# Myelin mechanisms of brain synaptic dysfunction in breast cancer therapy survivors

> **NIH NIH P20** · UNIV OF ARKANSAS FOR MED SCIS · 2023 · $205,200

## Abstract

Myelin mechanisms of brain synaptic dysfunction in breast cancer therapy survivors. Breast cancer 
therapy, particularly chemotherapy involving doxorubicin (DOX), negatively impacts brain health, leading to 
cognitive deficits in over 75% of survivors. These cognitive difficulties encompass learning, memory, executive 
function, and psychomotor speed, affecting daily functioning. Chemotherapy disrupts neuronal metabolism, 
myelin formation, and neuroplasticity. While the functional detriments associated with DOX-chemotherapy are 
clinically obvious, the very nature of chemotherapy-induced changes in myelin-related synaptic health across 
the brain remains elusive. Recent research has observed that structural integrity (measured by diffusion 
fraction of anisotropy) and N-acetylaspartate (NAA) are both reduced bilaterally in the posterior cingulate gyrus 
of breast chemotherapy patients, and total creatine (tCr) is abnormally reduced in these same areas. Separate 
studies performed in breast cancer survivors also report that (i) the cingulate cortex shows reduced function 
during task and at rest and (ii) myelin fractions are lower in the cingulate’s interconnecting white matter (e.g., 
cingulum bundle, prefrontal, thalamic radiations). Given the primal role the cingulate cortex plays in cognition, 
these findings indicate that myelin-related synaptic dysfunction may play a mechanistic role in cancer therapy 
induced cognitive impairments. Investigating this further is a necessary step to the development of preventive 
and regenerative interventions. Despite the understanding that activity-dependent myelination is a known 
mechanism of adult brain plasticity that is reported to restore function in other conditions of aplastic 
myelination, this knowledge cannot be implemented in breast chemotherapy patients until more is known about 
treatment’s effects on synaptic health. The overall objective of this proposal is to investigate the alterations in 
synaptic health that occur in breast cancer survivors to inform possible future mitigation strategies. Our central 
hypothesis posits that cognitive impairments post-chemotherapy correlate with reduced NAA and myelination 
loss, which in turn leads to lasting deficits. The study plans to measure molecular markers of synaptic health, 
myelination integrity, and neurocognitive function in a longitudinal study of DOX-treated breast cancer patients 
to understand these relationships and elucidate possible future mitigation strategies. Our aims include: (1) 
Characterize synaptic dysfunction across brain networks of cognition post-cancer treatment; (2) Characterize 
myelination health across brain networks of cognition; and (3) Investigate the association between myelinrelated 
synaptic dysfunction and cognitive function. Overall, this research aims to shed light on the 
mechanisms behind cognitive impairments in breast cancer survivors.

## Key facts

- **NIH application ID:** 11158460
- **Project number:** 5P20GM109005-09
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** Tatiana Wolfe
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $205,200
- **Award type:** 5
- **Project period:** 2023-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11158460

## Citation

> US National Institutes of Health, RePORTER application 11158460, Myelin mechanisms of brain synaptic dysfunction in breast cancer therapy survivors (5P20GM109005-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11158460. Licensed CC0.

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