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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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“These findings are consistent with neuropathological loss of myelinated axons at histopathological studies of postmortem brains [95].”
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Patterns of cognitive impairment in Alzheimer's disease: assessment and differential diagnosis
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“Studies have shown that white matter lesions are common in AD patients (Scheltens et al., 1995), which may affect the normal alterations in white matter fiber diffusivity.”
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“Small vessel disease in the kidney might lead to elevated renal biomarkers, and similar vascular deterioration in the brain (more likely the deep perforating arterioles supplying the deep white matter regions; Scheltens et al., 1995) might lead to subtle and distributed atrophy, contributing to cognitive decline and t…”
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“Individuals with AD, however, demonstrate more marked deep WM demyelination as well as nearly doubled thickness of the adventitia of deep WM arteries over OC individuals [4] and WM atherosclerosis as well as WMSA burden are associated with higher Braak [50] scores in aging populations [8].”
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Physical Exercise Counteracts Aging-Associated White Matter Demyelination Causing Cognitive Decline
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“An analysis of postmortem AD brains revealed that the accumulation of WMH is associated with myelin pallor and axonal demyelination [41-43].”
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“One potential mechanism through which WMH may affect basal ganglia connectivity is via degeneration of myelin and axons connecting the basal ganglia and the cortex (Scarpelli et al., 1994; Scheltens et al., 1995); this in turn may result in a reconfiguration of the connections within the basal ganglia.”
Connectivity-Based Topographical Changes of the Corpus Callosum During Aging
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“The greater water content associated with atrophy in the aging brain could cause the increase of AD and MD, and the loss of myelinated fibers and decreased axonal density would result in the increase of RD and lower FA (Scheltens et al., 1995; Moseley, 2002).”
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“The development of WMHs has been found to correlate with degeneration of myelin and axons (Scarpelli et al., 1994; Scheltens et al., 1995).”
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“In addition to proximity, MRI studies have demonstrated the breakdown of the ventricular lining in AD, rendering it more accessible to proteins in the local interstitium (37), which could include Vilip-1 released upon neuronal death in the ERC.”
BackgroundGeodesic regression on orientation distribution functions with its application to an aging study
Du, J. T., Goh, A., Kushnarev, S., & Qiu, A. (2013) · NeuroImage · doi:10.1016/j.neuroimage.2013.06.081 · Cited by 16
“The decrease in diffusion anisotropy in white matter may be indicative of mild demyelination and loss of myelinated axons observed in postmortem MRI as well as in histological studies of normal aging (Scheltens et al., 1995).”
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“This may be a cumulative effect of atherosclerosis induced by non-specific vascular risk factors and also of AD pathology, but it is also likely a reflection of convergent processes [2-4,63-65].”
BackgroundResultAnalysis of ependymal abnormalities in subjects with schizophrenia, bipolar disorder, and depression
Gilmore, J. H., & Bouldin, T. W. (2002) · Schizophrenia Research · doi:10.1016/s0920-9964(01)00294-8 · Cited by 17
“It has been hypothesized that disruption of the ependyma allows toxic substances, including cytokines, to damage adjacent white matter in premature infants and in adults with Alzheimer’s dementia (Kuban et al., 1999; Scheltens et al., 1995).”
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“Another explanation for the clinical variety due to WMH could be changes of microstructural integrity that are invisible on conventional MRI but are nevertheless expected to contribute substantially to clinical symptoms.(7) Unfortunately, conventional MRI commonly used in clinical practice are insufficiently sensitive…”
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Dysregulated Cholinergic Signaling Inhibits Oligodendrocyte Maturation Following Demyelination
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“Post-mortem studies have shown WML to be histopathologically heterogeneous (Scheltens et al., 1995; Gouw et al., 2011).”
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“WM fibers in this region are affected first by AD, as found from histopathology (Scheltens et al., 1995) and our prior knowledge (Solodkin et al., 2013).”
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VITA study: white matter hyperintensities of vascular and degenerative origin in the elderly
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“Instead, these changes may primarily be associated with neurodegenerative disease [14], ageing [54], hypertension and smoking [2,11], genetics [55], or combinations of these factors.”
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“tricular WMH was often “blurred,” preventing a clear distinction.(25) Evidence supports the presence of a vascular zone at risk for ischemia fed by arterioles extending centripetally from the”
BackgroundStrukturelle Magnetresonanztomographie in der Diagnose und Erforschung der Demenz vom Alzheimer-Typ
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“…correlates of WMH include myelin and axonal loss, astrogliosis, reduction of oligodendrocytes, mild microglial activation and dilated perivascular spaces to variable degrees providing support for the notion of heterogeneity in WMH pathology (Fazekas et al., 1991, 1993; Scheltens et al., 1995).”
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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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