Gray matter atrophy correlates with MS disability progression measured with MSFC but not EDSS
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Updated: Jun 26, 2026
Comprehensive Autopsy Program for Individuals with Multiple Sclerosis
Published on: July 19, 2019
Richard A Rudick1, Jar-Chi Lee, Kunio Nakamura
1Mellen Center for MS Treatment and Research U10, Neurologic Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA. rudickr@ccf.org
Background:
Gray matter (GM) pathology is an important component of the multiple sclerosis (MS) disease process. Accelerated gray matter atrophy has been observed in MS patients, but its relationship to neurological disability is not defined. This study was done to determine the relationship between whole brain, GM, and white matter (WM) atrophy and MS disability progression.
Methods:
Patients with MS and Clinically Isolated Syndromes (CIS), and age- and gender-matched healthy controls were entered into an observational protocol. Baseline brain parenchymal fraction (BPF), GM fraction, and WM fraction, and change over 4 years were correlated with sustained disability progression over the entire study duration. Disability progression was measured using the Multiple Sclerosis Functional Composite (MSFC) and the Expanded Disability Status Scale (EDSS).
Results:
Seventy MS and CIS patients and 17 HCs were studied for an average of 6.6 years (range, 3.6-7.8 years). At the final visit, 7 patients were classified as CIS, 36 as relapsing-remitting MS (RRMS), and 27 as secondary progressive MS (SPMS). Baseline whole brain, GM, and WM atrophy predicted EDSS >6.0 at the last study visit. Twenty-one (33%) patients worsened using the EDSS to define disability progression; 29 (46%) worsened using MSFC to define disability progression. Patients with MSFC progression had significantly higher GM atrophy rates compared with patients who were stable on MSFC. White matter atrophy was similar in patients with and without disability progression. Atrophy rates were not different in patients with or without disability progression defined using EDSS.
Conclusions:
Whole brain, GM, and WM atrophy predicted MS disability progression observed over the next 6.6 years. Gray matter atrophy rates over 4 years correlated with disability progression measured with the MSFC, but not EDSS. This indicates that MSFC defined disability progression is more closely linked to brain atrophy than EDSS defined disability progression, and provides important new insight into the poor correlation between MRI and clinical disability in MS. The findings confirm the clinical relevance of gray matter atrophy in MS.
Insights
Brain atrophy, particularly gray matter atrophy, predicts multiple sclerosis (MS) disability progression. The Multiple Sclerosis Functional Composite (MSFC) better reflects this progression than the Expanded Disability Status Scale (EDSS).
Area of Science:
- Neuroimaging
- Neurology
- Medical Research
Background:
- Gray matter (GM) pathology is a key aspect of multiple sclerosis (MS).
- Accelerated GM atrophy occurs in MS, but its link to neurological disability is unclear.
- This study investigates the relationship between brain atrophy (GM and white matter) and MS disability progression.
Purpose of the Study:
- To determine the relationship between whole brain, GM, and white matter (WM) atrophy and MS disability progression.
- To compare the sensitivity of the Multiple Sclerosis Functional Composite (MSFC) and the Expanded Disability Status Scale (EDSS) in reflecting atrophy-related disability progression.
Main Methods:
- An observational study included patients with MS, Clinically Isolated Syndromes (CIS), and healthy controls (HCs).
- Baseline and 4-year changes in brain parenchymal fraction (BPF), GM fraction, and WM fraction were assessed.
- Disability progression was measured using MSFC and EDSS over an average follow-up of 6.6 years.
Main Results:
- Baseline whole brain, GM, and WM atrophy predicted a high EDSS score at the final visit.
- MSFC progression was associated with significantly higher GM atrophy rates compared to stable patients.
- WM atrophy and EDSS-defined progression showed no significant differences between patients with or without disability progression.
Conclusions:
- Whole brain, GM, and WM atrophy predict MS disability progression over time.
- GM atrophy rates correlate with MSFC-defined disability progression, highlighting its clinical relevance in MS.
- MSFC is more closely linked to brain atrophy than EDSS, offering new insights into MRI-clinical disability correlations in MS.
