Neuropathologic Correlates of White Matter Hyperintensities in a Community-Based Cohort of Older Adults

Arfanakis, Konstantinos; Evia, Arnold M.; Leurgans, Sue E.; Cardoso, Luís; Kulkarni, Arman P.; Alqam, Nabil; Lopes, Lucas Farias; Vieira, Diego M.; Bennett, David A.; Schneider, Julie A.

doi:10.3233/jad-190687

Cited by 59 publications

(71 citation statements)

References 61 publications

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“…To translate our pathology findings to neuroimaging, we leveraged available whole brain measures of ex-vivo WMH data ( N = 389). WMH lesions in aging have often been used as a surrogate marker for SVD in clinical studies and shown to be associated with arteriolosclerosis pathology in imaging-pathologic studies [ 2 , 4 ]. Out of 389 participants, 19% had WMH burden = 1 (mild), 37% had WMH burden = 2 (moderate), and 44% had WMH burden = 3 (severe).…”

Section: Resultsmentioning

confidence: 99%

“…The hemisphere was positioned with the medial aspect facing the bottom of container. Ex-vivo MRI data were collected on 3 Tesla scanners using 2D fluid-attenuated inversion recovery (FLAIR) and 2D multi-echo spin-echo (ME-SE) sequences, as previously described [ 4 ]. All data were collected sagittally and were converted to the axial plane (trilinear interpolation was used).…”

Section: Methodsmentioning

confidence: 99%

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Association of small vessel disease with tau pathology

Kapasi

Petyuk

et al. 2022

Acta Neuropathol

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Emerging evidence suggests that small vessel disease (SVD) is a risk factor for clinical dementia and may contribute to AD neuropathological changes. Watershed brain regions are located at the most distal areas between arterial territories, making them vulnerable to SVD-related changes. We examined the association of pathologic markers of SVD, specifically arteriolosclerosis in watershed brain regions, with AD pathologic changes. Participants (N = 982; mean age-at-death = 90; 69% women) were enrolled as part of one of two cohort studies of aging and dementia. At autopsy, neuropathological evaluation included semi-quantitative grading of arteriolosclerosis pathology from 2 cortical watershed regions: the anterior watershed (AWS) and posterior watershed (PWS), densities for cortical β-amyloid and tau-tangle pathology, and other common age-related pathologies. Linear regression models examined the association of watershed arteriolosclerosis pathology with β-amyloid and tau-tangle burden. In follow-up analyses, available ex-vivo MRI and proteomics data in a subset of decedents were leveraged to examine the association of whole brain measure of WMH, as a presumed MRI marker of SVD, with β-amyloid and tau-tangle burden, as well as to examine the association of watershed arteriolosclerosis with proteomic tau. Watershed arteriolosclerosis was common, with 45% of older persons having moderate-to-severe arteriolosclerosis pathology in the AWS region, and 35% in the PWS. In fully adjusted models that controlled for demographics and common age-related pathologies, an increase in severity of PWS arteriolosclerosis was associated with a higher burden of tau-tangle burden, specifically neocortical tau burden, but not with β-amyloid. AWS arteriolosclerosis was not associated with β-amyloid or tau pathology. Ex-vivo WMH was associated with greater tau-tangle pathology burden but not β-amyloid. Furthermore, PWS arteriolosclerosis was associated with higher abundance of tau phosphopeptides, that promote formation of tau aggregates. These data provide compelling evidence that SVD, specifically posterior watershed arteriolosclerosis pathology, is linked with tau pathological changes in the aging brain.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Association of small vessel disease with tau pathology

Kapasi

Petyuk

et al. 2022

Acta Neuropathol

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“…Hypertension results in impairment of vascular integrity including arteriosclerosis, microatheroma, and microaneurysms, which decrease cerebral blood flow and as a result cause loss of myelin and gliosis 15,16 . These pathological changes manifest on MRI as WMH 17,18 . Therefore, WMH is an important marker of hypertensive brain injury.…”

Section: Discussionmentioning

confidence: 99%

Effect of intensive blood pressure control on the prevention of white matter hyperintensity: Systematic review and meta‐analysis of randomized trials

Lai

Jiang

et al. 2020

J of Clinical Hypertension

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Hypertension is an important cause of cerebral small vessel disease, especially of white matter hyperintensity (WMH). The ability of intensive blood pressure (BP) control in preventing this pathological progression remains unclear. The authors systematically searched PubMed, EMBASE, SCOPUS, and Cochrane library for publications until July 20, 2020. Studies included were clinical trials with random allocation to an antihypertensive medication against placebo, or different treatment targets. The primary outcome was intergroup differences in the change of WMH volume. A random‐effect model was applied for pooling effect measures. Subgroup analysis and meta‐regression were conducted to explore heterogeneity. Seven studies with 2693 patients were identified. Compared with the control group, patients in the intensive BP control group had a slower progression of WMH, with a pooled intergroup standard mean difference (SMD) for WMH change of −0.22 (95% CI: −0.35 ~ −0.09, I2 = 63%). For studies comparing intensive and standard BP target, the pooled SMD is −0.37 (95% CI:‐0.50~‐0.24, I2 = 0%), while the pooled SMD of studies comparing active antihypertensive medication and placebo was only −0.08 (95% CI: −0.17 ~ 0.01, I2 = 0%). Meta‐regression analysis showed that the reduction in WMH progression is proportional to the magnitude of intensive BP control (β = −0.028, P < .001). In conclusion, intensive BP control prevents WMH progression, and its effect is associated with the magnitude of intensive BP control.

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“…These findings are consistent with an early role of PVS dilation and potential exacerbation of arteriolar sclerosis, as has been reported previously. 47 Based on this interpretation, the perivascular edema evident in earlier Saito et al-32 stages due to failure of interstitial fluid drainage would damage perivascular tissue and astrocytes, resulting in myelin loss and clasmatodendrosis, consistent with some of the pathological features in the WMH revealed by imaging. 2,14,39,40 At the advanced stage, loss of autoregulatory contractility due to vascular remodeling such as alterations of stiffness within arterioles would lead to further tissue rarefaction, lumen occlusion and eventually ischemic necrotic foci followed by gliosis.…”

Section: Saito Et Al-30mentioning

confidence: 79%

Small Vessel Diseases: 3D Characteristics of the Vasculature and White Matter

Saito

Tainaka

Nozaki

et al. 2021

Preprint

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Cerebral small vessel disease (SVD) is associated with white matter hyperintensities (WMHs), thereby contributing to vascular dementia and movement disorder. However, the pathomechanisms responsible for WMH-related small vessel degeneration remain poorly understood due to the technical limitations of current methods. The aim of this study was to clarify the 2- and 3-dimensional (2D and 3D) pathological features of small vessels and white matter (WM) in the brains of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), HTRA1-autosomal dominant disease (HTRA1-AD) and sporadic SVD (sSVD). From a cohort of 86 consecutive autopsied patients with SVDs, we retrieved those with genetically confirmed CADASIL and HTRA1-AD (three and three, respectively), and four with sSVD. We quantitatively evaluated WM and vascular changes in the frontal portion of the centrum semiovale and temporal lobe using conventional 2D and chemically cleared 3D analytical methods with light-sheet fluorescence microscopy. Quantitatively, the WM pathology, including the density of myelin, axons and gliosis, was most severe in CADASIL, but unexpectedly sSVD was second in order of severity, followed by HTRA1-AD. The density of clasmatodendrocytes, known to be irreversibly injured astrocytes, was considerably highest in HTRA1-AD. The vascular pathology, including arteriole and capillary sclerosis and the extent of the perivascular space, was most severe in CADASIL, whereas the density of smooth muscle actin (SMA) positivity was most decreased in HTRA1-AD. 3D immunohistochemistry for SMA demonstrated two distinct patterns of SMA loss within the vessels: (1) CADASIL and sSVD: diffuse loss, being prominent in small branches, (2) HTRA1-AD: selective loss in main branches. Overall, the extent of WM and vascular degeneration is most severe in CADASIL, whereas SMA loss is most evident in HTRA1-AD. These differences in the size and distribution of affected vessels may be related to the heterogeneous WM pathology and underlying pathomechanisms of SVD.

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Neuropathologic Correlates of White Matter Hyperintensities in a Community-Based Cohort of Older Adults

Cited by 59 publications

References 61 publications

Association of small vessel disease with tau pathology

Association of small vessel disease with tau pathology

Effect of intensive blood pressure control on the prevention of white matter hyperintensity: Systematic review and meta‐analysis of randomized trials

Small Vessel Diseases: 3D Characteristics of the Vasculature and White Matter

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