Histopathological correlates of hemorrhagic lesions on ex vivo MRI in immunized Alzheimer’s disease cases.

Abstract

Hemorrhagic Amyloid-Related Imaging Abnormalities (ARIA-H) on MRI are frequently observed adverse events in the context of amyloid β (Aβ) immunotherapy trials in patients with Alzheimer’s disease (AD). The underlying histopathology and pathophysiological mechanisms of ARIA-H remain largely unknown, although coexisting cerebral amyloid angiopathy (CAA) may play a key role. Here, we used ex vivo MRI in cases that underwent Aβ immunotherapy during life to screen for hemorrhagic lesions and assess underlying tissue and vascular alterations. We hypothesized that these lesions would be associated with severe CAA.
Ten cases were selected from the long-term follow-up study of patients who enrolled in the first clinical trial of active Aβ immunization with AN1792 for AD (iAD cases). Eleven matched non-immunized AD cases from an independent brain brank were used as ‘controls’ (cAD cases). Formalin-fixed occipital brain slices were imaged at 7T MRI to screen for hemorrhagic lesions (i.e. microbleeds and cortical superficial siderosis). Samples with and without hemorrhagic lesions were cut and stained. AI-assisted quantification of Aβ plaque area, cortical and leptomeningeal CAA area, density of iron and calcium positive cells, and reactive astrocytes and activated microglia was performed.
On ex vivo MRI, cortical superficial siderosis was observed in 5/10 iAD cases compared to 1/11 cAD cases (κ = 0.5). On histopathology, these areas revealed iron and calcium positive deposits in the cortex. Within the iAD group, areas with siderosis on MRI revealed greater leptomeningeal CAA and concentric splitting of the vessel walls compared to areas without siderosis. Moreover, greater density of iron positive cells in the cortex was associated with lower Aβ plaque area and a trend towards increased post-vaccination antibody titers.
This work highlights the use of ex vivo MRI to investigate the neuropathological correlates of hemorrhagic lesions observed in the context of Aβ immunotherapy. These findings suggest a possible role for CAA in the formation of ARIA-H, awaiting confirmation in future studies that include brain tissue of patients who received passive immunotherapy against Aβ with available in vivo MRI during life.

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Identifiers

ORCID for James Nicoll: orcid.org/0000-0002-9444-7246

ORCID for Delphine Boche: orcid.org/0000-0002-5884-130X

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