Neuroimaging assessment of facility-bound severely-affected MS reveals the critical role of cortical gray matter pathology: results from the CASA–MS case-controlled study

Background: A subgroup of people with multiple sclerosis (pwMS) will develop severe disability. The pathophysiology underlying severe MS is unknown. The comprehensive assessment of severely affected MS (CASA–MS) was a case-controlled study that compared severely disabled in skilled nursing (SD/SN) (EDSS ≥ 7.0) to less-disabled (EDSS 3.0–6.5) community dwelling (CD) progressive pwMS, matched on age-, sex- and disease-duration (DDM). Objectives: To identify neuroimaging and molecular biomarker characteristics that distinguish SD/SN from DDM–CD progressive pwMS. Methods: This study was carried at SN facility and at a tertiary MS center. The study collected clinical, molecular (serum neurofilament light chain, sNfL and glial acidic fibrillary protein, sGFAP) and MRI quantitative lesion-, brain volume-, and tissue integrity-derived measures. Statistical analyses were controlled for multiple comparisons. Results: 42 SD/SN and 42 DDM–CD were enrolled. SD/SN pwMS showed significantly lower cortical volume (CV) (p < 0.001, d = 1.375) and thalamic volume (p < 0.001, d = 0.972) compared to DDM–CD pwMS. In a logistic stepwise regression model, the SD/SN pwMS were best differentiated from the DDM–CD pwMS by lower CV (p < 0.001) as the only significant predictor, with the accuracy of 82.3%. No significant differences between the two groups were observed for medulla oblongata volume, a proxy for spinal cord atrophy and white matter lesion burden, while there was a statistical trend for numerically higher sGFAP in SD/SN pwMS. Conclusions: The CASA–MS study showed significantly more gray matter atrophy in severe compared to less-severe progressive MS.