Longitudinal Measurement of Neurodegeneration in two Murine Models of Multiple Sclerosis: A Clinical and Histopathologic Validation Study

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PROJECT SUMMARY Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system whereby relentless demyelination and neuroaxonal loss are the primary cause of irreversible disability. Testing strategies to address the neurodegenerative component of the disease, in an attempt to halt the progression and promote functional recovery, is a significant focus of translational research in MS. However, a lack of suitable biomarkers to monitor disease progression is a significant impediment to this effort. Recent advances in neuroimaging offer novel opportunities to develop and validate biomarkers of neurodegeneration as valuable adjuncts to diagnostic and monitoring tools. To this end, recent work performed at Vanderbilt University Medical Center led to the technical development of two innovative quantitative magnetic resonance imaging (MRI) techniques, i.e., the selective inversion recovery quantitative magnetization transfer imaging (SIR-qMT) and the diffusion imaging using the spherical mean technique (SMT). SIRqMT and SMT provide a novel framework for non-invasive quantification of myelin and axonal injury, respectively. Several animal models of MS are currently available to study different clinical and biological features of the disease. For example, the myelin proteolipid protein (PLP)-induced experimental allergic encephalomyelitis (EAE) resembles the relapsing-remitting MS phenotype (R-EAE) and serves as a valuable model to study the development of relapses, acute inflammation and demyelination/remyelination. Conversely, the Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) mouse model uniquely reproduces clinical and pathological features of progressive MS, such as demyelination, chronic neuroinflammation, and axonal damage, leading to slowly progressing disability. The two models provide complementary information regarding MS development and evolution and together form an ideal model system to test the potentials of novel therapies. Accordingly, we hypothesize that the pool saturation ratio (PSR) derived from SIR-qMT and the (apparent) axonal volume fraction (Vax) derived from SMT will provide early and sensitive biomarkers of myelin and axonal injury, respectively, in the brain and spinal cord of the two murine models. Brain and spinal cord MRIs will be longitudinally performed in R-EAE, TMEV-IDD and age-matched sham- treated mice, using histology and behavioral analysis to validate imaging derived biometrics. The short-term goal and objective of this study are to apply SIR-qMT and SMT in two clinically distinct mouse models of MS to validate PSR and Vax against histopathologic and clinical counterparts. The long-term goal of our research is to develop more effective and non-invasive biomarkers of neurodegeneration and repair that can be used to investigate changes of MS, both in animal models and humans, during natural history studies and experimental clinical trials.