Relating Genetic and Environmental Risk Scores to Multiple Sclerosis Susceptibility

Objective. The overall objective of this study is to investigate the genetic, immune, and neuroimaging profiles that may increase a person s risk of developing multiple sclerosis (MS) in order to identify and validate predictive biomarkers in populations at risk for this disorder. Study population. There will be three study populations: 1. Individuals at risk for developing MS As part of the Genes and Environment in Multiple Sclerosis (GEMS) study, we plan to recruit up to 1000 first-degree relatives of MS patients. GEMS is a study aiming to recruit 5000 individuals that is being led by our collaborators at Columbia University Medical Center. For the purposes of this study, a first-degree relative may be a parent, sibling, or child between 18 and 50 years of age but must not carry a diagnosis of MS. The first-degree relative must have the ability to provide consent and be willing to participate in the study. Two potentially overlapping subsets of these individuals will undergo detailed testing at the NIH: 1. The cross-sectional subcohort will consist of up to 150 participants with combined genetic and environmental risk scores (GERS), defined in the protocol, in the highest and lowest 20 percent of the entire study population. Selected participants may be invited for follow-up studies based on data obtained at baseline if symptoms develop. 2. The NINDS longitudinal subcohort will consist of up to 10 participants, ages 18 to 40,who express willingness to be followed for 20 years at the NIH, whose GERS falls in the top 20 percent of the entire study population, and who have a first-degree relative with MS who is participatipate 2. MS patients - We plan to recruit up to 1000 MS patients whose first-degree relatives are enrolled this study. These participants either: (A) will be evaluated under other Neuroimmunology Branch Clinic protocols and will not undergo separate evaluation under this protocol; or (B) will send us medical records confirming their MS diagnosis via mail/fax/secure email, without the requirement to participate in another NIH protocol. The purpose of including this cohort in the current study is to allow access to their clinical, biological, and imaging data for comparison with first-degree relatives, if available, and to confirm that existing GEMS participants have a first-degree relative diagnosed with MS. 3. Healthy volunteers - We plan to recruit up to 80 healthy volunteers, ages 18-50, who do not have a known first-degree relative with MS. The purpose of including this cohort in the current study is to allow quantification of the degree and extent of abnormalities, including abnormalities of the blood-brain barrier, in individuals at risk for developing MS. Without imaging data obtained from healthy volunteers, there is no way to determine whether subtle clinical and neuroimaging findings in the at-risk cohort are truly abnormal, or to correctly threshold and quantify the observed abnormalities. Design. This is a prospective cohort natural-history study. All GEMS participants will complete the following study procedures, which can be performed offsite: informed consent; study questionnaire; saliva sample; and blood draw. The questionnaire will be repeated 1 year after enrollment. There will two additional substudies conducted at NIH: a cross-sectional substudy and a longitudinal substudy. Participants in these substudies will be evaluated with clinical, radiological, and laboratory procedures. Participants in the cross-sectional cohort will undergo evaluation at the NIH at a single time point (with optional longitudinal follow up), whereas participants in the longitudinal cohort will undergo evaluation at the NIH for 20 years. There will be an interim analysis 5 years after the 50th participant is recruited to the longitudinal cohort, and the study of this cohort may be terminated if we have not observed the development of MS-related radiological or laboratory abnormalities in any of the participants. Participants with MS will provide informed consent to allow access to their own research data, but the data themselves will be (or will have already been) collected under other Neuroimmunology Clinic clinical protocols. NIH is a unique site within the overall GEMS study, for the following reasons: (1) It is the only site at which imaging is being performed, as part of the cross-sectional and longitudinal substudies; (2) GEMS participants seen at NIH may undergo additional procedures that are not part of the overall GEMS study; (3) Data from participants in the NIH substudy will be directly linked to data from their own relatives with MS. Outcome measures. For participants in the overall GEMS study, the primary outcome measure is the GERS itself, as most participants in this cohort will not undergo further testing. For participants in the cross-sectional cohort, which consists of individuals at highest and lowest risk for MS, the primary outcome measure is the presence or absence of lesions on T2-weighted brain MRI that meet the 2010 MRI criteria for dissemination in space - a finding that, in this population, may well be related to MS. For participants in the longitudinal cohort, the study endpoint is a clinical diagnosis of MS according to the same 2010 criteria. Secondary outcome measures include: (1) The age at which participants develop MS-related abnormalities on brain imaging studies, abnormalities on laboratory testing, and clinical symptoms and signs; (2) The time lag between defined exposures (for example, infectious mononucleosis) and the appearance of MS-related radiological, laboratory, and clinical abnormalities; (3) The time lag between the appearance of asymptomatic radiological and laboratory abnormalities and the onset of clinical symptoms; and (4) Additional exploratory clinical, imaging, and biological data in the crosssectional that may suggest subclinical MS disease activity.