Fiscal Year 2019 has 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. To understand whether the presence of a central vein may help distinguish MS lesions from their mimickers -- an idea that remains controversial but to which we mostly subscribe -- we previously developed a rapid imaging approach for clinical 3-tesla MRI called FLAIR*. Two studies to assess the utility of FLAIR* for diagnosis and characterization of MS lesions have been published in the last year (9, 27), and a patent incorporating this technology has been submitted (22). We found that FLAIR* is able to significantly improve diagnostic confidence in a variety of settings, including the so-called radiologically isolated syndrome. Our technique is now in use at more than 30 around the world, and with the North American Imaging in MS (NAIMS) cooperative, we are conducting a multicenter pilot clinical trial to assess whether FLAIR* allows earlier and more confident diagnosis of the disease. A U01 grant to extend this to a full-scale trial has been submitted to NINDS extramural, and we will collaborate should it be funded. In related work, we have established the long-term deleterious consequences of perivenular inflammation in the white matter, finding that perivenular collagen type I deposition is widespread in the MS brain and may impair the proliferation and differentiation of myelin-repairing cells (1) With respect to lesion outcomes, we previously 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 large cross-sectional and longitudinal study showing that such lesions can expand slowly over time and are associated with clinical disability progression (2). With the NINDS Neuroimmunology Clinic, we are conducting a clinical trial to test whether corticosteroids prevent the evolution of acute to chronically inflamed lesions, and we have recently initiated a new trial to assess whether the inflammation in these lesions can be abrogated. We have also increased our focus on the characterization of 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 we recently submitted a patent application for a new technique to visualize these lesions on clinical MRI scanners (20). We have also followed up our prior discovery of the imaging correlate of inflammation in the leptomeninges (the membranes that surround the brain) by collaborating with colleagues at Johns Hopkins on a clinical trial of intrathecal rituximab, which was unfortunately unsuccessful (4). Additionally under Aim 1, we have continued our work on improving methods for image acquisition and analysis (8, 10, 11, 13, 14, 18, 19, 23, 24, 26).
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. We have since shown directly that the plasma protein fibrinogen leaks into the brain parenchyma prior to demyelination, and that fibrinogen can also be seen in chronically inflamed lesions in people with MS. In the past year, we have published the first radiological-pathological correlative study of spinal cord lesions in marmoset EAE 15). We also collaborated with NINDS colleagues to describe the effects of herpesvirus inoculation on the course of experimental disease in this model (16). 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 (12, 17, 18).
| Dworkin, J D; Linn, K A; Oguz, I et al. (2018) An Automated Statistical Technique for Counting Distinct Multiple Sclerosis Lesions. AJNR Am J Neuroradiol 39:626-633 |
| Brugarolas, Pedro; Reich, Daniel S; Popko, Brian (2018) Detecting Demyelination by PET: The Lesion as Imaging Target. Mol Imaging 17:1536012118785471 |
| Lee, Nathanael J; Ha, Seung-Kwon; Sati, Pascal et al. (2018) Spatiotemporal distribution of fibrinogen in marmoset and human inflammatory demyelination. Brain 141:1637-1649 |
| Basuli, Falguni; Zhang, Xiang; Brugarolas, Pedro et al. (2018) An efficient new method for the synthesis of 3-[18 F]fluoro-4-aminopyridine via Yamada-Curtius rearrangement. J Labelled Comp Radiopharm 61:112-117 |
| Oh, Jiwon; Bakshi, Rohit; Calabresi, Peter A et al. (2018) The NAIMS cooperative pilot project: Design, implementation and future directions. Mult Scler 24:1770-1772 |
| de Zwart, Jacco A; van Gelderen, Peter; Schindler, Matthew K et al. (2018) Impulse response timing differences in BOLD and CBV weighted fMRI. Neuroimage 181:292-300 |
| Solomon, Andrew J; Watts, Richard; Ontaneda, Daniel et al. (2018) Diagnostic performance of central vein sign for multiple sclerosis with a simplified three-lesion algorithm. Mult Scler 24:750-757 |
| Papinutto, Nico; Bakshi, Rohit; Bischof, Antje et al. (2018) Gradient nonlinearity effects on upper cervical spinal cord area measurement from 3D T1 -weighted brain MRI acquisitions. Magn Reson Med 79:1595-1601 |
| Reich, Daniel S; Lucchinetti, Claudia F; Calabresi, Peter A (2018) Multiple Sclerosis. N Engl J Med 378:169-180 |
| Beck, Erin S; Reich, Daniel S (2018) Brain atrophy in multiple sclerosis: How deep must we go? Ann Neurol 83:208-209 |
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