clinical topic updates

Imaging and Nonimaging Biomarkers in Multiple Sclerosis

by Robert A. Bermel, MD, MBA


Magnetic resonance imaging (MRI) remains the standard for assessment and monitoring in multiple sclerosis (MS). Recent developments in brain imaging acquisition and post-processing have advanced the field, and biomarkers for neurodegeneration and inflammatory disease activity continue to be pursued.

Expert Commentary

Robert A. Bermel, MD, MBA

Staff Neurologist
Mellen Center for Multiple Sclerosis
Cleveland Clinic
Cleveland, OH

“. . . the appearance of new MRI lesions during treatment is likely the best biomarker that we have for identifying nonresponse or nonadherence to therapy.”

Robert A. Bermel, MD, MBA

The most common biomarker that is currently in use is MRI, which is used to determine disease status and to assess the patient’s response to treatment. In fact, the appearance of new MRI lesions during treatment is likely the best biomarker that we have for identifying nonresponse or nonadherence to therapy. Patients with MS who have been reliably stable can be monitored with MRI scanning approximately once per year, while more frequent imaging is needed when the MS diagnosis is recent or when there has been a change in therapy or a recent uptick in disease activity.

For some time, the measurement of whole-brain atrophy (eg, brain parenchymal fraction) has been of interest in MS research, neurodegeneration, and disability. One of the newer developments has been the introduction of imaging software designed to detect changes in a patient’s total brain volume that may be brought on by neurodegenerative processes. Some of these measures are available via US Food and Drug Administration–approved commercial software that interprets MRI scans quantitatively and compares individual brain volume or brain parenchymal fraction measurements with a normative database. Brain volume is a close imaging surrogate for disability, as measured by the Kurtzke Expanded Disability Status Scale, and for cognitive disability, as measured by neuropsychological testing. 

Gray matter volume measurement is not widely available in the clinic, but it is of great interest because it may be associated with less fluctuation over time than total brain volume and it tracks closely with physical and cognitive disabilities. Another advanced biomarker, neurite orientation dispersion and density imaging, is a research measure that seems to have a high specificity and a high sensitivity for neurodegeneration. Magnetization transfer imaging that is measured as a magnetization transfer ratio, either in a voxel of interest or the whole brain, correlates with myelin content in the area of the brain that is measured. 

The last category of biomarkers that is showing a lot of promise in MS is nonimaging or liquid biomarkers for neurodegeneration and inflammatory disease activity. One of the most promising of these biomarkers is neurofilament light, which is a protein component of the neuronal cytoskeleton that gets sloughed off when nerve cells are damaged. This protein ends up in the spinal fluid in somewhat substantial quantities and in the peripheral blood in much lower quantities. We can measure neurofilament light reliably at very low levels in the peripheral blood using a technique called the single molecule immunoassay technique. The ability to measure neurofilament light, which increases with inflammatory disease activity and, to a lesser extent, with neurodegeneration, may allow us to measure MS disease activity in the peripheral blood in the future.


Cortese R, Collorone S, Ciccarelli O, Toosy AT. Advances in brain imaging in multiple sclerosis. Ther Adv Neurol Disord. 2019;12:1756286419859722. doi:10.1177/1756286419859722

Goodkin O, Prados F, Vos SB, et al; MAGNIMS Study Group. FLAIR-only joint volumetric analysis of brain lesions and atrophy in clinically isolated syndrome (CIS) suggestive of multiple sclerosis. Neuroimage Clin. 2021;29:102542. doi:10.1016/j.nicl.2020.102542

Kapoor R, Smith KE, Allegretta M, et al. Serum neurofilament light as a biomarker in progressive multiple sclerosis. Neurology. 2020;95(10):436-444. doi:10.1212/WNL.0000000000010346

Rudick RA, Fisher E, Lee JC, Simon J, Jacobs L. Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group. Neurology. 1999;53(8):1698-1704. doi:10.1212/wnl.53.8.1698

Wattjes MP, Ciccarelli O, Reich DS, et al; Magnetic Resonance Imaging in Multiple Sclerosis Study Group; Consortium of Multiple Sclerosis Centres; North American Imaging in Multiple Sclerosis Cooperative MRI Guidelines Working Group. 2021 MAGNIMS-CMSC-NAIMS consensus recommendations on the use of MRI in patients with multiple sclerosis. Lancet Neurol. 2021;20(8):653-670. doi:10.1016/S1474-4422(21)00095-8

Ziemssen T, Akgün K, Brück W. Molecular biomarkers in multiple sclerosis. J Neuroinflamation. 2019;16(1):272. doi:10.1186/s12974-019-1674-2

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