Objective: Cerebral amyloid angiopathy (CAA) is characterized by the progressive deposition of amyloid-β (Aβ) protein in the walls of small/medium sized arteries of cerebral cortex and leptomeninges, representing an important cause of spontaneous intracerebral haemorrhage and cognitive impairment. A subgroup of CAA patients develop perivascular inflammation linked to the Aβ laden vessels, associated with vasogenic edema (VE) and to a rapid cognitive decline, leading to a condition known as CAA-related inflammation (CAA-ri). This syndrome has parallels with what observed in about 10% of patients affected by Alzheimer's disease (AD) who developed reversible VE after immunization with the anti-Aβ antibody bapineuzumab, where postmortem examination revealed inflammation and/or vasculitis associated with CAA, implying the discontinuation of therapeutic protocols. Recent MRI data have also shown that up to 17% of the treated patients have signs of VE directly related to the drug dose, even if in the absence of clinical correlates. Methods: thanks to a novel technique for the ultra sensitive evaluation (patent application pending), we followed the concentration of anti-Aβ antibodies in the CSF of 10 CAA-ri patient during the acute phase (acCAA-ri) and after the remission phase (rpCAA-ri), compared to 8 non-inflammatory CAA, 10 AD, 10 MS and 20 healthy control subjects. Results: we demonstrated that the concentration of anti-Aβ antibodies is specifically increased in the CSF of acCAA-ri patients, followed by a progressive reduction of their concentration after steroid treatment, accordingly to clinical-radiological improvements. Moreover, we observed a spontaneous decrease of these autoantibodies in rpCAA-ri patients without any immunosuppressant treatment, finally proving that the event is not secondary to an unspecific effect of treatment, but strictly related to disease progression. Conclusions: our data support the hypothesis that the pathogenesis of CAA-ri is caused by a specific autoimmune reaction against Aβ, directly mediated by anti-Aβ autoantibodies. Since an invasive procedure such as brain biopsy is still needed for a definite diagnosis of CAA-ri, the outcomes implied by anti-Aβ dosage in CSF may be proposed to support future targets for early diagnosis and follow-up, in association with clinical and radiological features, and as a surrogate biomarker for clinical trials of disease modifying therapies.

Piazza, F., Greenberg, S., Savoiardo, M., Gardinetti, M., Chiapparini, L., Raicher, I., et al. (2012). Immune-mediated mechanisms in the pathogenesis of cerebral amyloid angiopathy-related inflammation and Alzheimer's disease: Role of anti-Aβ auto-antibodie. In ISNI 2012 Abstracts B cells and antibodies - Proceedings of the XI International Congress of Neuroimmunology (ISNI) - Boston 4/8 November 2012.

Immune-mediated mechanisms in the pathogenesis of cerebral amyloid angiopathy-related inflammation and Alzheimer's disease: Role of anti-Aβ auto-antibodie

Piazza, F;Ferrarese, C;Di Francesco, JC
2012

Abstract

Objective: Cerebral amyloid angiopathy (CAA) is characterized by the progressive deposition of amyloid-β (Aβ) protein in the walls of small/medium sized arteries of cerebral cortex and leptomeninges, representing an important cause of spontaneous intracerebral haemorrhage and cognitive impairment. A subgroup of CAA patients develop perivascular inflammation linked to the Aβ laden vessels, associated with vasogenic edema (VE) and to a rapid cognitive decline, leading to a condition known as CAA-related inflammation (CAA-ri). This syndrome has parallels with what observed in about 10% of patients affected by Alzheimer's disease (AD) who developed reversible VE after immunization with the anti-Aβ antibody bapineuzumab, where postmortem examination revealed inflammation and/or vasculitis associated with CAA, implying the discontinuation of therapeutic protocols. Recent MRI data have also shown that up to 17% of the treated patients have signs of VE directly related to the drug dose, even if in the absence of clinical correlates. Methods: thanks to a novel technique for the ultra sensitive evaluation (patent application pending), we followed the concentration of anti-Aβ antibodies in the CSF of 10 CAA-ri patient during the acute phase (acCAA-ri) and after the remission phase (rpCAA-ri), compared to 8 non-inflammatory CAA, 10 AD, 10 MS and 20 healthy control subjects. Results: we demonstrated that the concentration of anti-Aβ antibodies is specifically increased in the CSF of acCAA-ri patients, followed by a progressive reduction of their concentration after steroid treatment, accordingly to clinical-radiological improvements. Moreover, we observed a spontaneous decrease of these autoantibodies in rpCAA-ri patients without any immunosuppressant treatment, finally proving that the event is not secondary to an unspecific effect of treatment, but strictly related to disease progression. Conclusions: our data support the hypothesis that the pathogenesis of CAA-ri is caused by a specific autoimmune reaction against Aβ, directly mediated by anti-Aβ autoantibodies. Since an invasive procedure such as brain biopsy is still needed for a definite diagnosis of CAA-ri, the outcomes implied by anti-Aβ dosage in CSF may be proposed to support future targets for early diagnosis and follow-up, in association with clinical and radiological features, and as a surrogate biomarker for clinical trials of disease modifying therapies.
Si
abstract + slide
Amyloid, autoantibodies, ARIA, CAA
English
ISNI International Society of Neuroimmunology: B cells and antibodies November 4 - 8
http://www.jni-journal.com/article/S0165-5728(12)00304-9/pdf
Piazza, F., Greenberg, S., Savoiardo, M., Gardinetti, M., Chiapparini, L., Raicher, I., et al. (2012). Immune-mediated mechanisms in the pathogenesis of cerebral amyloid angiopathy-related inflammation and Alzheimer's disease: Role of anti-Aβ auto-antibodie. In ISNI 2012 Abstracts B cells and antibodies - Proceedings of the XI International Congress of Neuroimmunology (ISNI) - Boston 4/8 November 2012.
Piazza, F; Greenberg, S; Savoiardo, M; Gardinetti, M; Chiapparini, L; Raicher, I; Sakaguchi, H; Brioschi, M; Billo, G; Colombo, A; Lanzani, F; Piscosquito, G; Carriero, M; Giaccone, G; Tagliavini, F; Ferrarese, C; Di Francesco, J
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/105179
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