Description (from grant): 

Significance: This proposal aims to address the important problem of currently being unable to accurately predict the course of multiple sclerosis (MS) in individual people. In ongoing efforts to improve care, we are developing a multi-faceted approach to readily predict and monitor (through state- of-the-art high-resolution brain and retinal imaging) disease severity and progression, with the goal of guiding individualized therapeutic decision-making among people with MS. One of the challenges facing treatment of people with multiple sclerosis (pwMS) is determining their likelihood of progression. We need to estimate CNS tissue microstructure status (myelin, axons, iron laden microglia [ILM]) to elucidate mechanisms of neurodegeneration in pwMS and their clinical relevance, and 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. 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. Our hypotheses are (i) HHA is a marker of retrograde TSD that occurs due to destructive PVP lesions, (ii) QSM-based susceptibility (ꭓ)-separation into positive (ILM) and negative (myelin) susceptibility provides additional information to quantitative lesion T1 for myelin, and (iii) reduced oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen (CMRO2) from MRI identify hypometabolism/neuronal dysfunction. Our aims are: 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 are indicators of metabolic stress that precede neurodegeneration and disability progression in MS.

Shin HG, Kim W, Lee JH, Lee HS, Nam Y, Kim J, Li X, van Zijl PCM, Calabresi PA, Lee J, Jang J. Association of iron deposition in MS lesion with remyelination capacity using susceptibility source separation MRI. Neuroimage Clin. 2025;45:103748. PMCID: PMC11847087.