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Updated: Jun 23, 2026
Comprehensive Autopsy Program for Individuals with Multiple Sclerosis
Published on: July 19, 2019
Diffusely abnormal white matter in chronic multiple sclerosis: imaging and histopathologic analysis
Alexandra Seewann1, Hugo Vrenken, Paul van der Valk
1Department of Neurology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands. a.seewann@vumc.nl
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.
Insights
Diffuse white matter abnormalities (DAWM) in multiple sclerosis (MS) show distinct pathology, including axonal loss and gliosis, differing from normal tissue and focal lesions. These findings suggest DAWM significantly contributes to MS progression and disability.
Area of Science:
- Neuroimaging
- Neuropathology
- Multiple Sclerosis Research
Background:
- Diffuse white matter abnormalities (DAWM) on MRI may drive clinical disability in multiple sclerosis (MS).
- The underlying pathology and MRI characteristics of DAWM in chronic MS remain largely uncharacterized.
Purpose of the Study:
- To elucidate the histopathologic and radiologic features of DAWM in chronic multiple sclerosis.
- To differentiate DAWM from normal-appearing white matter and focal lesions in MS.
Main Methods:
- Postmortem correlative study combining MRI and histopathology on 17 brain slices from 10 chronic MS patients.
- Region-of-interest analysis comparing radiologically defined DAWM, normal-appearing WM, and focal WM lesions.
- Correlation of quantitative MRI measures (T1/T2 relaxation times, fractional anisotropy) with histopathologic findings (axonal loss, myelin density, gliosis).
Main Results:
- DAWM exhibits extensive axonal loss, reduced myelin density, and chronic fibrillary gliosis, distinct from normal WM and focal lesions.
- Increased T1 and T2 relaxation times and decreased fractional anisotropy were observed in DAWM.
- These MRI changes correlated with significant axonal loss, reduced myelin density, and chronic gliosis.
Conclusions:
- DAWM represents a distinct pathological entity in chronic MS, differing from normal-appearing WM and focal lesions.
- DAWM likely arises from cumulative inflammation and axonal damage, contributing significantly to MS disease progression.
- DAWM may serve as a novel imaging biomarker for neurodegeneration in MS clinical trials.
