Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology.
Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology.
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血浆p-tau231：阿尔茨海默病早期病理的新生物标志物。
DOI：
10.1007/s00401-021-02275-6
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发表时间：
2021-05
影响因子：
12.7
通讯作者：
Blennow K
中科院分区：
文献类型：
--
作者：
Ashton NJ;Pascoal TA;Karikari TK;Benedet AL;Lantero-Rodriguez J;Brinkmalm G;Snellman A;Schöll M;Troakes C;Hye A;Gauthier S;Vanmechelen E;Zetterberg H;Rosa-Neto P;Blennow K
脑脊液或血浆中磷酸化tau的定量检测在检测阿尔茨海默病(AD)的病理生理学方面显示出巨大的前景。在苏氨酸231位发生磷酸化的tau(p-tau231)就是脑脊液中这样的生物标记物，但它作为血液生物标记物的作用目前尚不清楚。在这里，我们开发了一种用于血浆p-tau231定量的超灵敏单分子阵列(SIMOA)，该阵列在四个独立的队列(n = 588)中得到了验证，这些队列在不同的环境中进行了验证，包括完整的AD连续谱和非AD神经退行性疾病。血浆p-tau231能够高精度地识别AD患者，并将他们与淀粉样蛋白β阴性的认知未受损(CU)老年人区分开来(AUC = 0.92-0.94)。血浆p-tau231还可区分AD患者和非AD神经退行性疾病患者(AUCMCI 0.93)，以及淀粉样蛋白β阴性的MCI患者(AUCMCI)(AUCMIC0.89)。在一个神经病理队列中，在死后4.2年前采集的平均样本中的血浆p-tau231与非AD神经退行性疾病(AUC = 0.99)相比非常准确地识别了AD神经病理，尽管所有患者在生前都被诊断为AD痴呆。血浆p-tau231与脑脊液p-tau231、脑脊液p-tau231、脑淀粉样变性[18F]AZD469PET和脑淀粉样变性高度相关。值得注意的是，血浆p-tau231的拐点随着连续的[18F]AZD469PET标准化摄取比值的增加而增加，显示出早于淀粉样蛋白-β阳性的标准阈值和血浆p-tau181的增加。此外，血浆p-tau231在淀粉样蛋白-βPET 2-4四分位显著增加，而脑脊液p-tau217和血浆p-tau181分别仅在3-4和4四分位增加。最后，血浆p-tau231在整个Braak分期谱中分化，包括从Braak 0到Braak I-II的Braak分期，这在血浆p-tau181中没有观察到。总之，这种新的血浆p-tau231检测方法与血浆p-tau181一样能识别AD的临床分期和神经病理，但增加得更早，在达到淀粉样蛋白-β阳性阈值之前，已经伴随着微小的淀粉样蛋白-β沉积，并且也是对早期脑tau沉积的响应。因此，血浆p-tau231是一种有希望的新的AD病理生物标志物，有可能促进临床试验，以识别低于淀粉样蛋白β阳性或明显内嗅tau沉积的易感人群。网上版载有补充材料，可在10.1007/s00401-021-02275-6查阅。
The quantification of phosphorylated tau in biofluids, either cerebrospinal fluid (CSF) or plasma, has shown great promise in detecting Alzheimer’s disease (AD) pathophysiology. Tau phosphorylated at threonine 231 (p-tau231) is one such biomarker in CSF but its usefulness as a blood biomarker is currently unknown. Here, we developed an ultrasensitive Single molecule array (Simoa) for the quantification of plasma p-tau231 which was validated in four independent cohorts (n = 588) in different settings, including the full AD continuum and non-AD neurodegenerative disorders. Plasma p-tau231 was able to identify patients with AD and differentiate them from amyloid-β negative cognitively unimpaired (CU) older adults with high accuracy (AUC = 0.92–0.94). Plasma p-tau231 also distinguished AD patients from patients with non-AD neurodegenerative disorders (AUC = 0.93), as well as from amyloid-β negative MCI patients (AUC = 0.89). In a neuropathology cohort, plasma p-tau231 in samples taken on avergae 4.2 years prior to post-mortem very accurately identified AD neuropathology in comparison to non-AD neurodegenerative disorders (AUC = 0.99), this is despite all patients being given an AD dementia diagnosis during life. Plasma p-tau231 was highly correlated with CSF p-tau231, tau pathology as assessed by [18F]MK-6240 positron emission tomography (PET), and brain amyloidosis by [18F]AZD469 PET. Remarkably, the inflection point of plasma p-tau231, increasing as a function of continuous [18F]AZD469 amyloid-β PET standardized uptake value ratio, was shown to be earlier than standard thresholds of amyloid-β PET positivity and the increase of plasma p-tau181. Furthermore, plasma p-tau231 was significantly increased in amyloid-β PET quartiles 2–4, whereas CSF p-tau217 and plasma p-tau181 increased only at quartiles 3–4 and 4, respectively. Finally, plasma p-tau231 differentiated individuals across the entire Braak stage spectrum, including Braak staging from Braak 0 through Braak I–II, which was not observed for plasma p-tau181. To conclude, this novel plasma p-tau231 assay identifies the clinical stages of AD and neuropathology equally well as plasma p-tau181, but increases earlier, already with subtle amyloid-β deposition, prior to the threshold for amyloid-β PET positivity has been attained, and also in response to early brain tau deposition. Thus, plasma p-tau231 is a promising novel biomarker of emerging AD pathology with the potential to facilitate clinical trials to identify vulnerable populations below PET threshold of amyloid-β positivity or apparent entorhinal tau deposition. The online version contains supplementary material available at 10.1007/s00401-021-02275-6.
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DOI：
10.1084/jem.20200861
发表时间：
2020-11-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Barthélemy NR;Horie K;Sato C;Bateman RJ
通讯作者：
Bateman RJ
DOI：
10.1002/alz.12236
发表时间：
2021-05
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Karikari TK;Emeršič A;Vrillon A;Lantero-Rodriguez J;Ashton NJ;Kramberger MG;Dumurgier J;Hourregue C;Čučnik S;Brinkmalm G;Rot U;Zetterberg H;Paquet C;Blennow K
通讯作者：
Blennow K
影响因子：
9.9
作者：
Hanes J;Kovac A;Kvartsberg H;Kontsekova E;Fialova L;Katina S;Kovacech B;Stevens E;Hort J;Vyhnalek M;Boonkamp L;Novak M;Zetterberg H;Hansson O;Scheltens P;Blennow K;Teunissen CE;Zilka N
通讯作者：
Zilka N
影响因子：
4.8
作者：
Amniai, Laziza;Barbier, Pascale;Landrieu, Isabelle
通讯作者：
Landrieu, Isabelle
影响因子：
7.1
作者：
Horie, Kanta;Barthelemy, Nicolas R.;Sato, Chihiro
通讯作者：
Sato, Chihiro