Gray Matter Damage Predicts Disability Worsening, Cognitive Decline, and Mortality in Multiple Sclerosis after 26 Years
Massimo Filippi1, Paolo Preziosa2, Alessandro Meani4, Nicolò Tedone3, Irene Gattuso5, Marco Rovaris6, Maria Rocca2
1Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, Neurorehabilitation Unit, and Neurophysiology Service, 2Neuroimaging Research Unit, Division of Neuroscience, and Neurology Unit, 3Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute; and Vita-Salute San Raffaele University, 4Neuroimaging Research Unit, Division of Neuroscience, 5Neurology Unit, IRCCS San Raffaele Scientific Institute, 6IRCCS Fondazione Don Carlo Gnocchi ONLUS
Objective:
To evaluate whether baseline and 12-month changes in lesional, volumetric, and magnetization transfer (MT) MRI measures of white matter (WM) and gray matter (GM) damage predict long-term clinical outcomes in relapse-onset multiple sclerosis (MS).
Background:
GM damage is a critical determinant of disability and cognitive decline in MS, yet its long-term prognostic value remains unclear.
Design/Methods:
Seventy-three MS patients underwent 1.5T brain MRI scans at baseline and after 12 months. Baseline and 12-month changes of T2-hyperintense and T1-hypointense lesion volumes, fractions (F) of GM, WM and thalamus, and MT ratio (MTR) of WM lesions, GM, normal-appearing WM, and thalamus were measured. MS patients were prospectively followed for a median of 25.9 years (IQR=18.1;27.1). A neuropsychological assessment was also performed at follow-up when feasible. Stepwise multivariable logistic regressions identified predictors of Expanded Disability Status Scale (EDSS) score worsening, progression to a more severe disease stage, cognitive decline, and MS-related death.
Results:
At follow-up, 58 (79%) MS patients showed EDSS worsening, 46 (63%) progressed to a more severe disease stage, 18 (25%) died from MS, and 17/43 (40%) exhibited cognitive decline. Lower baseline GM fraction (odds ratio [OR]=0.58; p=0.002), greater 12-month GM MTR decline (OR=0.86; p=0.042), and treatment escalation (OR=6.46; p=0.040) independently predicted EDSS worsening (c-index=0.872). Higher 12-month EDSS score change (OR=6.73, p=0.028), higher 12-month T2-hyperintense WM lesion volume increase (OR=1.20, p=0.069), and lower baseline GMF (OR=0.84, p=0.084) (c-index=0.821) predicted disease phase progression. Higher baseline EDSS score (OR=1.68, p=0.015), lower baseline GMF (OR=0.74, p=0.046), and higher 12-month thalamic MTR percentage decrease (OR=0.92, p=0.049) predicted MS-related death (c-index=0.914). Older age (OR=1.23, p=0.013) and lower baseline GM MTR (OR=0.51, p=0.027) predicted cognitive deterioration (c-index=0.932).
Conclusions:
Atrophy and microstructural abnormalities of the GM predict long-term outcomes in MS. Their use may help identify high-risk patients, inform prognosis, and guide timely use of HE-DMTs.
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