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MRI phenotypes in MS: Longitudinal changes and miRNA signatures
Christopher C Hemond1, Brian C Healy1, Shahamat Tauhid1
1Departments of Neurology (C.C.H., B.C.H., S.T., M.A.M., F.J.Q., R.G., H.L.W, R.B.) and Department of Radiology (R.B.); Brigham and Women's Hospital (C.C.H., B.C.H., S.T., M.A.M., F.J.Q., R.G., H.L.W, R.B.); Laboratory for Neuroimaging Research (C.C.H., S.T., R.H.); Partners Multiple Sclerosis Center (C.C.H., B.C.H., S.T., M.A.M., F.J.Q., R.G., H.L.W, R.B.); Ann Romney Center for Neurologic Diseases (C.C.H., B.C.H., S.T., M.A.M., F.J.Q., R.G., H.L.W, R.B.); and Harvard Medical School (C.C.H., B.C.H., S.T., M.A.M., F.J.Q., R.G., H.L.W., R.B.), Boston, MA.
Objective:
To classify and immunologically characterize persons with MS based on brain lesions and atrophy and their associated microRNA profiles.
Methods:
Cerebral T2-hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) were quantified and used to define MRI phenotypes as follows: type I: low T2LV, low atrophy; type II: high T2LV, low atrophy; type III: low T2LV, high atrophy; type IV: high T2LV, high atrophy, in a large cross-sectional cohort (n = 1,088) and a subset with 5-year lngitudinal follow-up (n = 153). Serum miRNAs were assessed on a third MS cohort with 2-year MRI phenotype stability (n = 98).
Results:
One-third of the patients had lesion-atrophy dissociation (types II or III) in both the cross-sectional and longitudinal cohorts. At 5 years, all phenotypes had progressive atrophy (p < 0.001), disproportionally in type II (BPF -2.28%). Only type IV worsened in physical disability. Types I and II showed a 5-year MRI phenotype conversion rate of 33% and 46%, whereas III and IV had >90% stability. Type II switched primarily to IV (91%); type I switched primarily to II (47%) or III (37%). Baseline higher age (p = 0.006) and lower BPF (p < 0.001) predicted 5-year phenotype conversion. Each MRI phenotype demonstrated an miRNA signature whose underlying biology implicates blood-brain barrier pathology: hsa.miR.22.3p, hsa.miR.361.5p, and hsa.miR.345.5p were the most valid differentiators of MRI phenotypes.
Conclusions:
MRI-defined MS phenotypes show high conversion rates characterized by the continuation of either predominant neurodegeneration or inflammation and support the partial independence of these 2 measures. MicroRNA signatures of these phenotypes suggest a role for blood-brain barrier integrity.
Insights
Multiple sclerosis (MS) brain imaging phenotypes show distinct progression patterns and microRNA signatures, suggesting a role for blood-brain barrier integrity in disease course.
Area of Science:
- Neurology
- Immunology
- Biomarker Discovery
Background:
- Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system.
- Brain lesions and atrophy are key indicators of MS progression.
- Understanding distinct MS phenotypes is crucial for targeted treatment strategies.
Purpose of the Study:
- To classify and immunologically characterize individuals with MS based on brain lesion and atrophy patterns.
- To identify associated microRNA (miRNA) profiles for each MRI-defined phenotype.
- To investigate the dynamic changes and conversion rates between phenotypes over time.
Main Methods:
- Quantified cerebral T2-hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) in a large cohort of MS patients.
- Defined four MRI phenotypes (I-IV) based on T2LV and atrophy levels.
- Assessed serum miRNAs in a separate cohort with stable MRI phenotypes.
Main Results:
- One-third of patients exhibited lesion-atrophy dissociation.
- All phenotypes showed progressive atrophy over 5 years, with Type II exhibiting the most significant BPF reduction.
- Type IV was the only phenotype to worsen in physical disability.
- Phenotypes I and II had higher conversion rates (33% and 46%) compared to III and IV (>90% stability).
- Age and baseline BPF predicted 5-year phenotype conversion.
- Distinct miRNA signatures were identified for each MRI phenotype, with hsa.miR.22.3p, hsa.miR.361.5p, and hsa.miR.345.5p being key differentiators.
Conclusions:
- MRI-defined MS phenotypes demonstrate dynamic conversion patterns, reflecting distinct underlying pathological processes (neurodegeneration vs. inflammation).
- The identified miRNA signatures suggest a role for blood-brain barrier integrity in MS pathogenesis and progression.
- These findings support the partial independence of neurodegeneration and inflammation measures in MS.
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