Frontal white matter lesions in Alzheimer's disease are associated with both small vessel disease and AD-associated cortical pathology.
Frontal white matter lesions in Alzheimer's disease are associated with both small vessel disease and AD-associated cortical pathology.
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DOI：
10.1007/s00401-021-02376-2
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发表时间：
2021-12
影响因子：
12.7
通讯作者：
Attems J
中科院分区：
文献类型：
--
作者：
McAleese KE;Miah M;Graham S;Hadfield GM;Walker L;Johnson M;Colloby SJ;Thomas AJ;DeCarli C;Koss D;Attems J
脑白色病变（WML）包括轴突丢失和脱髓鞘，并被认为与小血管疾病（SVD）相关的缺血有关。然而，我们先前在顶叶白色物质的研究表明，阿尔茨海默病（AD）中的WML与继发于皮质AD病理沉积的退行性轴突丢失有关。此外，神经影像学数据表明，WML发展的病理机制在前叶和后叶之间存在差异，AD相关的退行性机制驱动后部白色物质破坏，AD相关的退行性和血管机制均导致前部物质破坏。在这项初步研究中，我们使用人类死后的脑组织来调查AD和非痴呆对照的额叶WML的组成和病因，以确定额叶WML是否与SVD相关，并揭示WML发病机制的任何区域差异。对40例人类死后脑（AD，n = 19;对照，n = 21）的额叶WML组织切片进行定量评估，以确定脱髓鞘、轴突丢失、皮质过度磷酸化tau（HPτ）和淀粉样蛋白β（Aβ）负荷以及小动脉硬化作为SVD的指标。生化评估包括沃勒变性相关蛋白酶钙蛋白酶和髓鞘相关糖蛋白与蛋白脂质蛋白的比例作为生前缺血的指标。在AD和非痴呆对照组中，发现动脉硬化严重程度与额叶WML严重程度相关，并且是额叶WML严重程度的重要预测因素。有趣的是，AD组中额叶轴突丢失也与HPτ相关，钙蛋白酶水平与Aβ负荷增加相关，提示了其他退行性影响。总之，该初步数据表明，AD中的额叶WML可能是由增加的小动脉硬化和AD相关的退行性变化引起的。这些初步研究结果与先前发表的数据相结合，初步表明AD中WML病因的区域差异，这在痴呆亚型的临床诊断中应予以考虑：后部WML可能与继发于AD病理学的退行性机制相关，而前部WML可能与SVD相关和退行性机制相关。在线版本包含补充材料，可通过10.1007/s 00401 -021-02376-2获得。
Cerebral white matter lesions (WML) encompass axonal loss and demyelination and are assumed to be associated with small vessel disease (SVD)-related ischaemia. However, our previous study in the parietal lobe white matter revealed that WML in Alzheimer’s disease (AD) are linked with degenerative axonal loss secondary to the deposition of cortical AD pathology. Furthermore, neuroimaging data suggest that pathomechanisms for the development of WML differ between anterior and posterior lobes with AD-associated degenerative mechanism driving posterior white matter disruption, and both AD-associated degenerative and vascular mechanisms contributed to anterior matter disruption. In this pilot study, we used human post-mortem brain tissue to investigate the composition and aetiology of frontal WML from AD and non-demented controls to determine if frontal WML are SVD-associated and to reveal any regional differences in the pathogenesis of WML. Frontal WML tissue sections from 40 human post-mortem brains (AD, n = 19; controls, n = 21) were quantitatively assessed for demyelination, axonal loss, cortical hyperphosphorylated tau (HPτ) and amyloid-beta (Aβ) burden, and arteriolosclerosis as a measure of SVD. Biochemical assessment included Wallerian degeneration-associated protease calpain and the myelin-associated glycoprotein to proteolipid protein ratio as a measure of ante-mortem ischaemia. Arteriolosclerosis severity was found to be associated with and a significant predictor of frontal WML severity in both AD and non-demented controls. Interesting, frontal axonal loss was also associated with HPτ and calpain levels were associated with increasing Aβ burden in the AD group, suggestive of an additional degenerative influence. To conclude, this pilot data suggest that frontal WML in AD may result from both increased arteriolosclerosis and AD-associated degenerative changes. These preliminary findings in combination with previously published data tentatively indicate regional differences in the aetiology of WML in AD, which should be considered in the clinical diagnosis of dementia subtypes: posterior WML maybe associated with degenerative mechanisms secondary to AD pathology, while anterior WML could be associated with both SVD-associated and degenerative mechanisms. The online version contains supplementary material available at 10.1007/s00401-021-02376-2.
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影响因子：
12.7
作者：
Grinberg LT;Thal DR
通讯作者：
Thal DR
影响因子：
--
作者：
HACHINSKI, VC;POTTER, P;MERSKEY, H
通讯作者：
MERSKEY, H
影响因子：
14.5
作者：
ENGLUND, E;BRUN, A;ALLING, C
通讯作者：
ALLING, C
影响因子：
8.3
作者：
Lee DY;Fletcher E;Martinez O;Zozulya N;Kim J;Tran J;Buonocore M;Carmichael O;DeCarli C
通讯作者：
DeCarli C
DOI：
10.1093/brain/awy229
发表时间：
2018-10-01
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Araque Caballero MÁ;Suárez-Calvet M;Duering M;Franzmeier N;Benzinger T;Fagan AM;Bateman RJ;Jack CR;Levin J;Dichgans M;Jucker M;Karch C;Masters CL;Morris JC;Weiner M;Rossor M;Fox NC;Lee JH;Salloway S;Danek A;Goate A;Yakushev I;Hassenstab J;Schofield PR;Haass C;Ewers M
通讯作者：
Ewers M