There is emerging evidence that gray matter (GM) degeneration is common in multiple sclerosis (MS), and more closely linked with disability than white matter (WM) injury. Indeed, WM volumes, as measured by high resolution MRI, wax and wane as a reflection of inflammation, whereas GM atrophy accelerates with time in MS. Whether GM degeneration purely results from WM injury or may also occur as a primary process in MS is unclear. More recently there has been growing evidence that primary neuronal loss in the cortex and retina may occur in MS, independent of demyelination or axonal injury. The retina, although an unmyelinated brain structure, is now recognized to be a frequent site of inflammation, blood-retinal-barrier disruption, and neuronal loss in MS, highlighting the retina as an opportune site to study the mechanisms by which inflammation directly mediates neurodegeneration in MS, and link these processes back to what is occurring in the brain. However, the interplay between changes in retinal layers over time, and the relationships of these changes with brain-substructure changes in MS remains unclear, and we propose to investigate this in the current application. Herein, we hypothesize that ONL atrophy is the consequence of INL inflammation, and signifies increased susceptibility for global neurodegeneration in MS as a consequence of inflammation. The completion of the experiments outlined in this application will reveal novel insights into the pathobiological mechanisms through which inflammation mediates neurodegeneration in myelinated and unmyelinated regions of the brain in MS. Specifically, we plan to determine if primary neuronal mechanisms of pathology are operative in MS retina, and if this primary neuronopathy is predictive of GM atrophy and the accrual of clinical disability in MS. The results could provide evidence to challenge the paradigm that MS is a myelin dependant disorder, and directly impact present concepts of how to target degeneration and disease progression in MS.

Public Health Relevance

There is emerging evidence that gray matter (GM) degeneration is common in multiple sclerosis (MS), and more closely linked with disability than white matter (WM) injury. This project will utilize a novel technology called optic coherence tomography (OCT) with deep retinal neuronal layer segmentation to image neurons in the inner and outer nuclear layers of the retina and study how they degenerate. These data will be used in longitudinal models to determine if retinal degeneration can predict GM atrophy in other parts of the brain and clinical disability. Understanding the mechanisms of neurodegeneration and developing predictive imaging biomarkers of neurodegeneration is critically important for developing better therapies to target this untreatable aspect of MS, which ultimately is what causes long-term disability, loss of quality of life, premature departure from the work-force and billions of dollars cost to society.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Utz, Ursula
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Johns Hopkins University
Schools of Medicine
United States
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Kimbrough, Dorlan J; Sotirchos, Elias S; Wilson, James A et al. (2015) Retinal damage and vision loss in African American multiple sclerosis patients. Ann Neurol 77:228-36
Bhargava, Pavan; Calabresi, Peter A (2013) The expanding spectrum of aetiologies causing retinal microcystic macular change. Brain 136:3212-4