Pathological Correlates of White Matter Hyperintensities on Magnetic Resonance Imaging

Shim, Yong S.; Yang, Dong Won; Roe, Catherine M.; Coats, Mary A.; Benzinger, Tammie L.S.; Xiong, Chengjie; Galvin, James E.; Cairns, Nigel J.; Morris, John C.

doi:10.1159/000366411

Cited by 82 publications

(108 citation statements)

References 70 publications

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“…WMH are strongly related to vascular risk factors and cerebrovascular disease and serve as one of the “classical” MRI markers of CSVD [39]. The present study found that the internetwork FC between the DLPFC and the DMN in the bilateral PCC and right precuneus was negatively correlated with DWMH volume in CSVD subjects; a greater DWMH volume was associated with lower FC between the DLPFC and the DMN.…”

Section: Discussionsupporting

confidence: 54%

Distinctive and Pervasive Alterations of Functional Brain Networks in Cerebral Small Vessel Disease with and without Cognitive Impairment

Liu

et al. 2019

Dement Geriatr Cogn Disord

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Objective: To explore the within- and between-network patterns of the default mode network (DMN), the frontoparietal control network (FPCN), and the dorsal attention network (DAN) in cerebral small vessel disease (CSVD) with and without cognitive impairment (CI). Methods: Twenty CSVD with CI subjects, 21 CSVD without CI subjects, and 25 healthy elderly controls were recruited. The within- and between-network patterns of the networks were identified based on resting-state functional magnetic resonance imaging data. Results: Compared with the control group, both the CSVD with CI group and the CSVD without CI group displayed decreased within-network function of the DMN and lower negative connectivity between the DMN and other networks (i.e., DMN and DAN, DMN and FPCN), whereas the CSVD with CI group additionally showed within- and between-network alterations of the FPCN (i.e., increased within-network function of the FPCN and lower negative connectivity between the FPCN and the DMN). Furthermore, these alterations of the FPCN were correlated with the cognitive function of CSVD subjects. Interestingly, the between-network connectivity of the FPCN and the DMN was negatively correlated with deep white matter hyperintensities (DWMH) volume in CSVD subjects. Conclusion: These findings suggest that cognitive alterations of CSVD subjects may be mainly regulated by the FPCN that correlates with DWMH burden, and shed light on the investigation of surrogate markers of CSVD.

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Section: Discussionsupporting

confidence: 54%

Distinctive and Pervasive Alterations of Functional Brain Networks in Cerebral Small Vessel Disease with and without Cognitive Impairment

Liu

et al. 2019

Dement Geriatr Cogn Disord

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“…The few ex vivo studies that have examined the association between ante-mortem WMH and ADNP have reported mixed findings, including positive [54], inverse [21], and no significant associations [56]. Reasons for the inconsistent findings could be related to sample differences in the presence and severity of ADNP and comorbid pathologies, methods used to quantitate WMH (e.g., use of visual rating scales), the lack of an ADNP− comparison group, and/or a failure to control for key confounding variables that contribute to ADNP (e.g., APOE ε4 carrier status).…”

Section: Discussionmentioning

confidence: 99%

“…WMH refer to regions in the white matter that appear hyperintense on T2 fluid attenuated inversion recovery (FLAIR) sequences. The etiologies of WMH are multifaceted (e.g., gliosis, axonal loss) [9–15], but WMH accompany aging and cardiovascular disease and are often presumed to be of vascular origin and reflect small vessel cerebrovascular disease (CBVD) [9,16–21]. International consensus-based guidelines emphasize the pathologies underlying WMH (along with cerebral amyloid angiopathy [CAA], microbleeds, microinfarcts, among others) as mechanisms of vascular cognitive impairment (VCI) [22].…”

Section: Introductionmentioning

confidence: 99%

“…A recent ex vivo study further linked parietal white matter lesions with demyelination and axonal loss (and not ischemic injury) in participants with AD potentially reflecting Wallerian degeneration subsequent to cortical AD pathology; cortical phosphorylated tau (p-tau) pathology further correlated with white matter lesion severity [15]. Past work has found an inverse relationship between quantitatively measured WMH and Braak stage [21], and research from the Ischemic Vascular Dementia Program Project found no association between quantitated WMH and ADNP [56]. …”

Section: Introductionmentioning

confidence: 99%

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A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer’s Disease Neuropathology

Alosco

Sugarman

Besser

et al. 2018

JAD

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Background: White matter hyperintensities (WMH) on magnetic resonance imaging have been postulated to be a core feature of Alzheimer’s disease. Clinicopathological studies are needed to elucidate and confirm this possibility. Objective: This study examined: 1) the association between ante-mortem WMH and autopsy-confirmed Alzheimer’s disease neuropathology (ADNP), 2) the relationship between WMH and dementia in participants with ADNP, and 3) the relationships among cerebrovascular disease, WMH and ADNP. Methods: The sample included 82 participants from the National Alzheimer’s Coordinating Center’s Data Sets who had quantitated volume of WMH from ante-mortem FLAIR MRI and available neuropathological data. The Clinical Dementia Rating (CDR) scale (from MRI visit) operationalized dementia status. ADNP+ was defined by moderate to frequent neuritic plaques and Braak stage III-VI at autopsy. Cerebrovascular disease neuropathology included infarcts or lacunes, microinfarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy. Results: 60/82 participants were ADNP+. Greater volume of WMH predicted increased odds for ADNP (p=0.037). In ADNP+ participants, greater WMH corresponded with increased odds for dementia (CDR≥1; p=0.038). WMH predicted cerebral amyloid angiopathy, microinfarcts, infarcts and lacunes (p’s<0.04). ADNP+ participants were more likely to have moderate-severe arteriolosclerosis and cerebral amyloid angiopathy compared to ADNP− participants (p’s<0.04). Conclusions: This study found a direct association between total volume of WMH and increased odds for having ADNP. In patients with Alzheimer’s disease, FLAIR MRI WMH may be able to provide key insight into disease severity and progression. The association between WMH and ADNP may be explained by underlying cerebrovascular disease.

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“…Although mild arteriolosclerosis was present, and there was mild atheroma in rare leptomeningeal vessels in subcortical regions and the circle of Willis, mild pathological changes such as these are commonly seen incidentally in healthy aging and in dementia. In a study of the pathological correlates of WMH in a mixed cohort of cases (aged controls, AD, and individuals with significant vascular risk factors) mild arteriosclerosis was present in 56/57 cases and not significantly different between those with and without WMH (Shim et al, 2015). A lack of correlation between markers of ischaemia and small vessel sclerosis and parietal white matter lesions was observed in two studies of AD (McAleese et al, 2015, 2017).…”

Section: Discussionmentioning

confidence: 99%

Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia

et al. 2018

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White matter hyperintensities (WMH) are often seen on MRI brain scans in frontotemporal dementia (FTD) due to progranulin (GRN) mutations, but their pathological correlates are unknown. We examined the histological changes underlying WMH in a patient with GRN mutation associated behavioral variant FTD. In vivo and cadaveric MRI showed progressive, asymmetric frontotemporal and parietal atrophy, and asymmetrical WMH predominantly affecting frontal mid-zones. We first performed segmentation and localization analyses of WMH present on cadaveric MRI FLAIR images, then selected five different brain regions directly matched to differing severities of WMH for histological analysis. We used immunohistochemistry to assess vascular pathology, degree of spongiosis, neuronal and axonal loss, TDP-43, demyelination and astrogliosis, and microglial burden and morphology. Brain regions with significant WMH displayed severe cortical and white matter pathology, and prominent white matter microglial activation and microglial dystrophy, but only mild axonal loss and minimal vascular pathology. Our study suggests that WMH in GRN mutation carriers are not secondary to vascular pathology. Whilst cortical pathology induced axonal degeneration could contribute to white matter damage, individuals with GRN mutations could develop selective white matter vulnerability and myelin loss due to chronic, regional microglial dysfunction arising from GRN haploinsufficiency.

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Pathological Correlates of White Matter Hyperintensities on Magnetic Resonance Imaging

Cited by 82 publications

References 70 publications

Distinctive and Pervasive Alterations of Functional Brain Networks in Cerebral Small Vessel Disease with and without Cognitive Impairment

Distinctive and Pervasive Alterations of Functional Brain Networks in Cerebral Small Vessel Disease with and without Cognitive Impairment

A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer’s Disease Neuropathology

Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia

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