Biology-Driven Cognitive Profiling in Huntington's Disease

Huntington's disease (HD) is a genetic, progressive neurodegenerative disorder characterized by early and widespread brain changes that can begin more than a decade before the onset of unequivocal motor signs. Although biological indicators of neurodegeneration-including striatal and cortical atrophy, white-matter disruption, and elevated plasma and CSF biomarkers-are detectable during the premanifest stage, cognitive performance typically appears within normal limits when assessed with conventional neuropsychological instruments. In symptomatic HD, cognitive impairment is highly heterogeneous among individuals with similar CAG repeat length, suggesting that mechanisms beyond the primary HTT mutation contribute to variable clinical expression. The objective of this study is to develop and validate novel cognitive assessment instruments that are sensitive to early disease-related changes and capable of characterizing distinct cognitive phenotypes across the HD spectrum. Specifically, the investigators aim to: 1. identify cognitive measures related to brain alterations occurring in premanifest and early-manifest HD; 2. develop approaches for precise cognitive stratification of symptomatic patients; 3. generate predictive models of cognitive trajectories; and 4. explore additional pathophysiological mechanisms-particularly tau-related pathology-that may modulate neurodegeneration and cognitive heterogeneity. To address these objectives, the study integrates multimodal biomarkers, including PET imaging with the tau tracer 18F-PI-2620, structural MRI, plasma biomarkers (neurofilament light chain and tau), and detailed cognitive testing. PET with 18F-PI-2620 will be used to quantify regional tau burden and to examine associations with cognitive performance, neurodegenerative patterns, and clinical phenotypes in HD. This tracer has demonstrated an adequate safety profile in prior human studies and is currently used at the study institution in other research protocols.