Biology-Driven Cognitive Profiling in Huntington's Disease

NCT07503743 | Active Not Recruiting DMC

• 2 other identifiers: IIBSP-FPI-2021-128PI21/01758
• Study Type: observational
• Target: 90
• Locations: 1 country
• Sites: 1

Brief 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. 1.identify cognitive measures related to brain alterations occurring in premanifest and early-manifest HD;
2. 2.develop approaches for precise cognitive stratification of symptomatic patients;
3. 3.generate predictive models of cognitive trajectories; and
4. 4.explore additional pathophysiological mechanisms-particularly tau-related pathology-that may modulate neurodegeneration and cognitive heterogeneity.

Conditions

Huntington's Disease (HD)

Keywords

PI-2620; Tau; Huntington's disease

Outcome Measures

Primary Outcomes (1)

• Regional Tau PET Binding (SUVR) Using 18F-PI-2620

  Standardized uptake value ratios (SUVR) derived from 18F-PI-2620 PET imaging will be calculated to quantify regional tau tracer uptake in predefined cortical and subcortical brain regions. SUVR values will be computed using the cerebellum as the reference region.

  Day 1

Secondary Outcomes (7)

• Cortical Thickness Measured by Structural MRI

  Day 1

• Subcortical Volume Measured by Structural MRI

  Day 1

• Plasma Neurofilament Light Chain (NfL)

  Within 15 days of PET imaging

• Plasma Total Tau

  Within 15 days of PET imaging

• Plasma Phosphorylated Tau

  Within 15 days of PET imaging

Study Arms (3)

Healthy Control Cohort

Participants without a family history of Huntington's disease, without neurological or psychiatric disorders, and with normal cognitive functioning. This cohort provides reference values for PET tau binding (18F-PI-2620), structural MRI, plasma biomarkers, and cognitive performance. Controls undergo the same procedures as the HD cohorts, including PET imaging, MRI, cognitive assessment, and blood sampling.

Premanifest Huntington's Disease Gene Carrier Cohort

Individuals who carry the pathogenic HTT CAG expansion but do not yet meet clinical criteria for motor diagnosis. Premanifest participants may present subtle or no detectable cognitive changes on standard neuropsychological testing but show biological markers of early neurodegeneration. This cohort is used to identify sensitive cognitive measures that align with early pathological changes and to evaluate early tau PET signal, MRI abnormalities, and plasma biomarker alterations.

Early/Intermediate Manifest Huntington's Disease Cohort

Participants with a confirmed clinical diagnosis of Huntington's disease in the early or intermediate symptomatic stages. These individuals typically display measurable cognitive impairment and heterogeneous cognitive profiles. This cohort is examined to characterize cognitive phenotypes, relate them to tau PET signal and multimodal biomarkers, and develop biologically driven stratification approaches for use in future therapeutic trials.

Eligibility Criteria

• Age: 30 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

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

You may qualify if:

• 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:
• No history of neurological or psychiatric disorders
• No family history of Huntington's disease
• Normal cognitive status based on clinical evaluation
• Participants in the Premanifest Huntington's disease gene carrier cohort must meet the following criteria:
• Genetically confirmed HTT CAG expansion (CAG \> 38)
• CAP score \> 250
• Unified Huntington's Disease Rating Scale - Total Motor Score (UHDRS-TMS) \< 4
• Total Functional Capacity (TFC) = 13
• 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:
• Genetically confirmed HTT CAG expansion (CAG \> 38)

You may not qualify if:

• 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

Sponsors & Collaborators

• Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau: lead

Study Sites (1)

Hospital de la Sant aCreu i Sant Pau

Barcelona, Spain

Location

Biospecimen

Retention: SAMPLES WITHOUT DNA

Blood samples will be collected from all participants for the acquisition of plasma. The purpose of these samples is to quantify circulating biomarkers of neurodegeneration and proteinopathy relevant to Huntington's disease. Plasma will be processed according to standardized protocols to ensure biomarker stability and stored at -80°C until analysis. Plasma biomarkers to be measured include, but are not limited to: Neurofilament light chain (NfL), as an established marker of axonal injury Total tau and phosphorylated tau, to explore tau-related pathology and its contribution to cognitive and neurodegenerative variability Additional exploratory biomarkers of neuronal damage, inflammation, or protein aggregation, depending on assay availability No genetic analyses will be performed on plasma samples. All specimens will be coded to maintain participant confidentiality, stored in secure biorepository facilities, and used exclusively for the objectives specified in the study protocol.

MeSH Terms

Conditions

Huntington Disease; Pick Disease of the Brain

Condition Hierarchy (Ancestors)

Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Dementia; Chorea; Dyskinesias; Movement Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Frontotemporal Dementia; Frontotemporal Lobar Degeneration

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: November 28, 2025
• First Posted: March 31, 2026
• Study Start: September 1, 2021
• Primary Completion: September 1, 2025
• Study Completion (Estimated): July 1, 2026
• Last Updated: March 31, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

ES (1)