Diffusely Abnormal White Matter in Chronic Multiple Sclerosis: Imaging and Histopathologic Analysis

Abstract

BACKGROUND: Diffuse abnormalities in the white matter (WM), ie, the so-called diffusely abnormal WM (DAWM), as observed on magnetic resonance imaging (MRI), may contribute to the development of clinical disability in multiple sclerosis (MS). Underlying pathologic and MRI characteristics of DAWM are largely unknown. OBJECTIVES: To explore and describe the histopathologic and radiologic characteristics of DAWM in chronic MS. DESIGN: An MRI and histopathologic postmortem correlative study. METHODS: We analyzed 17 formalin-fixed hemispheric brain slices from 10 patients with chronic MS using histopathologic analysis and qualitative and quantitative MRI. A region-of-interest approach was applied to compare radiologically defined DAWM, normal-appearing WM, and focal WM lesions and to correlate quantitative MRI measures with histopathologic findings. MAIN OUTCOME MEASURES: The DAWM consisted of extensive axonal loss, decreased myelin density, and chronic fibrillary gliosis, all of which were substantially abnormal compared with normal-appearing WM and significantly different from focal WM lesion pathology. Increased T1- and T2-relaxation times and decreased fractional anisotropy values were found in DAWM regions of interest, in association with extensive axonal loss and reduced myelin density. Increased T1- and T2-relaxation times were associated with chronic gliosis. CONCLUSIONS: This study classifies DAWM in chronic MS as an abnormality that is different from normal-appearing WM and focal WM lesions, most likely resulting from the cumulative effects of ongoing inflammation and axonal pathology. As such, DAWM is likely to substantially contribute to disease progression and may prove to be an important new disease marker in clinical trials focusing on the neurodegenerative aspects of MS.