Tryptophan Metabolism and Neurodegeneration: Longitudinal Associations of Kynurenine Pathway Metabolites with Cognitive Performance and Plasma Alzheimer's Disease and Related Dementias Biomarkers in the Duke Physical Performance Across the LifeSpan Study.

Abstract

Background

The kynurenine pathway (KP) comprises a family of tryptophan-derived metabolites that some studies have reported are associated with poorer cognitive performance and an increased risk of Alzheimer's disease and related dementias (ADRD).

Objective

The objective of this study was to determine the associations of plasma KP metabolites (kynurenine [KYN], kynurenic acid [KA], and tryptophan [TRP]) with a panel of plasma ADRD biomarkers (Aβ42/ β40 ratio, pTau-181, glial fibrillary acidic protein [GFAP], and neurofilament light [NfL]) and cognitive performance in a subset of older adults drawn from the Duke Physical Performance Across the LifeSpan (PALS) study.

Methods

The Montreal Cognitive Assessment (MoCA) was used to assess cognitive performance. We used multivariate multiple regression to evaluate associations of the KYN/TRP and KA/KYN ratios with MoCA score and plasma ADRD biomarkers at baseline and over two years (n = 301; Age = 74.8±8.7).

Results

Over two years, an increasing KYN/TRP ratio was associated with increasing plasma concentrations of plasma p-Tau181 (β= 6.151; 95% CI [0.29, 12.01]; p = 0.040), GFAP (β= 11.12; 95% CI [1.73, 20.51]; p = 0.020), and NfL (β= 11.13; 95% CI [2.745, 19.52]; p = 0.009), but not MoCA score or the Aβ42/Aβ40 ratio. There were no significant associations of KA/KYN with MoCA score or plasma ADRD biomarkers.

Conclusion

Our findings provide evidence that greater concentrations of KP metabolites are associated longitudinally over two years with greater biomarker evidence of neurofibrillary tau pathology (pTau-181), neuroinflammation (GFAP), and neurodegeneration (NfL), suggesting that dysregulated KP metabolism may play a role in ADRD pathogenesis.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.3233/jad-220906

Publication Info

Parker, Daniel C, William E Kraus, Heather E Whitson, Virginia B Kraus, Patrick J Smith, Harvey Jay Cohen, Carl F Pieper, Richard A Faldowski, et al. (2022). Tryptophan Metabolism and Neurodegeneration: Longitudinal Associations of Kynurenine Pathway Metabolites with Cognitive Performance and Plasma Alzheimer's Disease and Related Dementias Biomarkers in the Duke Physical Performance Across the LifeSpan Study. Journal of Alzheimer's disease : JAD. pp. 1–10. 10.3233/jad-220906 Retrieved from https://hdl.handle.net/10161/26546.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.

Scholars@Duke

Parker

Daniel Christopher Parker

Assistant Professor of Medicine

Biological aging is the greatest risk factor for most chronic diseases, including frailty and dementia. The geroscience hypothesis posits that interventions that target aspects of biological aging may delay or prevent many of these diseases simultaneously. My research centers on understanding the mechanisms of interventions that affect biological aging, like exercise training and caloric restriction and using that understanding to develop therapies that maintain cognitive and physical function in older adults.

Whitson

Heather Elizabeth Whitson

Professor of Medicine

Dr. Whitson's research is focused on improving care options and resilience for people with multiple chronic conditions.  In particular, she has interest and expertise related to the link between age-related changes in the eye and brain (e.g., How does late-life vision loss impact the aging brain or cognitive outcomes?  Is Alzheimer's disease associated with distinctive changes in the retina, and could such changes help diagnose Alzheimer's disease early in its course?).  Dr. Whitson leads a collaborative Alzheimer's Disease initiative that brings together investigators from Duke University and the University of North Carolina (UNC) at Chapel Hill, with a bold vision to transform dementia research and care across Eastern North Carolina. Dr. Whitson is also interested in improving health services to better meet the needs of medically complex patients.  Within the Duke Aging Center, she leads research efforts aimed at promoting resilience to late-life stressors (e.g., surgery, sensory loss, infection).  She has developed a novel rehabilitation model for people with co-existing vision and cognitive deficits, and she is part of a inter-disciplinary team seeking to improve peri-operative outcomes for frail or at-risk seniors who must undergo surgery.  As a co-leader of a national resilience collaborative, she seeks to better understand the biological and psychological factors that determine how well we "bounce back" after health stressors.  

Pieper

Carl F. Pieper

Professor of Biostatistics & Bioinformatics

Analytic Interests.

1) Issues in the Design of Medical Experiments: I explore the use of reliability/generalizability models in experimental design. In addition to incorporation of reliability, I study powering longitudinal trials with multiple outcomes and substantial missing data using Mixed models.

2) Issues in the Analysis of Repeated Measures Designs & Longitudinal Data: Use of Hierarchical Linear Models (HLM) or Mixed Models in modeling trajectories of multiple variables over time (e.g., physical and cognitive functioning and Blood Pressure). My current work involves methodologies in simultaneous estimation of trajectories for multiple variables within and between domains, modeling co-occuring change.

Areas of Substantive interest: (1) Experimental design and analysis in gerontology and geriatrics, and psychiatry,
(2) Multivariate repeated measures designs,

Hall

Katherine Shepherd Hall

Associate Professor in Medicine

My research is focused on developing evidence-based physical activity interventions for older adults with an eye to preserving functional independence and quality of life. I am particularly interested in developing exercise programs to promote physical and psychological well-being among older veterans with posttraumatic stress disorder (PTSD). 

Ilkayeva

Olga Ilkayeva

Assistant Professor in Medicine

Olga Ilkayeva, Ph.D., is the Director of the Metabolomics Core Laboratory at Duke Molecular Physiology Institute. She received her Ph.D. training in Cell Regulation from UT Southwestern Medical Center at Dallas, TX. Her postdoctoral research in the laboratory of Dr. Chris Newgard at Duke University Medical Center focused on lipid metabolism and regulation of insulin secretion. As a research scientist at the Stedman Nutrition and Metabolism Center, Dr. Ilkayeva expanded her studies to include the development of targeted mass spectrometry analyses. Currently, she works on developing and validating quantitative mass spectrometry methods used for metabolic profiling of various biological models with emphasis on diabetes, obesity, cardiovascular disease, and the role of gut microbiome in both health and disease.

Bain

James R. Bain

Professor in Medicine
Newby

Laura Kristin Newby

Professor of Medicine

Research Description

General Focus: Clinical investigation the process and treatment of acute and chronic coronary artery disease and systems issues for delivery of care to patients with these illnesses. Particular interests include management of patients with chest pain and unstable angina, evaluation of the use of biochemical markers other than CK-MB for diagnosis and risk stratification in these patients, issues related to coronary artery disease in women, and systems issues regarding optimizing the process of delivery of care to patients with acute and chronic coronary artery disease. Finally, I have a strong interest in defining the genetic contribution to development of coronary artery disease.


Key words: coronary artery disease acute myocardial infarction unstable angina chest pain women biochemical markers risk stratification genetics

Huffman

Kim Marie Huffman

Associate Professor of Medicine

Determining the role of physical activity in modulating health outcomes (cardiovascular disease risk) in persons with rheumatologic diseases (rheumatoid arthritis, gout, osteoarthritis)

Integrating clinical rheumatology, basic immunology, metabolism, and exercise science in order to reduce morbidity in individuals with arthritis

Evaluating relationships between circulating and intra-muscular metabolic intermediates and insulin resistance in sedentary as well as individuals engaging in regular exercise

Addressing the role of physical activity in modulating inflammation, metabolism, and functional health in aging populations


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