Symptomatic amyloid-related imaging abnormalities in an APOE ε4/ε4 patient treated with aducanumab.

INTRODUCTION: Amyloid-related imaging abnormalities (ARIA) are a common, dose-dependent effect of amyloid-targeting antibodies, strongly associated with the apolipoprotein E (APOE) ε4 allele. METHODS: We describe the clinical course and management of a 66-year-old white male (APOE ε4/ε4) enrolled in an observational study that included amyloid and tau positron emission tomography (PET), who received aducanumab through the ENGAGE clinical trial. RESULTS: Acute symptoms included headache and encephalopathy, and magnetic resonance imaging revealed ARIA-E and ARIA-H. Malignant hypertension and epileptiform activity were treated with nicardipine and levetiracetam. Subsequent clinical/imaging worsening prompted a course of methylprednisolone. Symptoms and ARIA-E resolved over 6 months, while ARIA-H persisted. Quantitative analysis of interval amyloid PET showed reduced signal in pre-existing areas but increased signal posteriorly; while tau PET showed increased signal overall. DISCUSSION: In an APOE ε4/ε4 patient, ARIA symptoms were accompanied by malignant hypertension and epileptiform activity, and pulsed steroids reversed edema. Studies from larger cohorts may clarify the optimal treatment and pathophysiology of ARIA.

The route of bacterial uptake by macrophages influences the repertoire of epitopes presented to CD4 T cells.

We studied MHC class II (MHC-II)-restricted antigen processing of viable Streptococcus pyogenes by murine macrophages for presentation of two CD4 T cell epitopes of the surface M5 protein. We show that presentation of both epitopes was prevented if actin polymerization was inhibited by cytochalasin D, but not if clathrin-dependent receptor-mediated endocytosis was prevented, suggesting uptake of streptococci by phagocytosis or macropinocytosis was required for presentation of the surface M protein. However, treatment of macrophages with amiloride, which selectively blocks membrane ruffling and subsequent macropinocytosis, inhibited the response to one epitope (M5(308-319)), but had no effect on presentation of the other (M5(17-31)). The effect of the inhibitors on uptake of streptococci was analyzed by electron microscopy. Cytochalasin D completely blocked uptake of streptococci, while dimethyl-amiloride only inhibited uptake into spacious compartments. Neither of the inhibitors altered the cell-surface expression of MHC-II and costimulatory molecules analyzed by flow cytometry. The data suggest that distinct epitopes of a protein associated with viable bacteria may be presented optimally following different uptake mechanisms in the same antigen-presenting cells.