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

https://doi.org/10.1016/j.jns.2008.11.018Get rights and content

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.

Introduction

Multiple sclerosis has historically been classified as a white matter disease. Conspicuous foci of demyelination are evident post-mortem, and are easily visualized by magnetic resonance imaging (MRI), explaining why MS has long been perceived as a white matter disease. Recently, many studies have demonstrated prominent pathological changes in GM in MS brains as well. These changes include widespread demyelination, activated microglia, apoptotic neurons, and atrophy affecting the cortex, and deep GM structures [1], [2], [3], [4]. Focal GM lesions are not well visualized by conventional MRI scanning, however. Therefore, the time course and relevance of GM pathology has not been fully elucidated.

Magnetic resonance imaging studies have documented that GM volumes are lower in MS patients than in healthy age-matched controls, and some studies have suggested that GM atrophy may begin early in the course of disease [5], [6], [7], [8], [9], [10], [11]. Evolution of GM atrophy over the course of MS, its relationship to disability, and the pathogenesis of GM pathology remain important questions in the MS field. The objective of this study was to determine the clinical relevance of GM atrophy in a spectrum of MS patients, by correlating correlate whole brain, GM, and WM atrophy with sustained disability progression.

Section snippets

Research subjects

Patients and age- and gender-matched HC subjects were recruited from the Mellen Center. The study was approved by the Cleveland Clinic Institutional Review Board and each subject provided informed consent. Subjects with MS met the International Panel criteria [12] and each had a cranial MRI demonstrating lesions consistent with MS. Patients were classified as RRMS if they had 2 or more relapses with significant neurologic recovery in the prior 3 years, or as SPMS if they reported continued

Results

One hundred six research subjects were enrolled in the original study. Nineteen subjects discontinued the protocol for various reasons; this report provides information on the remaining 87 subjects. These 87 research subjects were observed for a mean of 6.6 years (range: 3.6–7.8 years). Eight of 15 subjects who initially entered with a diagnosis of CIS transitioned to MS during the course of the study; 7 to RRMS, and 1 to SPMS. The remaining 7 CIS patients remained stable and were still

Discussion

Accelerated rates of brain volume loss have been reported in MS patients [16], [17], [18]. Over the years, brain volume declines 5–8 times faster in MS patients than healthy, age-matched controls, leading to the obvious interpretation that loss of brain volume is an end stage consequence of the pathologic processes operating in the disease. However, measures of brain volume are pathologically nonspecific. Fluid shifts may increase or decrease brain volume; gliosis may increased brain volume;

Acknowledgements

This study was supported by the National Institutes of Health NINDS (P01-NS38667) and the National Multiple Sclerosis Society (RG-3099-A). The authors would like to thank Patricia Jagodnik for help with image data management and image analysis, Dee Ivancic, and Claire Hara-Cleaver for assistance with patient visits, Swati Chakraborty, Vicky Konig, and Alan Liu for database development and management, and all the patients and volunteers who kindly agreed to participate in this long-term

References (35)

  • C.M. Dalton et al.

    Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes

    Brain

    (May 2004)
  • D.T. Chard et al.

    Brain atrophy in clinically early relapsing–remitting multiple sclerosis

    Brain

    (Feb 2002)
  • M. Tiberio et al.

    Gray and white matter volume changes in early RRMS: a 2-year longitudinal study

    Neurology

    (Mar 22 2005)
  • D.T. Chard et al.

    Progressive grey matter atrophy in clinically early relapsing–remitting multiple sclerosis

    Mult Scler

    (Aug 2004)
  • E. Fisher et al.

    Gray matter atrophy in multiple sclerosis: a longitudinal study

    Ann Neurol

    (Jul 25 2008)
  • C.H. Polman et al.

    Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”

    Ann Neurol

    (Dec 2005)
  • G.R. Cutter et al.

    Development of a multiple sclerosis functional composite as a clinical trial outcome measure

    Brain

    (May 1999)
  • Cited by (107)

    • Gait abnormalities in minimally disabled people with Multiple Sclerosis: A 3D-motion analysis study

      2019, Multiple Sclerosis and Related Disorders
      Citation Excerpt :

      Therefore, the DT paradigm is an excellent experimental strategy to investigate the ability to perform two different tasks simultaneously (Leone et al., 2015), allowing to detect the cognitive-motor interference and quantifying the reciprocal effect (Wajda et al., 2013). White-matter lesions are one of the magnetic resonance imaging (MRI) features of MS. Their number, location and size are taken into account when formulating the diagnosis of MS. However, the correlation between physical disability and lesion load (LL) is weak or moderate (Koopmans et al., 1989; Miki et al., 1997) while brain atrophy, that may occur early in the course of MS, may predict future clinical disability (Eshaghi et al., 2018; Minagar et al., 2013; Rudick et al., 2009). The present study was addressed to evaluate whether in relapsing-remitting pwMS (pwRR-MS) without any clinically detectable gait abnormality or other influencing factors (i.e. fatigue, depression, cognitive impairment), 3D-GA may detect changes of gait pattern.

    View all citing articles on Scopus
    1

    Tel.: +1 216 444 8602.

    2

    Tel.: +1 216 444 9920.

    3

    Tel.: +1 216 445 3217 (EF), +1 216 445 0591 (KN).

    View full text