Abstract
Cerebral white matter lesions (WML) encompass axonal loss and demyelination, and the pathogenesis is assumed to be small vessel disease (SVD)-related ischemia. However, WML may also result from the activation of Wallerian degeneration as a consequence of cortical Alzheimer’s disease (AD) pathology, i.e. hyperphosphorylated tau (HPτ) and amyloid-beta (Aβ) deposition. WML seen in AD have a posterior predominance compared to non-demented individuals but it is unclear whether the pathological and molecular signatures of WML differ between these two groups. We investigated differences in the composition and aetiology of parietal WML from AD and non-demented controls. Parietal WML tissue from 55 human post-mortem brains (AD, n = 27; non-demented controls, n = 28) were quantitatively assessed for axonal loss and demyelination, as well as for cortical HPτ and Aβ burden and SVD. Biochemical assessment included Wallerian degeneration protease calpain and the myelin-associated glycoprotein (MAG) to proteolipid protein (PLP) ratio (MAG:PLP) as a measure of hypoperfusion. WML severity was associated with both axonal loss and demyelination in AD, but only with demyelination in controls. Calpain was significantly increased in WML tissue in AD, whereas MAG:PLP was significantly reduced in controls. Calpain levels were associated with increasing amounts of cortical AD-pathology but not SVD. We conclude that parietal WML seen in AD differ in their pathological composition and aetiology compared to WML seen in aged controls: WML seen in AD may be associated with Wallerian degeneration that is triggered by cortical AD-pathology, whereas WML in aged controls are due to ischaemia. Hence, parietal WML as seen on MRI should not invariably be interpreted as a surrogate biomarker for SVD as they may be indicative of cortical AD-pathology, and therefore, AD should also be considered as the main underlying cause for cognitive impairment in cases with parietal WML.
Highlights
Cerebral white matter lesions (WML) are a frequent finding at post-mortem histological examination of brains from both demented and non-demented elderly
Increasing severity of WML in Alzheimer’s disease (AD) is associated with both axonal loss and demyelination, in contrast to non-demented individuals in which WML are associated with demyelination only
Biochemical analysis indicated an increase in calpain2 levels in the white matter of AD cases, which is suggestive of increased Wallerian degeneration that is associated with increasing cortical burden of AD-related pathologies but not with small vessel disease (SVD)
Summary
Cerebral white matter lesions (WML) are a frequent finding at post-mortem histological examination of brains from both demented and non-demented elderly. They primarily encompass loss of integrity of the cerebral white matter due to rarefaction, which morphologically appear as demyelination when visualized with histochemical myelin stains and may be due to loss of the axonal myelin sheath or axonal loss [25]. WML appear as white matter hyperintensities (WMH) on pre- and post-mortem T2-weighted magnetic resonance imaging (MRI) [27], and as altered diffusivity on. WML/WMH are usually assumed to represent ischemiaassociated demyelination and axonal loss due to arteriopathy of the white matter arteries and arterioles, i.e. small vessel disease (SVD) [47]. Impaired axonal transport leads to axonal dysregulation and increased intracellular calcium concentration activating the calcium-dependent cysteine protease calpain that mediates cytoskeletal breakdown, demyelination and axonal fragmentation [12, 13, 39]
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