# Multi-scale, multi-modal imaging assessment of trajectories of cognitive impairment in Multiple Sclerosis

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $694,369

## Abstract

Cognitive impairment is highly prevalent in patients with multiple sclerosis (MS) and increases in severity with
disease progression. Unfortunately, treatment options for MS-related cognitive impairment are limited in that
they are not neurobiologically-based or personalized. Moreover, to date there are no approved pharmaceutical
treatments to manage chronic cognitive symptoms. Brain network studies using diffusion MRI (dMRI) to measure
white matter structural connectivity (SC) and functional MRI (fMRI) to measure functional connectivity (FC) have
identified specific networks related to cognitive impairment in MS. However, both increased and decreased FC
have been associated with lower cognitive performance, leading to unresolved questions regarding the response
of brain networks to the pathology of MS. There is an urgent, unmet need to understand the directionality of this
relationship, and mechanisms driving these brain activity changes, if we are to design neurobiologically-based
cognition-preserving therapies. Our overall objective is to utilize a multi-scale, multi-modal, longitudinal imaging
approach to examine the association of cognitive function with both macroscopic and microscopic changes in
brain function, anatomy, and neuronal integrity, and to create clinically applicable models that can identify
patients at risk for cognitive decline. We will utilize MRI to examine FC and SC brain networks (macroscopic)
and [11C] Flumazenil (FMZ) positron emission tomography (PET) to measure concurrent receptor-level neuronal
integrity (microscopic). We our hypotheses are based on a three-stage trajectory of cognitive decline in MS i)
early “adaptive” stage where increased FC is related to intact neuronal integrity and cognitive resilience, ii) middle
“adaptive exhaustion” stage of cognitive decline wherein FC continues to increase but with decreasing efficacy
due to loss of neuronal integrity and continued SC damage and, finally, iii) “decline” or network collapse stage
wherein all imaging markers decline with cognition. Here, we focus on the first two stages of the trajectory, as
our aim is to identify mechanistic targets prior to overall decline. In Aim 1, we will examine the association
between cognition and each imaging modality (and their changes) over 4 years in 66 people with MS and 30
controls. Our hypothesis is that larger FC/FMZ-PET binding potential and more intact SC/gray matter volume
will be related to preserved cognition in the “adaptive” stage of cognitive decline, while higher FC and reduced
SC/FMZ-PET and gray matter volume will be related to worse cognition in the “adaptive exhaustion” stage. In
Aim 2, we hypothesize multi-modal, multi-scale imaging will reveal i) positive correlations between neuronal
integrity and FC and ii) negative correlations between neuronal integrity and SC in the “adaptive” stage; both of
these relationships will reverse in the “adaptive exhaustion” stage. Lastly, in Aim 3, we will use MRI-based
measure...

## Key facts

- **NIH application ID:** 10981498
- **Project number:** 1R01NS134646-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Susan A Gauthier
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $694,369
- **Award type:** 1
- **Project period:** 2024-08-08 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981498

## Citation

> US National Institutes of Health, RePORTER application 10981498, Multi-scale, multi-modal imaging assessment of trajectories of cognitive impairment in Multiple Sclerosis (1R01NS134646-01A1). Retrieved via AI Analytics 2026-06-13 from https://api.ai-analytics.org/grant/nih/10981498. Licensed CC0.

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