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Histopathology of diffusion-weighted imaging-positive lesions in cerebral amyloid angiopathy

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Abstract

Small subclinical hyperintense lesions are frequently encountered on brain diffusion-weighted imaging (DWI) scans of patients with cerebral amyloid angiopathy (CAA). Interpretation of these DWI+ lesions, however, has been limited by absence of histopathological examination. We aimed to determine whether DWI+ lesions represent acute microinfarcts on histopathology in brains with advanced CAA, using a combined in vivo MRI—ex vivo MRI—histopathology approach. We first investigated the histopathology of a punctate cortical DWI+ lesion observed on clinical in vivo MRI 7 days prior to death in a CAA case. Subsequently, we assessed the use of ex vivo DWI to identify similar punctate cortical lesions post-mortem. Intact formalin-fixed hemispheres of 12 consecutive cases with CAA and three non-CAA controls were subjected to high-resolution 3 T ex vivo DWI and T2 imaging. Small cortical lesions were classified as either DWI+/T2+ or DWI−/T2+. A representative subset of lesions from three CAA cases was selected for detailed histopathological examination. The DWI+ lesion observed on in vivo MRI could be matched to an area with evidence of recent ischemia on histopathology. Ex vivo MRI of the intact hemispheres revealed a total of 130 DWI+/T2+ lesions in 10/12 CAA cases, but none in controls (p = 0.022). DWI+/T2+ lesions examined histopathologically proved to be acute microinfarcts (classification accuracy 100%), characterized by presence of eosinophilic neurons on hematoxylin and eosin and absence of reactive astrocytes on glial fibrillary acidic protein-stained sections. In conclusion, we suggest that small DWI+ lesions in CAA represent acute microinfarcts. Furthermore, our findings support the use of ex vivo DWI as a method to detect acute microinfarcts post-mortem, which may benefit future histopathological investigations on the etiology of microinfarcts.

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Acknowledgements

The authors would like to thank the families of the patients who generously donated their brains to our research studies. The authors would also like to thank Dr. Ana Amaral and Dr. Patrick Dooley for their excellent technical assistance and Dr. Alberto Serrano-Pozo for helpful discussions. The work described in this study was supported by the Van Leersum Grant of the Royal Netherlands Academy of Arts and Sciences and an Alzheimer Nederland fellowship to AtT, and the National Institutes of Health (NINDS R01 NS096730, NIA K99 AG059893, NINDS RF1 NS110054, and NIA R21 AG046657). During this study, SJvV received funding from the Netherlands Organisation for Scientific Research (Veni Grant 91619021). MD received funding from the Radboud Excellence Initiative (18U.018651). FEdL was supported by a clinical established investigator grant of the Dutch Heart Foundation (Grant 2014 T060), and by a VIDI innovational grant from The Netherlands Organisation for Health Research and Development, ZonMw (Grant 016126351).

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Authors and Affiliations

  1. MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, 114 16th Street, Charlestown, MA, 02129, USA

    Annemieke ter Telgte, Ashley A. Scherlek, Brian J. Bacskai, Matthew P. Frosch & Susanne J. van Veluw

  2. Department of Neurology, J. Philip Kistler Stroke Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Annemieke ter Telgte, Yael D. Reijmer, Thijs van Harten, Steven M. Greenberg & Susanne J. van Veluw

  3. Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands

    Annemieke ter Telgte, Marco Duering & Frank-Erik de Leeuw

  4. Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

    Yael D. Reijmer

  5. Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA

    Andre J. van der Kouwe

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

    Thijs van Harten

  7. Institute for Stroke and Dementia Research (ISD), University Hospital LMU Munich, Munich, Germany

    Marco Duering

  8. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

    Marco Duering

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

    Matthew P. Frosch

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  1. Annemieke ter Telgte
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Correspondence to Susanne J. van Veluw.

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ter Telgte, A., Scherlek, A.A., Reijmer, Y.D. et al. Histopathology of diffusion-weighted imaging-positive lesions in cerebral amyloid angiopathy. Acta Neuropathol 139, 799–812 (2020). https://doi.org/10.1007/s00401-020-02140-y

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