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|Title:||Systemic perturbations of the kynurenine pathway precede progression to dementia independently of amyloid-β.||Austin Authors:||Cespedes, Marcela;Jacobs, Kelly R;Maruff, Paul;Rembach, Alan;Fowler, Christopher J;Trounson, Brett;Pertile, Kelly K;Rumble, Rebecca L;Rainey-Smithe, Stephanie R;Rowe, Christopher C ;Villemagne, Victor L ;Bourgeat, Pierrick;Lim, Chai K;Chatterjee, Pratishtha;Martins, Ralph N;Ittner, Arne;Masters, Colin L ;Doecke, James D;Guillemin, Gilles J;Lovejoy, David B||Affiliation:||Australian eHealth Research Centre, CSIRO, Herston, Queensland, Australia..
Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia..
Cogstate Limited, Melbourne, Victoria, Australia..
The Florey Institute of Neuroscience and Mental Health
Centre for Healthy Ageing, Health Futures Institute, Murdoch University, Murdoch, Western Australia, Australia..
Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia..
Molecular Imaging and Therapy
The University of Pittsburgh, Pittsburgh, USA..
Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia..
Sir James McCusker Alzheimer's Disease Research Unit (Hollywood Private Hospital), Perth, Western Australia, Australia..
Dementia Research Centre and Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia..
|Issue Date:||Sep-2022||metadata.dc.date:||2022||Publication information:||Neurobiology of Disease 2022; 171: 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.||URI:||https://ahro.austin.org.au/austinjspui/handle/1/30315||DOI:||10.1016/j.nbd.2022.105783||ORCID:||0000-0001-8969-9193
|PubMed URL:||35675895||PubMed URL:||https://pubmed.ncbi.nlm.nih.gov/35675895/||Type:||Journal Article||Subjects:||Alzheimer's disease
|Appears in Collections:||Journal articles|
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