s Disease Rating Scale (UHDRS) and an extensive neuropsychological test battery addressing global cognitive function, memory, language and executive function. Rate of Change (RoC) analysis was performed to measure longitudinal differences between carriers and non-carriers. Carriers performed consistently worse on executive function (Symbol Digit Modalities Test (SDMT), Stroop, Trail Making Test (TMT) and WAIS-R arithmetic). Over the years, carriers showed a decline in memory and concentration function (Wechsler Memory Scale (WMS)) and in motor function (UHDRS motor scale). Changes over time could be particularly ascribed to carriers converting to manifest HD. These results demonstrate that standardized motor assessments and objective memory and concentration tasks are sensitive to change over a period of 7 years, specifically in carriers converting to manifest HD. Executive tasks also showed subtle cognitive abnormalities in premanifest HD, but a decline over time could not be demonstrated.

Cognitive decline in prodromal Huntington Disease: implications for clinical trials

“…Stroop interference requires inhibition whereas Trails B depends upon efficient response shifting; both showed substantial effects for all three prodromal HD groups. These findings are consistent with those in the literature suggesting that measures of working memory,9 11 response shifting and concentration10 15 showed change over time in prodromal HD. All findings in this publication can be understood in terms of neural circuitry believed to underlie HD.…”

“…The largest effect size was found for the SDMT, a task requiring coordination of visual scanning, working memory, fine motor speed, and concentration. These findings replicate those reported in the literature from at least six different studies7 8 10 11 13 15 and suggest that this task is highly sensitive and consistent for tracking decline in prodromal HD. Longitudinal change for every prodromal group was substantially different from the normal control group, suggesting the SDMT might serve as a sufficient outcome measure to detect alleviation of decline over time from an effective compound or intervention.…”

Surface-based morphometry reveals caudate subnuclear structural damage in patients with premotor Huntington disease

“…Executive function and working memory are especially vulnerable to early brain changes in pmHD (Duff et al 2010; Hart et al 2011; Stout et al 2011). We assessed cognitive function in these domains by using the National Institutes of Health (NIH) EXAMINER (Kramer et al 2014) Executive Composite and Working Memory Score.…”

Abnormal synchrony of resting state networks in premanifest and symptomatic Huntington disease: the IMAGE-HD study

“…We selected motor (i.e., precision of self-paced tapping fast [target rate of 3 Hz]) and cognitive (Stroop word reading and SDMT) tasks previously shown to be sensitive to progression of Huntington disease. 44,45 The calculation for timing precision is 1 ÷ the standard deviation of the intertap interval in seconds. 44,46 We also selected DBS as a symptom-free measure of gene expression across both Huntington disease groups.…”