Multimorbidity in the ageing human brain :associations between Alzheimer's disease pathology and white matter hyperintensities

Abstract

Background: In the brains of both demented and non-demented subjects the most common pathologies are Alzheimer’s disease (AD) related pathologies and white matter lesions (WML). It is widely assumed that small vessel disease (SVD) is the main cause of WML, although evidence suggests neurodegenerative pathologies may also be involved in the pathogenesis of WML. However, investigation of these pathologies is hindered due lack of standardized histological criteria for WML assessment and the current use of semi-quantitative assessment is incapable of detecting subtle variations in pathologic burden across cases. The main aim of this study was to improve the post mortem assessment of WML/WMH and AD-related pathology in the ageing human brain by the use of post mortem MRI and quantitative neuropathological assessment, and to investigate possible associations between AD pathology and white matter integrity.! Methods: Formalin fixed brains underwent post mortem MRI and white matter hyperintensitites (WMH) were assessed according to the Age-Related White Matter Change (ARWMC) scale. ARWMC scores were compared with corresponding semi-quantitative neuropathological scores obtained by an extensive assessment of the white matter. In a cohort of AD and control brains semi-quantitative and quantitative assessment of hyperphosphorylated tau (HPT), amyloid-beta (Aβ) pathology and SVD were compared. The influence of AD-related pathology and SVD on white matter integrity was then investigated using a combination of post mortem MRI-based WMH assessment, quantitative neuropathological assessment using Tissue Micro Array (TMA) methodology and Sclerotic Index. Key findings: MRI-based assessment of fixed post mortem brains was found to be a practical method that reliably reflects WML in the frontal, parietal and occipital WM comparable with an extensive histological assessment at 7 mm intervals. Digital quantification of cortical HPT, Aβ and SVD pathology revealed widespread variations in pathological burden. HPT, Aβ pathology and SVD had a significant influence on WMH severity in both non-demented normal aged and AD brains, however, HPT, but not SVD, was the most significant predictor of WMH score. Conclusion: This study showed that MRI-based assessment of fixed post mortem brains is a practical method for the assessment of white matter integrity and TMA is a practical method for quantitative neuropathological assessment of degenerative neocortical pathologies. HPT was found to be the strongest predictor of WMH. However, further studies are required to elucidate the different patho-physiological mechanisms that may underlie WM damage in the ageing brain.