RT Journal Article
SR Electronic
T1 Small Vessel Diseases: 3D Characteristics of the Vasculature and White Matter
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.06.30.450101
DO 10.1101/2021.06.30.450101
A1 Rie Saito
A1 Kazuki Tainaka
A1 Hiroaki Nozaki
A1 Masahiro Uemura
A1 Yasuko Toyoshima
A1 Masahiro Suzuki
A1 Masaharu Tanaka
A1 Arika Hasegawa
A1 Takashi Abe
A1 Aki Sato
A1 Hideki Hashidate
A1 Shuichi Igarashi
A1 Ryoko Koike
A1 Akihiko Ueda
A1 Mitsuharu Ueda
A1 Yukio Ando
A1 Kohei Akazawa
A1 Osamu Onodera
A1 Akiyoshi Kakita
YR 2021
UL http://biorxiv.org/content/early/2021/07/01/2021.06.30.450101.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.