Multimodal MRI in Multiple Sclerosis

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications, trials & patents

Abstract

In Fiscal Year 2023, we continued to pursue our Specific Aims: to study the pathophysiology of MS through neuroimaging, to study the biology of inflammatory demyelination in a translationally relevant primate model of MS, and to develop markers, and design and conduct clinical trials, for treating chronic inflammation and promoting tissue protection and remyelination in MS. We have seen significant progress toward accomplishing all these Aims, some of which is detailed here. For Aim 1, we continued our analysis of perivenular lesion formation (the radiological central vein sign or CVS), a phenomenon that appears relatively specific to MS and hence may hold diagnostic and prognostic significance. We showed that gadolinium-based contrast agent use in conjunction with MRI increases CVS detection on FLAIR* images (a type of MRI that we pioneered), thereby increasing sensitivity of CVS for MS diagnosis (4), and we reviewed advanced imaging methods to identify lesions with the CVS (16). We also continued work on early development of MS lesions (10). In prior research, we showed that we can reliably identify chronically inflamed lesions on clinical MRI systems. Over the past year, we have further reviewed the radiological characteristics and clinical and biological associations of these lesions (14). We also demonstrated that such lesions are associated with inflammatory markers in the cerebrospinal fluid (9) and identified their signatures on high-resolution, postmortem MRI (8). We performed a longitudinal clinical study and in silico analysis to determine that such lesions are not resolved by the most potent current MS disease-modifying therapy, B cell depletion with monoclonal antibodies (18). With the NINDS Neuroimmunology Clinic, we are conducting clinical trials to test whether corticosteroids prevent the evolution of acute to chronically inflamed lesions, assess whether the inflammation in these lesions can be abrogated by IL-1 receptor blockade, and determine the effect of Brutons tyrosine kinase inhibition on these lesions using a small brain-penetrant molecule (Aim 3). We also continue to characterize MS lesions affecting the cerebral cortex, which are difficult to detect by MRI, unlike their white matter counterparts. Our approach here has been to evaluate new MRI approaches with potentially higher sensitivity than previously described methods, taking advantage of the 7-tesla research systems at NIH and of our collaborations with MRI pulse sequence developers at NIH (25), in the extramural community (3, 19), and in industry. Using a method we previously developed that more than doubles the sensitivity for cortical lesion detection, we have identified hotspots for cortical lesion development (2), and we are now analyzing scans acquired over several years to assess for new cortical lesions. Work in the last year has revived an earlier line of research in the lab, which aimed to image inflammation in the fluid spaces of the brain, including the subarachnoid and perivascular spaces. In addition to reviewing these topics in detail (12, 13, 22), we performed a correlative MRI and neuropathology study and showed that enlarged, MRI-visible perivascular spaces surround arteries and not veins (11). We further studied a highly sensitive MRI approach for assessing abnormal leakage of blood vessels in the subarachnoid space (21), a phenomenon we previously had shown to be related to inflammation in this compartment. To further Aim 2, we created a detailed single-cell transcriptomic atlas of the healthy marmoset brain, sampling different regions in white and gray matter (17). We found, among other things, that certain glial cells (microglia, astrocytes, and oligodendrocyte precursor cells) are highly specialized according to their location in the brain, whereas others (oligodendrocytes, principally) are not. This resource, and an accompanying web browser (http://cjpca.ninds.nih.gov), is now widely available to the research community. In the past year, we also published a study, performed under a Cooperative Research and Development Agreement (CRADA) with Vertex Pharmaceuticals, in which we showed that serial MRI can accurately assess whether individual demyelinating lesions in marmoset experimental autoimmune encephalomyelitis (EAE) repair successfully in the months after they form (5). This finding paves the way for proof-of-concept preclinical and clinical trials to test putative remyelinating drugs in MS. Under Aim 3, we reviewed the literature on circulating free DNA biomarkers of neurological disorders (7), a promising approach that could serve as an adjunct to imaging-based trials. We also pioneered the use of ultra-low-field, portable MRI in multiple sclerosis (1), which we believe will be useful not only for enhancing clinical trials but also for future screening and early detection efforts, a cornerstone of primary prevention. Such efforts are enhanced by genetic studies, which we undertook in collaboration for the first time during the past year (6). Finally, we continue to contribute to review and position papers with various national and international consortia (15, 24).