# Detection, characterization and treatment of chronic microglial inflammation in established MS lesions

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $346,631

## Abstract

PROJECT SUMMARY
It is critical to monitor inflammation in multiple sclerosis (MS) patients for prognostication and optimization of
treatment. In current clinical practice, inflammation is inferred from accumulation of gadolinium (Gd) in acute
lesions where the blood brain barrier is disrupted. However, the substantial and long-lasting microglial
inflammation in established lesions occurring behind an intact blood brain barrier cannot be detected with
conventional MRI.
In this proposal we will address this unmet need by exploring the ability of quantitative susceptibility mapping
(QSM) to quantify microglial activation in white matter lesions. QSM is a post-processing tool that extracts
tissue magnetic susceptibility from gradient echo (GRE) data and is thus highly sensitive to iron. A striking
feature of chronically activated microglia within MS lesions and the lesion perimeter is their high iron content,
which can be detected by QSM. We hypothesize that iron is a sensitive biomarker for chronic, neurotoxic
microglial activation in MS lesions and can be accurately detected with QSM. We further hypothesize that
dimethyl fumarate (Tecfidera®), a FDA-approved MS treatment, prevents iron uptake by microglia and
concurrent tissue damage in chronic lesions in MS patients.
We will test our hypotheses in a multipronged approach, by confirming that accumulation of iron is associated
with a proinflammatory, cytotoxic phenotype in cultured human microglia and in human MS autopsy tissue and
that dimethyl fumarate (Tecfidera®) reduces iron uptake and proinflammatory polarization in cultured microglia.
Moreover, we will combine imaging of MS autopsy tissue with its histopathological analysis to confirm the
accuracy of QSM in detecting iron-positive microglia. We will finally conduct a clinical study in which we test
the ability of Tecfidera® to prevent iron accumulation (and thus proinflammatory microglial activation) and
concomitant tissue damage in white matter lesions of MS patients.
In summary, we are characterizing, quantifying and targeting in MS patients a novel pathomechanisms,
persistent proinflammatory activation of microglia, which may contribute to neurodegeneration and disease
severity. QSM can be easily implemented in clinical practice and may become a routine MRI technique to aid
treatment decisions for patients that appear stable on conventional MRI but contain a high burden of lesional
microglial activation.

## Key facts

- **NIH application ID:** 10245035
- **Project number:** 5R01NS102267-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** David Pitt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $346,631
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10245035

## Citation

> US National Institutes of Health, RePORTER application 10245035, Detection, characterization and treatment of chronic microglial inflammation in established MS lesions (5R01NS102267-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10245035. Licensed CC0.

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