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      The Role of T1-Weighted Derived Measures of Neurodegeneration for Assessing Disability Progression in Multiple Sclerosis

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          Abstract

          Introduction

          Multiple sclerosis (MS) is characterised by the accumulation of permanent neurological disability secondary to irreversible tissue loss (neurodegeneration) in the brain and spinal cord. MRI measures derived from T1-weighted image analysis (i.e., black holes and atrophy) are correlated with pathological measures of irreversible tissue loss. Quantifying the degree of neurodegeneration in vivo using MRI may offer a surrogate marker with which to predict disability progression and the effect of treatment. This review evaluates the literature examining the association between MRI measures of neurodegeneration derived from T1-weighted images and disability in MS patients.

          Methods

          A systematic PubMed search was conducted in January 2017 to identify MRI studies in MS patients investigating the relationship between “black holes” and/or atrophy in the brain and spinal cord, and disability. Results were limited to human studies published in English in the previous 10 years.

          Results

          A large number of studies have evaluated the association between the previous MRI measures and disability. These vary considerably in terms of study design, duration of follow-up, size, and phenotype of the patient population. Most, although not all, have shown that there is a significant correlation between disability and black holes in the brain, as well as atrophy of the whole brain and grey matter. The results for brain white matter atrophy are less consistently positive, whereas studies evaluating spinal cord atrophy consistently showed a significant correlation with disability. Newer ways of measuring atrophy, thanks to the development of segmentation and voxel-wise methods, have allowed us to assess the involvement of strategic regions of the CNS (e.g., thalamus) and to map the regional distribution of damage. This has resulted in better correlations between MRI measures and disability and in the identification of the critical role played by some CNS structures for MS clinical manifestations.

          Conclusion

          The evaluation of MRI measures of atrophy as predictive markers of disability in MS is a highly active area of research. At present, measurement of atrophy remains within the realm of clinical studies, but its utility in clinical practice has been recognized and barriers to its implementation are starting to be addressed.

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          Most cited references 136

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          Gray matter atrophy in multiple sclerosis: a longitudinal study.

          To determine gray matter (GM) atrophy rates in multiple sclerosis (MS) patients at all stages of disease, and to identify predictors and clinical correlates of GM atrophy. MS patients and healthy control subjects were observed over 4 years with standardized magnetic resonance imaging (MRI) and neurological examinations. Whole-brain, GM, and white matter atrophy rates were calculated. Subjects were categorized by disease status and disability progression to determine the clinical significance of atrophy. MRI predictors of atrophy were determined through multiple regression. Subjects included 17 healthy control subjects, 7 patients with clinically isolated syndromes, 36 patients with relapsing-remitting MS (RRMS), and 27 patients with secondary progressive MS (SPMS). Expressed as fold increase from control subjects, GM atrophy rate increased with disease stage, from 3.4-fold normal in clinically isolated syndromes patients converting to RRMS to 14-fold normal in SPMS. In contrast, white matter atrophy rates were constant across all MS disease stages at approximately 3-fold normal. GM atrophy correlated with disability. MRI measures of focal and diffuse tissue damage accounted for 62% of the variance in GM atrophy in RRMS, but there were no significant predictors of GM atrophy in SPMS. Gray matter tissue damage dominates the pathological process as MS progresses, and underlies neurological disabillity. Imaging correlates of gray matter atrophy indicate that mechanisms differ in RRMS and SPMS. These findings demonstrate the clinical relevance of gray matter atrophy in MS, and underscore the need to understand its causes.
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            Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis.

            Multiple sclerosis (MS) is the most frequent chronic inflammatory disease of the CNS, and imposes major burdens on young lives. Great progress has been made in understanding and moderating the acute inflammatory components of MS, but the pathophysiological mechanisms of the concomitant neurodegeneration--which causes irreversible disability--are still not understood. Chronic inflammatory processes that continuously disturb neuroaxonal homeostasis drive neurodegeneration, so the clinical outcome probably depends on the balance of stressor load (inflammation) and any remaining capacity for neuronal self-protection. Hence, suitable drugs that promote the latter state are sorely needed. With the aim of identifying potential novel therapeutic targets in MS, we review research on the pathological mechanisms of neuroaxonal dysfunction and injury, such as altered ion channel activity, and the endogenous neuroprotective pathways that counteract oxidative stress and mitochondrial dysfunction. We focus on mechanisms inherent to neurons and their axons, which are separable from those acting on inflammatory responses and might, therefore, represent bona fide neuroprotective drug targets with the capability to halt MS progression.
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              Association between pathological and MRI findings in multiple sclerosis.

              The identification of pathological processes that could be targeted by therapeutic interventions is a major goal of research into multiple sclerosis (MS). Pathological assessment is the gold standard for such identification, but has intrinsic limitations owing to the limited availability of autopsy and biopsy tissue. MRI has gained a leading role in the assessment of MS because it allows doctors to obtain an ante mortem picture of the degree of CNS involvement. A number of correlative pathological and MRI studies have helped to define in vivo the pathological substrates of MS in focal lesions and normal-appearing white matter, not only in the brain, but also in the spinal cord. These studies have resulted in the identification of aspects of pathophysiology that were previously neglected, including grey matter involvement and vascular pathology. Despite these important achievements, numerous open questions still need to be addressed to resolve controversies about how the pathology of MS results in fixed neurological disability. Copyright © 2012 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                1664-2295
                04 September 2017
                2017
                : 8
                Affiliations
                1Neuroimaging Research Unit, Institute of Experimental Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University , Milan, Italy
                2Department of Neurology, Institute of Experimental Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University , Milan, Italy
                Author notes

                Edited by: Achim Gass, Universitätsmedizin Mannheim (UMM), Germany

                Reviewed by: Menno Michiel Schoonheim, VU University Medical Center, Netherlands; Alex Rovira, Hospital Universitari Vall d’Hebron, Spain

                *Correspondence: Maria A. Rocca, rocca.mara@ 123456hsr.it

                Specialty section: This article was submitted to Applied Neuroimaging, a section of the journal Frontiers in Neurology

                Article
                10.3389/fneur.2017.00433
                5591328
                Copyright © 2017 Rocca, Comi and Filippi.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 2, Tables: 3, Equations: 0, References: 136, Pages: 25, Words: 14980
                Categories
                Neuroscience
                Review

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