Clinical Study to Monitor Plasma Levels of 24OHC in Subject with HD

Completed

• Conditions: Huntington Disease
• Interventions: Diagnostic Test: Brain MRI

• Registration Number: NCT04257513
• Lead Sponsor: Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta

Brief Summary

A 2-year clinical longitudinal study to measure plasma concentrations of 24S-hydroxycholesterol, a brain-derived cholesterol catabolite, in subjects with Huntington disease, from the presymptomatic to the symptomatic stages.

Detailed Description

In cross-sectional studies, the plasma level of brain-derived 24S-hydroxycholesterol (24OHC) has been found to be significantly diminished in HD patients from the first stages of the disease. Furthermore, in HD gene-positive pre-symptomatic (pre-HD) the plasma levels can predict the development of motor signs of disease in subjects closer to onset, better than in subjects far from onset. These data suggest that circulating 24OHC might be a candidate biomarker for phenotypic conversion and for disease progression in different stages of the disease.

Detailed neurological, cognitive and imaging data and blood samples will be collected at baseline, and after two years to investigate the rate of changes along the longitudinal study. Isotope dilution mass spectrometry (assay performed at Istituto di Ricerche Farmacologiche Mario Negri IRCCS) will be used to measure the plasma levels of brain-derived 24OHC and other sterols reflecting peripheral cholesterol synthesis. The investigators expect to establish whether changes in plasma 24OHC mark disease progression and, eventually, phenoconversion from pre-symptomatic to symptomatic stages in combination with clinical, cognitive and imaging parameters.

Study Timeline

• Study Start: 2019-10-31
• Study First Submitted: 2020-01-31
• Study First Submitted QC: 2020-02-03
• Study First Posted: 2020-02-06
• Primary Completion: 2023-03-06
• Study Completion: 2023-06-02
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-08
• Last Update Posted: 2024-11-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

Symptomatic HD subjects

1. Age ≥ 18 years
2. Known family history of HD and genetically confirmed disease by direct DNA test (CAG expansion > 35 repeats)
3. Clinical diagnostic motor features of HD, defined as score> 5 at the motor Unified Huntington Disease Rating Scale (mUHDRS)
4. Stage I or II or III HD, defined as UHDRS Total Functional Capacity (TFC) scores between 3 and 13 inclusive (Marder, 2000)

Presymptomatic HD subjects

1. Age ≥ 18 years
2. Known family history of HD and genetically confirmed mutation by direct DNA test (CAG expansion > 35 repeats)
3. Absence of clinical motor features of HD, defined as mUHDRS rating scale ≤ 5

Healthy Subjects

1. Age ≥ 18 years
2. Absence of known family history of HD or genetically confirmed negative DNA test for HD (CAG expansion ≤ 35 repeats)
3. Absence of clinical motor features of HD, defined as mUHDRS rating scale ≤ 5

Exclusion Criteria

1. Participation in clinical pharmacological trials
2. Inability to undergo and tolerate MRI scans (e.g. claustrophobia, severe chorea, MRI-incompatible intrauterine devices, metal implants, ect)
3. Inability or unwillingness to undertake any of the study procedures

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Healthy controls subjects	Brain MRI	Subjects without known family history of HD, or tested negative for the HD expansion mutation.
Presymptomatic HD subjects:	Brain MRI	Subjects HD gene expansion carriers who not have clinical diagnostic motor features of HD.
Symptomatic HD subjects	Brain MRI	Subjects HD gene expansion carriers who have clinical diagnostic motor symptoms of defined HD, and disease stage I to III.

Primary Outcome Measures

Name	Time	Method
plasmatic 24OHC levels	at baseline and after 2-years follow up visit	Changes in plasmatic 24OHC levels measured

Secondary Outcome Measures

Name	Time	Method
Changes in the score of the Unified Huntington Disease Rating Scale (UHDRS)	after 2-years follow up visit	The concentration of 24OHC will be correlated with clinical evaluation to the stage of the disease and its progression.
Changes in score at the Digit Symbol Modalities Test (DSMT)	after 2-years follow up visit	The concentration of 24OHC will be correlated with cognitive evaluation to the stage of the disease and its progression.
Changes in caudate nucleus volume measured at MRI	after 2-years follow up visit	The concentration of 24OHC will be correlated with Imaging the stage of the disease and its progression.

Trial Locations

Locations (1)

UOC Genetica Medica e Neurogenetica; 🇮🇹 Milano, Italy