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

Background There are a number of instruments that describe severity and progression of multiple sclerosis and they are increasingly used as endpoints to assess the effectiveness of therapeutic interventions. We examined to what extent the psychometric properties of two accepted instruments – EDSS and MSFC – meet methodological standards and the value they have in clinical trials. Methods We conducted a systematic literature search in relevant databases [MEDLINE (PubMed), ISI Web of Science, EMBASE, PsycINFO & PSYNDEX, CINAHL] yielding 3,860 results. Relevant full-text publications were identified using abstract and then full-text reviews, and the literature was reviewed. Results For evaluation of psychometric properties (validity, reliability, sensitivity of change) of EDSS and MSFC, 120 relevant full-text publications were identified, 54 of them assessed the EDSS, 26 the MSFC and 40 included both instruments. The EDSS has some documented weaknesses in reliability and sensitivity to change. The main limitations of the MSFC are learning effects and the z-scores method used to calculate the total score. However, the methodological criterion of validity applies sufficiently for both instruments. For use in clinical studies, we found the EDSS to be preferred as a primary and secondary outcome measure in recent studies (50 EDSS, 9 MSFC). Conclusions Recognizing their strengths and weaknesses, both EDSS and MSFC are suitable to detect the effectiveness of clinical interventions and to monitor disease progression. Almost all publications identify the EDSS as the most widely used tool to measure disease outcomes in clinical trials. Despite some limitations, both instruments are accepted as endpoints and neither are discussed as surrogate parameters in identified publications. A great advantage of the EDSS is its international acceptance (e.g. by EMA) as a primary endpoint in clinical trials and its broad use in trials, enabling cross-study comparisons.

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.

The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) includes representatives from advocacy organizations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with multiple sclerosis (MS). One of the MSOAC goals is acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful in MS. This article addresses the history, application, and psychometric properties of one such MSOAC metric of ambulation or walking namely, the timed 25-foot walk (T25FW). The T25FW has strong reliability over both brief and long periods of time in MS across a large range of disability levels. The outcome of walking speed from the T25FW has obvious real-world relevance and has correlated strongly with other measures of walking and lower extremity function. The T25FW is responsive for capturing intervention effects in pharmacological and rehabilitation trials and has an established value for capturing clinically meaningful change in ambulation. Directions for future research involve validating clinically meaningful improvements on the T25FW as well as determining whether 20% change is clinically meaningful across the disability spectrum. Researchers might further consider synchronizing accelerometers and motion sensors with the T25FW for capturing walking speed in everyday life and the patient’s real environment.