Document text
Principal Investigator: Matthew Ryan Brier
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $232,918
Funding agency: National Institute of Neurological Disorders and Stroke
ABSTRACT
Multiple sclerosis (MS) is an immune-mediated, demyelinating, and degenerative disease of the central
nervous system and is a leading cause of disability in young people. Most patients begin with a relapsing-
remitting (RRMS) course. Clinical relapse and new white matter lesion formation is dramatically reduced by
current therapies. However, despite evidently efficacious treatment of RRMS, many patients eventually
develop progressive MS (PMS) wherein disability accumulates refractory to treatment. Progressive disability is
driven by neurodegeneration which begins early in the disease, occurs independent of relapses, and is poorly
understood. Two potential contributors to neurodegeneration are subclinical inflammation and metabolic stress.
Clinical relapses and new lesion formation are driven by inflammatory demyelination, but additional
inflammation is present outside of discrete lesions. This inflammation is associated with chronic demyelination
and increased metabolic demand. Both inflammation and metabolic stress may lead to neurodegeneration,
either alone or in combination.
This study will use a novel positron emission tomography (PET) imaging agent, 11C-CS1P1, which binds to
sphingosine-1-phosphate-receptor 1 (S1PR1) as a marker of inflammation. S1PR1 signaling is critical to MS as
evidenced by four FDA approved S1P-modulators with high efficacy for reducing relapses in RRMS.
Additionally, we will use metabolic imaging with 18F-FDG PET and advanced, oxygen-sensitive magnetic
resonance imaging (MRI) to measure cerebral glucose and oxygen utilization, respectively. These
measurements will be made in a cohort of heathy control participants, RRMS patients who will be initiating an
S1P-modulating drug and RRMS patients initiating a similarly efficacious non-S1P-modulating drug (B-cell
depleting therapies). Patients will be imaged prior to and 3-months following initiation of treatment. These data
will allow for testing the hypotheses that subclinical inflammation and metabolic stress are present in RRMS
and are incompletely mitigated by current treatments. This study will address three Specific Aims. The first aim
tests the hypothesis that inflammation is increased outside of MS lesions in seemingly normal appearing tissue
and is reduced by S1P-modulation. The second aim will examine the metabolic needs and stress of normal
appearing white matter and gray matter in MS patients compared to controls. The first two aims will compare
their respective biomarkers pre- vs. post-initiation of an S1P-modualting drug. The final aim investigates how
S1PR1 expression and metabolic stress are modulated by an efficacious, but not S1P-modualting therapy.
Completion of this study will provide new understanding of processes that drive neurodegeneration in
MS and contribute to clinical morbidity and disability.
Terms: <18-FDG><18F- FDG><18FDG><2 Fluoro 2 deoxy D glucose><2-Fluoro-2-deoxyglucose><Affect><Age><Atrophic><Atrophy><Autoregulation><Axon><B blood cells><B cell><B cell depletion therapy><B cell directed therapy><B cell targeted therapy><B cell therapies><B cell therapy><B cells><B-Cells><B-Lymphocytes><B-cell><BBB crossing><Binding><Biological Markers><Body Tissues><Brain Inflammation><CNS Degenerative Diseases><CNS Degenerative Disorders><Career Development Awards><Career Development Awards and Programs><Career Development Programs K-Series><Cell Body><Cell Communication and Signaling><Cell Death><Cell Signaling><Cells><Central Nervous System Degenerative Diseases><Cerebrum><Clinical><Clinical assessments><D-Glucose><Data><Demyelinating Diseases><Demyelinating Disorders><Demyelinations><Dextrose><Disability status><Disease><Disease remission><Disorder><Disseminated Sclerosis><Drug Modulation><Drugs><Dysfunction><Edg Receptors><Encephalitis><Equilibrium><Evaluation><FDA approved><Failure><Functional disorder><Glucose><Glycolysis><Homeostasis><Image><Immune><Immunes><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Inflammation><Inflammatory><Inflammatory Response><Injury><Intermediary Metabolism><Intracellular Communication and Signaling><K-Awards><K-Series Research Career Programs><Knowledge><Lesion><MR Imaging><MR Tomography><MRI><MRIs><MS Lesions><MS patient><MS treatment><Magnetic Resonance Imaging><Measurement><Measures><Mediating><Medical><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medication><Mentors><Metabolic><Metabolic Processes><Metabolic stress><Metabolism><Mice><Mice Mammals><Modeling><Molecular Interaction><Monitor><Morbidity><Morbidity - disease rate><Multiple Sclerosis><Multiple Sclerosis Lesions><Murine><Mus><Myelin><NMR Imaging><NMR Tomography><Nature><Nerve Degeneration><Neurological disability><Neuron Degeneration><Nuclear Magnetic Resonance Imaging><O element><O2 element><Outcome><Oxygen><PET><PET Scan><PET imaging><PETSCAN><PETT><Participant><Pathology><Patients><Persons><Pharmaceutical Preparations><Physiological Homeostasis><Physiopathology><Position><Positioning Attribute><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Process><Rad.-PET><Refractory><Relapse><Relapsing-Remitting Multiple Sclerosis><Remission><Research Career Program><S1P Receptor><Scanning><Signal Transduction><Signal Transduction Systems><Signaling><Sphingosine-1-Phosphate Receptor><Stress><Testing><Therapeutic><Tissues><Zeugmatography><ages><anti-CD20><balance><balance function><bio-markers><biologic marker><biological signal transduction><biomarker><blood-brain barrier crossing><bloodbrain barrier crossing><brain tissue><cerebral><chronic demyelination><cohort><compare to control><comparison control><de-myelinating diseases><de-myelinating disorders><demyelinate><demyelinating conditions><demyelination diseases><demyelination disorders><disability><drug/agent><effective therapy><effective treatment><efficacious therapy><efficacious treatment><fluorodeoxyglucose><glucose uptake><gray matter><imaging><imaging agent><inflammation marker><inflammatory marker><injuries><insular sclerosis><interest><kinetic model><lymphocyte trafficking><metabolic imaging><metabolic rate><multiple sclerosis patient><multiple sclerosis therapy><multiple sclerosis treatment><necrocytosis><nerve injury><neural degeneration><neural imaging><neural injury><neuro-imaging><neurodegeneration><neurodegenerative><neuroimaging><neurological degeneration><neurological imaging><neuronal degeneration><novel><overexpress><overexpression><pathophysiology><patients with MS><patients with multiple sclerosis><people with Multiple sclerosis><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><radiolabel><radiolabels><radiotracer><recruit><repair><repaired><response><substantia alba><substantia grisea><treatment effect><treatment strategy><uptake><white matter>