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Journal of Neuroinflammation

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Open Access 01-12-2023 | Research

Cortical superficial siderosis is associated with reactive astrogliosis in cerebral amyloid angiopathy

Authors: Corinne A. Auger, Valentina Perosa, Steven M. Greenberg, Susanne J. van Veluw, Mariel G. Kozberg

Published in: Journal of Neuroinflammation | Issue 1/2023

Abstract

Background

Cortical superficial siderosis (cSS) has recently emerged as one of the most important predictors of symptomatic intracerebral hemorrhage and is a risk factor for post-stroke dementia in cerebral amyloid angiopathy (CAA). However, it remains unknown whether cSS is just a marker of severe CAA pathology or may itself contribute to intracerebral hemorrhage risk and cognitive decline. cSS is a chronic manifestation of convexal subarachnoid hemorrhage and is neuropathologically characterized by iron deposits in the superficial cortical layers. We hypothesized that these iron deposits lead to local neuroinflammation, a potentially contributory pathway towards secondary tissue injury.

Methods

Accordingly, we assessed the distribution of inflammatory markers in relation to cortical iron deposits in post-mortem tissue from CAA cases. Serial sections from the frontal, parietal, temporal, and occipital lobes of nineteen autopsy cases with CAA were stained with Perls’ Prussian blue (iron) and underwent immunohistochemistry against glial fibrillary acidic protein (GFAP, reactive astrocytes) and cluster of differentiation 68 (CD68, activated microglia/macrophages). Digitized sections were uploaded to the cloud-based Aiforia^® platform, where deep-learning algorithms were utilized to detect tissue, iron deposits, and GFAP-positive and CD68-positive cells.

Results

We observed a strong local relationship between cortical iron deposits and reactive astrocytes. Like cSS-related iron, reactive astrocytes were mainly found in the most superficial layers of the cortex. Although we observed iron within both astrocytes and activated microglia/macrophages on co-stains, there was no clear local relationship between the density of microglia/macrophages and the density of iron deposits.

Conclusion

Iron deposition resulting from cSS is associated with local reactive astrogliosis.

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Viswanathan A, Greenberg SM. Cerebral amyloid angiopathy in the elderly. Ann Neurol. 2011;70(6):871. https://doi.org/10.1002/ANA.22516.CrossRefPubMedPubMedCentral

Kozberg MG, Perosa V, Gurol ME, van Veluw SJ. A practical approach to the management of cerebral amyloid angiopathy. Int J Stroke. 2021;16(4):356–69. https://doi.org/10.1177/1747493020974464.CrossRefPubMed

Linn J, et al. Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy(CME). Neurology. 2010;74(17):1346. https://doi.org/10.1212/WNL.0B013E3181DAD605.CrossRefPubMedPubMedCentral

Charidimou A, Perosa V, Frosch MP, Scherlek AA, Greenberg SM, Van Veluw SJ. Neuropathological correlates of cortical superficial siderosis in cerebral amyloid angiopathy. Brain. 2020;143(11):3343–51. https://doi.org/10.1093/brain/awaa266.CrossRefPubMedPubMedCentral

Charidimou A, et al. Cortical superficial siderosis: detection and clinical significance in cerebral amyloid angiopathy and related conditions. Brain. 2015;138(Pt 8):2126–39. https://doi.org/10.1093/BRAIN/AWV162.CrossRefPubMed

Charidimou A, et al. The Boston criteria version 2.0 for cerebral amyloid angiopathy: a multicentre, retrospective, MRI–neuropathology diagnostic accuracy study. Lancet Neurol. 2022;21(8):714–25. https://doi.org/10.1016/S1474-4422(22)00208-3.CrossRefPubMedPubMedCentral

Charidimou A, et al. Cortical superficial siderosis and first-ever cerebral hemorrhage in cerebral amyloid angiopathy. Neurology. 2017;88(17):1607–14. https://doi.org/10.1212/WNL.0000000000003866.CrossRefPubMedPubMedCentral

Boulouis G, et al. Hemorrhage recurrence risk factors in cerebral amyloid angiopathy: Comparative analysis of the overall small vessel disease severity score versus individual neuroimaging markers. J Neurol Sci. 2017;380:64–7. https://doi.org/10.1016/J.JNS.2017.07.015.CrossRefPubMedPubMedCentral

Greenberg SM, Charidimou A. Diagnosis of cerebral amyloid angiopathy: evolution of the boston criteria. Stroke. 2018;49(2):491. https://doi.org/10.1161/STROKEAHA.117.016990.CrossRefPubMedPubMedCentral

10.

Charidimou A, Boulouis G, Greenberg SM, Viswanathan A. Cortical superficial siderosis and bleeding risk in cerebral amyloid angiopathy: a meta-analysis. Neurology. 2019;93(24): e2192. https://doi.org/10.1212/WNL.0000000000008590.CrossRefPubMedPubMedCentral

11.

Moulin S, et al. Dementia risk after spontaneous intracerebral haemorrhage: a prospective cohort study. Lancet Neurol. 2016;15(8):820–9. https://doi.org/10.1016/S1474-4422(16)00130-7.CrossRefPubMed

12.

Thal DR, Ghebremedhin E, Rüb U, Yamaguchi H, Del Tredici K, Braak H. Two types of sporadic cerebral amyloid angiopathy. J Neuropathol Exp Neurol. 2002;61(3):282–93. https://doi.org/10.1093/JNEN/61.3.282.CrossRefPubMed

13.

Kozberg MG, et al. Blood-brain barrier leakage and perivascular inflammation are associated with microhemorrhage-related vascular remodeling in cerebral amyloid angiopathy. Brain Commun. 2022. https://doi.org/10.1093/braincomms/fcac245.CrossRefPubMedPubMedCentral

14.

Perosa V, et al. Deep learning assisted quantitative assessment of histopathological markers of Alzheimer’s disease and cerebral amyloid angiopathy. Acta Neuropathol Commun. 2021;9(1):141–53. https://doi.org/10.1186/S40478-021-01235-1.CrossRefPubMedPubMedCentral

15.

Fischl B, Dale AM. Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci USA. 2000;97(20):11050–5. https://doi.org/10.1073/PNAS.200033797.CrossRefPubMedPubMedCentral

16.

Paxinos G et al. The human nervous system. 2022. www.academicpress.com. Accessed 20 Oct 2004

17.

Bates D, Mächler M, Bolker BM, Walker SC. Fitting linear mixed-effects models using lme4. J Stat Softw. 2015;67(1):1–48. https://doi.org/10.18637/JSS.V067.I01.CrossRef

18.

Nieuwenhuis R, Te Grotenhuis M, Pelzer B. influenceME: tools for detecting influential data in mixed effects models. R J. 2012;4(2):38–47. https://doi.org/10.32614/RJ-2012-011.CrossRef

19.

Emsley JG, Macklis JD. Astroglial heterogeneity closely reflects the neuronal-defined anatomy of the adult murine CNS. Neuron Glia Biol. 2006;2(3):175. https://doi.org/10.1017/S1740925X06000202.CrossRefPubMedPubMedCentral

20.

Takata N, Hirase H. Cortical Layer 1 and layer 2/3 astrocytes exhibit distinct calcium dynamics in vivo. PLoS ONE. 2008;3(6):e2525. https://doi.org/10.1371/JOURNAL.PONE.0002525.CrossRefPubMedPubMedCentral

21.

Schallner N, et al. Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1. J Clin Invest. 2015;125(7):2609. https://doi.org/10.1172/JCI78443.CrossRefPubMedPubMedCentral

22.

McIntosh A, et al. Iron accumulation in microglia triggers a cascade of events that leads to altered metabolism and compromised function in APP/PS1 mice. Brain Pathol. 2019;29(5):606–21. https://doi.org/10.1111/BPA.12704.CrossRefPubMedPubMedCentral

23.

Askenase MH, et al. Longitudinal transcriptomics define the stages of myeloid activation in the living human brain after intracerebral hemorrhage. Sci Immunol. 2021. https://doi.org/10.1126/SCIIMMUNOL.ABD6279.CrossRefPubMedPubMedCentral

24.

Shtaya A, et al. Innate immune anti-inflammatory response in human spontaneous intracerebral hemorrhage. Stroke. 2021;52(11):3613–23. https://doi.org/10.1161/STROKEAHA.121.034673.CrossRefPubMedPubMedCentral

25.

van Veluw SJ, et al. Different microvascular alterations underlie microbleeds and microinfarcts. Ann Neurol. 2019;86(2):279–92. https://doi.org/10.1002/ana.25512.CrossRefPubMedPubMedCentral

26.

Kozberg MG, et al. Blood-brain barrier leakage and perivascular inflammation in cerebral amyloid angiopathy. Brain Commun. 2022. https://doi.org/10.1093/BRAINCOMMS/FCAC245.CrossRefPubMedPubMedCentral

27.

Kozberg MG, Van Veluw SJ, Frosch MP, Greenberg SM. “Hereditary cerebral amyloid angiopathy, Piedmont-type mutation. Neurol Genet. 2020. https://doi.org/10.1212/NXG.0000000000000411.CrossRefPubMedPubMedCentral

28.

Leyh J, et al. Classification of microglial morphological phenotypes using machine learning. Front Cell Neurosci. 2021. https://doi.org/10.3389/FNCEL.2021.701673.CrossRefPubMedPubMedCentral

29.

Escartin C, et al. Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci. 2021;24(3):312. https://doi.org/10.1038/S41593-020-00783-4.CrossRefPubMedPubMedCentral

30.

Love S, et al. Development, appraisal, validation and implementation of a consensus protocol for the assessment of cerebral amyloid angiopathy in post-mortem brain tissue. Am J Neurodegener Dis. 2014;3(1):19.PubMedPubMedCentral

31.

Greenberg SM, Vonsattel JPG. Diagnosis of cerebral amyloid angiopathy. Stroke. 1997;28(7):1418–22. https://doi.org/10.1161/01.STR.28.7.1418.CrossRefPubMed

32.

Montine TJ, et al. National Institute on Aging-Alzheimer’s association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol. 2012;123(1):1. https://doi.org/10.1007/S00401-011-0910-3.CrossRefPubMed

Title: Cortical superficial siderosis is associated with reactive astrogliosis in cerebral amyloid angiopathy
Authors: Corinne A. Auger
Valentina Perosa
Steven M. Greenberg
Susanne J. van Veluw
Mariel G. Kozberg
Publication date: 01-12-2023
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2023
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-023-02872-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Cortical superficial siderosis is associated with reactive astrogliosis in cerebral amyloid angiopathy

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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