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Principal Investigator: Daniel Reich
Organization: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
Fiscal Year: 2021
Award: $5,061,016
Funding agency: National Institute of Neurological Disorders and Stroke
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.
Terms: <3-D Imaging><3D imaging><Acute><Adrenal Cortex Hormones><Affect><Agammaglobulinaemia tyrosine kinase><Algorithms><Animal Model><Animal Models and Related Studies><Animals><Astrocytes><Astrocytus><Astroglia><Autopsy><Axon><B cell progenitor kinase><BBB permeabilization><BBB permeable><Biology><Blood - brain barrier anatomy><Blood Serum><Blood-Brain Barrier><Body Tissues><Brain><Brain Nervous System><Bruton's tyrosine kinase><CNS Nervous System><CNS degeneration><Callithrix><Central Nervous System><Cerebral cortex><Chronic><Clinic><Clinical><Clinical Trials><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Collaborations><Communities><Conduct Clinical Trials><Correlative Study><Corticoids><Corticosteroids><Data><Demyelinations><Detection><Development><Diagnostic><Diffuse><Disease><Disorder><Disseminated Sclerosis><Disturbance in cognition><Dysfunction><EAE><EXTMR><Encephalon><Event><Evolution><Experimental Allergic Encephalitis><Experimental Allergic Encephalomyelitis><Experimental Autoimmune Encephalitis><Experimental Autoimmune Encephalomyelitis><Extramural><Extramural Activities><Functional disorder><General Radiology><Goals><Hapale><Hemato-Encephalic Barrier><Hortega cell><Hour><IL-1 Receptors><IL1 Receptors><Image><Imaging Procedures><Imaging Technics><Imaging Techniques><Immune Surveillance><Immunologic Surveillance><Immunologic Surveillances><Immunological Surveillance><Immunological Surveillances><Immunosurveillance><Impaired cognition><Industry><Inflammation><Inflammatory><Interleukin-1 Receptors><International><Investigation><Knowledge><Lesion><Light><Location><Long-Term Effects><Longitudinal Studies><Longterm Effects><Lymphatic cell><Lymphocyte><Lymphocytic><MR Imaging><MR Tomography><MRI><MS Lesions><Magnetic Resonance Imaging><Marmosets><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Meninges><Methods><Microglia><Microscopy><Modeling><Molecular><Monkeys><Mononuclear><Motion><Multiple Sclerosis><Multiple Sclerosis Lesions><Myelin><NIH><NINDS><NMR Imaging><NMR Tomography><National Institute of Neurological Diseases and Stroke><National Institute of Neurological Disorders and Stroke><National Institutes of Health><Natural History><Nerve Degeneration><Nervous System Diseases><Neuraxis><Neurologic Disorders><Neurological Disorders><Neuron Degeneration><Nuclear Magnetic Resonance Imaging><Onset of illness><Outcome><Paper><Pathologic><Patients><Pattern><Permeability><Phase><Phenotype><Photoradiation><Physiologic pulse><Physiopathology><Play><Position><Positioning Attribute><Primates><Primates Mammals><Prognosis><Publishing><Pulse><Radiology><Radiology Specialty><Reporting><Research><Resolution><Scanning><Serum><Serum Markers><Short-Tusked Marmoset><Sight><Spectroscopy><Spectrum Analyses><Spectrum Analysis><System><Techniques><Testing><Therapeutic Intervention><Three-Dimensional Imaging><Time><Tissues><United States National Institutes of Health><Veins><Vision><Work><Zeugmatography><accurate diagnosis><astrocytic glia><autoimmune encephalomyelitis><base><blood-brain barrier permeabilization><blood-brain barrier permeable><bloodbrain barrier><bloodbrain barrier permeabilization><bloodbrain barrier permeable><bpk protein><btk protein><central nervous system degeneration><cognitive dysfunction><cognitive loss><design><designing><developmental><disease onset><disorder onset><experiment><experimental research><experimental study><gitter cell><image processing><image-based method><imaging><imaging biomarker><imaging marker><imaging method><imaging modality><imaging-based biological marker><imaging-based biomarker><imaging-based marker><immunoneurology><improved><insular sclerosis><intervention therapy><intra-vital imaging><intravital imaging><long-term study><longitudinal outcome studies><longterm study><lymph cell><mesoglia><microglial cell><microgliocyte><model of animal><model organism><multi-modality><multimodality><necropsy><nervous system disorder><neural degeneration><neurodegeneration><neurodegenerative><neurofilament><neuroimmunology><neurological degeneration><neurological disease><neuronal degeneration><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><non-human primate><nonhuman primate><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><pathophysiology><perivascular glial cell><postmortem><pre-clinical study><preclinical study><predicting response><prediction of response><predictive response><predictor of response><prevent><preventing><radio frequency><radiofrequency><remyelination><repair><repaired><response prediction><spatiotemporal><substantia alba><systems research><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><tissue repair><ultra high resolution><visual function><white matter>