Biology-Driven Cognitive Profiling in Huntington's Disease

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene that results in the production of mutant huntingtin protein (mHTT). The mutation initiates a cascade of cellular dysfunctions leading to progressive neuronal injury and cell death. Although the clinical diagnosis of HD remains based on the presence of unequivocal motor abnormalities, extensive evidence indicates that neurodegeneration begins many years before motor onset during the premanifest stage.

Neuroimaging and biomarker studies have consistently demonstrated early striatal atrophy, cortical thinning, white-matter degeneration, and metabolic alterations long before clinical diagnosis. In addition, biomarkers of neuronal injury such as neurofilament light chain (NfL) and tau are elevated in cerebrospinal fluid and plasma during the premanifest stage. These findings suggest that substantial biological disease burden is already present many years prior to overt clinical manifestations.

Despite these early biological abnormalities, conventional neuropsychological assessments frequently fail to detect consistent cognitive impairment in premanifest gene carriers. This discrepancy highlights an important limitation of currently available neuropsychological instruments, which often lack the sensitivity required to capture subtle early disease-related changes. The development of biologically informed cognitive outcome measures is therefore a critical need, particularly as disease-modifying therapeutic strategies increasingly target individuals during the earliest stages of the disease.

Cognitive impairment in symptomatic HD is also characterized by considerable heterogeneity. Individuals with comparable CAG repeat length, age, and educational background may present markedly different cognitive profiles and rates of progression. Previous studies have shown that these cognitive phenotypes are associated with distinct patterns of neurodegeneration affecting different neural networks. Such variability suggests that mechanisms beyond the primary effects of the HTT mutation contribute to disease expression and progression.

Emerging evidence indicates that tau-related pathology may represent one such mechanism. Although HD has not traditionally been classified as a primary tauopathy, postmortem studies have identified tau aggregates-frequently corresponding to Braak stages I-III-in a substantial proportion of HD brains. Additional research has suggested that HD may involve secondary tau pathology characterized by 4R tau isoforms, with tau inclusions observed in the striatum, limbic structures, and cortical regions. Experimental findings further indicate that mutant huntingtin may promote tau hyperphosphorylation and aggregation, potentially contributing to neuronal injury and cognitive dysfunction.

Elevated tau concentrations have also been reported in the cerebrospinal fluid of individuals with HD, with levels comparable to those observed in several other neurodegenerative disorders. Preliminary data generated at the study institution indicate that tau-related changes may be associated with patterns of brain degeneration that differ from those linked to neurofilament light chain or mutant huntingtin-related processes. These observations raise the possibility that tau pathology contributes to the heterogeneity of cognitive impairment and neurodegenerative trajectories in HD.

Advances in molecular imaging now allow in vivo assessment of protein aggregates through positron emission tomography (PET). The tau radiotracer 18F-PI-2620 has demonstrated favorable imaging characteristics and safety profiles in human studies. This tracer enables the quantification of regional tau burden across brain networks implicated in neurodegenerative disease. The use of tau PET imaging therefore offers a unique opportunity to investigate the role of tau pathology in HD and its relationship with neurodegeneration and cognitive performance.

The present study is designed as a pilot, open-label, single-center Phase IIa investigation evaluating the use of 18F-PI-2620 PET imaging in individuals across the Huntington's disease spectrum. The study will enroll a total of 90 participants, including three groups: 30 cognitively healthy controls, 30 premanifest HD gene carriers, and 30 individuals with early-to-intermediate stage symptomatic HD. Participants with HD will be recruited from the Huntington's disease clinic within the Movement Disorders Unit of Hospital de la Santa Creu i Sant Pau, while healthy controls will be recruited from volunteers participating in other observational studies conducted at the same institution.

Following informed consent, participants will undergo a PET imaging procedure using the radiotracer 18F-PI-2620. A single intravenous dose of approximately 185 MBq will be administered through a peripheral venous catheter. After tracer injection, dynamic brain PET imaging will be acquired for approximately 90 minutes using a PET-CT scanner (Philips Gemini TF or Philips Vereos Digital). Participants will remain in a supine position during the acquisition to minimize motion artifacts.

PET imaging data will be processed using established neuroimaging pipelines. Images will be co-registered with structural magnetic resonance imaging (MRI) scans to allow accurate anatomical localization. Standardized uptake value ratios (SUVR) will be calculated using the cerebellum as the reference region. Regional SUVR values will provide quantitative estimates of tau tracer uptake and distribution across brain regions implicated in HD.

Structural MRI data will be analyzed using automated morphometric tools to derive measures of cortical thickness and subcortical volumes. Voxel-based morphometry and surface-based analyses will be performed to identify patterns of neurodegeneration associated with tau tracer binding. Integration of PET and MRI data will allow the investigation of relationships between molecular pathology and structural brain changes.

Blood samples will also be collected for the measurement of plasma biomarkers, including neurofilament light chain, total tau, and phosphorylated tau. These biomarkers will be analyzed to evaluate their association with imaging measures and cognitive performance.

Cognitive assessment will include both standardized neuropsychological instruments and experimental tasks designed to probe cognitive processes that may be affected early in HD. These tasks evaluate domains such as attentional selection, sensory integration, visuospatial processing, temporal prediction, and complex executive control. The objective of this cognitive evaluation is to identify measures that are sensitive to early disease-related changes and capable of distinguishing among cognitive phenotypes in symptomatic HD.

The primary outcome of the study is the regional SUVR derived from 18F-PI-2620 PET imaging, representing the distribution and burden of tau pathology in the brain. Secondary outcomes include associations between PET imaging measures, structural MRI indices of brain atrophy, plasma biomarker levels, and cognitive performance.

Statistical analyses will include group comparisons of regional SUVR values across healthy controls, premanifest gene carriers, and symptomatic HD participants. Correlation analyses will be conducted to evaluate relationships between imaging metrics, cognitive outcomes, and biomarker levels. Imaging analyses will include voxel-based and region-of-interest approaches implemented using established neuroimaging software platforms.

Safety monitoring will be conducted throughout the study. Participants will remain under medical observation for approximately two hours following tracer administration. Potential adverse events will be assessed through direct observation during the imaging session and through a structured telephone follow-up approximately 24 hours after tracer injection. Previous studies using 18F-labeled PET tracers indicate that adverse effects are uncommon and typically limited to minor injection-site discomfort or transient symptoms.

The expected outcome of this research is the identification of biologically informed cognitive measures that align with disease-related brain changes in Huntington's disease. By integrating multimodal biomarkers, neuroimaging measures, and detailed cognitive assessment, the study aims to advance understanding of the mechanisms underlying cognitive heterogeneity in HD and to facilitate the development of sensitive outcome measures for future therapeutic trials.