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Histopathologic correlates of white matter changes on MRI in Alzheimer's disease and normal aging
Abstract
We investigated the histopathologic correlates of white matter changes in Alzheimer's disease (AD) patients (n = 6) and controls (n = 9) using postmortem MRI. White matter changes were rated on a 0 to 3 scale in 51 regions. Histopathologically, we subjectively rated the loss of myelinated axons in the deep and periventricular white matter, denudation of the ventricular ependyma, gliosis, width of the perivascular spaces, and leptomeningeal congophilic angiopathy; we measured structural changes in the walls of the blood vessels in the white matter in micrometers. The AD brains displayed significantly more white matter hyperintensities on MRI than controls. Histopathologically, the denudation of the ventricular ependyma and the gliosis were significantly more severe in AD than in controls, and there was a trend toward more loss of myelinated axons in the deep white matter in the AD brains (p = 0.07). The MRI abnormalities correlated with the loss of myelinated axons in the deep white matter (r' = 0.37; p < 0.01) and with the denudation of the ventricular lining (r' = 0.54; p < 0.01). We could not find any evidence for arteriolosclerosis, but the mean thickness of the adventitia of the arteries of the deep white matter in AD almost doubled the value in control brains (p = 0.0009). We conclude that white matter abnormalities in AD patients and controls consist of loss of myelinated axons, probably caused by arterial changes and breakdown of the ventricular lining. Since imaging/histopathologic correlation was similar in AD patients and controls, these changes probably represent some form of accelerated aging.
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“AD subjects show more pervasive white matter change [42–46].”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [45]
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“…large white matter lesions observed as white matter hyperintensities (WMH) on T2-weighted MRI that are elevated in AD (Brickman, 2013, for review; Scheltens et al., 1995) show no association with amyloid burden in clinically normal individuals (e.g., Hedden et al., 2012; Marchant et al., 2012;…”
Casta�o, E. M., Maarouf, C. L., Wu, T., Leal, M. C., Whiteside, C. M., Lue, L., Kokjohn, T. A., Sabbagh, M. N., Beach, T. G., & Roher, A. E. (2012) · Neurochemistry International · doi:10.1016/j.neuint.2012.12.001 · Cited by 61
“…fibrosis of small vessels, loss of microvessels, interstitial fluid stasis and chronic inflammation (Brun and Englund, 1986; Englund and Brun, 1990; Scheltens et al., 1995; Kalaria, 2002; Bronge et al., 2002; Roher et al., 2003b; Sjobeck et al., 2006; Kalback et al., 2004; Beach et al., 1989;…”
BackgroundTissue magnetic susceptibility mapping as a marker of tau pathology in Alzheimer's disease
O’Callaghan, J. M., Holmes, H. E., Powell, N. M., Wells, J. A., Ismail, O., Harrison, I. F., Siow, B. M., Johnson, R. A., Ahmed, Z., Fisher, A., et al. (2017) · NeuroImage · doi:10.1016/j.neuroimage.2017.08.003 · Cited by 63
“, 2008), as well as denudation of the ventricular ependyma, gliosis and the loss of myelinated axons (Scheltens et al., 1995).”
Functional connectivity of white matter as a biomarker of cognitive decline in Alzheimer’s disease
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InfluentialWhite Matter Lesions in Alzheimer Patients Are Influenced by Apolipoprotein E Genotype
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“Although AD is considered as a gray matter disease, postmortem AD brains clearly show white matter damages (Scheltens et al., 1995; Gouw et al., 2008; Nasrabady et al., 2018), and a number of studies have shown that the extent of myelin loss correlates with Aβ burden (Grimmer et al.”
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“Increased frequency of white matter lesions has been reported in association with cognitive impairment(36-38) and AD.(38-41) Neuropathological studies have also demonstrated that chronic hypoperfusion can lead to subcortical alterations.”
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Park, J., Kwon, H., Lee, J., Kim, D. ‐., & Ovbiagele, B. (2014) · European Journal of Neurology · doi:10.1111/ene.12431 · Cited by 55
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The impact of vascular burden on late-life depression
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“Occasional T2-visible abnormalities of the elderly have been associated with various pathological substrates, including dilatation of Virchow-Robin spaces, white matter rarefaction, fibrohyalinotic vascular changes, perivenous hypomyelination, spongiform white matter changes and discrete infarcts [8, 18, 31].”
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“One phenomenon we speculate may explain the strong relationship found in this study between increasing ventricular volume and diffusivity of WMC, independently of decreasing total WM volume, is the denudation of the ventricular ependyma, which is severe in AD [8] and may permit leakage of cerebrospinal fluid into the…”
BackgroundResultStructural Neuroimaging Studies in Late-Life Depression: A Review
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Abe, K., Fujimura, H., Kobayashi, Y., et al. (1997) · Journal of Neuroimaging · doi:10.1111/jon199774208 · Cited by 52
“This suggests the possibility that proton density-weighted images [23, 24] are superior to other imaging modalities in detecting pathological changes in the IC of ALS patients / and that signal changes in the premortem MRI of normal I control subjects may not be explained solely by the de creased myelin density.”
BackgroundMagnetic resonance imaging in dementia: a study of brain white matter changes
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“Findings most often reported as being associated with hyperintense lesions include myelin rarefaction, arteriosclerosis, dilated perivascular spaces, vascular ectasia, ependymal loss, and cerebral ischemia (Awad et al., 1986; Kirkpatrick and Hayman, 1987; Fazekas et al., 1991; Scheltens et al., 1995).”
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“Although AD affects primarily GM, WM disruption is also widespread (Scheltens et al., 1995; Smith et al., 2000; Gouw et al., 2008; Huang et al., 2012).”
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“Those with vascular risk factors are likely to experience onset of depression in late life due to an underlying cerebrovascular pathology which may have implications for prognosis, treatment and clinical outcomes [114–116].”
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“Altered microstructure is strongly implicated in the cognitive changes that occur throughout disease progression (Scheltens et al. 1995; Takahashi et al. 2002; Bozzali et al. 2002; Huang et al. 2007; Zhuang et al. 2013).”
BackgroundCerebral white matter disease is associated with Alzheimer pathology in a prospective cohort
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“Scheltens et al [32] in a small study found that in persons with AD, there was evidence of axonal loss, denudation of the ventricular lining, and arteriosclerosis.”
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“The role of high signal abnormalities as a marker of disease type is also confounded by the description of extensive white matter abnormality in patients with Alzheimer’s disease (AD) (16, 17), normal pressure hydrocephalus (18), Lewy body dementia (LBD) (11) and frontotemporal dementia (FTD) (19).”
BackgroundPeriventricular White Matter Hyperintensities on MRI: Correlation With Neuropathologic Findings
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Metadata
- Authors
- Scheltens, P., Barkhof, F., Leys, D., Wolters, E. C., Ravid, R., & Kamphorst, W.
- Affiliations
- From the Departments of Neurology (Drs. Scheltens and Wolters), Diagnostic Radiology (Dr. BarkhoO, and Neuropathology (Dr. Kamphorst), Academisch Ziekenhuis W, and the Netherlands Brain Bank (Dr. Ravid), Amsterdam, the Netherlands; and the Department of Neurology (Dr. Leys), Hospital B, University of Lille, Lille, France.
- Université de Lille (FR)
- Venue
- Neurology
- Published
- 1995-05
- Volume
- 45
- Issue
- 5
- Pages
- 883-888
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- OpenAlex
- W2043592305
- Cited by
- 344
- References
- 0
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 6 · 2023: 6 · 2022: 6 · 2021: 4 · 2020: 10 · 2019: 7 · 2018: 6 · 2017: 9 · 2016: 10 · 2015: 13 · 2014: 22 · 2013: 11 · 2012: 10
- FWCI
- 8.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurology (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- Alzheimer's disease, white matter hyperintensities, normal aging, gliosis, arteriolosclerosis, adventitial thickening, postmortem MRI, accelerated aging
- MeSH terms
- Aged, Aged, 80 and over, Aging, Alzheimer Disease, Brain, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged
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