Clinicopathological MRI and CSF Correlates in Huntington's Disease.

Recruiting

• Conditions: Huntington Disease
• Interventions: Diagnostic Test: 7T MRI-scan; Diagnostic Test: CSF collection via lumbar puncture; Diagnostic Test: Blood withdrawal; Diagnostic Test: Clinical measures

• Registration Number: NCT05534139
• Lead Sponsor: Leiden University Medical Center

Brief Summary

In this study the investigators will link brain iron levels obtained from quantitative susceptibility maps of HD patients with specific and well-known clinical CSF markers for iron accumulation, neurodegeneration and neuroinflammation. The relationship between iron accumulation and neuroinflammation, and the clinical and genetic characteristics of HD will be investigated. This will provide an important basis for the evaluation of brain iron levels as an imaging biomarker for disease state in HD and their relationship with the salient pathomechanisms of the disease.

Detailed Description

This investigator-initiated, single-site cross-sectional study looks at iron accumulation using 7T MR-imaging, CSF and blood. This will be achieved in a two-day visit involving clinical assessments, MRI-scanning of the brain, followed by a lumbar puncture the next day, after overnight fasting. Sixty-five volunteers with HD and 25 volunteers without HD will be included. Of these 65 volunteers with HD, 25 will be premanifest, 20 early manifest and 20 moderate manifest, in order to cover the wide-spectrum of Huntington's Disease.

Study Timeline

• Study Start: 2021-08-11
• Study First Submitted: 2022-08-15
• Status Verified: 2022-09
• Study First Submitted QC: 2022-09-05
• Last Update Submitted: 2022-09-05
• Study First Posted: 2022-09-09
• Last Update Posted: 2022-09-09
• Primary Completion: 2023-08-31
• Study Completion: 2024-08-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 90

Inclusion Criteria

• Native Dutch/Flemish speaker
• Ability to undergo MRI scanning;
• Written informed consent must be obtained from the participant.

And in addition:

If the participant is a pre-manifest HD gene carrier:

• CAG expansion ≥ 40;
• UHDRS Total Motor Score (TMS) ≤ 5;
• Total Functional Capacity (TFC) = 13;
• Diagnostic Confidence Score < 4.

If the participant is an early-manifest HD gene carrier:

• CAG expansion ≥ 36;
• Diagnostic Confidence Score = 4;
• HD stage I: TFC scores between 11 and 13 inclusive.

If the participant is a moderate manifest HD gene carrier:

• CAG expansion ≥ 36;
• Diagnostic Confidence Score = 4;
• HD stage II: TFC scores between 7 and 11 inclusive.

If the participant is a control subject:

• Partner/spouse of a patient not at risk of HD OR sibling with genetic test results available that show a normal CAG repeat length for both HTT alleles (<36);
• No other known cognitive, neurological or psychiatric disorders.

Exclusion Criteria

• Additional major comorbidities not related to HD (e.g. cardiovascular diseases, coagulopathy, hypertension, diabetes mellitus, and/or other neurological disorders);

• History of severe head injury;

• Status of the participant after brain surgery;

• Past erythrocyte transfusions;

• Use of investigational drugs or participation in a clinical drug trial within 30 days prior to study visit;

• Current intoxication, drug or alcohol abuse or dependence;

• Pregnancy;

• Inability to understand the information about the protocol;

• Severe physical restrictions (completely wheelchair dependent);

• Severe chorea that, in the investigator's judgment, precludes the patient's participation in and completion of the MRI and/or lumbar puncture.

• Contra-indication to MRI scanning, such as:

  • Claustrophobia;
  • Pacemakers and defibrillators;
  • Nerve stimulators;
  • Intracranial clips;
  • Intraorbital or intraocular metallic fragments;
  • Cochlear implants;
  • Ferromagnetic implants;
  • Hydrocephalus pump;
  • Intra-utrine device (not all types);
  • Permanent make-up;
  • Tattoos above the shoulders (not all).

• Contraindications for a lumbar puncture, including:

  • Screening blood test results outside normal ranges(white cell count, neutrophil count, lymphocyte count, hemoglobin, platelets, Prothrombin time (PT), activated partial thromboplastin time (APTT), C-reactive protein (CRP) and serum ferritin) if only marginally decreased or increased this will be decided by the clinical PI;
  • Signs and symptoms of increased intracranial pressure which will be confirmed on the 7T MRI (T1 and FLAIR scan) or by a fundoscopy;
  • Local infections of the skin;
  • Use of anti-coagulant drugs within the last 14 days prior lumbar puncture.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Healthy controls	CSF collection via lumbar puncture	Partner/spouse of a patient not at risk of HD OR sibling with genetic test results available that show a normal CAG repeat length for both HTT alleles (\<36); No other known cognitive, neurological or psychiatric disorders.
Early Manifest HD patient	CSF collection via lumbar puncture	HDGEC after clincial onset: TMS \>5, DCL = 4. Early stage of disease: TFC 11-13. No other major comorbidity.
Moderate Manifest HD patient	7T MRI-scan	HDGEC after clincial onset: TMS \>5, DCL = 4. Moderate stage of disease: TFC 7-10. No other major comorbidity.
Healthy controls	7T MRI-scan	Partner/spouse of a patient not at risk of HD OR sibling with genetic test results available that show a normal CAG repeat length for both HTT alleles (\<36); No other known cognitive, neurological or psychiatric disorders.
Healthy controls	Blood withdrawal	Partner/spouse of a patient not at risk of HD OR sibling with genetic test results available that show a normal CAG repeat length for both HTT alleles (\<36); No other known cognitive, neurological or psychiatric disorders.
Premanifest HD expanded gene carrier	Clinical measures	HDGEC before clinical onset: TMS \<5, DCL \<4, TFC = 13. No other major comorbidity.
Moderate Manifest HD patient	Blood withdrawal	HDGEC after clincial onset: TMS \>5, DCL = 4. Moderate stage of disease: TFC 7-10. No other major comorbidity.
Premanifest HD expanded gene carrier	7T MRI-scan	HDGEC before clinical onset: TMS \<5, DCL \<4, TFC = 13. No other major comorbidity.
Premanifest HD expanded gene carrier	Blood withdrawal	HDGEC before clinical onset: TMS \<5, DCL \<4, TFC = 13. No other major comorbidity.
Early Manifest HD patient	7T MRI-scan	HDGEC after clincial onset: TMS \>5, DCL = 4. Early stage of disease: TFC 11-13. No other major comorbidity.
Early Manifest HD patient	Clinical measures	HDGEC after clincial onset: TMS \>5, DCL = 4. Early stage of disease: TFC 11-13. No other major comorbidity.
Moderate Manifest HD patient	CSF collection via lumbar puncture	HDGEC after clincial onset: TMS \>5, DCL = 4. Moderate stage of disease: TFC 7-10. No other major comorbidity.
Early Manifest HD patient	Blood withdrawal	HDGEC after clincial onset: TMS \>5, DCL = 4. Early stage of disease: TFC 11-13. No other major comorbidity.
Healthy controls	Clinical measures	Partner/spouse of a patient not at risk of HD OR sibling with genetic test results available that show a normal CAG repeat length for both HTT alleles (\<36); No other known cognitive, neurological or psychiatric disorders.
Premanifest HD expanded gene carrier	CSF collection via lumbar puncture	HDGEC before clinical onset: TMS \<5, DCL \<4, TFC = 13. No other major comorbidity.
Moderate Manifest HD patient	Clinical measures	HDGEC after clincial onset: TMS \>5, DCL = 4. Moderate stage of disease: TFC 7-10. No other major comorbidity.

Primary Outcome Measures

Name	Time	Method
Iron in CSF	At baseline	Amount of iron and ferritin measured in CSF
Quantified Susceptibility Mapping	At baseline	MRI analysis to quantify iron accumulation

Secondary Outcome Measures

Name	Time	Method
Neuroinflammation and neurodegeneration biomarkers in CSF	Baseline	- YKL-40: ng/mL
Cognitive score	At baseline	Assessment of cognitive tests.
Iron in blood	At baseline	Amount of iron and ferritin measured in blood
Clinical motor signs	At baseline	Motor signs obtained using the Unified Huntington's Disease Rating Scale - Total Motor Score. This is a scale assessing motor symptoms of HD, ranging from a score of 0 to 124, where higher scores mean a worse outcome.
Neuropsychiatric symptoms	At baseline	Assessment of short Problem Behaviour Assessment. Each symptom is rated for severity on a 5-point scale : 0 = "not at all"; 1 = trivial; 2 = mild; 3 = moderate (disrupting everyday activities) and 4 = severe or intolerable. Each symptom is also scored for frequency on a 5-point scale as follows: 0 = symptom absent; 1 = less than once weekly; 2 = at least once a week; 3 = most days (up to and including some part of everyday); and 4 = all day, every day. Severity and frequency scores are multiplied to produce an overall 'PBA score' for each symptom.

Trial Locations

Locations (1)

Leiden University Medical Centre; 🇳🇱 Leiden, Zuid-Holland, Netherlands