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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.

Publication ,  Journal Article
Parker, DC; Kraus, WE; Whitson, HE; Kraus, VB; Smith, PJ; Cohen, HJ; Pieper, CF; Faldowski, RA; Hall, KS; Huebner, JL; Ilkayeva, OR; Bain, JR ...
Published in: J Alzheimers Dis
2023

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.

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Published In

J Alzheimers Dis

DOI

EISSN

1875-8908

Publication Date

2023

Volume

91

Issue

3

Start / End Page

1141 / 1150

Location

Netherlands

Related Subject Headings

  • Tryptophan
  • Neurology & Neurosurgery
  • Longevity
  • Kynurenine
  • Humans
  • Cognition
  • Biomarkers
  • Alzheimer Disease
  • Aged, 80 and over
  • Aged
 

Citation

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Parker, D. C., Kraus, W. E., Whitson, H. E., Kraus, V. B., Smith, P. J., Cohen, H. J., … Huffman, K. M. (2023). 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. J Alzheimers Dis, 91(3), 1141–1150. https://doi.org/10.3233/JAD-220906
Parker, Daniel C., William E. Kraus, Heather E. Whitson, Virginia B. Kraus, Patrick J. Smith, Harvey Jay Cohen, Carl F. Pieper, et al. “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.J Alzheimers Dis 91, no. 3 (2023): 1141–50. https://doi.org/10.3233/JAD-220906.
Parker DC, Kraus WE, Whitson HE, Kraus VB, Smith PJ, Cohen HJ, Pieper CF, Faldowski RA, Hall KS, Huebner JL, Ilkayeva OR, Bain JR, Newby LK, Huffman KM. 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. J Alzheimers Dis. 2023;91(3):1141–1150.

Published In

J Alzheimers Dis

DOI

EISSN

1875-8908

Publication Date

2023

Volume

91

Issue

3

Start / End Page

1141 / 1150

Location

Netherlands

Related Subject Headings

  • Tryptophan
  • Neurology & Neurosurgery
  • Longevity
  • Kynurenine
  • Humans
  • Cognition
  • Biomarkers
  • Alzheimer Disease
  • Aged, 80 and over
  • Aged