Document Type

Journal Article

Publication Title

Neurobiology of Disease

Volume

171

PubMed ID

35675895

Publisher

Elsevier

School

School of Medical and Health Sciences / Centre of Excellence for Alzheimer's Disease Research and Care

Funders

National Health and Medical Research Council

Grant Number

NHMRC Number : APP1128849

Grant Link

http://purl.org/au-research/grants/nhmrc/1128849

Comments

Cespedes, M., Jacobs, K. R., Maruff, P., Rembach, A., Fowler, C. J., Trounson, B., ... & Lovejoy, D. B. (2022). Systemic perturbations of the kynurenine pathway precede progression to dementia independently of amyloid-β. Neurobiology of Disease, 171 105783. https://doi.org/10.1016/j.nbd.2022.105783

Abstract

Increasing evidence suggests that kynurenine pathway (KP) dyshomeostasis may promote disease progression in dementia. Studies in Alzheimer's disease (AD) patients confirm KP dyshomeostasis in plasma and cerebrospinal fluid (CSF) which correlates with amyloid-β and tau pathology. Herein, we performed the first comprehensive study assessing baseline levels of KP metabolites in participants enrolling in the Australian Imaging Biomarkers Flagship Study of Aging. Our purpose was to test the hypothesis that changes in KP metabolites may be biomarkers of dementia processes that are largely silent. We used a cross-sectional analytical approach to assess non-progressors (N = 73); cognitively normal (CN) or mild cognitive impairment (MCI) participants at baseline and throughout the study, and progressors (N = 166); CN or MCI at baseline but progressing to either MCI or AD during the study. Significant KP changes in progressors included increased 3-hydroxyanthranilic acid (3-HAA) and 3-hydroxyanthranilic acid/anthranilic acid (3-HAA/AA) ratio, the latter having the largest effect on the odds of an individual being a progressor (OR 35.3; 95% CI between 14 and 104). 3-HAA levels were hence surprisingly bi-phasic, high in progressors but low in non-progressors or participants who had already transitioned to MCI or dementia. This is a new, unexpected and interesting result, as most studies of the KP in neurodegenerative disease show reduced 3-HAA/AA ratio after diagnosis. The neuroprotective metabolite picolinic acid was also significantly decreased while the neurotoxic metabolite 3-hydroxykynurenine increased in progressors. These results were significant even after adjustment for confounders. Considering the magnitude of the OR to predict change in cognition, it is important that these findings are replicated in other populations. Independent validation of our findings may confirm the utility of 3-HAA/AA ratio to predict change in cognition leading to dementia in clinical settings.

DOI

10.1016/j.nbd.2022.105783

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Included in

Diseases Commons

Share

 
COinS