Biology-Driven Cognitive Profiling in Huntington's Disease

Plain-language summary

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. This pilot, open-label, single-center Phase IIa study will recruit 90 participants: 30 healthy controls, 30 premanifest HD gene carriers, and 30 early-to-intermediate stage symptomatic patients. All participants will undergo a single administration of 185 MBq of 18F-PI-2620 followed by a 90-minute dynamic PET acquisition. Imaging data will be co-registered with MRI and analyzed using standardized uptake value ratios (SUVR) with the cerebellum as reference region. Cognitive assessments and blood sampling will be completed within 15 days of PET imaging. Primary outcome measures include regional SUVR values obtained from 18F-PI-2620 PET and their association with early neurodegenerative changes. Secondary outcomes include correlations between PET measures, cognitive performance, MRI-derived cortical and subcortical atrophy, and plasma biomarkers. Safety will be assessed through direct observation for two hours following tracer administration and through a structured follow-up telephone call at 24 hours. The overarching goal of the study is to establish biologically guided cognitive instruments capable of detecting subtle premanifest changes, capturing the heterogeneous cognitive expression of HD, and supporting future therapeutic trials, particularly in individuals at the earliest disease stages.

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