Background. The data emerged from the two phase 3 bapineuzumab trials provided valuable insights into its mechanism of action and the need of biomarkers in trial safety, highlighting the APOEε4 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, confirming the hypothesis that anti-Aβ antibody and vasogenic edema are linked to a transient vascular leakage at the sites of major vascular Aβ clearance. Since new AD clinical trials have been launched, the opportunity to better explore autoantibody dosage as biomarkers for patient enrichment and ARIA safety would be highly desirable. Methods. World-wide case-control study in patients coming from the iCAβ International Network. By a novel ultra-sensitive technique, we evaluated the anti-Aβ autoantibody concentration in the CSF of CAA-ri, CAA, AD, MS and healthy-control. All patients undertaken T2*/DWI and FLAIR MRI analyses. 15/45 CAA-ri underwent brain biopsy for pathological confirmation. Aβ40, Aβ42, tau, P-181 tau and APOE4 were investigated. Results. In CAA-ri, a higher amount of anti-Aβ autoantibodies is accompanied by massive drainage of Aβ from the 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 AD carrying the APOE4 allele has been also observed. Diagnostic cut-off for CSF anti-Aβ autoantibodies, by ROC curve analyses, has been determined. Conclusions. ARIA may represent a transient event preceding the downstream beneficial amyloid 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, opening also a new scenario for CAA therapy

Piazza, F. (2014). Anti-Aβ autoantibodies in CAA-ri vs AD patients: different singers for the same ARIA?. Intervento presentato a: Alzheimer's Association International Conference (AAIC) 12 – 17 July, Copenhagen, Denmark [10.1016/j.jalz.2014.04.304].

Anti-Aβ autoantibodies in CAA-ri vs AD patients: different singers for the same ARIA?

PIAZZA, FABRIZIO
2014

Abstract

Background. The data emerged from the two phase 3 bapineuzumab trials provided valuable insights into its mechanism of action and the need of biomarkers in trial safety, highlighting the APOEε4 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, confirming the hypothesis that anti-Aβ antibody and vasogenic edema are linked to a transient vascular leakage at the sites of major vascular Aβ clearance. Since new AD clinical trials have been launched, the opportunity to better explore autoantibody dosage as biomarkers for patient enrichment and ARIA safety would be highly desirable. Methods. World-wide case-control study in patients coming from the iCAβ International Network. By a novel ultra-sensitive technique, we evaluated the anti-Aβ autoantibody concentration in the CSF of CAA-ri, CAA, AD, MS and healthy-control. All patients undertaken T2*/DWI and FLAIR MRI analyses. 15/45 CAA-ri underwent brain biopsy for pathological confirmation. Aβ40, Aβ42, tau, P-181 tau and APOE4 were investigated. Results. In CAA-ri, a higher amount of anti-Aβ autoantibodies is accompanied by massive drainage of Aβ from the 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 AD carrying the APOE4 allele has been also observed. Diagnostic cut-off for CSF anti-Aβ autoantibodies, by ROC curve analyses, has been determined. Conclusions. ARIA may represent a transient event preceding the downstream beneficial amyloid 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, opening also a new scenario for CAA therapy
slide + paper
Cerebral amyloid angiopathy, alzheimer's disease, male, female, microhemorrhage, amyloid related imaging abnormalities, clinical trial, biomarker
English
Alzheimer's Association International Conference (AAIC) 12 – 17 July
2014
2014
10
4
221
221
none
Piazza, F. (2014). Anti-Aβ autoantibodies in CAA-ri vs AD patients: different singers for the same ARIA?. Intervento presentato a: Alzheimer's Association International Conference (AAIC) 12 – 17 July, Copenhagen, Denmark [10.1016/j.jalz.2014.04.304].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/52391
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