Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Department of Neuroradiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Brain. 2022 Nov 21;145(11):4032-4041. doi: 10.1093/brain/awac297.
Phosphorylated Tau181 (pTau181) in CSF and recently in plasma has been associated with Alzheimer's disease. In the absence of amyloidopathy, individuals with increased total Tau levels and/or temporal lobe atrophy experience no or only mild cognitive decline compared with biomarker-negative controls, leading to the proposal to categorize this constellation as suspected non-Alzheimer's disease pathophysiology (SNAP). We investigated whether the characteristics of SNAP also applied to individuals with increased CSF-pTau181 without amyloidopathy. In this long-term observational study, 285 non-demented individuals, including 76 individuals with subjective cognitive impairment and 209 individuals with mild cognitive impairment, were classified based on their CSF levels of pTau181 (T), total Tau (N), amyloid-β42 (Aβ42) and Aβ42/Aβ40 ratio (A) into A+T+N±, A+T-N±, A-T+N±, and A-T-N-. The longitudinal analysis included 154 subjects with a follow-up of more than 12 months who were followed to a median of 4.6 years (interquartile range = 4.3 years). We employed linear mixed models on psychometric tests and region of interest analysis of structural MRI data. Cognitive decline and hippocampal atrophy rate were significantly higher in A+T+N± compared to A-T+N±, whereas there was no difference between A-T+N± and A-T-N-. Furthermore, there was no significant difference between A-T+N± and controls in dementia risk [hazard ratio 0.3, 95% confidence interval (0.1, 1.9)]. However, A-T+N± and A-T-N- could be distinguished based on their Aβ42 and Aβ40 levels. Both Aβ40 and Aβ42 levels were significantly increased in A-T+N± compared to controls. Long term follow-up of A-T+N± individuals revealed no evidence that this biomarker constellation was associated with dementia or more severe hippocampal atrophy rates compared to controls. However, because of the positive association of pTau181 with Aβ in the A-T+N± group, a link to the pathophysiology of Alzheimer's disease cannot be excluded in this case. We propose to refer to these individuals in the SNAP group as 'pTau and Aβ surge with subtle deterioration' (PASSED). The investigation of the circumstances of simultaneous elevation of pTau and Aβ might provide a deeper insight into the process under which Aβ becomes pathological.
磷酸化 Tau181(pTau181)在脑脊液中，最近在血浆中与阿尔茨海默病有关。在没有淀粉样蛋白病的情况下，与生物标志物阴性对照相比，总 Tau 水平升高和/或颞叶萎缩的个体经历的认知能力下降没有或只有轻微，导致提出将这种组合归类为疑似非阿尔茨海默病病理生理学(SNAP)。我们研究了在没有淀粉样蛋白病的情况下，CSF-pTau181 升高的个体是否也具有 SNAP 的特征。在这项长期观察性研究中，根据 CSF 中 pTau181(T)、总 Tau (N)、淀粉样蛋白-β42(Aβ42)和 Aβ42/Aβ40 比值 (A)，将 285 名非痴呆个体，包括 76 名有主观认知障碍的个体和 209 名有轻度认知障碍的个体，分为 A+T+N±、A+T-N±、A-T+N± 和 A-T-N-。纵向分析包括 154 名随访时间超过 12 个月的受试者，中位随访时间为 4.6 年(四分位距=4.3 年)。我们对认知测试和结构 MRI 数据的感兴趣区域分析采用线性混合模型。与 A-T+N±相比，A+T+N±的认知下降和海马萎缩率显著更高，而 A-T+N±与 A-T-N-之间无差异。此外，A-T+N±与对照组在痴呆风险方面无显著差异[风险比 0.3，95%置信区间(0.1，1.9)]。然而，A-T+N±和 A-T-N-可以根据其 Aβ42 和 Aβ40 水平来区分。与对照组相比，A-T+N±中的 Aβ40 和 Aβ42 水平均显著升高。对 A-T+N±个体的长期随访并未表明该生物标志物组合与痴呆或更严重的海马萎缩率相关。然而，由于 A-T+N±组中 pTau181 与 Aβ 的正相关，因此不能排除这种情况与阿尔茨海默病的病理生理学有关。我们建议将 SNAP 组中的这些个体称为“pTau 和 Aβ 激增伴轻微恶化”(PASSED)。研究 pTau 和 Aβ 同时升高的情况可能会更深入地了解 Aβ 变得病理性的过程。
