# Novel Imaging Biomarker for Treating Spatial Memory Loss in Prodromal Alzheimer's Disease Models

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2021 · $558,744

## Abstract

Project Summary / Abstract: There is an urgent need for disease-modifying treatment of
Alzheimer's disease (AD) starting at its very onset. This knowledge gap remains because
conventional approaches cannot measure in vivo brain region-specific biomarkers of the earliest
relevant dysfunction underlying abnormal behavior. Often, spatial disorientation is observed
during prodromal AD, and its occurrence predicts later dementia. A brain region contributing to
this spatial confusion is the CA1 subfield of hippocampus because of its essential role in
encoding spatial information. HC oxidative stress is most commonly identified at the very start of
AD, and in experimental models of AD. Yet, it has not been possible to prove that prodromal
oxidative stress in the relevant CA1 subfield plays a pathogenic role in at-risk patients showing
impaired spatial memory because conventional methods only measure oxidative stress from
post-mortem tissue. Addressing this major knowledge gap requires a new paradigm that
compares antioxidant treatment efficacy in HC CA1 subregions in vivo with improved spatial
learning and memory in experimental models, and that can then be translated into patients. In
this proposal, we present a transformative solution to this problem based on a novel method
recently discovered by our lab: QUEnch-assiSTed MRI (QUEST MRI). QUEST MRI is a robust
and sensitive tool that has been validated against “gold standard” methods and maps in vivo
excessive free radical production in, for example, murine dorsal CA1. The QUEST MRI index of
abnormally high production of paramagnetic free radicals in specific brain regions is a greater-
than-normal spin-lattice relaxation rate R1 (1/T1) that can be returned to baseline after acute
antioxidant administration. Our QUEST MRI studies have confirmed dorsal HC CA1-specific
oxidative stress in spontaneous and familial AD mouse models with declines in spatial learning
and memory in conjunction with HC CA1 oxidative stress measured ex vivo. We also find
downstream consequences of oxidative stress such as greater-than-normal amounts of the lipid
peroxidation product 4-hydroxynonenal (HNE), dorsal HC CA1 calcium dysregulation and
reductions in dorsal HC CA1 calcium-dependent afterhyperpolarization (AHP). To improve
statistical power, this proposal is tightly focused on uniquely testing a specific working
hypothesis that oxidative stress in dorsal CA1 in vivo causes deterioration of spatial memory in
experimental models. Our highly innovative studies by an experienced team of experts will
validate a new bridging tool for testing in vivo antioxidant therapeutic strategies to mitigate a
clinically important early decline in spatial memory preceding later loss of personhood in AD.

## Key facts

- **NIH application ID:** 10165441
- **Project number:** 5R01AG058171-05
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** BRUCE A. BERKOWITZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $558,744
- **Award type:** 5
- **Project period:** 2017-09-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165441

## Citation

> US National Institutes of Health, RePORTER application 10165441, Novel Imaging Biomarker for Treating Spatial Memory Loss in Prodromal Alzheimer's Disease Models (5R01AG058171-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10165441. Licensed CC0.

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