背景:异常tau蛋白是认知障碍的独立因素。然而,并非所有暴露于高水平tau病理的个体都会出现认知功能障碍。我们旨在构建一个模型来预测这一高危人群的认知轨迹。
方法:181名非痴呆成年人的纵向数据(平均年龄=73.1;女性=45%),通过脑脊液(CSF)测量磷酸化tau(ptau181)或总tau,来自阿尔茨海默病神经影像学倡议(ADNI)数据库。认知下降被定义为迷你精神状态检查分数在三年内下降≥3。使用逐步向后回归方法构建了预测列线图。歧视,校准,并评估列线图的临床有用性。通过横截面集(n=149,平均年龄=73.9,女性=51%)和纵向集(n=40,平均年龄=75,女性=48%),在另外189名非痴呆成年人中验证了该模型。最后,在延长的8年随访期间,研究了计算出的风险评分与认知功能下降和阿尔茨海默病风险的关系.
结果:海马体积减小(比值比[OR]=0.37,p<0.001),CSFsTREM2水平较低(OR=0.76,p=0.003),阿尔茨海默病评估量表-认知(OR=1.15,p=0.001)和功能活动问卷(OR=1.16,p=0.016)得分较高,和APOEε4的数量(OR=1.88,p=0.039)与较高的认知下降风险相关,而与淀粉样蛋白状态无关,并包括在最终模型中。对于训练集,列线图的曲线下面积(AUC)值为0.91,横截面验证集0.93,纵向验证集为0.91。在8年的随访中,高危人群表现出更快的认知功能下降(p<0.001)和更高的阿尔茨海默痴呆风险(HR=6.21,95%CI=3.61-10.66,p<0.001).
结论:APOEε4状态,大脑储备能力,神经炎症标志物,神经心理学评分可以帮助预测tau病理负担较高的非痴呆成年人的认知能力下降,独立于淀粉样蛋白病理学的存在。
BACKGROUND: Abnormal tau proteins are independent contributors to cognitive impairment. Nevertheless, not all individuals exposed to high-level tau pathology will develop cognitive dysfunction. We aimed to construct a model to predict cognitive trajectory for this high-risk population.
METHODS: Longitudinal data of 181 non-demented adults (mean age= 73.1; female= 45%), who were determined to have high cerebral burden of abnormal tau by cerebrospinal fluid (CSF) measurements of phosphorylated tau (ptau181) or total tau, were derived from the Alzheimer\'s Disease Neuroimaging Initiative (ADNI) database. Cognitive decline was defined as Mini-Mental State Examination scores decline ≥ 3 over three years. A predictive nomogram was constructed using stepwise backward regression method. The discrimination, calibration, and clinical usefulness of the nomogram were evaluated. The model was validated in another 189 non-demented adults via a cross-sectional set (n=149, mean age = 73.9, female = 51%) and a longitudinal set (n= 40, mean age = 75, female = 48%). Finally, the relationships of the calculated risk scores with cognitive decline and risk of Alzheimer\'s disease were examined during an extended 8-year follow-up.
RESULTS: Lower volume of hippocampus (odds ratio [OR] = 0.37, p< 0.001), lower levels of CSF sTREM2 (OR = 0.76, p = 0.003), higher scores of Alzheimer\'s Disease Assessment Scale-Cognitive (OR = 1.15, p = 0.001) and Functional Activities Questionnaire (OR = 1.16, p = 0.016), and number of APOE ε4 (OR = 1.88, p = 0.039) were associated with higher risk of cognitive decline independent of the amyloid status and were included in the final model. The nomogram had an area of under curve (AUC) value of 0.91 for training set, 0.93 for cross-sectional validation set, and 0.91 for longitudinal validation set. Over the 8-year follow-up, the high-risk group exhibited faster cognitive decline (p< 0.001) and a higher risk of developing Alzheimer\'s dementia (HR= 6.21, 95% CI= 3.61-10.66, p< 0.001 ).
CONCLUSIONS: APOE ε4 status, brain reserve capability, neuroinflammatory marker, and neuropsychological scores can help predict cognitive decline in non-demented adults with high burden of tau pathology, independent of the presence of amyloid pathology.