背景:在患有阿尔茨海默病遗传形式的人群中,如唐氏综合征和常染色体显性遗传的阿尔茨海默病,阿尔茨海默病特有的病理变化(即,淀粉样蛋白和tau的积累)发生在年轻的大脑中,当不存在与衰老相关的合并症时。包括这些队列在内的研究可以,因此,提高我们对阿尔茨海默病早期发病机制的认识,并在设计针对疾病病理的预防性干预措施或计划临床试验时有用。我们比较了震级,空间范围,唐氏综合征和常染色体显性遗传阿尔茨海默病患者tau传播的时间顺序。
方法:在这项横断面观察研究中,我们纳入了两项队列研究的参与者(年龄≥25岁).首先,我们从显性遗传阿尔茨海默氏症网络研究(DIAN-OBS和DIAN-TU)收集数据,其中包括在澳大利亚招募的常染色体显性遗传阿尔茨海默病基因突变携带者和非携带者家族对照,欧洲,和美国在2008年至2022年之间。第二,我们从阿尔茨海默症生物标志物联盟-唐氏综合症研究中收集数据,其中包括唐氏综合症患者和2015年至2021年从英国和美国招募的兄弟姐妹控制。将两项研究的对照合并为一组家族性对照。所有参与者均完成了结构MRI和tauPET(18F-flortaucipir)成像。我们应用高斯混合建模来分别识别高tauPET负荷的区域和每个队列的tau结合最早变化的区域。我们估计了两个队列的区域tauPET负荷与皮质淀粉样蛋白负荷的关系。最后,我们比较了tauPET相对于淀粉样蛋白的时间模式。
结果:我们纳入了137名唐氏综合征患者(平均年龄38·5岁[SD8·2],74[54%]男性,和63[46%]女性),49例常染色体显性遗传性阿尔茨海默病患者(平均年龄43·9岁[11·2],22[45%]男性,和27[55%]女性),和85个家族控制,从两项研究中汇总(平均年龄41·5岁[12·1],28[33%]男性,和57[67%]女性),谁满足tau-PET成像处理的PET质量控制程序。134人(98%)患有唐氏综合症,44(90%)患有常染色体显性遗传的阿尔茨海默病,77名(91%)的对照组也在tauPET成像的3年内完成了淀粉样蛋白PET扫描。空间上,tauPET负荷在唐氏综合征患者的皮质下和内侧颞区最常见,常染色体显性遗传的阿尔茨海默病患者的颞叶内侧。穿过大脑,与常染色体显性遗传阿尔茨海默病患者相比,在给定淀粉样蛋白水平下,唐氏综合征患者的tau蛋白浓度更高.暂时,与常染色体显性遗传的阿尔茨海默病相比,唐氏综合征患者tau蛋白的增加与淀粉样蛋白的增加更密切相关。
结论:尽管对于唐氏综合征患者和常染色体显性阿尔茨海默病患者,淀粉样蛋白和tau蛋白的总体进展相似,我们发现了空间分布的细微差异,定时,以及这两个队列之间tau负担的大小。这些差异可能具有重要意义;tau积累的时间模式的差异可能会影响临床试验中药物给药的时间。而tau负荷的空间格局和大小的差异可能会影响疾病进展。
背景:无。
BACKGROUND: In people with genetic forms of Alzheimer\'s disease, such as in Down syndrome and autosomal-dominant Alzheimer\'s disease, pathological changes specific to Alzheimer\'s disease (ie, accumulation of amyloid and tau) occur in the brain at a young age, when comorbidities related to ageing are not present. Studies including these cohorts could, therefore, improve our understanding of the early pathogenesis of Alzheimer\'s disease and be useful when designing preventive interventions targeted at disease pathology or when planning clinical trials. We compared the magnitude, spatial extent, and temporal ordering of tau spread in people with Down syndrome and autosomal-dominant Alzheimer\'s disease.
METHODS: In this cross-sectional observational
study, we included participants (aged ≥25 years) from two cohort studies. First, we collected data from the Dominantly Inherited Alzheimer\'s Network studies (DIAN-OBS and DIAN-TU), which include carriers of autosomal-dominant Alzheimer\'s disease genetic mutations and non-carrier familial controls recruited in Australia, Europe, and the USA between 2008 and 2022. Second, we collected data from the Alzheimer Biomarkers Consortium-Down Syndrome
study, which includes people with Down syndrome and sibling controls recruited from the UK and USA between 2015 and 2021. Controls from the two studies were combined into a single group of familial controls. All participants had completed structural MRI and tau PET (18F-flortaucipir) imaging. We applied Gaussian mixture modelling to identify regions of high tau PET burden and regions with the earliest changes in tau binding for each cohort separately. We estimated regional tau PET burden as a function of cortical
amyloid burden for both cohorts. Finally, we compared the temporal pattern of tau PET burden relative to that of
amyloid.
RESULTS: We included 137 people with Down syndrome (mean age 38·5 years [SD 8·2], 74 [54%] male, and 63 [46%] female), 49 individuals with autosomal-dominant Alzheimer\'s disease (mean age 43·9 years [11·2], 22 [45%] male, and 27 [55%] female), and 85 familial controls, pooled from across both studies (mean age 41·5 years [12·1], 28 [33%] male, and 57 [67%] female), who satisfied the PET quality-control procedure for tau-PET imaging processing. 134 (98%) people with Down syndrome, 44 (90%) with autosomal-dominant Alzheimer\'s disease, and 77 (91%) controls also completed an amyloid PET scan within 3 years of tau PET imaging. Spatially, tau PET burden was observed most frequently in subcortical and medial temporal regions in people with Down syndrome, and within the medial temporal lobe in people with autosomal-dominant Alzheimer\'s disease. Across the brain, people with Down syndrome had greater concentrations of tau for a given level of amyloid compared with people with autosomal-dominant Alzheimer\'s disease. Temporally, increases in tau were more strongly associated with increases in
amyloid for people with Down syndrome compared with autosomal-dominant Alzheimer\'s disease.
CONCLUSIONS: Although the general progression of amyloid followed by tau is similar for people Down syndrome and people with autosomal-dominant Alzheimer\'s disease, we found subtle differences in the spatial distribution, timing, and magnitude of the tau burden between these two cohorts. These differences might have important implications; differences in the temporal pattern of tau accumulation might influence the timing of drug administration in clinical trials, whereas differences in the spatial pattern and magnitude of tau burden might affect disease progression.
BACKGROUND: None.