# Healthy Skeletal Muscle, Healthy Brain: Are Kynurenine Metabolites the Link?

> **NIH NIH R03** · DUKE UNIVERSITY · 2020 · $161,000

## Abstract

ABSTRACT
There is increasing evidence that sarcopenia is a risk factor for Alzheimer’s disease and related dementias
(ADRD), but the potential mechanisms are unknown. The significance of this gap was highlighted at the 2019
NIA-sponsored U13 Osteoporosis & Soft Tissue Disorders Conference where improved understanding of the
relationship of skeletal muscle and cognitive impairment was identified as a priority. As recently updated by the
European Working Group on Sarcopenia in Older People (EWGSOP), sarcopenia is defined as the aging-
related accumulation of adverse muscle changes that culminates in muscle failure and is best characterized by
poor muscle strength. Age-related sarcopenia and ADRD may be mechanistically linked by dysregulated
kynurenine metabolism in skeletal muscle. Kynurenines are tryptophan metabolites with neurotoxic or
neuroprotective effects. Activity-induced skeletal muscle contraction may protect against ADRD by decreasing
accumulation of neurotoxic kynurenines in the brain, with effects regulated by activity-induced muscle
contractions.
In this study, I propose to measure plasma concentrations of kynurenine metabolites in a community-dwelling
older adults to determine the relationship between physical activity, skeletal muscle strength, and
neurocognitive outcomes at baseline and after two years. My central hypothesis is that physical inactivity leads
to skeletal muscle alterations and sarcopenia, characterized functionally by poor muscle strength and
molecularly by accumulation of neurotoxic kynurenines. Accumulation of neurotoxic kynurenines increases
ADRD risk, which is reflected by greater concentrations of plasma neurofilament light (NfL) – a biomarker of
neurodegeneration – and poorer cognitive performance. If the relationship between physical activity, skeletal
muscle strength, and cognitive performance is mediated by neurotoxic kynurenine metabolites, that will support
further studies investigating therapies directed to skeletal muscle to treat ADRD. Fortunately, I have the
unique opportunity to address this research question by leveraging an existing cohort of older adults with
baseline and two-year observational measures of actigraphy-based physical activity, physical performance,
and cognition as well as plasma available for kynurenine determination.
The goal of this project is closely aligned with the GEMSSTAR objective to support junior physician-scientists
bridging geriatrics and medical subspecialties – in this case, neurology and neuropsychology – to become
future leaders in aging research. Completion of these aims will support my professional development
objectives, outlined within this GEMSSTAR application, by developing cross-specialty expertise in two
common, co-occurring geriatric syndromes: sarcopenia and ADRD. I will develop expertise in the selection,
use, and analysis of neuropsychological assessments and refine my neuroscience mentoring and collaborative
networks. Results of this work will serve as ...

## Key facts

- **NIH application ID:** 10027781
- **Project number:** 1R03AG067987-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Daniel C Parker
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $161,000
- **Award type:** 1
- **Project period:** 2020-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10027781

## Citation

> US National Institutes of Health, RePORTER application 10027781, Healthy Skeletal Muscle, Healthy Brain: Are Kynurenine Metabolites the Link? (1R03AG067987-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10027781. Licensed CC0.

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