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Frontal white matter lesions in Alzheimer’s disease are associated with both small vessel disease and AD-associated cortical pathology
Acta Neuropathologica ( IF 9.3 ) Pub Date : 2021-10-04 , DOI: 10.1007/s00401-021-02376-2
Kirsty E McAleese 1 , Mohi Miah 1 , Sophie Graham 1 , Georgina M Hadfield 1 , Lauren Walker 1 , Mary Johnson 1 , Sean J Colloby 1 , Alan J Thomas 1 , Charles DeCarli 2 , David Koss 1 , Johannes Attems 1
Affiliation  

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.



中文翻译:

阿尔茨海默病的额叶白质病变与小血管疾病和 AD 相关的皮质病理学有关

脑白质病变 (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,我们之前对顶叶白质的研究表明,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损失有关。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。在这项试点研究中,我们使用了人类后期解剖脑组织以研究来自 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。对来自 40 个人类死后大脑(AD,n =  19;对照,n =  21)的额叶 WML 组织切片进行脱髓鞘、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的定量评估作为 SVD 的量度。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率作为生前测量缺血。发现动脉硬化严重程度与 AD 和非痴呆对照的额叶 WML 严重程度相关,并且是其重要的预测因子。有趣的是,额叶轴突损失也与 HPτ 有关,钙蛋白酶水平与 AD 组中 Aβ 负荷增加有关,这表明存在额外的退行性影响。总而言之,该初步数据表明 AD 中的额叶 WML 可能是由小动脉硬化增加和 AD 相关的退行性变化引起的。这些初步发现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,应在痴呆亚型的临床诊断中考虑:后部 WML 可能与继发于 AD 病理学的退行性机制有关,

更新日期:2021-10-06
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