# Superoxide-sensitive radiotracer as a predictive biomarker of Parkinson's disease progression

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $555,093

## Abstract

PROJECT SUMMARY
This proposal builds on decades of evidence supporting a crucial role for mitochondrial dysfunction and
inflammation in neurodegenerative disease. The goal of this proposal is to evaluate the potential of mitochondrial
stress signals as predictive biomarkers of Parkinson’s disease (PD) progression. Our working hypothesis is that
collective pressure from genetic and environmental risk factors impinges on mitochondrial homeostasis, inducing
the release of immunogenic stress signals that drive the aging brain into a pro-inflammatory state. If these stress
signals are not resolved, at-risk subjects will have a persistent elevation of oxidative stress that is above the
threshold for neurodegeneration, ultimately leading to the clinical manifestation of PD. To date, the earliest and
most established mitochondrial stress signal in PD is reactive oxygen species (ROS) production. One of the key
signaling functions of mitochondrial ROS is to alert the cellular environment of impending bioenergetic stress.
Mitochondrial ROS directly activate microglia, and boost the immunogenicity of other mitochondrial damage
associated patterns (mtDAMPs) and α-synuclein in the at-risk PD brain. The primary ROS produced by stressed
mitochondria and activated microglia is superoxide (O2-). Thus, O2- provides a signal of mitochondrial and
immune (mito-immune) stress. We will determine if this mito-immune signal is a critical driver of PD using the
first blood-brain barrier permeant, O2- - selective PET probe to track PD progression in vivo from the key
prodromal features to the end stages in distinct animal models. Our preliminary results support the hypothesis
that at-risk PD subjects have increased basal levels of oxidative stress that are 1) detectable by [18F]ROStrace,
2) correlate with PD progression, and 3) sensitize transgenic animals to toxins associated with PD. We now
propose to validate these findings in established PD mouse models with prodromal features specifically related
to mito-immune stress and α-synuclein pathology. The progression of the prodromal features will be monitored
by changes in dopaminergic signaling via PET/MRI, sleep-wake dynamics, and behavioral tests of mood,
olfaction, cognition, and autonomic function, prior to motor impairment caused by loss of dopaminergic neurons.
This approach will allow us to investigate the role of mito-immune signaling in conditions mimicking the
complexity of PD pathogenesis in the majority of late-onset patients. Our multi-tiered, highly translatable strategy
is designed to ensure direct application of this research to the clinic.

## Key facts

- **NIH application ID:** 9866160
- **Project number:** 1R01NS114656-01
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Meagan Joy McManus
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $555,093
- **Award type:** 1
- **Project period:** 2020-02-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9866160

## Citation

> US National Institutes of Health, RePORTER application 9866160, Superoxide-sensitive radiotracer as a predictive biomarker of Parkinson's disease progression (1R01NS114656-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9866160. Licensed CC0.

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