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.

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.

Inclusion Criteria:

• Age between 18 and 75 years

• Ability to provide written informed consent approved by the Ethics Committee

• Ability to comply with study procedures, including PET imaging, MRI, cognitive testing, and blood sampling

• Participants in the Healthy Control cohort must meet the following criteria:

  1. No history of neurological or psychiatric disorders
  2. No family history of Huntington's disease
  3. Normal cognitive status based on clinical evaluation

• Participants in the Premanifest Huntington's disease gene carrier cohort must meet the following criteria:

  1. Genetically confirmed HTT CAG expansion (CAG > 38)
  2. CAP score > 250
  3. Unified Huntington's Disease Rating Scale - Total Motor Score (UHDRS-TMS) < 4
  4. Total Functional Capacity (TFC) = 13
  5. Absence of manifest motor diagnosis (Diagnostic Confidence Level < 4)

• Participants in the Manifest Huntington's disease cohort (early-intermediate stage) must meet the following criteria:

  1. Genetically confirmed HTT CAG expansion (CAG > 38)
  2. Diagnostic Confidence Level (DCL = 4) confirming manifest Huntington's disease
  3. CAP score > 350
  4. Total Functional Capacity (TFC) > 6

Exclusion Criteria:

• Any severe medical condition or circumstance that, in the investigator's judgment, may compromise safe participation in the study
• Current or previous participation in the RG6042 / tominersen (mHTT-lowering) clinical trial
• Participation in any interventional clinical trial within the last 12 months
• Pregnancy or breastfeeding, or intention to become pregnant during the study period
• Contraindications to PET imaging, MRI, or venous blood sampling

This study will enroll a total of 90 participants distributed across three cohorts: healthy controls, premanifest Huntington's disease (HD) gene carriers, and individuals with early-to-intermediate manifest HD. Healthy controls will be adults with no neurological or psychiatric disorders and no family history of HD. Premanifest participants will be genetically confirmed HTT mutation carriers who do not yet meet diagnostic criteria for motor-manifest HD but show biological vulnerability to neurodegeneration. Manifest participants will include individuals with clinically diagnosed HD in the early or intermediate stages, characterized by a Diagnostic Confidence Level of 4 and preserved functional capacity. All participants must be able to undergo PET imaging, MRI, cognitive testing, and blood sampling. The study population is designed to capture the full early spectrum of HD-related change-from normal aging to premanifest pathology to clinically manifest disease-to enable biomarker-based

Individual participant data will not be shared because the study involves sensitive clinical, genetic, neuroimaging, and biomarker information from a vulnerable population. The protocol does not include a data-sharing framework, and the release of IPD is restricted by institutional policies and ethics committee requirements regarding confidentiality and secondary use of coded biological and imaging data.