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

Saito, R.; Tainaka, K.; Nozaki, H.; Uemura, M.; Toyoshima, Y.; Suzuki, M.; Tanaka, M.; Hasegawa, A.; Abe, T.; Sato, A.; Hashidate, H.; Igarashi, S.; Koike, R.; Ueda, A.; Ueda, M.; Ando, Y.; Akazawa, K.; ONODERA, O.; Kakita, A.

doi:10.1101/2021.06.30.450101

bioRxiv · 10.1101/2021.06.30.450101

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

Saito, R.·Tainaka, K.·Nozaki, H.·Uemura, M.·Toyoshima, Y.·Suzuki, M.·Tanaka, M.·Hasegawa, A.·Abe, T.·Sato, A.·Hashidate, H.·Igarashi, S.·Koike, R.·Ueda, A.·Ueda, M.·Ando, Y.·Akazawa, K.·ONODERA, O.·Kakita, A.

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Abstract

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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Saito, R., Tainaka, K., Nozaki, H., Uemura, M., Toyoshima, Y., Suzuki, M., Tanaka, M., Hasegawa, A., Abe, T., Sato, A., Hashidate, H., Igarashi, S., Koike, R., Ueda, A., Ueda, M., Ando, Y., Akazawa, K., ONODERA, O., Kakita, A.. 2021-07-01. Small Vessel Diseases: 3D Characteristics of the Vasculature and White Matter. https://doi.org/10.1101/2021.06.30.450101

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