Fabrizio Piazza1, Silvia Paola Caminiti2, Marialuisa Zedde2, Luca Presotto2, Jacopo C DiFrancesco2, Rosario Pascarella2, Alessia Giossi2, Maria Sessa2, Loris Poli2, Gianpaolo Basso2, Daniela Perani2. 1. From the CAA and AD Translational Research and Biomarkers Laboratory (F.P.), School of Medicine and Surgery (J.C.D., G.B.), iCAβ International Network (F.P., M.Z., J.C.D., A.G., M.S., Loris Poli, G.B.), and SINdem CAA Study Group (F.P., M.Z., D.P.), University of Milano-Bicocca, Monza; Vita-Salute San Raffaele University (S.P.C., D.P.), Milan; IRCCS San Raffaele Scientific Institute (S.P.C., Luca Presotto, D.P.), Milan; Neurology Unit (M.Z.), Stroke Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia; Neuroradiology Unit (R.P.), Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia; Neurology Unit (A.G.), Azienda Socio-Sanitaria Territoriale di Cremona; Neurology Unit (M.S.), Ospedale ASST Papa Giovanni XXIII, Bergamo; and Neurology Unit (Loris Poli), ASST Spedali Civili, Brescia, Italy. fabrizio.piazza@unimib.it. 2. From the CAA and AD Translational Research and Biomarkers Laboratory (F.P.), School of Medicine and Surgery (J.C.D., G.B.), iCAβ International Network (F.P., M.Z., J.C.D., A.G., M.S., Loris Poli, G.B.), and SINdem CAA Study Group (F.P., M.Z., D.P.), University of Milano-Bicocca, Monza; Vita-Salute San Raffaele University (S.P.C., D.P.), Milan; IRCCS San Raffaele Scientific Institute (S.P.C., Luca Presotto, D.P.), Milan; Neurology Unit (M.Z.), Stroke Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia; Neuroradiology Unit (R.P.), Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia; Neurology Unit (A.G.), Azienda Socio-Sanitaria Territoriale di Cremona; Neurology Unit (M.S.), Ospedale ASST Papa Giovanni XXIII, Bergamo; and Neurology Unit (Loris Poli), ASST Spedali Civili, Brescia, Italy.
Abstract
BACKGROUND AND OBJECTIVES: Amyloid-related imaging abnormalities suggestive of vasogenic edema or sulcal effusion (ARIA-E) are the most common adverse events complicating Alzheimer disease (AD) immunotherapy with anti-β-amyloid (Aβ) monoclonal antibodies. ARIA-E can also occur spontaneously in cerebral amyloid angiopathy-related inflammation (CAA-ri), a rare autoimmune encephalopathy associated with increased CSF levels of anti-Aβ autoantibodies. Although the pathophysiologic mechanisms of ARIA-E remain to be fully elucidated, experimental evidence from ex vivo studies suggests that gantenerumab and aducanumab enable microglial activation. However, the in vivo evidence for a direct association between neuroinflammation and ARIA-E in patients with high CSF anti-Aβ (auto)antibody levels has never been demonstrated. METHODS: The spatial distribution and temporal variations of microglial activation associated with levels of anti-Aβ autoantibodies at (sub)acute presentation of ARIA-E and after corticosteroid therapy were evaluated in a longitudinal case series of patients with CAA-ri, the spontaneous variant of the iatrogenic ARIA-E reported in Aβ-lowering immunotherapy with monoclonal antibodies. Multimodal and multiparametric MRI was used for CAA and ARIA-E severity quantification, according to validated scoring system; CSF testing for anti-Aβ autoantibodies and AD biomarkers; 11C-PK11195 PET for activated microglia. RESULTS: At (sub)acute presentation, we found focal peaks of microglial activation having a greater spatial colocalization with ARIA-E compared with chronic age-related white matter change imaging abnormalities. The severity of ARIA-E and the magnitude of the associated microglial activation were greater in patients having AD and severe CAA concomitant disease compared with patients having CAA only. CSF anti-Aβ autoantibodies at presentation were high in all patients and markedly decreased at posttreatment follow-up, in parallel with clinical resolution of acute symptoms, reduced ARIA-E severity, and reduced microglial activation. DISCUSSION: Our findings extend the current notion of ARIA-E by providing the first in vivo 11C-PK11195 PET evidence for an association between microglial activation and the magnitude and severity of ARIA-E in patients with increased CSF concentration of anti-Aβ autoantibodies and comorbid AD and CAA disease. Our results highlight CSF testing for anti-Aβ autoantibodies as a promising diagnostic, prognostic, and therapy response biomarker to help guide future treatment and management decisions in real clinical practice and clinical trials.
BACKGROUND AND OBJECTIVES: Amyloid-related imaging abnormalities suggestive of vasogenic edema or sulcal effusion (ARIA-E) are the most common adverse events complicating Alzheimer disease (AD) immunotherapy with anti-β-amyloid (Aβ) monoclonal antibodies. ARIA-E can also occur spontaneously in cerebral amyloid angiopathy-related inflammation (CAA-ri), a rare autoimmune encephalopathy associated with increased CSF levels of anti-Aβ autoantibodies. Although the pathophysiologic mechanisms of ARIA-E remain to be fully elucidated, experimental evidence from ex vivo studies suggests that gantenerumab and aducanumab enable microglial activation. However, the in vivo evidence for a direct association between neuroinflammation and ARIA-E in patients with high CSF anti-Aβ (auto)antibody levels has never been demonstrated. METHODS: The spatial distribution and temporal variations of microglial activation associated with levels of anti-Aβ autoantibodies at (sub)acute presentation of ARIA-E and after corticosteroid therapy were evaluated in a longitudinal case series of patients with CAA-ri, the spontaneous variant of the iatrogenic ARIA-E reported in Aβ-lowering immunotherapy with monoclonal antibodies. Multimodal and multiparametric MRI was used for CAA and ARIA-E severity quantification, according to validated scoring system; CSF testing for anti-Aβ autoantibodies and AD biomarkers; 11C-PK11195 PET for activated microglia. RESULTS: At (sub)acute presentation, we found focal peaks of microglial activation having a greater spatial colocalization with ARIA-E compared with chronic age-related white matter change imaging abnormalities. The severity of ARIA-E and the magnitude of the associated microglial activation were greater in patients having AD and severe CAA concomitant disease compared with patients having CAA only. CSF anti-Aβ autoantibodies at presentation were high in all patients and markedly decreased at posttreatment follow-up, in parallel with clinical resolution of acute symptoms, reduced ARIA-E severity, and reduced microglial activation. DISCUSSION: Our findings extend the current notion of ARIA-E by providing the first in vivo 11C-PK11195 PET evidence for an association between microglial activation and the magnitude and severity of ARIA-E in patients with increased CSF concentration of anti-Aβ autoantibodies and comorbid AD and CAA disease. Our results highlight CSF testing for anti-Aβ autoantibodies as a promising diagnostic, prognostic, and therapy response biomarker to help guide future treatment and management decisions in real clinical practice and clinical trials.
Authors: F Barkhof; M Daams; P Scheltens; H R Brashear; H M Arrighi; A Bechten; K Morris; M McGovern; M P Wattjes Journal: AJNR Am J Neuroradiol Date: 2013-02-22 Impact factor: 3.825
Authors: Susanne Ostrowitzki; Dennis Deptula; Lennart Thurfjell; Frederik Barkhof; Bernd Bohrmann; David J Brooks; William E Klunk; Elizabeth Ashford; Kisook Yoo; Zhi-Xin Xu; Hansruedi Loetscher; Luca Santarelli Journal: Arch Neurol Date: 2011-10-10
Authors: Vassilios Papadopoulos; Mario Baraldi; Tomás R Guilarte; Thomas B Knudsen; Jean-Jacques Lacapère; Peter Lindemann; Michael D Norenberg; David Nutt; Abraham Weizman; Ming-Rong Zhang; Moshe Gavish Journal: Trends Pharmacol Sci Date: 2006-07-05 Impact factor: 14.819
Authors: J Linn; A Halpin; P Demaerel; J Ruhland; A D Giese; M Dichgans; M A van Buchem; H Bruckmann; S M Greenberg Journal: Neurology Date: 2010-04-27 Impact factor: 9.910