Iatrogenic CAA-ri supported by ARIA-E, raised CSF anti-Aβ autoantibodies and sTREM2 after COVID-19 vaccination

Aim of the study Cerebral amyloid angiopathy–related inflammation (CAA-ri) is a rare autoimmune encephalopathy associated with spontaneous amyloid-related imaging abnormalities suggestive of vasogenic edema (ARIA-E) that are thought to reflect downstream autoantibody (aAbs) immune reaction effects on neuroinflammation and on β-amyloid (Aβ) clearance pathways in patients with CAA and Alzheimer disease (AD). As per Today, the term ARIA-E is most commonly used in clinical trials to describe the radiographic adverse events complicating AD immunotherapy with anti–Aβ monoclonal antibodies (mAbs). However, the last years of research has provided evidence for reconsidering therapy-induced ARIA-E as the iatrogenic manifestation of CAA-ri. A temporal and regional association between ARIA-E and microglia-PET reactivity has also been recently described. However, biomarker-based evidence of a direct association between aAbs levels and neuroinflammation and the occurrence of ARIA-E is still missing. Moreover, potential association between ARIA-E events and SARS CoV2 vaccination has been suggested. Here, we first provide biomarkers-based evidence for two patients who developed CAA-ri associated with ARIA-E and raised CSF concentrations of aAbs and sTREM2 early after administration of two different vaccines against SARS CoV-2. In this framework, the CSF testing for aAbs represents the most advanced candidate biomarker for the early diagnosis of CAA-ri, with the potential to overcome current limitations of MRI in the reporting and management of ARIA-E. Materials and Methods A longitudinal CSF quantification of aAbs, ATN biomarkers of AD biology and sTREM2 is performed. Biomarkers are studied in the well-defined sample cohort of the iCAB International Network and ARIA is CAAri NET. Results Case1 presented with acute-onset CAA-ri and radiographic ARIA-E 48h after vaccination with Tozinameran. CSF testing: markedly elevated aAbs (1.98ug/mL) and sTREM2 (529.77pg/mL), A+T-N- profile, and APOE3/4. Although clinical improvement after high-dose corticosteroids, CSF re-testing showed persistently high aAbs (0.91ug/mL) and +43% sTREM2. He died for pneumonia 3-weeks later. Case 2 presented with acute-onset CAA-ri and ARIA-E 24h after vaccination with AZD1222. CSF testing: raised aAbs (0.56ug/mL) and sTREM2 (4580.71pg/mL), A+T+N+ profile, and APOE3/3. CSF re-testing 2.5-months after high-dose corticosteroids showed persistently high aAbs (0.78ug/mL) and -39% sTREM2. Continued oral corticosteroid therapy for 6-months resulted in clinicoradiological resolution. Discussion and Conclusion We provided first biomarker-based evidence for acute-onset iatrogenic CAA-ri after anti-SARS-CoV2 vaccination. We suggest the immune response elicited by vaccination triggered the backgrounding aAbs-related immune reactivity risk for ARIA-E of patients with coexisting CAA and AD to overcome the threshold for CAA-ri.