Investigating amyloid-related imaging abnormalities (ARIA) using neurosurgical biopsies of CAA-related inflammation (CAA-ri): what constitutes a neuropathological diagnosis of CAA-ri?

Norton, Emma, Cro, Bethany, Highley, J. Robin, Kurian, Kathreena, Jaunmuktane, Zane, Fabian, Mark, Walker, Mark, Nicoll, James and Boche, Delphine (2025) Investigating amyloid-related imaging abnormalities (ARIA) using neurosurgical biopsies of CAA-related inflammation (CAA-ri): what constitutes a neuropathological diagnosis of CAA-ri? Neuropathology and Applied Neurobiology, 51 (Suppl. 1), e70003, [e70003]. (doi:10.1111/nan.70003).

Abstract

Background: spontaneous cerebral amyloid angiopathy–related inflammation (CAA-ri) has been proposed as a model for the amyloid-related imaging abnormalities (ARIA) seen following amyloid-beta (Aβ) immunotherapy. CAA-ri encompasses mild perivascular inflammation to severe angiitis/vasculitis, and consensus neuropathological criteria do not currently exist. We describe the histological features of biopsy-diagnosed CAA-ri compared to cases of non-inflammatory CAA (ni-CAA).

Methods: neurosurgical biopsies and anonymised pathology reports from 19 CAA-ri and 44 ni-CAA cases from four centres were identified by BRAIN UK. They were examined to determine the distribution and severity of vascular Aβ, immune infiltrate, vasculopathy and concurrent Alzheimer's pathology.

Results: CAA-ri was associated with more severe vascular Aβ deposition (extension into the surrounding neuropil, p = 0.016) and more frequent capillary angiopathy (p = 0.025) than ni-CAA. The size and composition of the inflammatory infiltrate varied. Intramural inflammation was observed in 68.4% of cases of CAA-ri. Features of vasculopathy, plaque removal and hemosiderin deposition were more frequent in CAA-ri than ni-CAA (p < 0.001, p < 0.001 and p = 0.001, respectively).

Discussion: neurosurgical biopsies of CAA-ri are readily available and a powerful resource for further study into the pathophysiology of CAA-ri and ARIA. CAA-ri represents a spectrum of disease, and the minimum severity of inflammation required for diagnosis is unknown. Attributing inflammation primarily to vascular Aβ requires neuropathological judgement and clinical context. This can be particularly challenging in limited and fragile biopsy material. The specific pathological factors associated with CAA-ri that correlate with clinical/radiological severity are poorly understood. Analysis of the degree and composition of inflammation in our cohort is ongoing.

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Contributors

Author: Emma Norton

Author: James Nicoll

Author: Delphine Boche

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