Fatal iatrogenic cerebral β-amyloid-related arteritis in a woman treated with lecanemab for Alzheimer's disease

Abstract

We report the case of a 79-year-old woman with Alzheimer's disease who participated in a Phase III randomized controlled trial called CLARITY-AD testing the experimental drug lecanemab. She was randomized to the placebo group and subsequently enrolled in an open-label extension which guaranteed she received the active drug. After the third biweekly infusion, she suffered a seizure characterized by speech arrest and a generalized convulsion. Magnetic resonance imaging revealed she had multifocal swelling and a marked increase in the number of cerebral microhemorrhages. She was treated with an antiepileptic regimen and high-dose intravenous corticosteroids but continued to worsen and died after 5 days. Post-mortem MRI confirmed extensive microhemorrhages in the temporal, parietal and occipital lobes. The autopsy confirmed the presence of two copies of APOE4, a gene associated with a higher risk of Alzheimer's disease, and neuropathological features of moderate severity Alzheimer's disease and severe cerebral amyloid angiopathy with perivascular lymphocytic infiltrates, reactive macrophages and fibrinoid degeneration of vessel walls. There were deposits of β-amyloid in meningeal vessels and penetrating arterioles with numerous microaneurysms. We conclude that the patient likely died as a result of severe cerebral amyloid-related inflammation.

Fig. 1. Neuroimaging evidence of cerebral edema and microhemorrhage.

A Pre-trial FLAIR shows pre-existing moderate white matter disease (a montage of additional MR images available in the Supplementary Fig. 1). B Susceptibility weighted minimum intensity projection imaging revealed four cortical microhemorrhages (two are visible in the selected images at the arrows; the others are marked in Supplementary Fig. 3). C Hospital-acquired FLAIR MR image shows increased hyperintensity, suggesting exacerbated white matter disease, and sulcal effacement/mass effect in the temporal, parietal, and occipital lobes, suggesting the emergence of edema after the trial (a montage of additional MR images available in the Supplementary Fig. 2). D Hospital-acquired gradient echo-T2* minimum intensity projection MR image revealed that the number of microhemorrhages increased to over 30 (eight are shown at the arrows; the rest can be seen in Supplementary Fig. 4). E–G Post-mortem susceptibility weighted imaging at 3 Tesla demonstrated extensive microhemorrhagic changes, most prominently in the temporal, parietal, and occipital lobes. H 7-Tesla MR imaging, paired with G shows that additional microhemorrhages are detected at higher field strength. I A few microhemorrhages (arrowhead) and superficial siderosis (arrow) were visible on gross sections. J More extensive microhemorrhagic changes were readily observed when the tissue was rendered translucent with optical clearance approaches and backlighting.

Fig. 2. Inflammatory and microhemorrhagic pathology.

A Lateral and B inferior views of the brain. Black stippling (arrows) in the temporal lobes consistent with petechial hemorrhage is best seen on the inferior view. C A coronal section through the brain shows additional microhemorrhages (arrows). D Methoxy-X04 staining of β-amyloid (blue), phospholipase D3 (green, staining neuronal lysosomes and dystrophic neurites) and Ionized calcium Binding Adaptor molecule 1 or IBA1 (red, staining microglia) shows a neuritic plaque surrounded by dystrophic neurites and activated microglia, 20 µm scale bar. This case met the criteria for moderate Alzheimer’s disease neuropathologic changes. Additional images of β-amyloid deposits in this case are shown in Supplementary Fig. 8. E Longitudinal and F cross-sectional images of penetrating arterioles in the affected region show intensive perivascular inflammatory infiltration and bleeding, stained with hematoxylin and eosin (H&E), 40 µm scale bar in E and 20 µm scale bar in F. A multinucleated giant cell is present at the arrow in E. G Immunostaining for β-amyloid demonstrates inflamed vessels have β-amyloid deposition, 20 µm scale bar. H Cross-sectional and I. longitudinal sections were immunostained for CD68 (Cluster of Differentiation 68), showing numerous macrophages on the inflamed vessels (20 µm scale bar in H and 80 µm scale bar in I); see also Fig. 3. J Serial sectioning through a microhemorrhage enabled visualization of the associated ruptured vessel, 200 µm scale bar. K The ruptured vessel associated with the microhemorrhage contains heavy β-amyloid deposits stained red, vascular marker isolectin in green, blood in non-specific yellowish autofluorescence around the vessel, 200 µm scale bar. L Meningeal whole-mount specimen overlying temporal lobe shows several microaneurysms, 200 µm scale bar. M Meningeal specimen from L stained with thiazine red for β-amyloid (red) and isolectin to label vessels (green) shows severe β-amyloid deposition, including in several microaneurysms (arrrows), 200 µm scale bar. The aneurysm in the white box is shown enlarged in N with a 50 µm scale bar.

Fig. 3. Characterization of cell types in perivascular inflammation.

A Hematoxylin and eosin staining (H&E) demonstrates inflammatory perivascular infiltrates, 20 µm scale bar. B Multinucleated giant cells are visible in this image, 40 µm scale bar. C CD68 (CD stands for Cluster of Differentiation) immunostaining shows that many of the inflammatory cells are macrophages and/or activated microglia, 20 µm scale bar. D CD11b, a marker of microglia and macrophages, shows numerous macrophages in the perivascular space around a vessel with heavy β-amyloid deposition (shown by red staining with Thiazine red), 40 µm scale bar. Images E–G show that the perivascular inflammatory infiltrate also contains T-cells, although they are less abundant than macrophages, 20 µm scale bars. Image E shows hematoxylin and eosin staining of an inflamed vessel, F CD8 staining and G. CD4 staining of the same vessel. Images H–J show patterns CD68 immunoreactivity which involve the leptomeninges (H & I), perivascular spaces (H & I), and parenchyma (all three images), 80 µm scale bar in H and 40 µm scale bars in I and J.