Abstract
ObjectiveTo enable use of clinical magnetic resonance images (MRIs) to quantify abnormalities in normal appearing (NA) white matter (WM) and gray matter (GM) in multiple sclerosis (MS) and to determine associations with MS‐related disability. Identification of these abnormalities heretofore has required specialized scans not routinely available in clinical practice.MethodsWe developed an analytic technique which normalizes image intensities based on an intensity atlas for quantification of WM and GM abnormalities in standardized MRIs obtained with clinical sequences. Gaussian mixture modeling is applied to summarize image intensity distributions from T1‐weighted and 3D‐FLAIR (T2‐weighted) images from 5010 participants enrolled in a multinational database of MS patients which collected imaging, neuroperformance and disability measures.ResultsIntensity distribution metrics distinguished MS patients from control participants based on normalized non‐lesional signal differences. This analysis revealed non‐lesional differences between relapsing MS versus progressive MS subtypes. Further, the correlation between our non‐lesional measures and disability was approximately three times greater than that between total lesion volume and disability, measured using the patient derived disease steps. Multivariate modeling revealed that measures of extra‐lesional tissue integrity and atrophy contribute uniquely, and approximately equally, to the prediction of MS‐related disability.InterpretationThese results support the notion that non‐lesional abnormalities correlate more strongly with MS‐related disability than lesion burden and provide new insight into the basis of abnormalities in NA WM. Non‐lesional abnormalities distinguish relapsing from progressive MS but do not distinguish between progressive subtypes suggesting a common progressive pathophysiology. Image intensity parameters and existing biomarkers each independently correlate with MS‐related disability.
Highlights
Multiple sclerosis (MS) is an inflammatory demyelinating disease[1] associated with neurodegeneration.[2]
FLAIR white matter (WM) σ was wider in all MS subtypes compared to controls (Fig. 2I)
These outcomes were the same whether or not lesions were included in the WM measure, indicating that normal-appearing WM (NAWM) is abnormally heterogenous in MS
Summary
Multiple sclerosis (MS) is an inflammatory demyelinating disease[1] associated with neurodegeneration.[2]. Non-lesional abnormalities are of critical importance in MS, yet are difficult to discern on routine MRIs.[10]
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