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Perivascular space dilation is associated with vascular amyloid-β accumulation in the overlying cortex

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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-β (Aβ) 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 Aβ 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.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

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

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’s Research UK (ARUK-IRG2019A-003), and the European Research Council (Starting Grant 677697, project “BUNGEE-TOOLS”).

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Authors and Affiliations

  1. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, J. Philip Kistler Stroke Research Center, Cambridge Str. 175, Suite 300, Boston, MA, 02114, USA

    Valentina Perosa, Anand Viswanathan, Steven M. Greenberg & Susanne J. van Veluw

  2. Department of Neurology, Otto-Von-Guericke University, Magdeburg, Germany

    Valentina Perosa

  3. German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany

    Valentina Perosa

  4. Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, USA

    Jan Oltmer, Andre J. van der Kouwe & Juan Eugenio Iglesias

  5. Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA, USA

    Leon P. Munting, Corinne A. Auger, Ashley A. Scherlek, Brian J. Bacskai, Matthew P. Frosch & Susanne J. van Veluw

  6. Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands

    Leon P. Munting, Whitney M. Freeze & Susanne J. van Veluw

  7. Department of Neuropsychology and Psychiatry, Maastricht University, Maastricht, The Netherlands

    Whitney M. Freeze

  8. Rush Alzheimer Disease Center, Rush University Medical Center, Chicago, IL, USA

    Ashley A. Scherlek

  9. Centre for Medical Image Computing, University College London, London, UK

    Juan Eugenio Iglesias & Alessia Atzeni

  10. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA

    Juan Eugenio Iglesias

  11. Neuropathology Service, C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Matthew P. Frosch

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  1. Valentina Perosa
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  2. Jan Oltmer
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Contributions

VP and SJvV designed the study. SMG and AV supported data collection. CAA and AAS processed histopathological material. AJvdK provided support in optimizing the scanning parameters. Data were analyzed by VP with support from JO, JEIG, WMF and AA. VP and SJvV drafted the manuscript and all the authors reviewed it and provided feedback. The project was supervised by SJvV.

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Correspondence to Valentina Perosa.

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Perosa, V., Oltmer, J., Munting, L.P. et al. Perivascular space dilation is associated with vascular amyloid-β accumulation in the overlying cortex. Acta Neuropathol 143, 331–348 (2022). https://doi.org/10.1007/s00401-021-02393-1

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  • DOI: https://doi.org/10.1007/s00401-021-02393-1

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