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Lookup NU author(s): Dr Kirsty McAleese, Dr Michael FirbankORCiD, Madhurima Dey, Dr Sean Colloby, Dr Lauren WalkerORCiD, Professor John-Paul TaylorORCiD, Professor Alan ThomasORCiD, Professor John O'Brien, Professor Johannes Attems
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Introduction Cerebral white matter lesions (WML), visualized as white matter hyperintensities (WMH) on T2-weighted MRI, encompass structural damage and loss of integrity of the cerebral white matter (WM) and are commonly assumed to be associated with small vessel disease (SVD). However, it has been suggested that WM damage may also be the result of degenerative axonal loss that is secondary to cortical Alzheimer’s disease (AD) pathologies i.e., hyperphosphorylated tau (HPτ) and amyloid-beta (Aβ). Here we investigate the influence of HPτ, Aβ and SVD on WMH severity. Results 36 human post-mortem right fixed cerebral hemispheres (mean age 84.4 ± 7.7 years; male: 16, female: 20) containing varying amounts of AD-pathology (AD: 23, controls: 13) underwent T2- weighted MRI with WMH assessed according to the age related white matter change scale (ARWMC). After dissection, using tissue samples from the frontal, temporal, parietal and occipital regions from the right hemisphere, we quantitatively assessed cortical HPτ and Aβ pathology burden by measuring the percentage area covered by AT8 immunoreactivity (HPτ-IR) and 4G8 immunoreactivity (Aβ-IR), and assessed the severity of WM SVD by calculating the sclerotic index (SI) of WM arteries/arterioles. HPτ-IR, Aβ-IR, and SI were compared with ARWMC scores. HPτ-IR, Aβ-IR and WM ARWMC scores were all significantly higher in AD cases compared to controls, while SI values were similar between groups. ARWMC scores correlated with HPτ-IR, Aβ-IR and SI in various regions, however, linear regression revealed that only HPτ-IR was a significant independent predictor of ARWMC scores. Conclusions Here we have shown that increasing cortical HPτ burden independently predicted the severity of WMH indicating its potentially important role in the pathogenesis of WM damage. Moreover, our findings suggest that in AD patients the presence of WMH may indicate cortical AD-associated pathology rather than SVD. Further studies are warranted to elucidate the pathological processes that lead to WM damage and to clarify if WMH may serve as a general biomarker for cortical AD-associated pathology.
Author(s): McAleese K, Firbank M, Dey M, Colloby SJ, Walker L, Johnson M, Beverley JR, Taylor JP, Thomas AJ, O'Brien JT, Attems J
Publication type: Article
Publication status: Published
Journal: Acta Neuropathologica Communications
Year: 2015
Volume: 3
Print publication date: 30/09/2015
Online publication date: 30/09/2015
Acceptance date: 17/09/2015
Date deposited: 20/10/2015
ISSN (electronic): 2051-5960
Publisher: BioMed Central Ltd.
URL: http://dx.doi.org/10.1186/s40478-015-0240-0
DOI: 10.1186/s40478-015-0240-0
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