Association of Microglial Activation With Spontaneous ARIA-E and CSF Levels of Anti-Aβ Autoantibodies.

Adrenal Cortex Hormones / therapeutic use Alzheimer Disease / complications Amyloid beta-Peptides Antibodies, Monoclonal / therapeutic use Autoantibodies Biomarkers Cerebral Amyloid Angiopathy / complications Humans Immunologic Factors / therapeutic use Inflammation / complications Magnetic Resonance Imaging Microglia

Journal

Neurology
ISSN: 1526-632X
Titre abrégé: Neurology
Pays: United States
ID NLM: 0401060

Informations de publication

Date de publication:
20 Sep 2022
Historique:
received: 20 09 2021
accepted: 13 05 2022
pubmed: 9 8 2022
medline: 14 10 2022
entrez: 8 8 2022
Statut: ppublish

Résumé

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. 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; 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. Our findings extend the current notion of ARIA-E by providing the first in vivo

Sections du résumé

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;
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

Identifiants

DOI: 10.1212/WNL.0000000000200892 PMID: 35940900 PMC: PMC9576297
pubmed: 35940900
pii: WNL.0000000000200892
doi: 10.1212/WNL.0000000000200892
pmc: PMC9576297
doi:

Substances chimiques

Adrenal Cortex Hormones 0
Amyloid beta-Peptides 0
Antibodies, Monoclonal 0
Autoantibodies 0
Biomarkers 0
Immunologic Factors 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

e1265-e1277

Informations de copyright

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

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Auteurs

Fabrizio Piazza (F)

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.
ORCID: 0000-0002-3385-3224

Silvia Paola Caminiti (SP)

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.
ORCID: 0000-0003-4568-1738

Marialuisa Zedde (M)

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.
ORCID: 0000-0001-7530-818X

Luca Presotto (L)

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.

Jacopo C DiFrancesco (JC)

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.
ORCID: 0000-0002-4102-1188

Rosario Pascarella (R)

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.
ORCID: 0000-0002-0512-9298

Alessia Giossi (A)

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.

Maria Sessa (M)

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.

Loris Poli (L)

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.
ORCID: 0000-0003-4912-818X

Gianpaolo Basso (G)

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.
ORCID: 0000-0002-6245-9402

Daniela Perani (D)

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.

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Classifications MeSH

questionsmedicales.fr › Hormones corticosurrénaliennes › Association of Microglial Activation With...
questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Démence › Maladie d'Alzheimer › Association of Microglial Activation With...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Peptides bêta-amyloïdes › Association of Microglial Activation With...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Anticorps monoclonaux › Association of Microglial Activation With...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Autoanticorps › Association of Microglial Activation With...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Association of Microglial Activation With...
questionsmedicales.fr › Maladies métaboliques et nutritionnelles › Maladies métaboliques › Troubles de l'homéostasie des protéines › Amyloïdose › Angiopathie amyloïde cérébrale › Association of Microglial Activation With...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Association of Microglial Activation With...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Facteurs immunologiques › Association of Microglial Activation With...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Inflammation › Association of Microglial Activation With...
questionsmedicales.fr › Diagnostic › Techniques et procédures diagnostiques › Imagerie diagnostique › Tomographie › Imagerie par résonance magnétique › Association of Microglial Activation With...
questionsmedicales.fr › Cellules › Névroglie › Microglie › Association of Microglial Activation With...