Department of Biomedical Sciences, Macquarie University, North Ryde, NSW, Australia.
School of Medical Health and Sciences, Edith Cowan University, Joondalup, WA, Australia.
J Neuroinflammation. 2019 Oct 10;16(1):186. doi: 10.1186/s12974-019-1567-4.
Blood markers indicative of neurodegeneration (neurofilament light chain; NFL), Alzheimer's disease amyloid pathology (amyloid-β; Aβ), and neuroinflammation (kynurenine pathway; KP metabolites) have been investigated independently in neurodegenerative diseases. However, the association of these markers of neurodegeneration and AD pathology with neuroinflammation has not been investigated previously. Therefore, the current study examined whether NFL and Aβ correlate with KP metabolites in elderly individuals to provide insight on the association between blood indicators of neurodegeneration and neuroinflammation.
Correlations between KP metabolites, measured using liquid chromatography and gas chromatography coupled with mass spectrometry, and plasma NFL and Aβ concentrations, measured using single molecule array (Simoa) assays, were investigated in elderly individuals aged 65-90 years, with normal global cognition (Mini-Mental State Examination Score ≥ 26) from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort.
A positive correlation between NFL and the kynurenine to tryptophan ratio (K/T) reflecting indoleamine 2,3-dioxygenase activity was observed (r = .451, p < .0001). Positive correlations were also observed between NFL and kynurenine (r = .364, p < .0005), kynurenic acid (r = .384, p < .0001), 3-hydroxykynurenine (r = .246, p = .014), anthranilic acid (r = .311, p = .002), and quinolinic acid (r = .296, p = .003). Further, significant associations were observed between plasma Aβ40 and the K/T (r = .375, p < .0005), kynurenine (r = .374, p < .0005), kynurenic acid (r = .352, p < .0005), anthranilic acid (r = .381, p < .0005), and quinolinic acid (r = .352, p < .0005). Significant associations were also observed between plasma Aβ42 and the K/T ratio (r = .215, p = .034), kynurenic acid (r = .214, p = .035), anthranilic acid (r = .278, p = .006), and quinolinic acid (r = .224, p = .027) in the cohort. On stratifying participants based on their neocortical Aβ load (NAL) status, NFL correlated with KP metabolites irrespective of NAL status; however, associations between plasma Aβ and KP metabolites were only pronounced in individuals with high NAL while associations in individuals with low NAL were nearly absent.
The current study shows that KP metabolite changes are associated with biomarker evidence of neurodegeneration. Additionally, the association between KP metabolites and plasma Aβ seems to be NAL status dependent. Finally, the current study suggests that an association between neurodegeneration and neuroinflammation manifests in the periphery, suggesting that preventing cytoskeleton cytotoxicity by KP metabolites may have therapeutic potential.
神经退行性疾病中已分别研究了指示神经退行性变的血液标志物（神经丝轻链；NFL）、阿尔茨海默病淀粉样蛋白病理学（β-淀粉样蛋白；Aβ）和神经炎症（犬尿氨酸途径；KP 代谢物）。然而，以前尚未研究这些神经退行性变和 AD 病理学的标志物与神经炎症之间的关联。因此，目前的研究检查了 NFL 和 Aβ是否与老年人的 KP 代谢物相关，以了解血液神经退行性变和神经炎症标志物之间的关联。
使用液相色谱和气相色谱与质谱联用技术测量 KP 代谢物，使用单分子阵列（Simoa）测定法测量老年人的血浆 NFL 和 Aβ 浓度，年龄在 65-90 岁之间，认知功能正常（Mini-Mental State Examination 评分≥26）来自 Kerr 英国圣公会退休村倡议在健康队列中。
观察到 NFL 与反映吲哚胺 2,3-双加氧酶活性的犬尿氨酸与色氨酸比值（K/T）之间存在正相关（r=0.451，p<0.0001）。还观察到 NFL 与犬尿氨酸（r=0.364，p<0.0005）、犬尿喹啉酸（r=0.384，p<0.0001）、3-羟基犬尿氨酸（r=0.246，p=0.014）、邻氨基苯甲酸（r=0.311，p=0.002）和喹啉酸（r=0.296，p=0.003）之间存在正相关。此外，还观察到血浆 Aβ40 与 K/T（r=0.375，p<0.0005）、犬尿氨酸（r=0.374，p<0.0005）、犬尿喹啉酸（r=0.352，p<0.0005）、邻氨基苯甲酸（r=0.381，p<0.0005）和喹啉酸（r=0.352，p<0.0005）之间存在显著关联。还观察到血浆 Aβ42 与 K/T 比值（r=0.215，p=0.034）、犬尿喹啉酸（r=0.214，p=0.035）、邻氨基苯甲酸（r=0.278，p=0.006）和喹啉酸（r=0.224，p=0.027）之间存在显著关联。在根据皮质内 Aβ 负荷（NAL）状态对参与者进行分层后，NFL 与 KP 代谢物相关，无论 NAL 状态如何；然而，只有在 NAL 较高的个体中，血浆 Aβ 与 KP 代谢物之间才存在显著关联，而在 NAL 较低的个体中，关联几乎不存在。
本研究表明 KP 代谢物的变化与神经退行性变的生物标志物证据有关。此外，KP 代谢物与血浆 Aβ 之间的关联似乎依赖于 NAL 状态。最后，本研究表明，神经退行性变和神经炎症之间的关联表现在外周，这表明通过 KP 代谢物预防细胞骨架细胞毒性可能具有治疗潜力。
