Clinicopathological MRI and CSF Correlates in Huntington's Disease.

Huntington Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05534139
• Other study ID #: P19.030
• Status: Recruiting
• Start date: August 11, 2021
• Est. completion date: August 31, 2024

Study information

• Verified date: September 2022
• Source: Leiden University Medical Center
• Contact: Nadine van de Zande, MD
• Phone: 071562131
• Email: n.a.van_de_zande[@]lumc.nl
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 90
• Est. completion date: August 31, 2024
• Est. primary completion date: August 31, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 21 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Huntington Disease

Intervention

Diagnostic Test:
• 7T MRI-scan
MRI-scanning of the brain using a 7T-MRI scanner
• CSF collection via lumbar puncture
CSF is collected by doing a lumbar puncture
• Blood withdrawal
Blood is collected by doing a blood withdrawal
• Clinical measures
UHDRS-Total motor score, UHDRS-short problem behaviour assessment, UHDRS-Cognitive assessments

Locations

Country	Name	City	State
Netherlands	Leiden University Medical Centre	Leiden	Zuid-Holland

Sponsors (3)

Lead Sponsor	Collaborator
Leiden University Medical Center	Brighton & Sussex Medical School, University of Ulm

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Quantified Susceptibility Mapping	MRI analysis to quantify iron accumulation	At baseline
Primary	Iron in CSF	Amount of iron and ferritin measured in CSF	At baseline
Secondary	Iron in blood	Amount of iron and ferritin measured in blood	At baseline
Secondary	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
Secondary	Neuroinflammation and neurodegeneration biomarkers in CSF	a.o.; NFL: pg/mL; CHIT1: pg/mL; IL-6: pg/mL	Baseline
Secondary	Neuroinflammation and neurodegeneration biomarkers in CSF	- YKL-40: ng/mL	Baseline
Secondary	Cognitive score	Assessment of cognitive tests.	At baseline
Secondary	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