期刊
ACTA NEUROPATHOLOGICA
卷 142, 期 6, 页码 937-950出版社
SPRINGER
DOI: 10.1007/s00401-021-02376-2
关键词
White matter lesion; White matter hyperintensity; Alzheimer's disease; Small vessel disease; Amyloid-beta; Hyperphosphorylated tau
资金
- Alzheimer's Society [AS-JF-18-01]
- UK Medical Research Council [G0400074]
- Alzheimer's Society
- Alzheimer's Research UK
Frontal white matter lesions in Alzheimer's disease may result from increased arteriolosclerosis and AD-associated degenerative changes. Axonal loss in the frontal lobe was associated with hyperphosphorylated tau, and calpain levels were associated with increasing amyloid-beta burden in the AD group, indicating an additional degenerative influence.
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 (HP tau) and amyloid-beta (A beta) 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 HP tau and calpain levels were associated with increasing A beta 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据