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.