Fabrizio Piazza, S M Greenberg, A Lleo Bisa, J F Vazquez Costa, R Nitrini, A Kakita, Y Hagiwara, G Giaccone, G Boncoraglio, M Glatzel, C Marini1, A Uncini, S Cirillo, F Tagliavini, C Ferrarese and J C DiFrancesco
Background: The data emerged from the two phase3 bapineuzumab trials provided valuable insights into its mechanism of action and the need of biomarkers in trial safety, highlighting the APOE?4 and dose-related development of Amyloid-Related Imaging Abnormalities (ARIA) as the most notable adverse event. Similar MRI abnormalities have been recently shown both in a human spontaneous model of ARIA, represented by Cerebral Amyloid Angiopathy-related inflammation (CAA-ri), and in immunized PDAPP mice, suggesting that Anti-Aβ antibody and vasogenic edema are linked to a transient vascular leakage at the sites of major vascular Aβ clearance. Methods: World-wide case-control study in 150 patients from the iCAβ Network. By a novel ultra-sensitive technique, we evaluated Anti-Aβ autoantibody concentration in the CSF of CAA-ri, CAA, AD, MS and healthy-control. All patients undertaken T2*/SWI and FLAIR MRI analyses. 15/45 CAA-ri underwent brain biopsy for pathological confirmation. Anti-Aβ40, Aβ42, tau, P-181 tau and APOE4 were investigated. Results: In CAA-ri, a higher amount of Anti-Aβ Autoantibodies are accompanied by massive drainage of A? from brain and vascular deposits into the soluble forms, followed by a reduction of both autoantibodies and neurodegenerative markers after remission. An increased concentration of autoantibodies in APO?4 carriers has been also observed in AD. Diagnostic cut-off for autoantibodies has been determined. Conclusions: ARIA may represent a transient event preceding the downstream beneficial A?-clearance effects of treatment, where increased CSF Anti-Aβ antibodies may cause a shift in CAA accumulation and increased vascular permeability. CSF Anti-Aβ autoantibody test as biomarkers for the CAA-related consequences of treatment could mark an important advance for the current ongoing clinical trials in AD, both for patient enrichment and ARIA safety, opening also a new scenario for CAA therapy. Biomarkers for the stratification, follow-up and monitoring of the safe and effective therapeutic response of amyloid-beta (Aβ) disease-modifying therapies (DMT) represent a research priority in Alzheimer’s disease (AD)
