当前位置: X-MOL 学术medRxiv. Neurol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Time course of phosphorylated tau181 in blood across the Alzheimer's disease spectrum
medRxiv - Neurology Pub Date : 2020-07-14 , DOI: 10.1101/2020.07.13.20152025
Alexis Moscoso , Michel J. Grothe , Nicholas J. Ashton , Thomas K Karikari , Juan Lantero Rodriguez , Anniina Snellman , Marc Suarez Calvet , Henrik Zetterberg , Kaj Blennow , Michael Schoell

Tau phosphorylated at threonine 181 (p-tau181) measured in blood plasma has recently been proposed as an accessible, scalable, and highly specific biomarker for Alzheimer's disease. Longitudinal studies, however, investigating the temporal dynamics of this novel biomarker are lacking. It is therefore unclear when in the disease process plasma p-tau181 increases above physiological levels and how it relates to the spatiotemporal progression of Alzheimer's disease-characteristic pathologies. We aimed to establish the natural time course of plasma p-tau181 across the sporadic Alzheimer's disease spectrum in comparison to those of established imaging- and fluid-derived biomarkers of Alzheimer's disease. We examined longitudinal data from a large prospective cohort of elderly individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n=1067) covering a wide clinical spectrum from normal cognition to dementia, and with measures of plasma p-tau181 and an [18F]florbetapir amyloid-β (Aβ) positron emission tomography (PET) scan at baseline. A subset of participants (n=864) also had measures of Aβ1-42 and p-tau181 levels in cerebrospinal fluid (CSF), and another subset (n=298) had undergone an [18F]flortaucipir tau PET scan six years later. We performed brain-wide analyses to investigate the associations of plasma p-tau181 baseline levels and longitudinal change with progression of regional Aβ pathology and tau burden six years later, and estimated the time course of changes in plasma p-tau181 and other Alzheimer's disease biomarkers employing a previously developed method for the construction of long-term biomarker temporal trajectories using shorter-term longitudinal data. Spline regressions demonstrated that earliest plasma p-tau181 changes occurred even before Aβ-markers reached abnormal levels, with greater rates of change correlating with increased Aβ pathology. Voxel-wise PET analyses yielded relatively weak, yet significant, associations of plasma p-tau181 with Aβ pathology in early-accumulating brain regions in cognitively healthy individuals, while the strongest associations with Aβ were observed in late-accumulating regions in patients with mild cognitive impairment. Cross-sectional and particularly longitudinal measures of plasma p-tau181 were associated with widespread cortical tau aggregation six years later, covering temporo-parietal regions typical for neurofibrillary tangle distribution in Alzheimer's disease. Finally, we estimated that plasma p-tau181 reaches abnormal levels approximately 6.5 and 5.7 years after CSF- and PET-measures of Aβ, respectively, following similar dynamics as CSF p-tau181. Our findings suggest that plasma p-tau181 increases are associated with the presence of widespread cortical Aβ pathology and with prospective Alzheimer's disease-typical tau aggregation, providing clear implications for the use of this novel blood biomarker as a diagnostic and screening tool for Alzheimer's disease.

中文翻译:

整个阿尔茨海默氏病谱图中血液中tau181磷酸化的时间过程

最近有人提出血浆中苏氨酸181磷酸化的Tau(p-tau181)被认为是阿尔茨海默氏病可及,可扩展且高度特异性的生物标志物。然而,缺乏纵向研究来研究这种新型生物标志物的时间动态。因此,尚不清楚血浆p-tau181在疾病过程中何时升高至高于生理水平,以及它与阿尔茨海默氏病特征性病理的时空进展如何相关。与已建立的成像和液体来源的阿尔茨海默氏病生物标志物相比,我们旨在在整个偶发性阿尔茨海默氏病谱中建立血浆p-tau181的自然时程。我们研究了来自阿尔茨海默氏症的大量前瞻性队列研究的纵向数据 疾病神经影像学倡议(ADNI)(n = 1067)涵盖了从正常认知到痴呆症的广泛临床范围,并测量了血浆p-tau181和[18F] florbetapir淀粉样蛋白-β(Aβ)正电子发射断层扫描(PET)扫描在基线。一部分参与者(n = 864)也测量了脑脊液(CSF)中Aβ1-42和p-tau181的水平,另一部分参与者(n = 298)于六年后接受了[18F]氟尿嘧啶tau PET扫描。我们进行了全脑分析,以调查血浆p-tau181基线水平和纵向变化与区域Aβ病理学进展和tau负担的关系,六年后,并估计了血浆p-tau181和其他阿尔茨海默氏病变化的时间过程 疾病生物标记物,采用先前开发的方法,利用短期纵向数据构建长期生物标记物的时间轨迹。样条回归表明,最早的血浆p-tau181变化甚至发生在Aβ标记达到异常水平之前,变化率更高与Aβ病理学增加相关。在认知健康个体的早期积累脑区域中,按体素进行PET分析得出血浆p-tau181与Aβ病理学的关联相对较弱,但意义显着,而在轻度认知障碍患者的晚期积累区域中观察到与Aβ的最强关联损害。血浆p-tau181的横截面测量,尤其是纵向测量,与六年后广泛的皮质tau聚集有关,涵盖了阿尔茨海默氏病中典型的神经原纤维缠结分布的颞顶区域。最后,我们估计血浆p-tau181分别在ASF的CSF和PET测量后约6.5年和5.7年达到异常水平,其动力学与CSF p-tau181类似。我们的研究结果表明血浆p-tau181的增加与广泛的皮质Aβ病理学的存在和预期的阿尔茨海默氏病-典型的tau聚集有关,这为将这种新型血液生物标记物用作阿尔茨海默氏病的诊断和筛选工具提供了明确的含义。遵循与CSF p-tau181类似的动力学。我们的研究结果表明血浆p-tau181的增加与广泛的皮质Aβ病理学的存在和预期的阿尔茨海默氏病-典型的tau聚集有关,这为将这种新型血液生物标记物用作阿尔茨海默氏病的诊断和筛选工具提供了明确的含义。遵循与CSF p-tau181类似的动力学。我们的研究结果表明血浆p-tau181的增加与广泛的皮质Aβ病理学的存在和预期的阿尔茨海默氏病-典型的tau聚集有关,这为将这种新型血液生物标记物用作阿尔茨海默氏病的诊断和筛选工具提供了明确的含义。
更新日期:2020-07-14
down
wechat
bug