Gray Matter Matters: A Longitudinal Magnetic Resonance Voxel-Based Morphometry Study of Primary Progressive Multiple Sclerosis

Background: Multiple Sclerosis (MS) lesions in white matter (WM) are easily detected with conventional MRI which induce inflammation thereby generating contrast. WM lesions do not consistently explain the extent of clinical disability, cognitive impairment, or the source of an exacerbation. Gray matter (GM) structures including the cerebral cortex and various deep nuclei are known to be affected early in Primary Progressive Multiple Sclerosis (PPMS) and drive disease progression, disability, fatigue, and cognitive dysfunction. However, little is known about how rapidly GM lesions develop and accumulate over time. Objective: The purpose of this study is to analyze the degree and rate of progression in 25 patients with PPMS using voxel-based automated volumetric quantitation. Methods: This is a retrospective single-center study which includes a cohort of 25 patients with PPMS scanned utilizing NeuroQuant® 3 dimensional voxel-based morphometry (3D VBM) automated analysis and database and restudied after a period of ~1 year (11–14 months). Comparisons with normative data were acquired for whole brain, forebrain parenchyma, cortical GM, hippocampus, thalamus, superior and inferior lateral ventricles. GM volume changes were correlated with their clinical motor and cognitive scores using Extended Disability Status Scales (EDSS) and Montreal Cognitive Assessments (MoCA). Results: Steep reductions occurred in cerebral cortical GM and deep GM nuclei volumes which correlated with each patient's clinical and cognitive impairment. The median observed percentile volume losses were statistically significant compared with the 50th percentile for each GM component. Longitudinal assessments of an unselected sample of one dozen patients involved in the PPMS study showed prominent losses occurring mainly in cortical GM and hippocampus which were reflected in their EDSS and MoCA. The longitudinal results were compared with a similar sample of patients having Relapsing MS (RMS) whose GM values were largely in normal range, annualized volume GM changes were much less, while WM hyperintensities were in abnormal range in half the unselected cases. Conclusions: Knowledge of the degree and rapidity with which cortical atrophy and deep GM volume loss develops clarifies the source of progressive cognitive and clinical decline in PPMS.