Comparison of tau spread in people with Down syndrome versus autosomal-dominant Alzheimer's disease: a cross-sectional study.

IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY
Julie K Wisch, Nicole S McKay, Anna H Boerwinkle, James Kennedy, Shaney Flores, Benjamin L Handen, Bradley T Christian, Elizabeth Head, Mark Mapstone, Michael S Rafii, Sid E O'Bryant, Julie C Price, Charles M Laymon, Sharon J Krinsky-McHale, Florence Lai, H Diana Rosas, Sigan L Hartley, Shahid Zaman, Ira T Lott, Dana Tudorascu, Matthew Zammit, Adam M Brickman, Joseph H Lee, Thomas D Bird, Annie Cohen, Patricio Chrem, Alisha Daniels, Jasmeer P Chhatwal, Carlos Cruchaga, Laura Ibanez, Mathias Jucker, Celeste M Karch, Gregory S Day, Jae-Hong Lee, Johannes Levin, Jorge Llibre-Guerra, Yan Li, Francisco Lopera, Jee Hoon Roh, John M Ringman, Charlene Supnet-Bell, Christopher H van Dyck, Chengjie Xiong, Guoqiao Wang, John C Morris, Eric McDade, Randall J Bateman, Tammie L S Benzinger, Brian A Gordon, Beau M Ances
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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.</p><p><strong>Methods: </strong>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 (<sup>18</sup>F-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. 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引用次数: 0

Abstract

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.

Findings: 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.

Interpretation: 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.

Funding: None.

唐氏综合征患者与常染色体显性遗传阿尔茨海默病患者 tau 扩散的比较:一项横断面研究。
背景:遗传性阿尔茨海默病(如唐氏综合征和常染色体显性遗传性阿尔茨海默病)患者的大脑在年轻时就会发生阿尔茨海默病特有的病理变化(即淀粉样蛋白和 tau 的积累),此时还不存在与衰老相关的合并症。因此,包括这些队列在内的研究可以增进我们对阿尔茨海默病早期发病机制的了解,并有助于设计针对疾病病理的预防干预措施或规划临床试验。我们比较了唐氏综合征患者和常染色体显性遗传阿尔茨海默病患者 tau 扩散的程度、空间范围和时间顺序: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,我们收集了显性遗传阿尔茨海默病网络研究(DIAN-OBS 和 DIAN-TU)的数据,其中包括 2008 年至 2022 年间在澳大利亚、欧洲和美国招募的常染色体显性阿尔茨海默病基因突变携带者和非携带者家族对照。其次,我们收集了阿尔茨海默氏症生物标志物联盟-唐氏综合征研究的数据,该研究包括 2015 年至 2021 年期间在英国和美国招募的唐氏综合征患者和同胞对照。两项研究的对照组合并为一组家族对照组。所有参与者都完成了结构性核磁共振成像和 tau PET(18F-flortaucipir)成像。我们应用高斯混合模型分别确定了每个队列的tau PET高负担区域和tau结合最早发生变化的区域。我们估算了两个队列的区域 tau PET 负担与皮质淀粉样蛋白负担的函数关系。最后,我们比较了tau PET负荷与淀粉样蛋白负荷的时间模式:我们纳入了 137 名唐氏综合征患者(平均年龄 38-5 岁 [SD 8-2],74 [54%] 名男性和 63 [46%] 名女性)、49 名常染色体显性遗传阿尔茨海默病患者(平均年龄 43-9 岁 [11-2],22 [45%] 名男性和 27 [55%] 名女性)、和 27 [55%] 名女性),以及 85 名家族性对照者,这 85 名对照者均来自两项研究(平均年龄 41-5 岁 [12-1],28 [33%] 名男性,57 [67%] 名女性),他们均符合 tau-PET 成像处理的 PET 质量控制程序。134名(98%)唐氏综合征患者、44名(90%)常染色体显性遗传阿尔茨海默病患者和77名(91%)对照组患者也在tau PET成像后3年内完成了淀粉样蛋白PET扫描。从空间上看,唐氏综合征患者的皮层下和颞叶内侧区域最常观察到tau PET负荷,而常染色体显性遗传阿尔茨海默病患者的皮层下和颞叶内侧区域则最常观察到tau PET负荷。在整个大脑中,与常染色体显性遗传阿尔茨海默病患者相比,唐氏综合征患者在一定的淀粉样蛋白水平下,tau的浓度更高。从时间上看,与常染色体显性阿尔茨海默氏症患者相比,唐氏综合征患者tau的增加与淀粉样蛋白的增加有更强的相关性:虽然唐氏综合征患者和常染色体显性遗传阿尔茨海默病患者的淀粉样蛋白和tau蛋白的总体进展相似,但我们发现这两个群体的tau蛋白负荷在空间分布、时间和程度上存在细微差别。这些差异可能会产生重要影响;tau积累的时间模式差异可能会影响临床试验中的用药时机,而tau负担的空间模式和程度差异可能会影响疾病的进展:无。
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来源期刊
Lancet Neurology
Lancet Neurology 医学-临床神经学
CiteScore
58.70
自引率
1.00%
发文量
572
审稿时长
6-12 weeks
期刊介绍: The Lancet Neurology is the world-leading clinical neurology journal. It publishes original research that advocates for change in, or sheds light on, neurological clinical practice. The topics covered include cerebrovascular disease, Alzheimer's disease and other dementias, epilepsy, migraine, neurological infections, movement disorders, multiple sclerosis, neuromuscular disorders, peripheral nerve disorders, pediatric neurology, sleep disorders, and traumatic brain injury. The journal publishes a range of article types, including Articles (including randomized clinical trials and meta-analyses), Review, Rapid Review, Comment, Correspondence, and Personal View. It also publishes Series and Commissions that aim to shape and drive positive change in clinical practice and health policy in areas of need in neurology. The Lancet Neurology is an internationally trusted source of clinical, public health, and global health knowledge. It has an Impact Factor of 48.0, making it the top-ranked clinical neurology journal out of 212 journals worldwide.
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