痴呆
犬尿氨酸
代谢物
犬尿氨酸途径
喹啉酸
混淆
神经保护
疾病
内科学
淀粉样蛋白(真菌学)
新喋呤
脑脊液
医学
优势比
心理学
神经科学
肿瘤科
病理
生物
生物化学
色氨酸
氨基酸
作者
Marcela I. Cespedes,Kelly R. Jacobs,Paul Maruff,Alan Rembach,Christopher Fowler,Brett Trounson,Kelly K. Pertile,Rebecca Rumble,Stephanie R. Rainey‐Smith,Christopher C. Rowe,Victor L. Villemagne,Pierrick Bourgeat,Chai K. Lim,Pratishtha Chatterjee,Ralph N. Martins,Arne Ittner,Colin L. Masters,James D. Doecke,Gilles J. Guillemin,David B. Lovejoy
标识
DOI:10.1016/j.nbd.2022.105783
摘要
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.
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