No replicating evidence for anti-amyloid-β autoantibodies in cerebral amyloid angiopathy-related inflammation

Abstract

Objective: elevated levels of anti-amyloid-β (anti-Aβ) autoantibodies in cerebrospinal fluid (CSF) have been proposed as a diagnostic biomarker for cerebral amyloid angiopathy-related inflammation (CAA-RI). We aimed to independently validate the immunoassay for quantifying these antibodies and evaluate its diagnostic value for CAA-RI.

Methods: we replicated the immunoassay to detect CSF anti-Aβ autoantibodies using CSF from CAA-RI patients and non-CAA controls with unrelated disorders, and further characterized its performance. Moreover, we conducted a literature review of CAA-RI case reports to investigate neuropathological and CSF evidence of the nature of the inflammatory reaction in CAA-RI.

Results: the assay demonstrated a high background signal in CSF, which increased and corresponded with higher total immunoglobulin G (IgG) concentration in CSF (rsp=0.51, p=0.02). Assay levels were not elevated in CAA-RI patients (n=6) compared to non-CAA controls (n=20; p=0.64). Literature review indicated only occasional presence of B-lymphocytes and plasma cells (i.e., antibody-producing cells), alongside abundant presence of activated microglial cells, T-cells and other monocyte lineage cells. CSF analysis did not convincingly indicate intrathecal IgG production.

Interpretation: we were unable to reproduce the reported elevation of anti-Aβ autoantibody concentration in CSF of CAA-RI patients. Our findings instead support nonspecific detection of IgG levels in CSF by the assay. Reviewed CAA-RI case reports suggested a widespread cerebral inflammatory reaction. In conclusion, our findings do not support anti-Aβ autoantibodies as a diagnostic biomarker for CAA-RI.

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Identifiers

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

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