Tau, amyloid, and cascading network failure across the Alzheimer's disease spectrum.
Tau, amyloid, and cascading network failure across the Alzheimer's disease spectrum.
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tau，淀粉样蛋白和级联网络失败在阿尔茨海默氏病谱系中。
DOI：
10.1016/j.cortex.2017.09.018
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发表时间：
2017-12
期刊：
影响因子：
--
通讯作者：
Jack CR Jr
中科院分区：
文献类型：
--
作者：
Jones DT;Graff-Radford J;Lowe VJ;Wiste HJ;Gunter JL;Senjem ML;Botha H;Kantarci K;Boeve BF;Knopman DS;Petersen RC;Jack CR Jr
功能相关的脑区选择性地易受阿尔茨海默病病理生理的影响。然而，这种病理生理学的分子标记（即β -淀粉样蛋白和tau蛋白聚集物）在这些选择性易感的大脑区域中具有不同的空间和时间模式。现有的还原论病理生理模型不能解释这些大规模的时空不一致性。然而，在最近提出的阿尔茨海默病的级联网络失效模型的框架内，这些大规模的模式是可以预期的。该模型假设如下：1)在临床正常个体中，tau相关的受限网络破坏发生在特定于给定表型的大脑区域；2)这种破坏可以触发与表型无关的、刻板的和淀粉样蛋白相关的代偿性脑网络的变化，这些变化是由默认模式网络的变化所指示的；3)淀粉样蛋白沉积标志着功能代偿的饱和，预示着刺激表型特异性和tau相关的网络故障的加速。随着体内tau病理分子成像的出现，结合淀粉样蛋白和功能网络成像，现在有可能在这些选择性脆弱的大脑区域内研究功能性脑网络、tau和淀粉样蛋白之间的关系。在一个大型队列（n = 218）中，从年轻、淀粉样蛋白阴性、认知正常的受试者到阿尔茨海默病痴呆，我们发现了几种不同的tau沉积空间模式，包括“braak样”和“非braak样”，跨越功能相关的大脑区域。根据我们对tau信号的区域模式进行的多次横断面分析得出的推断，tau信号升高似乎是全系统发生的，而不是局部出现并依次扩散。发病年龄较轻与tau蛋白的“非braak样”模式相关，提示与非典型临床表型相关。正如阿尔茨海默病的级联网络失效模型所预测的那样，我们发现淀粉样蛋白是功能网络失效与脑功能连接区域tau沉积之间关系的部分中介。这项研究暗示了tau沉积的病理生理学中的大规模脑网络，并为将大规模网络生理学纳入连接tau和淀粉样蛋白的疾病模型（如阿尔茨海默病的级联网络失效模型）提供了支持。
Functionally related brain regions are selectively vulnerable to Alzheimer’s disease pathophysiology. However, molecular markers of this pathophysiology (i.e., beta-amyloid and tau aggregates) have discrepant spatial and temporal patterns of progression within these selectively vulnerable brain regions. Existing reductionist pathophysiologic models cannot account for these large-scale spatiotemporal inconsistencies. Within the framework of the recently proposed cascading network failure model of Alzheimer’s disease, however, these large-scale patterns are to be expected. This model postulates the following: 1) a tau-associated, circumscribed network disruption occurs in brain regions specific to a given phenotype in clinically normal individuals; 2) this disruption can trigger phenotype independent, stereotypic, and amyloid-associated compensatory brain network changes indexed by changes in the default mode network; 3) amyloid deposition marks a saturation of functional compensation and portends an acceleration of the inciting phenotype specific, and tau-associated, network failure. With the advent of in vivo molecular imaging of tau pathology, combined with amyloid and functional network imaging, it is now possible to investigate the relationship between functional brain networks, tau, and amyloid across the disease spectrum within these selectively vulnerable brain regions. In a large cohort (n = 218) spanning the Alzheimer’s disease spectrum from young, amyloid negative, cognitively normal subjects to Alzheimer’s disease dementia, we found several distinct spatial patterns of tau deposition, including ‘Braak-like’ and ‘non-Braak-like’, across functionally related brain regions. Rather than arising focally and spreading sequentially, elevated tau signal seems to occur system-wide based on inferences made from multiple cross-sectional analyses we conducted looking at regional patterns of tau signal. Younger age-of-disease-onset was associated with ‘non-Braak-like’ patterns of tau, suggesting an association with atypical clinical phenotypes. As predicted by the cascading network failure model of Alzheimer’s disease, we found that amyloid is a partial mediator of the relationship between functional network failure and tau deposition in functionally connected brain regions. This study implicates large-scale brain networks in the pathophysiology of tau deposition and offers support to models incorporating large-scale network physiology into disease models linking tau and amyloid, such as the cascading network failure model of Alzheimer’s disease.
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影响因子：
3.8
作者：
Gunter, Jeffrey L.;Bernstein, Matt A.;Jack, Clifford R.
通讯作者：
Jack, Clifford R.
影响因子：
4.2
作者：
Duyckaerts, C;Bennecib, M;Hauw, JJ
通讯作者：
Hauw, JJ
影响因子：
9.9
作者：
Jack, Clifford R., Jr.;Wiste, Heather J.;Petersen, Ronald C.
通讯作者：
Petersen, Ronald C.
影响因子：
25
作者：
Bero AW;Yan P;Roh JH;Cirrito JR;Stewart FR;Raichle ME;Lee JM;Holtzman DM
通讯作者：
Holtzman DM
DOI：
10.1016/j.jalz.2011.03.008
发表时间：
2011-05
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Albert MS;DeKosky ST;Dickson D;Dubois B;Feldman HH;Fox NC;Gamst A;Holtzman DM;Jagust WJ;Petersen RC;Snyder PJ;Carrillo MC;Thies B;Phelps CH
通讯作者：
Phelps CH