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