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.
Neurobiol Dis. 2022 Sep;171:105783. doi: 10.1016/j.nbd.2022.105783. Epub 2022 Jun 5.
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.
越来越多的证据表明，犬尿氨酸途径（KP）的失衡可能会促进痴呆症的疾病进展。在阿尔茨海默病（AD）患者中的研究证实了 KP 失衡存在于血浆和脑脊液（CSF）中，且与淀粉样蛋白-β和tau 病理学相关。在此，我们进行了第一项全面研究，评估了澳大利亚影像学生物标志物老化旗舰研究入组参与者的 KP 代谢物基线水平。我们的目的是检验假设，即 KP 代谢物的变化可能是痴呆症过程的生物标志物，而这些过程在很大程度上是沉默的。我们使用横断面分析方法来评估非进展者（N=73）；认知正常（CN）或轻度认知障碍（MCI）参与者的基线和整个研究期间，以及进展者（N=166）；基线时为 CN 或 MCI，但在研究期间进展为 MCI 或 AD。进展者中 KP 的显著变化包括 3-羟基犬尿氨酸（3-HAA）和 3-羟基犬尿氨酸/犬尿氨酸（3-HAA/AA）的比值增加，后者对个体成为进展者的可能性影响最大（比值比 35.3；95%置信区间为 14 到 104）。因此，3-HAA 水平令人惊讶地呈双相性，进展者中水平较高，但非进展者或已经进展为 MCI 或痴呆症的参与者中水平较低。这是一个新的、意想不到的和有趣的结果，因为大多数神经退行性疾病中 KP 的研究表明，诊断后 3-HAA/AA 比值降低。神经保护代谢物吡啶酸也显著降低，而神经毒性代谢物 3-羟基犬尿氨酸在进展者中增加。即使在调整混杂因素后，这些结果仍然显著。考虑到预测认知变化的比值比的大小，这些发现需要在其他人群中得到复制。我们的研究结果的独立验证可能会确认 3-HAA/AA 比值预测认知变化并导致痴呆症的临床实用性。
