Lifelong cognitive engagement slows symptom progression and neurodegeneration in Huntington’s disease: a six year follow-up study

Name: Audrey De Paepe
School: Vagelos College of Physicians and Surgeons, Class of 2025
Mentor: Karen Marder, MD, MPH and Estela Camara, PhD

Abstract

This study investigates the effect of cognitive engagement on long-term clinical changes in HD as well as the structural brain mechanisms sustaining these effects. Lifelong cognitive engagement conveys cognitive benefits to individuals with Huntington’s disease (HD) in age of onset and symptom severity. However, the effect of cognitive engagement on the longitudinal progression of other symptomatic domains such as motor and psychiatric dysfunction remains unknown, as is its underlying neurobiological basis. Forty-five HD individuals (31 female) completed the Cognitive Reserve Questionnaire (CRQ) and longitudinal clinical evaluation (maximum total of six visits). Generalized linear mixed-effects models were executed to predict the effect of individual differences in cognitive engagement on HD symptom progression as measured by the Unified Huntington’s Disease Rating Scale and the short-Problem Behavior Assessment. Of these, 33 underwent longitudinal neuroimaging (18±6 month follow-up) to explore the impact of such cognitive engagement on whole-brain gray matter volume changes. High CRQ scores elucidated preserved functioning across cognitive, motor, and psychiatric symptom domains over time in terms of both overall severity and longitudinal progression. Moreover, those with higher CRQ scores demonstrated reduced gray matter volume loss in the middle frontal gyrus, supplementary motor area, and middle cingulate. An active cognitive lifestyle may ameliorate clinical progression not only in cognitive performance, but also motor and psychiatric domains. Such protection may be conferred by brain reserve, in which cognitive engagement preserves executive regions that concurrently integrate action and behavioral regulation, thereby encouraging therapeutic interventions that promote reserve even prior to diagnosis.