Heterogeneity of white matter hyperintensities in Alzheimer's disease: post-mortem quantitative MRI and neuropathology
Abstract
White matter hyperintensities (WMH) are frequently seen on T(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 post-mortem 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 +/- 10 years, eight females) and 15 slices from seven non-demented controls (mean age: 78 +/- 10 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 in T(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.
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- Authors
- Gouw, A. A., Seewann, A., Vrenken, H., van der Flier, W. M., Rozemuller, J. M., Barkhof, F., Scheltens, P., & Geurts, J. J. G.
- Affiliations
- Vrije Universiteit Amsterdam (NL)
- Medical University of Graz (AT)
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-10-16
- Volume
- 131
- Issue
- 12
- Pages
- 3286-3298
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2118521681
- Cited by
- 281
- References
- 43
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 19 · 2023: 16 · 2022: 16 · 2021: 12 · 2020: 15 · 2019: 9 · 2018: 13 · 2017: 21 · 2016: 15 · 2015: 20 · 2014: 20 · 2013: 20 · 2012: 15
- FWCI
- 11.45
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Keywords
- white matter hyperintensities, Alzheimer's disease, normal-appearing white matter, diffusion tensor imaging, fractional anisotropy, apparent diffusion coefficient, T1 relaxation time, microglial activation, astrocyte activation, myelin density, axon density, neuropathology, postmortem brain, FLAIR, cognitive decline
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Astrocytes, Axons, Brain, Brain Mapping, Female, Humans, Image Interpretation, Computer-Assisted, Magnetic Resonance Imaging, Male, Prospective Studies, Microglia
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