Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome: a cross-sectional study
Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome: a cross-sectional study
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DOI：
10.1016/s0140-6736(20)30689-9
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发表时间：
2020-06-27
期刊：
影响因子：
168.9
通讯作者：
Lleo, Alberto
中科院分区：
文献类型：
--
作者：
Fortea, Juan;Vilaplana, Eduard;Lleo, Alberto
背景阿尔茨海默病及其并发症是唐氏综合征成人死亡的主要原因。研究已经评估了患有唐氏综合征的个体的阿尔茨海默病，但唐氏综合征生物标志物变化的自然史尚未建立。我们的特点的顺序和时间的变化，阿尔茨海默氏病的生物标志物在人口中的成年人唐氏syndrome.Methods我们做了一个双中心的横断面研究，通过人口为基础的健康计划在巴塞罗那（西班牙）和通过服务的人与智力残疾的剑桥（英国）招募的成年人唐氏综合征。唐氏综合征参与者的认知障碍采用剑桥唐氏综合征老年人认知检查（CAMCOG-DS）进行分类。只有轻度或中度残疾的参与者被纳入，他们至少有以下一项阿尔茨海默病指标：载脂蛋白E等位基因携带状态;淀粉样β肽1-42和1-40的血浆浓度及其比值（A β（1-42/1-40））、总tau蛋白和神经丝轻链（NFL）;在苏氨酸181处磷酸化的tau（p-tau）和脑脊液（CSF）中的NFL;以及一种或多种使用F-18-氟脱氧葡萄糖的PET、使用淀粉样蛋白示踪剂的PET和MRI。从Sant Pau Initiative on Neurodegeneration中招募了年龄高达75岁且没有生物标志物异常的认知健康整倍体对照。我们使用一阶局部估计散点图平滑曲线来确定生物标志物变化开始时的顺序和年龄，并在适当的情况下报告了分歧时的最低年龄（95%CI）。2013年2月1日至2019年6月28日期间的发现（巴塞罗那），以及2009年6月1日至2014年12月31日期间（剑桥），我们纳入了388名唐氏综合征患者（257 [66%]无症状，48 [12%]有前驱阿尔茨海默病，83 [21%]有阿尔茨海默病痴呆）和242整倍体对照。唐氏综合征患者早在30岁时CSF A β 1-42/1-40和血浆NFL值就发生了变化，淀粉样蛋白PET摄取在40岁时发生了变化。（1）8 F-氟脱氧葡萄糖PET和CSF p-tau的变化发生在生命的第40年，随后是海马萎缩和认知的变化在生命的第50年。前驱阿尔茨海默病的中位年龄为50.2岁（IQR 47.5-54.1），阿尔茨海默病痴呆的中位年龄为53.7岁（49.5-57.2）。在唐氏综合征患者中，阿尔茨海默病的患病率随着年龄的增长而增加，在70岁时达到90-100%。解释唐氏综合征患者的阿尔茨海默病有一个很长的临床前阶段，其中生物标志物遵循可预测的变化顺序，超过20年。与散发性和常染色体显性阿尔茨海默氏病的相似性以及唐氏综合征的患病率使这一人群成为阿尔茨海默氏病预防性治疗的合适目标。资助机构：Instituto de Salud卡洛斯III、Fundacio Bancaria La Caixa、Fundacio La Marato de TV 3、医学研究理事会和国立卫生研究院。版权所有（c）2020作者。由Elsevier Ltd.发布。这是CC BY-NC-ND 4.0许可下的开放获取文章。
Background Alzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down syndrome, but the natural history of biomarker changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers of Alzheimer's disease in a population of adults with Down syndrome.Methods We did a dual-centre cross-sectional study of adults with Down syndrome recruited through a population-based health plan in Barcelona (Spain) and through services for people with intellectual disabilities in Cambridge (UK). Cognitive impairment in participants with Down syndrome was classified with the Cambridge Cognitive Examination for Older Adults with Down Syndrome (CAMCOG-DS). Only participants with mild or moderate disability were included who had at least one of the following Alzheimer's disease measures: apolipoprotein E allele carrier status; plasma concentrations of amyloid beta peptides 1-42 and 1-40 and their ratio (A beta(1-42/1-40)), total tau protein, and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid (CSF); and one or more of PET with F-18-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitively healthy euploid controls aged up to 75 years who had no biomarker abnormalities were recruited from the Sant Pau Initiative on Neurodegeneration. We used a first-order locally estimated scatterplot smoothing curve to determine the order and age at onset of the biomarker changes, and the lowest ages at the divergence with 95% CIs are also reported where appropriate.Findings Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009, and Dec 31, 2014 (Cambridge), we included 388 participants with Down syndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease, and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls. CSF A beta 1-42/1-40 and plasma NFL values changed in individuals with Down syndrome as early as the third decade of life, and amyloid PET uptake changed in the fourth decade. (1)8F-fluorodeoxyglucose PET and CSF p-tau changes occurred later in the fourth decade of life, followed by hippocampal atrophy and changes in cognition in the fifth decade of life. Prodromal Alzheimer's disease was diagnosed at a median age of 50.2 years (IQR 47.5-54.1), and Alzheimer's disease dementia at 53.7 years (49.5-57.2). Symptomatic Alzheimer's disease prevalence increased with age in individuals with Down syndrome, reaching 90-100% in the seventh decade of life.Interpretation Alzheimer's disease in individuals with Down syndrome has a long preclinical phase in which biomarkers follow a predictable order of changes over more than two decades. The similarities with sporadic and autosomal dominant Alzheimer's disease and the prevalence of Down syndrome make this population a suitable target for Alzheimer's disease preventive treatments.Funding Instituto de Salud Carlos III, Fundacio Bancaria La Caixa, Fundacio La Marato de TV3, Medical Research Council, and National Institutes of Health. Copyright (c) 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.