Multimodal MRI in Multiple Sclerosis

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

In Fiscal Year 2022, we continued to pursue our two Specific Aims: to study the pathophysiology of MS through high-resolution MRI, and to study the biology of inflammatory demyelination in a translationally relevant primate model of MS. We have seen significant progress toward accomplishing both Aims, some of which is detailed here. For Aim 1, the first project focuses on the early development of MS lesions. We continued our analysis of perivenular lesion formation (the radiological central vein sign or CVS), which is a phenomenon that appears relatively specific to MS and hence may hold diagnostic and prognostic significance. We showed that younger age and higher CVS+ percentage at baseline are associated with new CVS+ lesion development (2), that lesion-size measures add important information when using CVS+ lesion counts for MS diagnosis (3), that the CVS determined radiologically is histopathologically specific (3), and 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 (8). In prior work, we showed that we can reliably identify chronically inflamed lesions on clinical MRI systems. Over the past year, we have further defined the radiological characteristics and clinical associations of these lesions, demonstrating that they can be identified at 1.5 tesla, the most common clinical magnetic field strength (13), and that they are associated with inflammatory markers in the cerebrospinal fluid (12). We also described a new automatic method to identifying such lesions in images using advanced radiomic techniques (17). In a study that utilized single-nucleus RNA sequencing technology from postmortem tissue, we showed that chronic inflammation in these lesions is sustained by glial cells (principally microglia and astrocytes) under the influence of the peripheral immune system, and that the evolutionarily ancient innate immune system known as complement plays an important role in this process (1, 10). 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 to whose clinical development we have substantially contributed (22). 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 system at NIH and of our collaborations with MRI pulse sequence developers at NIH, in the extramural community, and in industry. Using a method we previously developed that more than doubles the sensitivity for cortical lesion detection, we have shown that cortical lesions are highly prevalent and are associated with disability and progressive disease, and that the burden of an important type of cortical lesion, which form at the surface of the cortex, is not strongly correlated with white matter lesion burden, suggesting differences in inflammation and repair mechanisms (7); this may be relevant for therapeutic development. To assist in further research into cortical lesions, we developed an automated algorithm to detect and segment them from MRI scans (16). Additionally under Aim 1, we have continued our work on improving methods for image acquisition (4) and analysis (9, 14, 18, 19, 21) and have used our imaging techniques to study other neurological diseases. Notable is the first report of MS lesions visualized using a portable, ultra-low magnetic field scanner, which is suitable for integration into a mobile clinical research unit (4). This technology, while less capable of uncovering disease biology than high- and ultra-high-field systems, has important clinical implications, especially with respect to bringing cutting-edge care to the neurologically underserved. 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). Work on this Aim was significantly slowed by the COVID-19 pandemic, but we continued to make progress on understanding the cellular and molecular architecture of healthy and inflamed brain cells and to lay the groundwork for resumption of our marmoset studies, which occurred in mid-2022. Results from these ongoing and planned studies 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 (5, 11, 15, 23, 24).