# Optimizing Glutamate Imaging using CEST MRI at 3T Clinical Scanners

> **NIH NIH R03** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $85,000

## Abstract

PROJECT SUMMARY
Glutamate (Glu) is the primary excitatory neurotransmitter in the brain, and disruptions of normal glutamate
levels are implicated in a variety of major neurological and psychiatric disorders, which has led to major efforts
to measure Glu non-invasively. 1H MRS has been exploited to measure Glu but in practice is limited by low
sensitivity, low spatial resolution, and partial volume effects. A potential approach to imaging Glu with high
sensitivity is to exploit the chemical exchange saturation transfer (CEST) effect between water protons and the
rapidly exchanging amine protons of Glu at  3 ppm from water. However, although CEST imaging of Glu,
named GluCEST, was introduced over 6 years ago and has been successfully applied in diagnosing many
preclinical neurological disease models (e.g. tauopathy, dopamine deficiency, Huntington’s disease, and
Alzheimer’s disease etc.), it has not been translated to clinical applications at 3 T MRI. This is due to two
reasons: First, Glu is in the fast exchange regime and coalesces with water especially at 3 T, which
significantly influences GluCEST signals, causing the appearance of false resonances and non-specificities.
Although there are many CEST analysis methods that attempt to isolate exchange effects, they are designed
only for the slow and intermediate exchange regimes and cannot solve this coalescence effect and fail to
quantify GluCEST properly; Second, the molecular origin of GluCEST has not been comprehensively
evaluated and its specificity is still under debate. For instance, although Glu has exchangeable amine protons
at  3 ppm, protein lysine amines have similar chemical shifts and exchange rates in the fast exchange regime,
and thus may not be easily distinguished from Glu using CEST. In previous validation of GluCEST, only
contributions from the major brain metabolites were considered, but contributions from proteins were ignored.
This may be due to that it is difficult in practice to precisely mimic the lysine residues of the wide variety of
proteins found in tissues using simple models. This application proposes to overcome those challenges and
develop a practical data analysis method to allow routine imaging of Glu. In Aim 1, we will develop and
implement a new metric, termed tAREX (tangent theta normalized apparent exchange-dependent relaxation) to
address the need for better quantification in the fast exchange limit. Our preliminary analysis and simulations
show that tAREX can successfully remove the coalescence effect. In Aim 2, we will use dialysis to remove Glu
and other small molecules from samples of brain tissue homogenates to investigate the influence of proteins
on GluCEST. Together with measurements on phantoms containing major metabolites, the dialysis of tissue
homogenates can provide a comprehensive investigation of the origins of GluCEST. Ultimately, the approach
will help future translation of measurements of Glu to clinical scanners and applications. It ma...

## Key facts

- **NIH application ID:** 9874354
- **Project number:** 1R03EB029078-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Zhongliang Zu
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $85,000
- **Award type:** 1
- **Project period:** 2020-06-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9874354

## Citation

> US National Institutes of Health, RePORTER application 9874354, Optimizing Glutamate Imaging using CEST MRI at 3T Clinical Scanners (1R03EB029078-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9874354. Licensed CC0.

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