@article{4702eca9a26641ffbfe9311e5e33821b,
title = "Quantitative signal properties from standardized MRIs correlate with multiple sclerosis disability",
abstract = "Objective: To 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. Methods: We 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. Results: Intensity 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. Interpretation: These 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.",
author = "Brier, {Matthew R.} and Snyder, {Abraham Z.} and Aaron Tanenbaum and Rudick, {Richard A.} and Elizabeth Fisher and Stephen Jones and Shimony, {Joshua S.} and Cross, {Anne H.} and Benzinger, {Tammie L.S.} and Naismith, {Robert T.}",
note = "Funding Information: MS PATHS is funded by Biogen. MRB, AZS, AT, and JS have no disclosures. RAR and EF are employees of Biogen, Inc. SJ received honoraria from Siemens, RadNet and St Jude Children's Research Hospital as well as research support from Biogen, St Jude, National Institutes of Health and performed consultation services for Monteris and Eisai. AHC was supported by the Manny & Rosalyn Rosenthal – Dr. John L. Trotter MS Center Chair in Neuroimmunology and has consulted for or received honoraria from Biogen, Celgene, EMD Serono/Merck, Genentech, Novartis, Greenwich Biosciences, Janssen Pharmaceuticals, and Roche, and is a site principal investigator in contracted research from Genentech and EMD Serono. TLSB is funded by the NIH, Alzheimer's Association, Barnes‐Jewish Hospital Foundation and Avid Radiopharmaceuticals, is a site investigator in clinical trials sponsored by Avid Radiopharmaceutical, Eli Lilly, Biogen, Janssen and Roche, and is on the Speaker's Bureau for Biogen. RTN has consulted for Alexion, Biogen, EMD Serono, Celgene, Genentech, Genzyme, NervGen Pharma, Novartis, Third Rock Ventures, Viela Bio. The above disclosures do not have direct bearing on this work, and the authors report no other conflicts of interest. Funding Information: MS PATHS is funded by Biogen. Computations were performed using the facilities of the Washington University Center for High Performance Computing, which were partially funded by National Institutes of Health grants 1S10RR022984‐01A1 and 1S10OD018091‐01. MRB is supported by National Institutes of Health‐NINDS grant 2R25NS090978‐06. AZS is supported by National Institutes of Health‐NINDS grant P30NS098577. AHC was supported by the Manny & Rosalyn Rosenthal ‐ Dr John L Trotter MS Center Chair in Neuroimmunology. Publisher Copyright: {\textcopyright} 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association",
year = "2021",
month = may,
doi = "10.1002/acn3.51354",
language = "English",
volume = "8",
pages = "1096--1109",
journal = "Annals of Clinical and Translational Neurology",
issn = "2328-9503",
number = "5",
}