Interplay between Sex and Disease Burden in Huntington's Disease: Clinical and Neuroimaging Perspectives

ABSTRACT Background Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion in the hungtintin gene. The disease exhibits sex-related differences in symptomatology and disease progression, but the effect on brain structural biomarkers and the interaction between sex and disease burden remain underexplored. Objectives To investigate the interplay between sex and disease burden on clinical measures and neuroimaging biomarkers in HD. Methods We retrospectively analyzed data from Enroll-HD, TRACK-HD/ON, PREDICT-HD, and IMAGE-HD studies, including a combined dataset of 19,738 participants with CAG>=40. Linear mixed models were employed to evaluate the influence of sex and the sex-disease burden interaction on clinical evaluations (Unified Huntington’s Disease Rating Scale and Problem Behaviors Assessment) and neuroimaging biomarkers (striatal volumes and cortical thickness), with CAG-Age Product Score (CAPS) used as a proxy for disease burden, while controlling for covariates. Results Female participants exhibited less pronounced striatal atrophy and cortical thinning with increasing CAPS (caudate: β male/female =–3.462/–2.935, p<0.05; putamen: β male/female =–4.775/–3.908, p<0.01). Regarding clinical measures, females experience greater motor decline with increasing CAPS (Total Motor Score: β male/female =3.024/3.244, p<0.0001), greater cognitive decline (Symbol Digit Modalities Test : β male/female =–34.89/–38.91, p<0.0001), and greater functional decline (Total Functional Capacity: β male/female =–6.449/–6.817, p<0.05; Independence Scale: β male/female =–32.44/– 34.99, p<0.001). Conclusions The sex-CAPS interaction significantly impacts both clinical and neuroimaging biomarkers of HD, underscoring the importance of incorporating sex-specific considerations into the clinical staging and management of HD.