@article{1712a6543b534c56a9477abcd3906d28,
title = "Perivascular space dilation is associated with vascular amyloid-β accumulation in the overlying cortex",
abstract = "Perivascular spaces (PVS) are compartments surrounding cerebral blood vessels that become visible on MRI when enlarged. Enlarged PVS (EPVS) are commonly seen in patients with cerebral small vessel disease (CSVD) and have been suggested to reflect dysfunctional perivascular clearance of soluble waste products from the brain. In this study, we investigated histopathological correlates of EPVS and how they relate to vascular amyloid-beta (A beta) in cerebral amyloid angiopathy (CAA), a form of CSVD that commonly co-exists with Alzheimer's disease (AD) pathology. We used ex vivo MRI, semi-automatic segmentation and validated deep-learning-based models to quantify EPVS and associated histopathological abnormalities. Severity of MRI-visible PVS during life was significantly associated with severity of MRI-visible PVS on ex vivo MRI in formalin fixed intact hemispheres and corresponded with PVS enlargement on histopathology in the same areas. EPVS were located mainly around the white matter portion of perforating cortical arterioles and their burden was associated with CAA severity in the overlying cortex. Furthermore, we observed markedly reduced smooth muscle cells and increased vascular A beta accumulation, extending into the WM, in individually affected vessels with an EPVS. Overall, these findings are consistent with the notion that EPVS reflect impaired outward flow along arterioles and have implications for our understanding of perivascular clearance mechanisms, which play an important role in the pathophysiology of CAA and AD.",
keywords = "Cerebral amyloid angiopathy, Cerebral small vessel disease, Clearance, Ex vivo MRI, Enlarged perivascular spaces, VIRCHOW-ROBIN SPACES, SMALL-VESSEL DISEASE, WHITE-MATTER, ALZHEIMERS-DISEASE, GLYMPHATIC DYSFUNCTION, MRI MARKER, BRAIN, ANGIOPATHY, PATHOLOGY, PATHWAY",
author = "V. Perosa and J. Oltmer and L.P. Munting and W.M. Freeze and C.A. Auger and A.A. Scherlek and {van der Kouwe}, A.J. and J.E. Iglesias and A. Atzeni and B.J. Bacskai and A. Viswanathan and M.P. Frosch and S.M. Greenberg and {van Veluw}, S.J.",
note = "Funding Information: We wish to thank Sjoerd van Duinen, Gisela Terwindt, Marieke Wermer, and Louise van der Weerd from Leiden University Medical Center (LUMC) for providing the brain sample of the D-CAA case. Furthermore, we thank the patients and their families for participating in the brain donation program. This work was supported by the Harvard Catalyst, Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR002541). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health. Funding Information: This work was funded by the National Institutes of Health (AG059893 to S.J.v.V., RF1 NS110054 to B.J.B.; 1RF1MH123195-01 and 1R01AG070988-01 to J.E.I.), the German Research Foundation (DFG) (454245528 to V.P.), Alzheimer{\textquoteright}s Research UK (ARUK-IRG2019A-003), and the European Research Council (Starting Grant 677697, project “BUNGEE-TOOLS”). Funding Information: We wish to thank Sjoerd van Duinen, Gisela Terwindt, Marieke Wermer, and Louise van der Weerd from Leiden University Medical Center (LUMC) for providing the brain sample of the D-CAA case. Furthermore, we thank the patients and their families for participating in the brain donation program. This work was supported by the Harvard Catalyst, Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR002541). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.",
year = "2022",
month = mar,
doi = "10.1007/s00401-021-02393-1",
language = "English",
volume = "143",
pages = "331--348",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer, Cham",
number = "3",
}