Heterogeneity of White Matter Hyperintensities in Alzheimer's Disease: Post-Mortem Quantitative MRI and Neuropathology

Abstract

White matter hyperintensities (WMH) are frequently seen onT 2 -weighted MRI scans of elderly subjects with and without Alzheimer's disease. WMH are only weakly and inconsistently associated with cognitive decline, which may be explained by heterogeneity of the underlying neuropathological substrates. The use of quantitative MRI could increase specificity for these neuropathological changes. We assessed whether post-mortem quantitative MRI is able to reflect differences in neuropathological correlates of WMH in tissue samples obtained postmortem from Alzheimer's disease patients and from non-demented elderly. Thirty-three formalin-fixed, coronal brain slices from 11 Alzheimer's disease patients (mean age: 83 AE10 years, eight females) and 15 slices from seven non-demented controls (mean age: 78 AE10 years, four females) with WMH were scanned at 1.5 T using qualitative (fluid-attenuated inversion recovery, FLAIR) and quantitative MRI [diffusion tensor imaging (DTI) including estimation of apparent diffusion coefficient (ADC) and fractional anisotropy (FA), and T 1 -relaxation time mapping based on flip-angle array). A total of 104 regions of interest were defined on FLAIR images in WMH and normal appearing white matter (NAWM). Neuropathological examination included (semi-)quantitative assessment of axonal density (Bodian), myelin density (LFB), astrogliosis (GFAP) and microglial activation (HLA-DR). Patient groups (Alzheimer's disease versus controls) and tissue types (WMH versus NAWM) were compared with respect to QMRI and neuropathological measures. Overall, Alzheimer's disease patients had significantly lower FA (P _ 0.01) and higher T 1 -values than controls (P = 0.04). WMH showed lower FA (P _ 0.01) and higher T 1 -values (P _ 0.001) than NAWM in both patient groups. A significant interaction between patient group and tissue type was found for the T 1 measurements, indicating that the difference inT 1 -relaxation time between NAWM and WMH was larger in Alzheimer's disease patients than in non-demented controls. All neuropathological measures showed differences between WMH and NAWM, although the difference in microglial activation was specific for Alzheimer's disease. Multivariate regression models revealed that in Alzheimer's disease, axonal density was an independent determinant of FA, whereas T 1 was independently determined by axonal and myelin density and microglial activation. Quantitative MRI techniques reveal differences in WMH between Alzheimer's disease and non-demented elderly, and are able to reflect the severity of the neuropathological changes involved.Keywords: age-related white matter hyperintensities; post-mortem MRI; Alzheimer's disease; neuropathological characteristics Abbreviations: 3D-FLAIR = 3D-fluid-attenuated inversion recovery; ADC = apparent diffusion coefficient; CERAD = Consortium to establish a Registry for Alzheimer's disease; DTI = diffusion tensor imaging; FA = fractional anisotropy; FLASH = fast low-angle shot; GFAP = glial fibrillary acidic protein; HE = haematoxylin^eosin; L...

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