阿尔茨海默病发病前 20 年的生物标志物变化。
Biomarker Changes during 20 Years Preceding Alzheimer's Disease.
机构信息
From the Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital (J.J., Y.N., M.C., Shuheng Wang, H.Y., F. Li, J.D., Yan Li, B.Z., W.Q., Q.W., Ying Li), Beijing Key Laboratory of Geriatric Cognitive Disorders, Clinical Center for Neurodegenerative Disease and Memory Impairment (J.J.), the Center of Alzheimer's Disease, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders (J.J.), and the Department of Neurology, Beijing Anding Hospital (Y.W.), Capital Medical University, Key Laboratory of Neurodegenerative Diseases, Ministry of Education (J.J.), the Center for Cognitive Disorders, Beijing Geriatric Hospital (J.L.), and the Department of Neurology, Beijing Jishuitan Hospital (X.Y.), Beijing, the Department of Neurology, Daqing Oilfield General Hospital, Daqing (S.Y.), the Department of Neurology, the 960th Hospital of the People's Liberation Army, Jinan (J.Z.), the Department of Neurology, Baotou Central Hospital, Baotou (F. Liang), the Department of Psychiatry, Zhejiang Provincial People's Hospital, Hangzhou (Z.L.), and the Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang (Shan Wang) - all in China.
出版信息
N Engl J Med. 2024 Feb 22;390(8):712-722. doi: 10.1056/NEJMoa2310168.
BACKGROUND
Biomarker changes that occur in the period between normal cognition and the diagnosis of sporadic Alzheimer's disease have not been extensively investigated in longitudinal studies.
METHODS
We conducted a multicenter, nested case-control study of Alzheimer's disease biomarkers in cognitively normal participants who were enrolled in the China Cognition and Aging Study from January 2000 through December 2020. A subgroup of these participants underwent testing of cerebrospinal fluid (CSF), cognitive assessments, and brain imaging at 2-year-to-3-year intervals. A total of 648 participants in whom Alzheimer's disease developed were matched with 648 participants who had normal cognition, and the temporal trajectories of CSF biochemical marker concentrations, cognitive testing, and imaging were analyzed in the two groups.
RESULTS
The median follow-up was 19.9 years (interquartile range, 19.5 to 20.2). CSF and imaging biomarkers in the Alzheimer's disease group diverged from those in the cognitively normal group at the following estimated number of years before diagnosis: amyloid-beta (Aβ), 18 years; the ratio of Aβ to Aβ, 14 years; phosphorylated tau 181, 11 years; total tau, 10 years; neurofilament light chain, 9 years; hippocampal volume, 8 years; and cognitive decline, 6 years. As cognitive impairment progressed, the changes in CSF biomarker levels in the Alzheimer's disease group initially accelerated and then slowed.
CONCLUSIONS
In this study involving Chinese participants during the 20 years preceding clinical diagnosis of sporadic Alzheimer's disease, we observed the time courses of CSF biomarkers, the times before diagnosis at which they diverged from the biomarkers from a matched group of participants who remained cognitively normal, and the temporal order in which the biomarkers became abnormal. (Funded by the Key Project of the National Natural Science Foundation of China and others; ClinicalTrials.gov number, NCT03653156.).
背景
在正常认知和散发性阿尔茨海默病诊断之间的时间段内发生的生物标志物变化在纵向研究中尚未得到广泛研究。
方法
我们对 2000 年 1 月至 2020 年 12 月期间参加中国认知与衰老研究的认知正常参与者进行了一项多中心、巢式病例对照研究，以研究阿尔茨海默病生物标志物。这些参与者中的一部分进行了脑脊液（CSF）检测、认知评估和脑成像检查，检查时间间隔为 2 年至 3 年。共有 648 名发生阿尔茨海默病的参与者与 648 名认知正常的参与者相匹配，对两组参与者的 CSF 生化标志物浓度、认知测试和影像学的时间轨迹进行了分析。
结果
中位随访时间为 19.9 年（四分位距，19.5 至 20.2）。在诊断前的估计年数上，阿尔茨海默病组的 CSF 和影像学生物标志物与认知正常组开始出现差异：β淀粉样蛋白（Aβ）为 18 年；Aβ/Aβ 为 14 年；磷酸化 tau181 为 11 年；总 tau 为 10 年；神经丝轻链为 9 年；海马体积为 8 年；认知能力下降为 6 年。随着认知障碍的进展，阿尔茨海默病组 CSF 生物标志物水平的变化最初加速，然后减缓。
结论
在这项研究中，我们观察了中国参与者在散发性阿尔茨海默病临床诊断前 20 年期间的 CSF 生物标志物的时间进程、与认知正常参与者相匹配的组之间生物标志物开始出现差异的时间、以及生物标志物变得异常的时间顺序。（由国家自然科学基金重点项目等资助；ClinicalTrials.gov 编号，NCT03653156。）
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