Data_Sheet_1_Microglial Activation, Tau Pathology, and Neurodegeneration Biomarkers Predict Longitudinal Cognitive Decline in Alzheimer’s Disease Continuum.docx

PurposeBiomarkers used for predicting longitudinal cognitive change in Alzheimer’s disease (AD) continuum are still elusive. Tau pathology, neuroinflammation, and neurodegeneration are the leading candidate predictors. We aimed to determine these three aspects of biomarkers in cerebrospinal fluid (CSF) and plasma to predict longitudinal cognition status using Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort.
Patients and MethodsA total of 430 subjects including, 96 cognitive normal (CN) with amyloid β (Aβ)-negative, 54 CN with Aβ-positive, 195 mild cognitive impairment (MCI) with Aβ-positive, and 85 AD with amyloid-positive (Aβ-positive are identified by CSF Aβ42/Aβ40 < 0.138). Aβ burden was evaluated by CSF and plasma Aβ42/Aβ40 ratio; tau pathology was evaluated by CSF and plasma phosphorylated-tau (p-tau181); microglial activation was measured by CSF soluble TREM2 (sTREM2) and progranulin (PGRN); neurodegeneration was measured by CSF and plasma t-tau and structural magnetic resonance imaging (MRI); cognition was examined annually over the subsequent 8 years using the Alzheimer’s Disease Assessment Scale Cognition 13-item scale (ADAS13) and Mini-Mental State Exam (MMSE). Linear mixed-effects models (LME) were applied to assess the correlation between biomarkers and longitudinal cognition decline, as well as their effect size on the prediction of longitudinal cognitive decline.
ResultsBaseline CSF Aβ42/Aβ40 ratio was decreased in MCI and AD compared to CN, while CSF p-tau181 and t-tau increased. Baseline CSF sTREM2 and PGRN did not show any differences in MCI and AD compared to CN. Baseline brain volumes (including the hippocampal, entorhinal, middle temporal lobe, and whole-brain) decreased in MCI and AD groups. For the longitudinal study, there were significant interaction effects of CSF p-tau181 × time, plasma p-tau181 × time, CSF sTREM2 × time, and brain volumes × time, indicating CSF, and plasma p-tau181, CSF sTREM2, and brain volumes could predict longitudinal cognition deterioration rate. CSF sTREM2, CSF, and plasma p-tau181 had similar medium prediction effects, while brain volumes showed stronger effects in predicting cognition decline.
ConclusionOur study reported that baseline CSF sTREM2, CSF, and plasma p-tau181, as well as structural MRI, could predict longitudinal cognitive decline in subjects with positive AD pathology. Plasma p-tau181 can be used as a relatively noninvasive reliable biomarker for AD longitudinal cognition decline prediction.

目的 用于预测阿尔茨海默病（Alzheimer’s disease, AD）连续体患者纵向认知变化的生物标志物仍有待明确。tau病理、神经炎症与神经退行性变是当前主要的候选预测因子。本研究旨在依托阿尔茨海默病神经影像倡议（Alzheimer’s Disease Neuroimaging Initiative, ADNI）队列，探究脑脊液（cerebrospinal fluid, CSF）与血浆中上述三类生物标志物的水平，以实现对纵向认知状态的预测。
患者与方法 本研究共纳入430名受试者，包括96名淀粉样β（amyloid β, Aβ）阴性的认知正常（cognitive normal, CN）者、54名Aβ阳性的CN者、195名Aβ阳性的轻度认知障碍（mild cognitive impairment, MCI）患者，以及85名Aβ阳性的AD患者（Aβ阳性通过脑脊液Aβ42/Aβ40比值<0.138鉴定）。采用脑脊液与血浆Aβ42/Aβ40比值评估Aβ负荷；通过脑脊液与血浆磷酸化tau181（phosphorylated-tau181, p-tau181）评估tau病理；采用脑脊液可溶性髓系细胞触发受体2（soluble TREM2, sTREM2）与颗粒蛋白前体（progranulin, PGRN）检测小胶质细胞激活状态；通过脑脊液与血浆总tau（t-tau）及结构磁共振成像（structural magnetic resonance imaging, MRI）评估神经退行性变程度；在后续8年中每年采用阿尔茨海默病评估量表认知13项版（Alzheimer’s Disease Assessment Scale Cognition 13-item scale, ADAS13）与简易精神状态检查表（Mini-Mental State Exam, MMSE）评估认知功能。本研究采用线性混合效应模型（Linear mixed-effects models, LME）分析生物标志物与纵向认知下降的相关性，并评估其对纵向认知下降的预测效应量。
结果 与CN组相比，MCI组与AD组的基线脑脊液Aβ42/Aβ40比值降低，而基线脑脊液p-tau181与t-tau水平升高。基线脑脊液sTREM2与PGRN水平在MCI组、AD组与CN组间无显著差异。MCI组与AD组的基线脑体积（包括海马、内嗅皮层、颞中叶及全脑体积）较CN组降低。纵向分析显示，脑脊液p-tau181×时间、血浆p-tau181×时间、脑脊液sTREM2×时间及脑体积×时间均存在显著交互效应，提示脑脊液与血浆p-tau181、脑脊液sTREM2及脑体积可预测纵向认知恶化速率。脑脊液sTREM2、脑脊液与血浆p-tau181的预测效应强度相近，均为中等水平，而脑体积对认知下降的预测效应更强。
结论 本研究证实，基线脑脊液sTREM2、脑脊液与血浆p-tau181，以及结构MRI均可用于预测AD病理阳性受试者的纵向认知下降。血浆p-tau181可作为一种相对无创的可靠生物标志物，用于AD患者纵向认知下降的预测。