Cognitive engagement may slow clinical progression and brain atrophy in Huntington's disease.

Lifelong cognitive engagement conveys benefits in Huntington's disease (HD) and may positively affect non-cognitive domains in other populations. However, the effect of lifelong cognitive engagement on the progression of motor and psychiatric domains in HD remains unknown, as is its neurobiological basis. Forty-five HD individuals completed the Cognitive Reserve Questionnaire (CRQ) and longitudinal clinical evaluation (maximum total of six visits, mean inter-assessment duration of 13.53 ± 4.1 months). Of these, thirty-three underwent longitudinal neuroimaging (18 ± 6 months follow-up). Generalized linear mixed-effects models were executed to predict the effect of individual differences in lifelong cognitive engagement on HD clinical progression and voxel-based morphometry to explore the impact of lifelong cognitive engagement on whole-brain gray matter volume atrophy. Controlling for age, disease stage, and sex, higher CRQ scores were associated with reduced overall severity and longitudinal progression across cognitive, motor, and psychiatric domains. Those with higher CRQ scores demonstrated reduced gray matter volume loss in the middle frontal gyrus, supplementary motor area, and middle cingulate. This putative impact on HD clinical progression may be conferred by preservation of brain volume in neural hubs that integrate executive function with action initiation and behavioral regulation, providing support for early cognitive engagement, even prior to diagnosis.