Multimodal MRI in Multiple Sclerosis

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications, trials & patents

Abstract

In Fiscal Year 2021, we have continued to pursue two specific aims: (1) to study the pathophysiology of MS through high-resolution MRI and (2) to study the biology of inflammatory demyelination in a translationally relevant primate model of MS. We have seen significant progress toward accomplishing both Specific Aims; some of this progress is detailed here. For Aim 1, the first project focuses on the early development of MS lesions. Previously, we studied two critical aspects of lesion development: the small veins around which white matter lesions form, and the short-to-medium-term outcomes of acute lesions. With respect to lesion outcomes, we established that there are two spatiotemporal patterns in MS lesions: a centrifugal pattern, in which serum contents leak from the center of the lesion and then proceed outward, over the course of minutes to hours, to fill the entire lesion; and a centripetal pattern, in which serum contents first appear on the periphery of the lesion and then proceed inward. These findings have important implications for understanding lesion development and its association with blood-brain-barrier permeability. In further work, we described how these permeability patterns help to determine the fashion in which acute MS lesions evolve into their chronic counterparts. Among other things, we found that very early events, perhaps occurring within the first month after lesion formation, appear to determine the efficacy of tissue repair, possibly including remyelination. We also showed that we can reliably identify chronically inflamed lesions on clinical MRI systems. In the past year, we have published a study showing that such lesions are specific to MS; are associated with a serum marker of neurodegeneration, neurofilament light chain; are associated with cognitive impairment); and can be automatically identified by image-processing techniques. We have developed MRI microscopy techniques to detect signatures of these lesions at ultra-high resolution. With the NINDS Neuroimmunology Clinic, we are conducting a clinical trial to test whether corticosteroids prevent the evolution of acute to chronically inflamed lesions, a second trial to assess whether the inflammation in these lesions can be abrogated by IL-1 receptor blockade, and a third trial, initiated in FY21, to assess the effect of Brutons tyrosine kinase inhibition on these lesions. We have also reported on the long-term effects of failed lesion repair, which can cause diffuse tissue abnormalities and loss. We also continue to characterize MS lesions affecting the cerebral cortex, which have proven 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 system at NIH and of our collaborations with MRI pulse sequence developers at NIH, in the extramural community, and in industry. In prior years, we described and are routinely using a method that more than doubles the sensitivity for cortical lesion detection, and in collaboration with another NINDS lab (the Advanced MRI Section), we have worked to improve its robustness through motion correction techniques. Additionally under Aim 1, we have continued our work on improving methods for image acquisition and analysis and have used our imaging techniques to study other neurological diseases. For Aim 2, we described the imaging and cellular/molecular events in early inflammatory demyelinating lesions that develop in the brains of marmoset monkeys with experimental autoimmune encephalomyelitis (EAE). We previously suggested, using coarse MRI techniques, that the blood-brain barrier becomes locally permeable up to four weeks prior to the onset of demyelination, and we showed that this permeability is associated with a perivascular lymphocytic and mononuclear infiltrate with parenchymal activation of microglia and astrocytes. In the past year, published the first radiological-pathological correlative study of cortical lesions in marmoset EAE. We also collaborated with the NINDS Intravital Imaging Section to study immune surveillance in the marmoset meninges. The results will pave the way toward using the marmoset model in preclinical studies to predict the response of people to novel treatments. Finally, we continue to contribute to review and position papers with various national and international consortia.