Imaging Neurodegeneration in Multiple Sclerosis

Project Summary/Abstract One of the challenges facing treatment of people with multiple sclerosis (pwMS) is determining their likelihood of progression. This is critical since it influences risk-benefit and therapy selection. We are validating objective state-of-the-art MRI methods (e.g. separation of myelin vs iron-based signal [chi [ꭓ] separation] with quantitative magnetic susceptibility mapping [QSM], quantitative T1 lesion mapping [QT1M], multi-shell diffusion MRI [dMRI], and tensor-valued dMRI) to estimate CNS tissue microstructure (myelin, axons, iron laden microglia [ILM]) to elucidate mechanisms of neurodegeneration in pwMS, and their clinical relevance, to monitor and predict MS disease progression. In the past cycle of this grant we demonstrated that anterograde trans‐synaptic degeneration (TSD) is a mechanism of neurodegeneration after acute optic neuritis in pwMS that is associated with worse visual outcomes. We have also found that some pwMS with posterior visual pathway (PVP) lesions exhibit anatomically correlating homonymous hemi-macular ganglion cell inner plexiform layer (GCIPL) atrophy (HHA) on optical coherence tomography (OCT), consistent with retrograde TSD. We found utilizing novel MRI sequences that oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) are abnormal in pwMS consistent with cerebral metabolic dysfunction, and that retinal OCT angiography (OCTA) derived superficial venous plexus (SVP) density provides insight into cerebral metabolic function. In this current study, we will determine the relevance of TSD in pwMS, the microstructural features of PVP lesions that cause vs. do not cause TSD, and how demyelination, metabolic dysfunction, vascular integrity, and axonal loss in the brain and retina are inter-connected, and their clinical relevance. This will allow the development of novel outcomes for assessing neuroprotection, remyelination, and ILM in clinical trials and precision care. Our hypotheses are that HHA is a marker of retrograde TSD that occurs due to destructive PVP lesions; QSM-based ꭓ separation into positive (ILM) and negative (myelin) susceptibility provides additional information to QT1M (lesion myelin); and that reduced OEF, CMRO2 and SVP density identify hypometabolism/neuronal dysfunction. Aim 1: To determine whether TSD is a predictor of whole brain atrophy and a signature of worsening MS. Aim 2: To determine whether the microstructural components of neurodegeneration can be estimated within and distant (TSD) to lesions, and if this predicts global neurodegeneration and future disability in pwMS. Aim 3: To determine whether reduced OEF, CMRO2, and retinal SVP density are indicators of metabolic stress that precede neurodegeneration and disability progression in MS.