and neurodegeneration often precede symptom onset in multiple sclerosis (MS).OBJECTIVE To investigate the prevalence of brain magnetic resonance imaging (MRI) and subclinical abnormalities among asymptomatic individuals at risk for MS.
DESIGN, SETTING, AND PARTICIPANTSThe Genes and Environment in Multiple Sclerosis (GEMS) project is a prospective cohort study of first-degree relatives of people with MS. Each participant's risk for MS was assessed using a weighted score (Genetic and Environmental Risk Score for Multiple Sclerosis Susceptibility [GERS MS ]) comprising an individual's genetic burden and environmental exposures. The study dates were August 2012 to July 2015.
MAIN OUTCOMES AND MEASURESParticipants in the top and bottom 10% of the risk distribution underwent standard and quantitative neurological examination, including disability status, visual, cognitive, motor, and sensory testing, as well as qualitative and quantitative neuroimaging with 3-T brain MRI and optical coherence tomography.
RESULTSThis study included 100 participants at risk for MS, with 41 at higher risk (40 women [98%]) and 59 at lower risk (25 women [42%]), at a mean (SD) age of 35.1 (8.7) years. Given the unequal sex distribution between the 2 groups, the analyses were restricted to women (n = 65). When considering all measured outcomes, higher-risk women differed from lower-risk women (P = .01 by omnibus test). Detailed testing with a vibration sensitivity testing device in a subgroup of 47 women showed that higher-risk women exhibited significantly poorer vibration perception in the distal lower extremities (P = .008, adjusting for age, height, and testing date). Furthermore, 5 of 65 women (8%) (4 at higher risk and 1 at lower risk) met the primary neuroimaging outcome of having T2-weighted hyperintense brain lesions consistent with the 2010 McDonald MRI criteria for dissemination in space. A subset of participants harbor many different neuroimaging features associated with MS, including perivenous T2-weighted hyperintense lesions and focal leptomeningeal enhancement, consistent with the hypothesis that these individuals are at higher risk of developing clinical symptoms of MS than the general population.CONCLUSIONS AND RELEVANCE Higher-risk asymptomatic family members of patients with MS are more likely to have early subclinical manifestations of MS. These findings underscore the importance of early detection in high-risk individuals.TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01353547
Background
MRI measures sensitive to myelin integrity such as the T1/T2 weighted ratio method (T1w/T2w; Glasser & Van Essen 2011) have been investigated as potential AD biomarkers. Many cohorts have transitioned to T1 and T2‐weighted Fluid Attenuated Inversion Recovery (FLAIR) acquisitions. Our goal was to validate the T1w/T2FLAIRw method in comparison to the T1w/T2w method in the same cohort.
Method
28 cognitively unimpaired (CU, cognitively normal and subjective cognitive decline) and 26 AD‐related cognitively impaired (CI, mild cognitive impairment and AD) individuals were analyzed to determine the correlative validity of association between T1w/T2FLAIRw and T1w/T2w methods. Image processing algorithms were designed in‐house for application to AD, building on previous methods and implemented in SPM12. White matter regions of interest (ROIs) from the Johns Hopkins ICBM‐DTI‐81 white‐matter labels atlas were masked excluding cerebrospinal fluid and white matter hyperintensities. Pearson correlation was used to test associations between the canonical method and our extension. Then, diagnostic group differences were assessed using regional independent sample T‐tests, with Bonferroni correction for independent components (8 independent factors identified by PCA of all white matter tracts).
Result
Myelinated regions associated with cognitive decline, as well as all other atlas ROIs, demonstrated significant (p <.01) positive correlations between T1w/T2w and T1w/T2FLAIR values (r values between .590 and .915) with the exception of the fornix, which was significant at the .05 level in CU. Between‐group analyses using T1w/T2FLAIRw showed lower ratios (reflecting reduced myelin) in CI. Significant differences in group T1w/T2FLAIRw ratios were seen in the left hippocampal cingulum (left, p=.011; right, p=.024), uncinate fasciculus (left, p=.007; right, p=.015), and the right anterior limb of the internal capsule (p=.019) and superior fronto‐occipital fasciculus (p=.011). After Bonferroni correction only the left hippocampal cingulum, left uncinate fasciculus and right superior fronto‐occipital fasciculus approached significance (p = .088; .088; .056 respectively).
Conclusion
Results suggest T1w/T2FLAIRw is a valid alternative to T1w/T2w ratios. Between groups, T1w/T2FLAIRw pointed towards lower myelin in intersecting white matter tracts in cognitively impaired individuals. Although initial results appear promising with reasonably large effect sizes, a larger sample needs to be assessed to provide sufficient statistical power to effectively assess the proposed method.
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