# Imaging Neurodegeneration in Multiple Sclerosis

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $662,494

## Abstract

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.

## Key facts

- **NIH application ID:** 10979187
- **Project number:** 2R01NS082347-11A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** PETER A CALABRESI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $662,494
- **Award type:** 2
- **Project period:** 2013-04-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979187

## Citation

> US National Institutes of Health, RePORTER application 10979187, Imaging Neurodegeneration in Multiple Sclerosis (2R01NS082347-11A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10979187. Licensed CC0.

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