Cerebrovascular disease promotes tau pathology in Alzheimer's disease.
Cerebrovascular disease promotes tau pathology in Alzheimer's disease.
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脑血管疾病促进阿尔茨海默病中的tau病理学
DOI：
10.1093/braincomms/fcaa132
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发表时间：
2020
影响因子：
4.8
通讯作者：
Alzheimer’s Disease Neuroimaging Initiative
中科院分区：
文献类型：
--
作者：
Laing KK;Simoes S;Baena-Caldas GP;Lao PJ;Kothiya M;Igwe KC;Chesebro AG;Houck AL;Pedraza L;Hernández AI;Li J;Zimmerman ME;Luchsinger JA;Barone FC;Moreno H;Brickman AM;Alzheimer’s Disease Neuroimaging Initiative
小血管脑血管疾病，在t2加权磁共振成像上表现为白质高信号，有助于阿尔茨海默病的临床表现。然而，脑血管疾病在多大程度上代表阿尔茨海默病的独立病理特征或直接促进阿尔茨海默病的病理尚不清楚。本研究的目的是研究白质高强度与血浆tau蛋白水平之间的关系，并确定白质高强度和tau蛋白水平是否相互作用，以预测阿尔茨海默病的诊断。为了证实脑血管疾病促进tau病理，我们在小鼠缺血损伤模型中检测了tau液体生物标志物浓度和病理。来自阿尔茨海默病神经影像学倡议的391名参与者（74.5±7.1岁）被纳入这项横断面分析。参与者测量了血浆总tau蛋白、脑脊液β -淀粉样蛋白和白质高信号，并被临床诊断为阿尔茨海默病（n = 97）、轻度认知障碍（n = 186）或认知正常对照（n = 108）。我们测试了诊断组血浆tau浓度与白质高强度体积之间的关系。我们还研究了白质高强度、血浆tau蛋白、淀粉样蛋白阳性状态以及白质高强度和血浆tau蛋白之间的相互作用对诊断类别的正确分类程度。白质高强度体积的增加与较高的血浆tau浓度相关，特别是在临床诊断为阿尔茨海默病的患者中。脑淀粉样蛋白的存在以及血浆tau和白质高强度体积之间的相互作用将阿尔茨海默病和轻度认知障碍参与者与对照组区分出来，准确率分别为77.6%和63.3%。在63名进行尸检的阿尔茨海默病神经影像学计划参与者中（死亡年龄为82.33±7.18岁），我们发现动脉硬化程度越高，Braak分期越高，表明脑血管疾病与神经原纤维病理呈正相关。在短暂性大脑中动脉闭塞小鼠模型中，接受短暂性大脑中动脉闭塞而非假手术的老年小鼠血浆和脑脊液中tau浓度升高，诱导髓磷脂丢失，同侧海马和大脑半球tau蛋白过度磷酸化。这些发现证明了脑血管疾病（表现为白质高信号）与血浆中tau水平之间的关系，表明低灌注损伤促进了tau病理。这种潜在的因果关系得到了一项研究的支持，即在老年成年小鼠中，短暂性脑动脉闭塞诱导白质损伤，增加tau生物流体标记物，并促进大脑tau过度磷酸化。血浆来源的总tau浓度与WMH体积高度相关，WMH体积是小血管缺血损伤的MRI标志物，特别是在临床阿尔茨海默病患者中。一个平行的小鼠模型证实了白质损伤，高磷酸化的tau病理和血浆和脑脊液中tau浓度升高是由于手术诱导的缺血损伤。
Small vessel cerebrovascular disease, visualized as white matter hyperintensities on T2-weighted magnetic resonance imaging, contributes to the clinical presentation of Alzheimer’s disease. However, the extent to which cerebrovascular disease represents an independent pathognomonic feature of Alzheimer's disease or directly promotes Alzheimer’s pathology is unclear. The purpose of this study was to examine the association between white matter hyperintensities and plasma levels of tau and to determine if white matter hyperintensities and tau levels interact to predict Alzheimer’s disease diagnosis. To confirm that cerebrovascular disease promotes tau pathology, we examined tau fluid biomarker concentrations and pathology in a mouse model of ischaemic injury. Three hundred ninety-one participants from the Alzheimer’s Disease Neuroimaging Initiative (74.5 ± 7.1 years of age) were included in this cross-sectional analysis. Participants had measurements of plasma total-tau, cerebrospinal fluid beta-amyloid, and white matter hyperintensities, and were diagnosed clinically as Alzheimer’s disease (n = 97), mild cognitive impairment (n = 186) or cognitively normal control (n = 108). We tested the relationship between plasma tau concentration and white matter hyperintensity volume across diagnostic groups. We also examined the extent to which white matter hyperintensity volume, plasma tau, amyloid positivity status and the interaction between white matter hyperintensities and plasma tau correctly classifies diagnostic category. Increased white matter hyperintensity volume was associated with higher plasma tau concentration, particularly among those diagnosed clinically with Alzheimer’s disease. Presence of brain amyloid and the interaction between plasma tau and white matter hyperintensity volume distinguished Alzheimer’s disease and mild cognitive impairment participants from controls with 77.6% and 63.3% accuracy, respectively. In 63 Alzheimer’s Disease Neuroimaging Initiative participants who came to autopsy (82.33 ± 7.18 age at death), we found that higher degrees of arteriosclerosis were associated with higher Braak staging, indicating a positive relationship between cerebrovascular disease and neurofibrillary pathology. In a transient middle cerebral artery occlusion mouse model, aged mice that received transient middle cerebral artery occlusion, but not sham surgery, had increased plasma and cerebrospinal fluid tau concentrations, induced myelin loss, and hyperphosphorylated tau pathology in the ipsilateral hippocampus and cerebral hemisphere. These findings demonstrate a relationship between cerebrovascular disease, operationalized as white matter hyperintensities, and tau levels, indexed in the plasma, suggesting that hypoperfusive injury promotes tau pathology. This potential causal association is supported by the demonstration that transient cerebral artery occlusion induces white matter damage, increases biofluidic markers of tau, and promotes cerebral tau hyperphosphorylation in older-adult mice. Plasma-derived total-tau concentration is highly correlated with WMH volume, an MRI marker of small vessel ischaemic damage, particularly among individuals with clinical Alzheimer’s disease. A parallel mouse model confirmed white matter damage, hyperphosphorylated tau pathology and elevated tau concentration in plasma and CSF due to surgically induced ischaemic injury.
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影响因子：
5.7
作者：
Fischl, B;Sereno, MI;Dale, AM
通讯作者：
Dale, AM
影响因子：
--
作者：
Brickman, Adam M.;Provenzano, Frank A.;Muraskin, Jordan;Manly, Jennifer J.;Blum, Sonja;Apa, Zoltan;Stern, Yaakov;Brown, Truman R.;Luchsinger, Jose A.;Mayeux, Richard
通讯作者：
Mayeux, Richard
DOI：
10.1523/jneurosci.2462-12.2012
发表时间：
2012-11-14
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Hedden T;Mormino EC;Amariglio RE;Younger AP;Schultz AP;Becker JA;Buckner RL;Johnson KA;Sperling RA;Rentz DM
通讯作者：
Rentz DM
影响因子：
48
作者：
Barnes, Deborah E.;Yaffe, Kristine
通讯作者：
Yaffe, Kristine
影响因子：
5.7
作者：
Dale, AM;Fischl, B;Sereno, MI
通讯作者：
Sereno, MI