Risk Factors in Early Multiple Sclerosis

Recruiting

• Conditions: Clinically Isolated Syndrome; Biomarkers; Multiple Sclerosis; Magnetic Resonance Imaging; Radiologically Isolated Syndrome
• Interventions: Diagnostic Test: Brain MRI

• Registration Number: NCT03586986
• Lead Sponsor: University of Colorado, Denver

Brief Summary

The central hypothesis of this protocol is that it is possible, using First Degree Relatives (FDRs) of patients with Multiple Sclerosis (MS) and assessing a variety of both known and unknown risk factors for MS, to define a risk algorithm for earliest signs of development of MS. The plan will be to do an abbreviated brain Magnetic Resonance Imaging (MRI) scan in asymptomatic, young FDRs, analyze blood for a variety of immunological, genetic, neuroaxonal damage, metabolic, viral serology and other markers, and have FDRs fill out a detailed bioscreen questionnaire about lifestyle factors and perform a cognitive screening test. The investigators will then compare the results of the various blood/other studies in FDRs with and without an MRI showing signs signs concerning for MS, as well as age-and sex-matched NON-FDRs who will have blood drawn and fill out the questionnaire. With this preliminary cross-sectional study, the investigators hope to begin to identify a risk stratification model for those at highest risk of developing MS, ie FDRs, with a long-term goal of developing a longitudinal study to increase sensitivity and specificity of the risk model.

Detailed Description

Specific Aims, among asymptomatic first degree relatives (FDRs), aged 18-30, of multiple sclerosis (MS) patients:

1. Determine the prevalence of brain MRI lesions disseminated in space (DIS), consistent with MS

2. Gather data on potential risk factors or early signs related to MS development, including markers for: genes, immunological function, environmental factors, neuroaxonal damage, Vitamin D levels, lipid metabolism, activity levels, mood abnormalities, and cognitive function. From this, develop a risk factor score, incorporating all relevant potential markers of increased risk of DIS.

3. To use this pilot, cross-sectional study as a base for development of a long-term, longitudinal, multi-center study to determine genetic and environmental risks for pre-symptomatic MS

4. To create and maintain a biobank of specimens for future analysis as other potential biomarkers become available.

5. Evaluate for potential dissemination in time (DIT) and dissemination in space (DIS) in asymptomatic FDRs through longitudinal assessment.

Sequences to include

1. Whole brain T1-weighted images acquired using 3-Dimensional fast spoiled-gradient recalled acquisitions (T1-3D-FSPGR) with 1 mm slice thickness and isotropic voxel dimensions.

2. Whole brain 3-Dimensional Double Inversion Recovery (DIR) acquisition with 1.5 mm slice thickness.

3. Whole brain T2-weighted Fluid Attenuated Inversion Recovery (FLAIR ) images with 1 mm slice thickness and isotropic voxel dimensions will be combined with

4. Whole brain T2\*-weighted segmented echo-planar imaging (segEPI) images with \<=1 mm slice thickness and isotropic voxel dimensions to obtain FLAIR\* images.

Blood analysis for:

1. Single Nucleotide Polymorphism analysis of greater than 200 known mutations associated with risk of MS, and do an human leukocyte antigen (HLA) analysis

2. CD20 on CD4+ cell analysis

3. B Cell Anergy analysis Lipid levels

4. Viral serologies (HSV, EBV, CMV, VZV)

5. Neurofilament Light

6. Vitamin D levels

Bioscreen analysis based on that from the Diabetes Autoimmunity Study in the Young (DAISY); and to include the Godin Leisure-Time Exercise Questionnaire (GLTEQ), which has been validated in both adults and children and a validated dietary/food frequency questionnaire. In addition perform a cognitive screen with a Symbol Digit Modality test.

Blood will also be stored for future potential analysis, including peripheral blood mononuclear cells, serum, and Ribonucleic acid (RNA).

Study Timeline

• Study First Submitted: 2018-05-15
• Study First Submitted QC: 2018-07-12
• Study First Posted: 2018-07-16
• Study Start: 2018-07-26
• Status Verified: 2023-02
• Last Update Submitted: 2023-02-02
• Last Update Posted: 2023-02-06
• Primary Completion: 2024-05
• Study Completion: 2024-05

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 300

Inclusion Criteria

• FDR Inclusion Criteria

  1. Male and female
  2. All races and ethnicities
  3. Ages 18-30
  4. Must have a parent, sibling or child with MS fulfilling McDonald 2017 criteria
  5. No symptoms suggestive of MS on formal screen
  6. Ability to undergo a non-contrast MRI and venipuncture, and perform an environmental screen, mood screen and cognitive test

• Non-FDR Inclusion Criteria

  1. Male and female
  2. All races and ethnicities
  3. Ages 18-30
  4. Must NOT have a FDR (parent, sibling, child) or second degree relative (grandparent, aunt or uncle) with MS fulfilling McDonald 2017 criteria
  5. No symptoms suggestive of MS on formal screen
  6. Ability to undergo venipuncture and perform an environmental screen.

Exclusion Criteria

• FDR Exclusion Criteria

  1. Symptoms suggestive of MS on formal screen
  2. Prior diagnosis of autoimmune disease that may be associated with CNS dysfunction and MRI lesions, e.g. Sjogren's

• Non-FDR Exclusion Criteria

  1. Symptoms suggestive of MS on formal screen
  2. Prior diagnosis of autoimmune disease that may be associated with CNS dysfunction and MRI lesions, e.g. Sjogren's

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
FDR with abnormal brain MRI	Brain MRI	First degree relatives fulfilling lesions disseminated in space on MRI
FDR with normal brain MRI	Brain MRI	First degree relatives not fulfilling lesions disseminated in space on MRI

Primary Outcome Measures

Name	Time	Method
Discovery of Lesions disseminated in space on brain MRI	At the subject's Initial Visit	Lesions disseminated in space on brain MRI. The presence or absence of these lesions will only be measured once at the initial visit.

Secondary Outcome Measures

Name	Time	Method
Define risk stratification algorithm for prediction of MS	Within 4 months of the Initial Visit	The investigators will evaluate cognitive functions using University of Colorado's NeuroQol Anxiety Scale, with the goal of defining an expanded risk stratification scheme. This assessment will be used to measure anxiety domains, with the highest raw score of 40 representing worse (undesirable) self-reported anxiety, and a raw score of 8 representing better (desirable) self-reported anxiety. These raw scores will be converted to T-scores, with 36.4 being the minimum and 76.8 being the maximum T-score.

Trial Locations

Locations (1)

University of Colorado Anschutz Medical Campus; 🇺🇸 Aurora, Colorado, United States