Investigating the inflammatory response to cerebral amyloid angiopathy (CAA-ri)

Cro, Bethany, Norton, Emma, Katharkamar, Athushan, Highley, J. Robin, Kurian, Kathreena M., Jaunmuktane, Zane, Fabian, Mark, Walker, Mark, Boche, Delphine and Nicoll, James (2025) Investigating the inflammatory response to cerebral amyloid angiopathy (CAA-ri). Neuropathology and Applied Neurobiology, 51 (Suppl. 1), e70003, [e70003]. (doi:10.1111/nan.70003).

Abstract

Background: amyloid (A)-β immunotherapy has been approved as treatment for Alzheimer's patients in some countries. However, clinical trials have highlighted side effects interpreted as brain oedema and microhaemorrhages, named amyloid-related imaging abnormalities (ARIA), for which tissue is unavailable to understand the underlying pathophysiomechanisms. Cerebral amyloid angiopathy–related inflammation (CAA-ri) is a condition presenting similarities with ARIA and is seen in a proportion of neurosurgical biopsies, thus presenting an opportunity to study ARIA.

Method: eight biopsies of CAA-ri and 11 CAA without inflammation, sourced from BRAIN UK, were immunolabelled for T lymphocytes (CD4 and CD8) and microglia/macrophages (CD68) and the staining quantified.

Results: preliminary results show increased intramural and perivascular CD8+ lymphocytes in CAA-ri vs. CAA (p < 0.001 and p = 0.004, respectively). There were also more perivascular CD4+ lymphocytes in CAA-ri (p = 0.006). In CAA-ri, a higher proportion of vessels were associated with CD8+ lymphocytes vs. CD4+ lymphocytes, both intramural and perivascular (p = 0.004 and p = 0.009, respectively). In CAA, more vessels were associated with perivascular CD8+ lymphocytes (p = 0.014), which co-localised with acute haemorrhage on H&E.

Conclusion: CAA-ri comprises both CD4 and CD8 lymphocytes, with the latter appearing to be a more prominent component. CD4 and CD8 lymphocytes both were detected in cerebral haemorrhage associated with CAA, which may skew the assessment. CD68 quantification to investigate a microglial/macrophage component is in process and additional biopsies are currently obtained to increase the power of the study. A better comprehension of CAA-ri may aid in understanding ARIA occurring in Alzheimer's patients treated with A-β immunotherapy.

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Contributors

Author: Emma Norton

Author: Delphine Boche

Author: James Nicoll

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