Clinicopathological MRI and CSF Correlates in Huntington's Disease.

Clinicopathological MRI and CSF Correlates of Iron Accumulation, Neurodegeneration and Neuroinflammation in Huntington's Disease.

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.

Study Overview

• Status: Recruiting
• Conditions: Huntington Disease
• Intervention / Treatment: Diagnostic test: 7T MRI-scan; Diagnostic test: CSF collection via lumbar puncture; Diagnostic test: Blood withdrawal; Diagnostic test: Clinical measures

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 Type: Observational
• Enrollment (Anticipated): 90

Contacts and Locations

• Study Contact: Name: Nadine van de Zande, MD; Phone Number: 071562131; Email: n.a.van_de_zande@lumc.nl
• Study Contact Backup: Name: Kasper van der Zwaan, drs; Email: k.f.van_der_zwaan@lumc.nl

Study Locations

• Netherlands
  • Zuid-Holland
    • Leiden, Zuid-Holland, Netherlands
      • Recruiting
      • Leiden University Medical Centre
      • Contact: Nadine van de Zande, MD
      • Contact: Kasper van der Zwaan, drs
      • Principal Investigator: Susanne de Bot, MD PhD
      • Sub-Investigator: Nadine van de Zande, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Pre-manifest HD gene carrier:

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

Early-manifest HD gene carrier:

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

Moderate manifest HD gene carrier:

• CAG expansion ≥ 36;
• Diagnostic Confidence Score = 4;
• HD stage II: TFC scores between 7 and 10

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.

Description

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 Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Healthy controls; 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.	Diagnostic test: 7T MRI-scan; MRI-scanning of the brain using a 7T-MRI scanner; Diagnostic test: CSF collection via lumbar puncture; CSF is collected by doing a lumbar puncture; Diagnostic test: Blood withdrawal; Blood is collected by doing a blood withdrawal; Diagnostic test: Clinical measures; UHDRS-Total motor score, UHDRS-short problem behaviour assessment, UHDRS-Cognitive assessments
Premanifest HD expanded gene carrier; HDGEC before clinical onset: TMS <5, DCL <4, TFC = 13. No other major comorbidity.	Diagnostic test: 7T MRI-scan; MRI-scanning of the brain using a 7T-MRI scanner; Diagnostic test: CSF collection via lumbar puncture; CSF is collected by doing a lumbar puncture; Diagnostic test: Blood withdrawal; Blood is collected by doing a blood withdrawal; Diagnostic test: Clinical measures; UHDRS-Total motor score, UHDRS-short problem behaviour assessment, UHDRS-Cognitive assessments
Early Manifest HD patient; HDGEC after clincial onset: TMS >5, DCL = 4. Early stage of disease: TFC 11-13. No other major comorbidity.	Diagnostic test: 7T MRI-scan; MRI-scanning of the brain using a 7T-MRI scanner; Diagnostic test: CSF collection via lumbar puncture; CSF is collected by doing a lumbar puncture; Diagnostic test: Blood withdrawal; Blood is collected by doing a blood withdrawal; Diagnostic test: Clinical measures; UHDRS-Total motor score, UHDRS-short problem behaviour assessment, UHDRS-Cognitive assessments
Moderate Manifest HD patient; HDGEC after clincial onset: TMS >5, DCL = 4. Moderate stage of disease: TFC 7-10. No other major comorbidity.	Diagnostic test: 7T MRI-scan; MRI-scanning of the brain using a 7T-MRI scanner; Diagnostic test: CSF collection via lumbar puncture; CSF is collected by doing a lumbar puncture; Diagnostic test: Blood withdrawal; Blood is collected by doing a blood withdrawal; Diagnostic test: Clinical measures; UHDRS-Total motor score, UHDRS-short problem behaviour assessment, UHDRS-Cognitive assessments

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantified Susceptibility Mapping	MRI analysis to quantify iron accumulation	At baseline
Iron in CSF	Amount of iron and ferritin measured in CSF	At baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Iron in blood	Amount of iron and ferritin measured in blood	At baseline
Clinical motor signs	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.	At baseline
Neuroinflammation and neurodegeneration biomarkers in CSF	a.o.; NFL: pg/mL; CHIT1: pg/mL; IL-6: pg/mL	Baseline
Neuroinflammation and neurodegeneration biomarkers in CSF	- YKL-40: ng/mL	Baseline
Cognitive score	Assessment of cognitive tests.	At baseline
Neuropsychiatric symptoms	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.	At baseline

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: University of Ulm; Brighton & Sussex Medical School
• Investigators: Principal Investigator: Susanne de Bot, MD PhD, Neurology

Study record dates

Study Major Dates

• Study Start (Actual): August 11, 2021
• Primary Completion (Anticipated): August 31, 2023
• Study Completion (Anticipated): August 31, 2024

Study Registration Dates

• First Submitted: August 15, 2022
• First Submitted That Met QC Criteria: September 5, 2022
• First Posted (Actual): September 9, 2022

Study Record Updates

• Last Update Posted (Actual): September 9, 2022
• Last Update Submitted That Met QC Criteria: September 5, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Neuroinflammation; Neurodegeneration; Huntington's Disease; Iron accumulation; Quantified susceptibility mapping; QSM; 7T-MRI; CSF
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Genetic Diseases, Inborn; Basal Ganglia Diseases; Movement Disorders; Neurodegenerative Diseases; Dyskinesias; Heredodegenerative Disorders, Nervous System; Dementia; Cognition Disorders; Chorea; Huntington Disease
• Other Study ID Numbers: P19.030

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No