Gray matter atrophy correlates with MS disability progression measured with MSFC but not EDSS

Abstract

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.

Figures

Figure 1. Percent Difference From Healthy Controls At Start Of Study

Mean percent difference in BPF, GMF, and WMF compared with healthy controls at the study baseline. Error bars are standard error of the mean. Corrected for disease duration, the average annual deviation from healthy controls for BPF was calculated as about -0.40% for both RRMS and SPMS patients.

Figure 2. Percent EDSS ≥ 6.0 At Last Visit According To Atrophy At Baseline Visit

Percentage of patients at different baseline atrophy scores who were classified as EDSS ≥ 6.0 at the last visit. Patients with MS were divided into quartiles of BPF, GMF, and WMF at study entry, and the proportion at the EDSS milestone at the last visit shown. Patients in the worst quartile had significantly higher risk of poor clinical outcome compared with subjects in the most favorable quartile.

Figure 3. Fold Increase In Atrophy Rates Compared With Healthy Controls By Disability Progression1

1Progression Defined Using MSFC Plot of the mean fold-increase over healthy controls in the annual rates of gray matter and white matter atrophy in MS patients with MSFC progression compared with stable patients. Gray matter atrophy was defined as the annualized percentage decline in the gray matter fraction. White matter atrophy was defined as the annualized percentage decline in the white matter fraction. Error bars are standard error of the mean. Compared to healthy control rates, gray matter atrophy was higher than white matter atrophy in both groups. In contrast to white matter atrophy, gray matter atrophy was higher in patients with disability progression measured with the MSFC.