Abstract
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.
Highlights
Cerebral white matter lesions (WML) histologically encompass rarefaction of the cerebral white matter, primarily presenting as demyelination with/without axonal loss with associated oedema and reactive gliosis [17]
A pivotal diffusion tensor imaging (DTI) study by Lee et al further investigated the rostral-caudal gradient of white matter hyperintensities (WMH) within the corpus callosum (CC) [25]; data from this study indicate that both Alzheimer’s disease (AD)-associated degenerative mechanisms and vascular processes contributed to white matter disruption within the anterior CC, in contrast to disruption in the posterior CC that was primarily driven by AD-associated degeneration
We reveal for the first time in human post-mortem tissue that the aetiology of frontal WML in AD is possibly the result of both small vessel disease (SVD)-associated mechanisms and degenerative changes secondary to the accumulation of AD pathology
Summary
Cerebral white matter lesions (WML) histologically encompass rarefaction of the cerebral white matter, primarily presenting as demyelination with/without axonal loss with associated oedema and reactive gliosis [17]. WML/WMH are highly associated with age [46], and are commonly seen in individuals with and without dementia [47] presumed to reflect chronic ischaemia-associated demyelination and axonal loss due to arteriopathy of the perforating white matter arteries and arterioles, i.e., type 1 arteriolosclerosis cerebral small vessel disease (SVD) [41, 42]. SVD itself is heterogeneous incorporating atherosclerosis, lipohyalinosis, arteriolosclerosis, blood-brain barrier (BBB) breakdown, fibroid necrosis, and calcification of the perforating arteries and/or arterioles. Cerebral amyloid angiopathy (CAA), characterized by the accumulation of amyloid-beta (Aβ) pathology in leptomeningeal, cortical, and capillary vessel walls (Type 2 cerebral SVD [42]), has been shown to be associated with white matter disruption and increased WMH volume [1, 31] as well as increased demyelination of associated white matter [53]
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