Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
Cognitive Neurology Center, Université de Paris Cité, GHU Nord APHP Hospital Lariboisière Fernand Widal, Paris, France.
Acta Neuropathol. 2024 Jan 6;147(1):12. doi: 10.1007/s00401-023-02659-w.
Post-mortem staging of Alzheimer's disease (AD) neurofibrillary pathology is commonly performed by immunohistochemistry using AT8 antibody for phosphorylated tau (p-tau) at positions 202/205. Thus, quantification of p-tau205 and p-tau202 in cerebrospinal fluid (CSF) should be more reflective of neurofibrillary tangles in AD than other p-tau epitopes. We developed two novel Simoa immunoassays for CSF p-tau205 and p-tau202 and measured these phosphorylations in three independent cohorts encompassing the AD continuum, non-AD cases and cognitively unimpaired participants: a discovery cohort (n = 47), an unselected clinical cohort (n = 212) and a research cohort well-characterized by fluid and imaging biomarkers (n = 262). CSF p-tau205 increased progressively across the AD continuum, while CSF p-tau202 was increased only in AD and amyloid (Aβ) and tau pathology positive (A+T+) cases (P < 0.01). In A+ cases, CSF p-tau205 and p-tau202 showed stronger associations with tau-PET (r = 0.67, r = 0.45) than Aβ-PET (r = 0.40, r = 0.09). CSF p-tau205 increased gradually across tau-PET Braak stages (P < 0.01), whereas p-tau202 only increased in Braak V-VI (P < 0.0001). Both showed stronger regional associations with tau-PET than with Aβ-PET, and CSF p-tau205 was significantly associated with Braak V-VI tau-PET regions. When assessing the contribution of Aβ and tau pathologies (indexed by PET) to CSF p-tau205 and p-tau202 variance, tau pathology was found to be the most prominent contributor in both cases (CSF p-tau205: R = 69.7%; CSF p-tau202: R = 85.6%) Both biomarkers associated with brain atrophy measurements globally (r = - 0.36, r = - 0.33) and regionally, and correlated with cognition (r = - 0.38/- 0.40, r = - 0.20/- 0.29). In conclusion, we report the first high-throughput CSF p-tau205 immunoassay for the in vivo quantification of tau pathology in AD, and a potentially cost-effective alternative to tau-PET in clinical settings and clinical trials.
阿尔茨海默病（AD）神经纤维病理的死后分期通常通过使用 AT8 抗体对磷酸化 tau（p-tau）在 202/205 位进行免疫组织化学检测。因此，脑脊液（CSF）中 p-tau205 和 p-tau202 的定量应该比其他 p-tau 表位更能反映 AD 中的神经纤维缠结。我们开发了两种新型 Simoa 免疫测定法用于 CSF p-tau205 和 p-tau202，并在包含 AD 连续体、非 AD 病例和认知未受损参与者的三个独立队列中测量了这些磷酸化：一个发现队列（n=47），一个未选择的临床队列（n=212）和一个通过液体和成像生物标志物充分表征的研究队列（n=262）。CSF p-tau205 在 AD 连续体中逐渐增加，而 CSF p-tau202 仅在 AD 和淀粉样蛋白（Aβ）和 tau 病理阳性（A+T+）病例中增加（P<0.01）。在 A+病例中，CSF p-tau205 和 p-tau202 与 tau-PET 的相关性强于 Aβ-PET（r=0.67，r=0.45）（r=0.40，r=0.09）。CSF p-tau205 随着 tau-PET Braak 阶段逐渐增加（P<0.01），而 p-tau202 仅在 Braak V-VI 中增加（P<0.0001）。两者与 tau-PET 的区域相关性均强于与 Aβ-PET 的相关性，CSF p-tau205 与 Braak V-VI tau-PET 区域显著相关。当评估 Aβ和 tau 病理学（由 PET 索引）对 CSF p-tau205 和 p-tau202 方差的贡献时，tau 病理学在两种情况下都是最主要的贡献者（CSF p-tau205：R=69.7%；CSF p-tau202：R=85.6%）。这两种生物标志物均与大脑整体萎缩测量相关（r=-0.36，r=-0.33）和区域相关，并与认知相关（r=-0.38/-0.40，r=-0.20/-0.29）。总之，我们报告了第一个用于 AD 中 tau 病理学体内定量的高通量 CSF p-tau205 免疫测定法，并且是临床环境和临床试验中 tau-PET 的潜在经济有效的替代方法。
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