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1. Brivaracetam as Early Add-On Treatment in Patients with Focal Seizures: A Retrospective, Multicenter, RealWorld Study

Author

Lattanzi, S., Canafoglia, L., Canevini, M. P., Casciato, S., Cerulli Irelli, E., Chiesa, V., Dainese, F., De Maria, G., Didato, G., Di Gennaro, G., Falcicchio, G., Fanella, M., Ferlazzo, E., Gangitano, M., La Neve, A., Mecarelli, O., Montalenti, E., Morano, A., Piazza, F., Pizzanelli, C., Pulitano, P., Ranzato, F., Rosati, E., Tassi, L., Di Bonaventura, C., Alicino, A., Ascoli, M., Assenza, G., Avorio, F., Badioni, V., Banfi, P., Bartolini, E., Basili, L. M., Belcastro, V., Beretta, S., Berto, I., Biggi, M., Billo, G., Boero, G., Bonanni, P., Bongorno, J., Brigo, F., Caggia, E., Cagnetti, C., Calvello, C., Cesnik, E., Chianale, G., Ciampanelli, D., Ciuffini, R., Cocito, D., Colella, D., Contento, M., Costa, C., Cumbo, E., D'Aniello, A., Deleo, F., Difrancesco, J. C., Di Giacomo, R., Di Liberto, A., Domina, E., Dono, F., Durante, V., Elia, M., Estraneo, A., Evangelista, G., Faedda, M. T., Failli, Y., Fallica, E., Fattouch, J., Ferrari, A., Ferreri, F., Fisco, G., Fonti, D., Fortunato, F., Foschi, N., Francavilla, T., Galli, R., Gazzina, S., Giallonardo, A. T., Giorgi, F. S., Giuliano, L., Habetswallner, F., Izzi, F., Kassabian, B., Labate, A., Luisi, C., Magliani, M., Maira, G., Mari, L., Marino, D., Mascia, A., Mazzeo, A., Meletti, S., Milano, C., Nilo, A., Orlando, B., Paladin, F., Pascarella, M. G., Pastori, C., Pauletto, G., Peretti, A., Perri, G., Pezzella, M., Piccioli, M., Pignatta, P., Pilolli, N., Pisani, F., Pisani, L. R., Placidi, F., Pollicino, P., Porcella, V., Pradella, S., Puligheddu, M., Quadri, S., Quarato, P. P., Quintas, R., Renna, R., Rizzo, G. R., Rum, A., Salamone, E. M., Savastano, E., Sessa, M., Stokelj, D., Tartara, E., Tombini, M., Tumminelli, G., Vaudano, A. E., Ventura, M., Vigano, I., Viglietta, E., Vignoli, A., Villani, F., Zambrelli, E., Zummo, L., Lattanzi, Simona, Canafoglia, Laura, Canevini, Maria Paola, Casciato, Sara, Cerulli Irelli, Emanuele, Chiesa, Valentina, Dainese, Filippo, De Maria, Giovanni, Didato, Giuseppe, Di Gennaro, Giancarlo, Falcicchio, Giovanni, Fanella, Martina, Ferlazzo, Edoardo, Gangitano, Massimo, La Neve, Angela, Mecarelli, Oriano, Montalenti, Elisa, Morano, Alessandra, Piazza, Federico, Pizzanelli, Chiara, Pulitano, Patrizia, Ranzato, Federica, Rosati, Eleonora, Tassi, Laura, and Di Bonaventura, Carlo

Subjects
Antiseizure medication, Focal seizures, Brivaracetam, Epilepsy, Neurology, Settore MED/26 - Neurologia, Neurology (clinical), Settore MED/26, Settore MED/39 - Neuropsichiatria Infantile
Abstract

Introduction: In randomized controlled trials, add-on brivaracetam (BRV) reduced seizure frequency in patients with drug-resistant focal epilepsy. Most real-world research on BRV has focused on refractory epilepsy. The aim of this analysis was to assess the 12-month effectiveness and tolerability of adjunctive BRV when used as early or late adjunctive treatment in patients included in the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST). Methods: BRIVAFIRST was a 12-month retrospective, multicenter study including adult patients prescribed adjunctive BRV. Effectiveness outcomes included the rates of sustained seizure response, sustained seizure freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events (AEs) and the incidence of AEs. Data were compared for patients treated with add-on BRV after 1-2 (early add-on) and ≥ 3 (late add-on) prior antiseizure medications. Results: A total of 1029 patients with focal epilepsy were included in the study, of whom 176 (17.1%) received BRV as early add-on treatment. The median daily dose of BRV at 12months was 125 (100-200) mg in the early add-on group and 200 (100-200) in the late add-on group (p

Published
2022

2. Correction to: Adjunctive Brivaracetam in Focal Epilepsy: Real‑World Evidence from the BRIVAracetam add‑on First Italian netwoRk Study (BRIVAFIRST) (CNS Drugs, (2021), 35, 12, (1289-1301), 10.1007/s40263-021-00856-3)

Author

Lattanzi, S., Canafoglia, L., Canevini, M. P., Casciato, S., Chiesa, V., Dainese, F., De Maria, G., Didato, G., Falcicchio, G., Fanella, M., Ferlazzo, E., Fisco, G., Gangitano, M., Giallonardo, A. T., Giorgi, F. S., La Neve, A., Mecarelli, O., Montalenti, E., Piazza, F., Pulitano, P., Quarato, P. P., Ranzato, F., Rosati, E., Tassi, L., Di Bonaventura, C., Alicino, A., Ascoli, M., Assenza, G., Avorio, F., Badioni, V., Banfi, P., Bartolini, E., Basili, L. M., Belcastro, V., Beretta, S., Berto, I., Biggi, M., Billo, G., Boero, G., Bonanni, P., Bongorno, J., Brigo, F., Caggia, E., Cagnetti, C., Calvello, C., Irelli, E. C., Cesnik, E., Chianale, G., Ciampanelli, D., Ciuffini, R., Cocito, D., Colella, D., Contento, M., Costa, C., Cumbo, E., D'Aniello, A., Deleo, F., Difrancesco, J. C., Gennaro, G., Di Giacomo, R., Di Liberto, A., Domina, E., Donato, F., Dono, F., Durante, V., Elia, M., Estraneo, A., Evangelista, G., Faedda, M. T., Failli, Y., Fallica, E., Fattouch, J., Ferrari, A., Ferreri, F., Fonti, D., Fortunato, F., Foschi, N., Francavilla, T., Galli, R., Gazzina, S., Giuliano, L., Habetswallner, F., Izzi, F., Kassabian, B., Labate, A., Luisi, C., Magliani, M., Maira, G., Mari, L., Marino, D., Mascia, A., Mazzeo, A., Meletti, S., Morano, A., Nilo, A., Orlando, B., Paladin, F., Pascarella, M. G., Pastori, C., Pauletto, G., Peretti, A., Perri, G., Pezzella, M., Piccioli, M., Pignatta, P., Pilolli, N., Pisani, F., Pisani, L. R., Placidi, F., Pollicino, P., Porcella, V., Pradella, S., Puligheddu, M., Quadri, S., Quintas, R., Renna, R., Rossi, J., Rum, A., Salamone, E. M., Savastano, E., Sessa, M., Stokelj, D., Tartara, E., Tombini, M., Tumminelli, G., Ventura, M., Vigano, I., Viglietta, E., Vignoli, A., Villani, F., Zambrelli, E., and Zummo, L.

Published
2021

3. Correction to: Adjunctive Brivaracetam in Focal Epilepsy: Real‑World Evidence from the BRIVAracetam add‑on First Italian netwoRk Study (BRIVAFIRST) (CNS Drugs, (2021), 10.1007/s40263-021-00856-3)

Author

Lattanzi, S., Canafoglia, L., Canevini, M. P., Casciato, S., Chiesa, V., Dainese, F., De Maria, G., Didato, G., Falcicchio, G., Fanella, M., Ferlazzo, E., Fisco, G., Gangitano, M., Giallonardo, A. T., Giorgi, F. S., La Neve, A., Mecarelli, O., Montalenti, E., Piazza, F., Pulitano, P., Quarato, P. P., Ranzato, F., Rosati, E., Tassi, L., Di Bonaventura, C., Alicino, A., Ascoli, M., Assenza, G., Avorio, F., Badioni, V., Banfi, P., Bartolini, E., Basili, L. M., Belcastro, V., Beretta, S., Berto, I., Biggi, M., Billo, G., Boero, G., Bonanni, P., Bongorno, J., Brigo, F., Caggia, E., Cagnetti, C., Calvello, C., Irelli, E. C., Cesnik, E., Chianale, G., Ciampanelli, D., Ciuffini, R., Cocito, D., Colella, D., Contento, M., Costa, C., Cumbo, E., D'Aniello, A., Deleo, F., Difrancesco, J. C., Gennaro, G., Di Giacomo, R., Di Liberto, A., Domina, E., Donato, F., Dono, F., Durante, V., Elia, M., Estraneo, A., Evangelista, G., Faedda, M. T., Failli, Y., Fallica, E., Fattouch, J., Ferrari, A., Ferreri, F., Fonti, D., Fortunato, F., Foschi, N., Francavilla, T., Galli, R., Gazzina, S., Giuliano, L., Habetswallner, F., Izzi, F., Kassabian, B., Labate, A., Luisi, C., Magliani, M., Maira, G., Mari, L., Marino, D., Mascia, A., Mazzeo, A., Meletti, S., Morano, A., Nilo, A., Orlando, B., Paladin, F., Pascarella, M. G., Pastori, C., Pauletto, G., Peretti, A., Perri, G., Pezzella, M., Piccioli, M., Pignatta, P., Pilolli, N., Pisani, F., Pisani, L. R., Placidi, F., Pollicino, P., Porcella, V., Pradella, S., Puligheddu, M., Quadri, S., Quintas, R., Renna, R., Rossi, J., Rum, A., Salamone, E. M., Savastano, E., Sessa, M., Stokelj, D., Tartara, E., Tombini, M., Tumminelli, G., Ventura, M., Vigano, I., Viglietta, E., Vignoli, A., Villani, F., Zambrelli, E., and Zummo, L.

Published
2021

4. Adjunctive Brivaracetam in Focal Epilepsy: Real-World Evidence from the BRIVAracetam add-on First Italian netwoRk STudy (BRIVAFIRST)

Author

Lattanzi, S., Canafoglia, L., Canevini, M. P., Casciato, S., Chiesa, V., Dainese, F., De Maria, G., Didato, G., Falcicchio, G., Fanella, M., Ferlazzo, E., Fisco, G., Gangitano, M., Giallonardo, A. T., Giorgi, F. S., La Neve, A., Mecarelli, O., Montalenti, E., Piazza, F., Pulitano, P., Quarato, P. P., Ranzato, F., Rosati, E., Tassi, L., Di Bonaventura, C., Alicino, A., Ascoli, M., Assenza, G., Avorio, F., Badioni, V., Banfi, P., Bartolini, E., Basili, L. M., Belcastro, V., Beretta, S., Berto, I., Biggi, M., Billo, G., Boero, G., Bonanni, P., Bongorno, J., Brigo, F., Caggia, E., Cagnetti, C., Calvello, C., Irelli, E. C., Cesnik, E., Chianale, G., Ciampanelli, D., Ciuffini, R., Cocito, D., Colella, D., Contento, M., Costa, C., Cumbo, E., D'Aniello, A., Deleo, F., Difrancesco, J. C., Di Gennaro, G., Di Giacomo, R., Di Liberto, A., Domina, E., Donato, F., Dono, F., Durante, V., Elia, M., Estraneo, A., Evangelista, G., Faedda, M. T., Failli, Y., Fallica, E., Fattouch, J., Ferrari, A., Ferreri, F., Fonti, D., Fortunato, F., Foschi, N., Francavilla, T., Galli, R., Gazzina, S., Giuliano, L., Habetswallner, F., Izzi, F., Kassabian, B., Labate, A., Luisi, C., Magliani, M., Maira, G., Mari, L., Marino, D., Mascia, A., Mazzeo, A., Meletti, S., Morano, A., Nilo, A., Orlando, B., Paladin, F., Pascarella, M. G., Pastori, C., Pauletto, G., Peretti, A., Perri, G., Pezzella, M., Piccioli, M., Pignatta, P., Pilolli, N., Pisani, F., Pisani, L. R., Placidi, F., Pollicino, P., Porcella, V., Pradella, S., Puligheddu, M., Quadri, S., Quintas, R., Renna, R., Rossi, J., Rum, A., Salamone, E. M., Savastano, E., Sessa, M., Stokelj, D., Tartara, E., Tombini, M., Tumminelli, G., Ventura, M., Vigano, I., Viglietta, E., Vignoli, A., Villani, F., Zambrelli, E., Zummo, L., Lattanzi S., Canafoglia L., Canevini M.P., Casciato S., Chiesa V., Dainese F., De Maria G., Didato G., Falcicchio G., Fanella M., Ferlazzo E., Fisco G., Gangitano M., Giallonardo A.T., Giorgi F.S., La Neve A., Mecarelli O., Montalenti E., Piazza F., Pulitano P., Quarato P.P., Ranzato F., Rosati E., Tassi L., and Di Bonaventura C.

Subjects
medicine.medical_specialty, business.industry, Context (language use), Brivaracetam, medicine.disease, Discontinuation, law.invention, Psychiatry and Mental health, Epilepsy, Randomized controlled trial, Tolerability, focal epilepsy, add-on therapy, seizure, law, Concomitant, Internal medicine, Medicine, Pharmacology (medical), Neurology (clinical), Levetiracetam, Original Research Article, business, medicine.drug
Abstract

Background: In randomized controlled trials, add-on brivaracetam (BRV) reduced seizure frequency in patients with drug-resistant focal epilepsy. Studies performed in a naturalistic setting are a useful complement to characterize the drug profile. Objective: This multicentre study assessed the effectiveness and tolerability of adjunctive BRV in a large population of patients with focal epilepsy in the context of real-world clinical practice. Methods: The BRIVAFIRST (BRIVAracetam add-on First Italian netwoRk STudy) was a retrospective, multicentre study including adult patients prescribed adjunctive BRV. Patients with focal epilepsy and 12-month follow-up were considered. Main outcomes included the rates of seizure‐freedom, seizure response (≥50% reduction in baseline seizure frequency), and treatment discontinuation. The incidence of adverse events (AEs) was also considered. Analyses by levetiracetam (LEV) status and concomitant use of strong enzyme-inducing antiseizure medications (EiASMs) and sodium channel blockers (SCBs) were performed. Results: A total of 1029 patients with a median age of 45years (33–56) was included. At 12 months, 169 (16.4%) patients were seizure-free and 383 (37.2%) were seizure responders. The rate of seizure freedom was 22.3% in LEV-naive patients, 7.1% in patients with prior LEV use and discontinuation due to insufficient efficacy, and 31.2% in patients with prior LEV use and discontinuation due to AEs (p&nbsp

Published
2021

7. Numerical modeling of an in-vessel flow limiter using an Immersed Boundary Approach

Author

Billo, G., CADARACHE, Bibliothèque, CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
[PHYS.NUCL] Physics [physics]/Nuclear Theory [nucl-th], [PHYS.NUCL]Physics [physics]/Nuclear Theory [nucl-th], [PHYS.NEXP] Physics [physics]/Nuclear Experiment [nucl-ex], [PHYS.NEXP]Physics [physics]/Nuclear Experiment [nucl-ex]
Abstract

International audience; The increasing performance and safety requirements for the third generation of nuclear reactors led tonew Research and Development studies. In this context, new innovative systems are designed to preventor soften potential accidental or incidental situations. For instance, a passive system to postpone thecore dewatering, in the case of a Large-Break Loss Of Coolant Accident in Pressurized Water Reactors,has been imagined and patented by CEA. This passive flow limiter is composed of fins which, inaccidental behavior (for instance fluid coming out from the vessel due a break on the cold leg), force thecreation of a large vortex of fluid and so reduce the flowrate going outflow of the vessel (i.e. postponethe core dewatering). For more information about the background, the interested reader can refer to reference below.Of course, the pressure drop induced by the device (in both nominal and accidental situations) is greatlyinfluenced by the shape of the fins. Thus, in order to optimize its geometry, a fast and robust numericaltool, able to faithfully model the flow limiter, is needed.

Published
2018

8. Numerical modeling of an in-vessel flow limiterusing an Immersed Boundary Approach

Author

Billo, G., Belliard, Michel, CADARACHE, Bibliothèque, CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
[PHYS.NUCL] Physics [physics]/Nuclear Theory [nucl-th], [PHYS.NUCL]Physics [physics]/Nuclear Theory [nucl-th], [PHYS.NEXP] Physics [physics]/Nuclear Experiment [nucl-ex], [PHYS.NEXP]Physics [physics]/Nuclear Experiment [nucl-ex], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2018

9. Anti-Aß autoantibodies in cerebral amyloid angiopathy-related inflammation: a human spontaneous model of amyloid-related imaging abnormalities (ARIA) in Alzheimer’s disease

Author

PIAZZA, FABRIZIO, FERRARESE, CARLO, DI FRANCESCO, JACOPO COSIMO, Greenberg, SM, Savoiardo, M, Gardinetti, M, Chiapparini, L, Raicher, I, Nitrini, R, Sakaguchi, H, Brioschi, M, Billo, G, Colombo, A, Lanzani, F, Piscosquito, G, Carriero, MR, Giaccone, G, Tagliavini, F, Piazza, F, Greenberg, S, Savoiardo, M, Gardinetti, M, Chiapparini, L, Raicher, I, Nitrini, R, Sakaguchi, H, Brioschi, M, Billo, G, Colombo, A, Lanzani, F, Piscosquito, G, Carriero, M, Giaccone, G, Tagliavini, F, Ferrarese, C, and DI FRANCESCO, J

Subjects
MED/04 - PATOLOGIA GENERALE, Alzheimer's disease, Cerebral Amyloid Angiopathy, BIO/14 - FARMACOLOGIA, MED/05 - PATOLOGIA CLINICA, MED/50 - SCIENZE TECNICHE MEDICHE APPLICATE
Abstract

Objective: cerebral Amyloid Angiopathy-related inflammation (CAA-ri) is characterized by vasogenic edema and multiple cortical/subcortical microbleeds, sharing several aspects with the recently defined Amyloid-Related Imaging Abnormalities (ARIA) reported in Alzheimer’s disease (AD) passive immunization therapies. Herein, we investigated the role of anti-amyloid beta (Aβ) autoantibodies in the acute and remission phases of CAA-ri. Methods: we used a novel ultra-sensitive technique on patients from a retrospective multicenter case-control study, and evaluated the anti-Aβ autoantibodies concentration in the cerebrospinal fluid (CSF) of 10 CAA-ri, 8 CAA, 14 multiple sclerosis and 25 control subjects. Levels of soluble Aβ40, Aβ42, tau, P-181 tau and APOE4 genotype were also investigated. Results: during the acute phase of CAA-ri, anti-Aβ autoantibodies were specifically increased and directly correlated with Aβ mobilization, together with augmented tau and P-181 tau. Following clinical and radiological remission, autoantibodies progressively returned to control levels, and both soluble Aβ and axonal degeneration markers decreased in parallel. Interpretation: our data support the hypothesis that the pathogenesis of CAA-ri may be mediated by a selective autoimmune reaction against cerebro-vascular Aβ, directly related to autoantibodies concentration and soluble Aβ. The CSF dosage of anti-Aβ autoantibodies with the technique here described can thus be proposed as a valid alternative tool for the diagnosis of CAA-ri. Moreover, given the similarities between ARIA developing spontaneously and those observed during immunization trials, anti-Aβ autoantibodies can be considered as novel potential biomarkers in future amyloid-modifying therapies for the treatment of AD and CAA

Published
2013

10. Anti-Aβ autoantibodies in cerebral amyloid angiopathy-related inflammation: Implications for amyloid-modifying therapies

Author

PIAZZA, FABRIZIO, Greenberg, SM, Savoiardo, M, GARDINETTI, MARGHERITA, Chiapparini, L, Raicher, I, Nitrini, R, Sakaguchi, H, Brioschi, M, Billo, G, Colombo, A, Lanzani, F, Piscosquito, G, Carriero, MR, Giaccone, G, Tagliavini, F, FERRARESE, CARLO, DI FRANCESCO, JACOPO COSIMO, Piazza, F, Greenberg, S, Savoiardo, M, Gardinetti, M, Chiapparini, L, Raicher, I, Nitrini, R, Sakaguchi, H, Brioschi, M, Billo, G, Colombo, A, Lanzani, F, Piscosquito, G, Carriero, M, Giaccone, G, Tagliavini, F, Ferrarese, C, and DI FRANCESCO, J

Subjects
Amyloid Related Imaging Abnormalities, ARIA, Alzheimer's disease, Cerebral Amyloid Angiopathy-related inflammation, CAA-ri, Cerebral Amyloid Angiopathy, auto-antibodies against Amyloid beta, beta Amyloid, MED/46 - SCIENZE TECNICHE DI MEDICINA DI LABORATORIO
Abstract

Objective: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is characterized by vasogenic edema and multiple cortical/subcortical microbleeds, sharing several aspects with the recently defined amyloid-related imaging abnormalities (ARIA) reported in Alzheimer's disease (AD) passive immunization therapies. Herein, we investigated the role of anti-amyloid β (Aβ) autoantibodies in the acute and remission phases of CAA-ri. Methods: We used a novel ultrasensitive technique on patients from a retrospective multicenter case-control study, and evaluated the anti-Aβ autoantibody concentration in the cerebrospinal fluid (CSF) of 10 CAA-ri, 8 CAA, 14 multiple sclerosis, and 25 control subjects. Levels of soluble Aβ40, Aβ42, tau, P-181 tau, and APOE genotype were also investigated. Results: During the acute phase of CAA-ri, anti-Aβ autoantibodies were specifically increased and directly correlated with Aβ mobilization, together with augmented tau and P-181 tau. Following clinical and radiological remission, autoantibodies progressively returned to control levels, and both soluble Aβ and axonal degeneration markers decreased in parallel. Interpretation: Our data support the hypothesis that the pathogenesis of CAA-ri may be mediated by a selective autoimmune reaction against cerebrovascular Aβ, directly related to autoantibody concentration and soluble Aβ. The CSF dosage of anti-Aβ autoantibodies with the technique here described can thus be proposed as a valid alternative tool for the diagnosis of CAA-ri. Moreover, given the similarities between ARIA developing spontaneously and those observed during immunization trials, anti-Aβ autoantibodies can be considered as novel potential biomarkers in future amyloid-modifying therapies for the treatment of AD and CAA.

Published
2013

11. Pathogenetic role of anti-AB autoantibodies in Cerebral Amyloid Angiopathy-related inflammation and Alzheimer's disease

Author

Piazza, F, 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, Piazza, F, 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, and Ferrarese, C

Subjects
Cerebral amyloid angiopathy, MED/46 - SCIENZE TECNICHE DI MEDICINA DI LABORATORIO
Abstract

Cerebral amyloid angiopathy (CAA) is pathologically characterized by the progressive deposition of amyloid-β (Aβ) protein in the walls of small/medium sized arteries and capillaries in the cerebral cortex and overlying leptomeninges, representing an important cause of spontaneous intracerebral haemorrhage and cognitive impairment. Interestingly, a subgroup of CAA patients has been shown to develop vascular inflammation of the affected vessels, associated with vasogenic edema (VE) and to a rapid cognitive decline. This condition, known as CAA-related inflammation (CAA-ri), presents with acute or subacute neurological impairment, behavioral changes, seizures and focal neurological deficits. A definite diagnosis of CAA-ri requires brain and leptomeningeal biopsy that shows perivascular inflammation associated with Aβ laden vessels and signs of vasculitis. This distinct syndrome has parallels with what observed in about 5-10% of patients affected by Alzheimer’s disease (AD) who developed reversible VE after passive immunization with the anti-Aβ antibody bapineuzumab, where postmortem examination revealed inflammation and/or vasculitis associated with CAA, implying the discontinuation of the therapeutic protocol. Moreover, recent imaging data on the location of ARIA-E have shown that up to 17% of the treated patients showed signs of VE, even if in the absence of clinical correlates and directly related to the drug dose. Herein, thanks to a novel technique for the ultra sensitive evaluation of anti-Aβ (patent application pending), for the first time, we confirmed a direct involvement of these antibodies during the course Pag. of disease in the CSF of 10 CAA-ri, compared to 8 CAA and 20 healthy subjects, demonstrating that the concentration of anti-Aβ is specifically increased during the acute phase of the disease. Moreover, we reported a progressive reduction of autoantibodies concentration following steroid treatment, according to clinical-radiological improvement. As a further proof, a spontaneous decrease of anti-Aβ in patients without any immunosuppressant treatment was observed, finally proving that this event is not secondary to an unspecific effect of treatment, but strictly related to the disease progression. Our data support the hypothesis that the pathogenesis of CAA-ri is caused by a specific autoimmune reaction directed against Aβ, directly mediated by anti-Aβ autoantibodies. The outcomes implied by antibodies dosage in the CSF may be proposed to support future accessible targets for early diagnosis and follow-up, and as a novel surrogate biomarkers for clinical trials of disease modifying therapies.

Published
2012

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

Author

Piazza, F, Greenberg, SM., Savoiardo, M, Gardinetti, M, Chiapparini, L, Raicher, I, Sakaguchi, H, Brioschi, M, Billo, G, Colombo, A, Lanzani, F, Piscosquito, G, Carriero, MR., Giaccone, G, Tagliavini, F, Ferrarese, C, Di Francesco, JC, 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, and Di Francesco, J

Subjects
BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, MED/04 - PATOLOGIA GENERALE, BIO/14 - FARMACOLOGIA, Amyloid, autoantibodies, ARIA, CAA, MED/05 - PATOLOGIA CLINICA, MED/50 - SCIENZE TECNICHE MEDICHE APPLICATE
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.

Published
2012

13. Rationale and design of a randomized, double-blind, parallel-group study of terutroban 30 mg/day versus aspirin 100 mg/day in stroke patients: the prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study

Author

Bousser, M, Amarenco, P, Chamorro, A, Fisher, M, Ford, I, Fox, K, Hennerici, M, Mattle, H, Rothwell, P, Julian, D, Fieschi, G, Fieschi, C, Boysen, G, Pocock, S, Conard, J, Orgogozo, J, Inzitari, D, Erkinjuntti, T, Pasquier, F, O'Brien, J, Mas, J, Gueret, P, Lenzi, G, Leys, D, Lopez Sendon, J, Norrving, B, Ferro, J, Thygesen, K, Cowpply, B, P, Ameriso, S, Donnan, D, Lang, W, Thijs, V, Fernandes, J, Stamenova, P, Teal, P, Lavados, P, Lu, C, Poljakovic, Z, Kalita, Z, Kaste, M, Moulin, T, Vemmos, K, Diener, H, Wong, L, Nagy, Z, Chopra, J, Mccormack, P, Gensini, G, Budrys, V, Droste, D, Tan, K, Benomar, A, Cantu Brito, C, Barber, A, Koudstaal, P, Thomassen, L, Czlonkowska, A, Cunha, L, Bajenaru, O, Yakhno, N, Chen, C, Lisy, L, Zvan, B, Bryer, A, Kim, J, Vivancos, J, Wahlgren, N, Liu, S, Poungvarin, N, Hentati, F, Bahar, S, Mischenko, T, Lees, K, Abdel Masih, M, Barboza, A, Cirio, J, Crespo, E, Escaray, G, Esnaola, M, Rojas Estol, C, Ferrari, J, Fraiman, H, Garrote, M, Gatto, E, Giannaula, R, Gori, H, Herrera, G, Ioli, P, Losano, J, Povedano Reich, E, Rey, R, Rotta Escalante, R, Saredo, G, Zurru, M, Anderson, C, Bladin, C, Crimmins, D, Davis, S, Donnan, G, Dunbabin, D, Frayne, J, Gates, P, Hankey, G, Helme, R, Herkes, G, Karrasch, J, Kimber, T, Jannes, J, Landau, P, Levi, C, Lueck, C, Markus, R, Phan, T, Schwartz, R, Schultz, D, Blacker, D, Read, S, Williams, M, Aichner, F, Auff, E, Bancher, C, Binder, H, Brainin, M, Brucke, T, Eggers, C, Fertl, E, Ladurner, G, Lalouschek, W, Mamoli, B, Mitrovic, N, Noisternig, G, Schmidt, R, Vosko, M, Willeit, J, Zaruba, E, Boon, P, Bourgeois, P, Caekebeke, J, Cals, N, Cras, P, Desfontaines, P, De Deyn, P, Dieudonne, L, De Klippel, N, Laloux, P, Maertens de Noordhout, A, Merlevede, K, Michotte, A, Pandolfo, M, Peeters, A, Peeters, D, Tack, P, Van Buggenhout, E, Van Landegem, W, Vanhooren, G, Vermylen, P, Annes, M, Brondani, R, De Carvalho, J, Cendes, F, Fabio, S, Ferraz, A, De Freitas, G, Gagliardi, R, Gomes Neto, A, Haussen, S, Kowacs, P, Martins, S, Minelli, C, Moro, C, Noujaim, J, Rocha, M, Da Silva, M, Silveira, J, Yamamoto, F, Zetola, V, Baldaranov, D, Deleva, N, Haralanov, L, Milanov, I, Mintchev, D, Petrova, N, Shotekov, P, Stamenov, B, Zahariev, Z, Arts, R, Bayer, N, Beaudry, M, Berger, L, Bozek, C, Collier, T, Cote, R, Desai, H, Durocher, A, Hachinski, V, Hill, M, Hoppe, B, Howse, D, Mackey, A, Maharaj, M, Minuk, J, Moddel, G, Novak, D, Penn, A, Rabinovitch, H, Selchen, D, Shuaib, A, Silva, J, Silver, F, Spence, D, Stotts, G, Tamayo, A, Teitelbaum, J, Veloso, F, Voll, C, Winder, T, Barrientos Uribe, N, Galdames Poblete, D, Garcia Figueroa, P, Gasic Yaconi, K, Jaramillo Munoz, A, Lavados Germain, P, Lavados Montes, M, Nancupil Bello, C, Prina Pacheco, L, Vargas Canas, A, Venegas, F, Chen, P, H, Cheng, Y, Cui, L, Di, Q, Dong, Q, Fan, D, Feng, H, Huang, Y, Li, J, Li, W, Li, Z, Lin, H, Liu, M, Miao, L, Ren, H, Wang, Y, Wu, J, Zhang, W, Zhao, G, Zhao, H, Zhou, H, Antoncic, I, Demarin, V, Lusic, I, Pavlicek, I, Soldo Butkovic, S, Bar, M, Bauer, J, Kalina, M, Kanovsky, P, Jura, R, Neumann, J, Rektor, I, Skoda, O, Vaclavik, D, Eerola, A, Hillbom, M, Kinnunen, E, Koivisto, K, Numminen, H, Rissanen, A, Roine, R, Sivenius, J, Alamowitch, S, Autret, A, Avendano, S, Bataillard, M, Berthier, E, Besson, G, Bille Turc, F, Boulliat, J, Boulesteix, J, Brosset, C, Cesaro, P, Albucher, J, Clavelou, P, Colamarino, R, Crassard, I, de Broucker, T, de Bray, J, Desbordes, P, Diot, E, Ducrocq, X, Ellie, E, Faucheux, J, Giroud, M, Godefroy, O, Guillon, B, Huttin, H, Just, A, Lamy, C, Lejeune, P, Lucas, C, Macian Montoro, F, Mackowiak, A, Maillet Vioud, M, Pico, F, Milandre, L, Milhaud, D, Malbec, M, Neau, J, Pinel, J, Robin, C, Rodier, G, Rosolacci, T, Rouanet, F, Rouhart, F, Sablot, D, Servan, J, Smadja, D, Trouillas, P, Valance, J, Viader, F, Viallet, F, Wolff, V, Zagnoli, F, Zuber, M, Angerer, M, Becker, U, Berlit, P, Berrouschot, J, Biniek, R, Bitsch, A, Brodhun, R, Dichgans, M, Druschky, K, Dux, R, Faiss, J, Ferbert, A, Gahn, G, Grotemeyer, K, Goertler, M, Grau, A, Griewing, B, Grond, M, Haan, J, Haberl, R, Hamann, G, Hamer, H, Harms, L, Heide, W, Henningsen, H, Hetzel, A, Hoffmann, F, Huber, R, Isenmann, S, Jander, S, Joerg, J, Kaps, M, Kastrup, A, Kessler, C, Koehler, W, Koelmel, H, Lichy, C, Luckner, K, Malessa, R, Mallmann, A, Meyding Lamade, U, Molitor, H, Mueller Jensen, A, Muellges, W, Noth, J, Nueckel, M, Ochs, G, Poppert, H, Roether, J, Rosenkranz, M, Sander, D, Schaebitz, W, Schlachetzki, F, Schlegel, U, Schmid, E, Schneider, D, Schwarz, M, Seidel, G, Sieble, M, Sliwka, U, Stingele, R, Stoegbauer, F, Szabo, K, Topper, R, Treib, J, Weissenborn, K, Widder, B, Witte, O, Karageorgiou, K, Mitsikostas, D, Papadimitriou, A, Papathanasopoulos, P, Chan, H, Ng, P, Tsoi, T, Bartos, L, Csanyi, A, Csiba, L, Csornai, M, Dioszeghy, P, Fazekas, A, Harcos, P, Horvath, S, Kaposzta, Z, Kerenyi, L, Kincses, J, Koves, A, Nikl, J, Panczel, G, Pongracz, E, Sebestyen, K, Semjen, J, Szabo, M, Szegedi, N, Valikovics, A, Varszegi, R, Vecsei, L, Borah, N, Ichaporia, N, Kaul, S, Meenakshi Sundaram, S, Mehndiratta, M, Misra, U, Murthy, J, Nayak, D, Poncha, F, Shah, A, Singh, G, Srinivasa, R, Venkateswarlu, K, Wadia, R, Collins, R, Harbison, J, Hickey, P, Kelly, P, Murphy, S, Adami, A, Agnelli, G, Agostoni, E, Anzola, G, Arnaboldi, M, Bassi, P, Billo, G, Bottacchi, E, Bovi, P, Cappa, S, Cappelletti, C, Carolei, A, Cavallini, A, Chiodo Grandi, F, Comi, G, Consoli, D, Corsi, F, Costanzo, E, De Falco, F, Devetag, F, Di Lazzaro, V, Di Piero, V, Diomedi, M, Fattorello Salimbeni, C, Federico, F, Feleppa, M, Ferrarese, C, Gandolfo, C, Giaccaglini, E, Giaquinto, S, Giobbe, D, Giometto, B, Greco, G, Guidetti, D, Guidotti, M, Iudice, A, Lembo, G, Marengo, C, Marini, P, Melis, M, Micieli, G, Musolino, R, Mutani, R, Neri, G, Parati, E, Pastore, L, Porazzi, D, Prati, P, Procaccianti, G, Rasura, M, Rossini, P, Santilli, I, Semplicini, A, Silvestrini, M, Tanganelli, P, Tedeschi, G, Tezzon, F, Tola, M, Villani, A, Zanferrari, C, Zarcone, D, Bickuviene, I, Gumbrevicius, G, Obelieniene, D, Skaringa, A, Virketiene, I, Tharakan, J, Aleman Pedroza, J, Escamilla Garza, J, Fernandez Vera, J, Leal Cantu, R, Leon Flores, L, Lopez Ruiz, M, Reyes Gutierrez, G, Reyes Morales, S, Rivera Castano, L, Rodrigues Leyva, I, Ruiz Sandoval, J, Vega Boada, F, Belahsen, F, Kissani, N, Mosseddaq, R, Slassi, I, Yahyaoui, M, Boiten, J, Bornebroek, M, De Kort, P, De Leeuw, H, Donders, R, Franke, C, Hertzberger, L, Jansen, B, Kappelle, L, Keizer, K, Kuster, J, Limburg, M, Mulleners, W, Pop, P, Van Den Berg, J, Van Gemert, H, Verbiest, H, Weinstein, H, Clark, M, Fink, J, Gommans, J, Jayathissa, S, Kilfoyle, D, Kumar, A, Hurtig, U, Indredavik, B, Kloster, R, Salvesen, R, Drozdowski, W, Fryze, W, Klimek, A, Kochanowski, J, Kozubski, W, Ksiazkiewicz, B, Kwiecinski, H, Kuczynska Zardzewialy, A, Motta, E, Nowacki, P, Nyka, W, Opala, G, Pierzchala, K, Pniewski, J, Podemski, R, Selmaj, K, Stelmasiak, Z, Stepien, A, Strzelecka Gorzynska, M, Szczudlik, A, Wajgt, A, Wiszniewska, M, Wlodek, A, Canhao, P, Correia, C, Grilo Goncalves, J, Machado Candido, J, Salgado, A, Bulboaca, A, Campeanu, A, Lazar, T, Marginean, I, Minea, D, Pascu, I, Pereanu, M, Perju Dumbrava, L, Popescu, C, Simu, M, Stefanache, F, Toldisan, I, Tuta, S, Zaharia, C, Alifirova, V, Arkhipov, S, Balunov, O, Balyazin, V, Belkin, A, Belova, A, Boiko, A, Bogdanov, E, Butko, D, Chukhlovina, M, Doronin, B, Ermilova, E, Evzelman, M, Fedin, A, Fedorova, N, Golikov, K, Golovkin, V, Gusev, E, Gustov, A, Jakupov, E, Kamchatnov, P, Khabirov, F, Kirienko, A, Klimov, I, Klocheva, E, Kotov, S, Kuznetsov, A, Laskov, V, Levin, Y, Mashkova, N, Nazarov, A, Novikova, L, Odinak, M, Parfenov, V, Pilipenko, P, Pokrovsky, A, Poverennova, I, Rodoman, G, Roshkovskaya, L, Shirokov, E, Shmyriov, V, Sholomov, I, Skoromets, A, Skvortsova, V, Spirin, N, Stakhovskaya, L, Sharov, M, Sherman, M, Shutov, A, Strachunskaya, E, Stulin, I, Suslina, Z, Volosevitch, A, Vorobiev, P, Vorobyeva, O, Voronkova, L, Voskresenskaya, O, Zhuliov, N, Chan, B, Chang, H, Ramani, N, Brozman, M, Dvorak, M, Dzugan, J, Garay, R, Gdovinova, Z, Gurcik, L, Krastev, G, Kukumberg, P, Kurca, E, Meluch, S, Nyeky, M, Turcani, P, Vyletelka, J, Klanjscek, G, Zujovic, E, Zupan, M, Bester, F, Carr, J, Coetzee, C, Frost, A, Gardiner, J, Giampaolo, D, Kesler, S, Lurie, D, Retief, C, Roos, J, Bae, H, Cha, J, Cho, K, Heo, J, Kim, E, Lee, B, Lee, K, Lee, J, Rha, J, Yoon, B, Alvarez Sabin, J, Arboix Damunt, A, De Arce Borda, A, Asensi Alvarez JM, Bermejo Pareja, F, Botia Paniagua, E, Casado, I, Naranjo, I, Castillo Sanchez, J, Chamorro Sanchez, A, Davalos Errando, A, Diaz Marin, C, Diez Tejedor, E, Egido Herrero JA, Fernandez Bolanos, R, Fernandez Fernandez, O, Figuerola Roig, A, Geffner Sclarsky, D, Gil Nunez, A, Gomez Sanchez JC, Gomez Escalonilla Escobar CI, Gonzalez Masegosa, A, Gonzalez Menacho, J, Gracia Fleta, F, Izquierdo Ayuso, G, Jimenez Hernandez, D, Jimenez Martinez, C, Lago Martin, A, Lainez Andres JM, Larracoechea Jausoro, J, Lopez Fernandez JC, Maestre Moreno, J, Marti Vilalta JL, Martin Gonzalez, R, Masjuan Vallejo, J, Medina Rodriguez, A, Molto Jorda JM, Moreno Carre tero MJ, Moris de le Tassa, G, Morlan Gracia, L, Mostacero Miguez, E, Osuna Pulido, T, Pareja Martinez, A, Pinedo Brochado, A, Pons Amate JM, Rodriguez Alvarez JR, Roquer Gonzalez, J, Sanahuja Montesinos, J, Sanchez Sanchez MC, Segura Martin, T, Serena Leal, J, Tejada Garcia, J, Trejo Gabriel JM, Vivancos Mora, J, Andersson, B, Bysell, S, Cederin, B, Laska, A, Lindgren, A, Petersson, T, Wallen, T, Baumgartner, R, Beer, H, Hirt, L, Hungerbuehler, H, Lyrer, P, Michel, P, Mueller, F, Tettenborn, B, Chang, K, Jeng, J, Lien, L, Lin, R, Liu, C, Po, H, Wu, S, Chankrachang, S, Laptikultham, S, Nidhinandana, S, Pongpakdee, S, Benammou, S, Frih Ayed, M, Gouider, R, Mhiri, C, M'Rabet, A, Mrissa, R, Balkan, S, Can, U, Dalkara, T, Kirbas, D, Kumral, E, Ozdemir, G, Ozeren, A, Ozmenoglu, M, Ozturk, S, Lebedynets, V, Maly, V, Moskovko, S, Orzheshkovskyy, V, Smolanka, V, Yavors'Ka, V, Zozulya, I, Bamford, J, Barber, M, Barer, D, Baron, J, Bath, P, Broughton, D, Brown, M, Chataway, J, Curless, R, Darawil, K, Datta, P, Dennis, M, Durairaj, R, Egbuji, J, Ellis, S, Ford, G, Freeman, A, Fulcher, R, Gray, C, Harrington, F, Hudson, C, Iveson, E, James, M, Jenkinson, D, Kalra, L, Kelly, D, Krishnamoorthy, S, Langhorne, P, Magorrian, M, Macleod, M, Macwalter, R, Markus, H, Muhiddin, K, Muir, K, Murphy, P, Power, M, Price, C, Rashed, K, Robinson, T, Rudd, A, Sanmuganathan, P, Sharma, J, Shaw, L, Shetty, H, Smithard, D, Tyrrell, P, Vahidassr, M, Venables, G, Watt, M, White, R, Bousser, M, Amarenco, P, Chamorro, A, Fisher, M, Ford, I, Fox, K, Hennerici, M, Mattle, H, Rothwell, P, Ferrarese, C, PERFORM study, I, PERFORM STUDY, Investigator, Tedeschi, Gioacchino, Cras, Patrick, De Deyn, Peter Paul, and et al.

Subjects
perform study, Male, Thromboxane, International Cooperation, Receptors, Thromboxane, antiplatelet therapy, terutroban, Cardiovascular Disease, Receptors, 80 and over, Stroke, Aged, 80 and over, Aspirin, Ischemic Attack, Transient, Ischemic Attack, Transient, Double-Blind Method, Endpoint Determination, Dose-Response Relationship, Drug, Humans, Aged, Propionates, Naphthalenes, Treatment Outcome, Platelet Aggregation Inhibitors, Cardiovascular Diseases, Middle Aged, Female, Propionic Acids, Neurology, Terutroban, Anesthesia, tp receptor antagonist, stroke, secondary prevention, aspirin, Cardiology, Platelet aggregation inhibitor, Settore MED/26 - Neurologia, stroke prevention, Drug, Cardiology and Cardiovascular Medicine, medicine.drug, Human, medicine.medical_specialty, Dose-Response Relationship, Internal medicine, medicine, Dementia, In patient, business.industry, Platelet Aggregation Inhibitor, schemic, medicine.disease, DementiaI, transient ischemic attack, Ischemic stroke, Human medicine, Neurology (clinical), business, Propionic Acid, Naphthalene
Abstract

Background: Ischemic stroke is the leading cause of mortality worldwide and a major contributor to neurological disability and dementia. Terutroban is a specific TP receptor antagonist with antithrombotic, antivasoconstrictive, and antiatherosclerotic properties, which may be of interest for the secondary prevention of ischemic stroke. This article describes the rationale and design of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic Attack (PERFORM) Study, which aims to demonstrate the superiority of the efficacy of terutroban versus aspirin in secondary prevention of cerebrovascular and cardiovascular events. Methods and Results: The PERFORM Study is a multicenter, randomized, double-blind, parallel-group study being carried out in 802 centers in 46 countries. The study population includes patients aged ≥55 years, having suffered an ischemic stroke (≤3 months) or a transient ischemic attack (≤8 days). Participants are randomly allocated to terutroban (30 mg/day) or aspirin (100 mg/day). The primary efficacy endpoint is a composite of ischemic stroke (fatal or nonfatal), myocardial infarction (fatal or nonfatal), or other vascular death (excluding hemorrhagic death of any origin). Safety is being evaluated by assessing hemorrhagic events. Follow-up is expected to last for 2–4 years. Assuming a relative risk reduction of 13%, the expected number of primary events is 2,340. To obtain statistical power of 90%, this requires inclusion of at least 18,000 patients in this event-driven trial. The first patient was randomized in February 2006. Conclusions: The PERFORM Study will explore the benefits and safety of terutroban in secondary cardiovascular prevention after a cerebral ischemic event.

Published
2009

14. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke

Author

Hacke, Werner, Kaste, Markku, Bluhmki, Erich, Brozman, Miroslav, Dávalos, Antoni, Guidetti, Donata, Larrue, Vincent, Lees, Kennedy R., Medeghri, Zakaria, Machnig, Thomas, Schneider, Dietmar, Von Kummer, Rüdiger, Wahlgren, Nils, Toni, Danilo, Hacke, W, Dávalos, A, Kaste, M, von Kummer, R, Larrue, V, Toni, D, Wahlgren, N, Lees, Kr, Heiss, Wd, Lesaffre, E, Orgogozo, Jm, Bastianello, S, Wardlaw, Jm, Peyrieux, Jc, Sauce, C, Medeghri, Z, Mazenc, R, Machnig, T, Bluhmki, E, Aichner, F, Alf, C, Baumhackl, U, Brainin, M, Eggers, C, Gruber, F, Ladurner, G, Niederkorn, K, Noistering, G, Willeit, J, Vanhooren, G, Blecic, S, Bruneel, B, Caekebeke, J, Laloux, P, Simons, Pj, Thijs, V, Bar, M, Dvorakova, H, Vaclavik, D, Boysen, G, Andersen, G, Iversen, Hk, Traberg-Kristensen, B, Marttila, R, Sivenius, J, Trouillas, P, Amarenco, P, Bouillat, J, Ducrocq, X, Giroud, M, Jaillard, A, Larrieu, Jm, Leys, D, Magne, C, Mahagne, Mh, Milhaud, D, Sablot, D, Saudeau, D, Busse, O, Berrouschot, J, Faiss, Jh, Glahn, J, Görtler, M, Grau, A, Grond, M, Haberl, R, Hamann, G, Hennerici, M, Koch, H, Krauseneck, P, Marx, J, Meves, S, Meyding-Lamadé, U, Ringleb, P, Schneider, D, Schwarz, A, Sobesky, J, Urban, P, Karageorgiou, K, Komnos, A, Csányi, A, Csiba, L, Valikovics, A, Agnelli, G, Billo, G, Bovi, P, Comi, G, Gigli, G, Guidetti, D, Inzitari, D, Marcello, N, Marini, C, Orlandi, G, Pratesi, M, Rasura, M, Semplicini, A, Serrati, C, Tassinari, T, Brouwers, Pj, Stam, J, Naess, H, Indredavik, B, Kloster, R, Czlonkowska, A, Kuczyńska-Zardzewialy, A, Nyka, W, Opala, G, Romanowicz, S, Cunha, L, Correia, C, Cruz, V, Pinho e Melo, T, Brozman, M, Dvorak, M, Garay, R, Krastev, G, Kurca, E, Alvarez-Sabin, J, Chamorro, A, del Mar Freijo Guerrero, M, Herrero, Ja, Gil-Peralta, A, Leira, R, Martí-Vilalta, Jl, Masjuan Vallejo, J, Millán, M, Molina, C, Mostacero, E, Segura, T, Serena, J, Vivancos Mora, J, Danielsson, E, Cederin, B, Von, Zweigberg, Wahlgren, Ng, Welin, L, Lyrer, P, Bogousslavsky, J, Hungerbühler, Hj, Weder, B, Ford, Ga, Jenkinson, D, Macleod, Mj, Macwalter, Rs, Markus, Hs, Muir, Kw, Sharma, Ak, Walters, Mr, Warburton, Ea, ACS - Amsterdam Cardiovascular Sciences, ANS - Amsterdam Neuroscience, and Neurology

Subjects
Adult, Male, Time Factors, medicine.medical_treatment, Placebo, Drug Administration Schedule, Brain Ischemia, Brain ischemia, Double-Blind Method, Fibrinolytic Agents, Modified Rankin Scale, medicine, Odds Ratio, Desmoteplase, Humans, Infusions, Intravenous, Stroke, Aged, business.industry, Cerebral infarction, Medicine (all), General Medicine, Thrombolysis, Middle Aged, medicine.disease, Logistic Models, Treatment Outcome, Anesthesia, Tissue Plasminogen Activator, Acute Disease, Female, business, Intracranial Hemorrhages, Fibrinolytic agent
Abstract

Background Intravenous thrombolysis with alteplase is the only approved treatment for acute ischemic stroke, but its efficacy and safety when administered more than 3 hours after the onset of symptoms have not been established. We tested the efficacy and safety of alteplase administered between 3 and 4.5 hours after the onset of a stroke. Methods After exclusion of patients with a brain hemorrhage or major infarction, as detected on a computed tomographic scan, we randomly assigned patients with acute ischemic stroke in a 1:1 double-blind fashion to receive treatment with intravenous alteplase (0.9 mg per kilogram of body weight) or placebo. The primary end point was disability at 90 days, dichotomized as a favorable outcome (a score of 0 or 1 on the modified Rankin scale, which has a range of 0 to 6, with 0 indicating no symptoms at all and 6 indicating death) or an unfavorable outcome (a score of 2 to 6 on the modified Rankin scale). The secondary end point was a global outcome analysis of four neurologic and disability scores combined. Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events. Results We enrolled a total of 821 patients in the study and randomly assigned 418 to the alteplase group and 403 to the placebo group. The median time for the administration of alteplase was 3 hours 59 minutes. More patients had a favorable outcome with alte plase than with placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; P = 0.04). In the global analysis, the outcome was also improved with alteplase as compared with placebo (odds ratio, 1.28; 95% CI, 1.00 to 1.65; P

Published
2008

16. Autologous anti-Aß antibodies in CAA-ri: New biomarker for detection of amyloid-related imaging abnormalities (ARIA) during Aß-disease modifying therapies for AD

Author

Piazza, F., primary, Greenberg, S.M., additional, Savoiardo, M., additional, Gardinetti, M., additional, Nitrini, R., additional, Sakaguchi, H., additional, Raicher, I., additional, Giaccone, G., additional, Chiapparini, L., additional, Brioschi, M., additional, Billo, G., additional, Colombo, A., additional, Lanzani, F., additional, Piscosquito, G., additional, Carriero, M., additional, Tagliavini, F., additional, Ferrarese, C., additional, and DiFrancesco, J.C., additional

Published
2013
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17. Brivaracetam as add-on treatment in patients with post-stroke epilepsy: real-world data from the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST)

Author

Simona Lattanzi, Laura Canafoglia, Maria Paola Canevini, Sara Casciato, Emanuele Cerulli Irelli, Valentina Chiesa, Filippo Dainese, Giovanni De Maria, Giuseppe Didato, Giancarlo Di Gennaro, Giovanni Falcicchio, Martina Fanella, Edoardo Ferlazzo, Massimo Gangitano, Angela La Neve, Oriano Mecarelli, Elisa Montalenti, Alessandra Morano, Federico Piazza, Chiara Pizzanelli, Patrizia Pulitano, Federica Ranzato, Eleonora Rosati, Laura Tassi, Carlo Di Bonaventura, Angela Alicino, Michele Ascoli, Giovanni Assenza, Federica Avorio, Valeria Badioni, Paola Banfi, Emanuele Bartolini, Luca Manfredi Basili, Vincenzo Belcastro, Simone Beretta, Irene Berto, Martina Biggi, Giuseppe Billo, Giovanni Boero, Paolo Bonanni, Jole Bongorno, Francesco Brigo, Emanuele Caggia, Claudia Cagnetti, Carmen Calvello, Edward Cesnik, Gigliola Chianale, Domenico Ciampanelli, Roberta Ciuffini, Dario Cocito, Donato Colella, Margerita Contento, Cinzia Costa, Eduardo Cumbo, Alfredo D'Aniello, Francesco Deleo, Jacopo C DiFrancesco, Roberta Di Giacomo, Alessandra Di Liberto, Elisabetta Domina, Fedele Dono, Vania Durante, Maurizio Elia, Anna Estraneo, Giacomo Evangelista, Maria Teresa Faedda, Ylenia Failli, Elisa Fallica, Jinane Fattouch, Alessandra Ferrari, Florinda Ferreri, Giacomo Fisco, Davide Fonti, Francesco Fortunato, Nicoletta Foschi, Teresa Francavilla, Rosita Galli, Stefano Gazzina, Anna Teresa Giallonardo, Filippo Sean Giorgi, Loretta Giuliano, Francesco Habetswallner, Francesca Izzi, Benedetta Kassabian, Angelo Labate, Concetta Luisi, Matteo Magliani, Giulia Maira, Luisa Mari, Daniela Marino, Addolorata Mascia, Alessandra Mazzeo, Chiara Milano, Stefano Meletti, Annacarmen Nilo, Biagio Orlando, Francesco Paladin, Maria Grazia Pascarella, Chiara Pastori, Giada Pauletto, Alessia Peretti, Gabriella Perri, Marianna Pezzella, Marta Piccioli, Pietro Pignatta, Nicola Pilolli, Francesco Pisani, Laura Rosa Pisani, Fabio Placidi, Patrizia Pollicino, Vittoria Porcella, Silvia Pradella, Monica Puligheddu, Stefano Quadri, Pier Paolo Quarato, Rui Quintas, Rosaria Renna, Giada Ricciardo Rizzo, Adriana Rum, Enrico Michele Salamone, Ersilia Savastano, Maria Sessa, David Stokelj, Elena Tartara, Mario Tombini, Gemma Tumminelli, Anna Elisabetta Vaudano, Maria Ventura, Ilaria Viganò, Emanuela Viglietta, Aglaia Vignoli, Flavio Villani, Elena Zambrelli, Lelia Zummo, Lattanzi S., Canafoglia L., Canevini M.P., Casciato S., Cerulli Irelli E., Chiesa V., Dainese F., De Maria G., Didato G., Di Gennaro G., Falcicchio G., Fanella M., Ferlazzo E., Gangitano M., La Neve A., Mecarelli O., Montalenti E., Morano A., Piazza F., Pizzanelli C., Pulitano P., Ranzato F., Rosati E., Tassi L., Di Bonaventura C., Alicino A., Ascoli M., Assenza G., Avorio F., Badioni V., Banfi P., Bartolini E., Basili L.M., Belcastro V., Beretta S., Berto I., Biggi M., Billo G., Boero G., Bonanni P., Bongiorno J., Brigo F., Caggia E., Cagnetti C., Calvello C., Cesnik E., Chianale G., Ciampanelli D., Ciuffini R., Cocito D., Colella D., Contento M., Costa C., Cumbo E., D'Aniello A., Deleo F., DiFrancesco J.C., Di Giacomo R., Di Liberto A., Domina E., Dono F., Durante V., Elia M., Estraneo A., Evangelista G., Faedda M.T., Failli Y., Fallica E., Fattouch J., Ferrari A., Ferreri F., Fisco G., Fonti D., Fortunato F., Foschi N., Francavilla T., Galli R., Gazzina S., Giallonardo A.T., Giorgi F.S., Giuliano L., Habetswallner F., Izzi F., Kassabian B., Labate A., Luisi C., Magliani M., Maira G., Mari L., Marino D., Mascia A., Mazzeo A., Milano C., Meletti S., Nilo A., Orlando B., Paladin F., Pascarella M.G., Pastori C., Pauletto G., Peretti A., Perri G., Pezzella M., Piccioli M., Pignatta P., Pilolli N., Pisani F., Pisani L.R., Placidi F., Pollicino P., Porcella V., Pradella S., Puligheddu M., Quadri S., Quarato P.P., Quintas R., Renna R., Rizzo G.R., Rum A., Salamone E.M., Savastano E., Sessa M., Stokelj D., Tartara E., Tombini M., Tumminelli G., Vaudano A.E., Ventura M., Vigano I., Viglietta E., Vignoli A., Villani F., Zambrelli E., and Zummo L.

Subjects
Adult, Antiseizure medication, Brivaracetam, Cerebrovascular diseases, Focal seizures, Stroke, Settore MED/26, Antiseizure medication, Brivaracetam, Focal seizures, Stroke, Cerebrovascular diseases, Double-Blind Method, Drug Therapy, Seizures, Humans, Aged, Retrospective Studies, Epilepsy, General Medicine, Middle Aged, Pyrrolidinones, Treatment Outcome, Neurology, Italy, Combination, Anticonvulsants, Drug Therapy, Combination, Neurology (clinical)
Abstract

Objective: Post-stroke epilepsy (PSE) is one of the most common causes of acquired epilepsy and accounts for about 10-15% of all newly diagnosed epilepsy cases. However, evidence about the clinical profile of antiseizure medications in the PSE setting is currently limited. Brivaracetam (BRV) is a rationally developed compound characterized by high-affinity binding to synaptic vesicle protein 2A. The aim of this study was to assess the 12-month effectiveness and tolerability of adjunctive BRV in patients with PSE treated in a real-world setting. Methods: This was a subgroup analysis of patients with PSE included in the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST). The BRIVAFIRST was a 12-month retrospective, multicentre study including adult patients prescribed adjunctive BRV. Effectiveness outcomes included the rates of seizure response (≥50% reduction in baseline seizure frequency), seizure‐freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events (AEs) and the incidence of AEs. Results: Patients with PSE included in the BRIVAFIRST were 75 and had a median age of 57 (interquartile range, 42-66) years. The median daily doses of BRV at 3, 6, and 12 months from starting treatment were 100 (100-150) mg, 125 (100-200) mg and 100 (100-200) mg, respectively. At 12 months, 32 (42.7%) patients had a reduction in their baseline seizure frequency by at least 50%, and the seizure freedom rates was 26/75 (34.7%). During the 1-year study period, 10 (13.3%) patients discontinued BRV. The reasons of treatment withdrawal were insufficient efficacy in 6 (8.0%) patients and poor tolerability in 4 (5.3%) patients. Adverse events were reported by 13 (20.3%) patients and were rated as mild in 84.6% and moderate in 15.4% of cases. Significance: Adjunctive BRV was efficacious and generally well-tolerated when used in patients with PSE in clinical practice. Adjunctive BRV can be a suitable therapeutic option for patients with PSE.

Published
2022

18. Immune-mediated mechanisms in the pathogenesis of cerebral amyloid angiopathy-related inflammation and Alzheimer's disease: Role of anti-A beta auto-antibodies

Author

Piazza, Fabrizio, Greenberg, Steven M., Savoiardo, Mario, Gardinetti, Margherita, Chiapparini, Luisa, Raicher, Irina, Sakaguchi, Hideya, Brioschi, Monica, Billo, Giuseppe, Colombo, Antonio, Lanzani, Francesca, Piscosquito, Giuseppe, Carriero, Maria R., Giaccone, Giorgio, Tagliavini, Fabrizio, Ferrarese, Carlo, Jacopo C. DiFrancesco, 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, and DI FRANCESCO, J

Subjects
Cerebral amyloid angiopathy-related inflammation, Alzheimer's disease, anti-A beta auto-antibodies, BIO/09 - FISIOLOGIA, BIO/14 - FARMACOLOGIA
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

20. A Liquid Chromatography-Mass Spectrometry Assay for Determination of Perampanel and Concomitant Antiepileptic Drugs in the Plasma of Patients With Epilepsy Compared With a Fluorescent HPLC Assay.

Author

de Grazia U, DʼUrso A, Ranzato F, De Riva V, Contarato G, Billo G, Perini F, and Galloni E

Subjects
Adolescent, Adult, Aged, Drug Interactions, Drug Therapy, Combination methods, Epilepsy blood, Female, Humans, Male, Middle Aged, Nitriles, Spectrometry, Fluorescence methods, Young Adult, Anticonvulsants blood, Chromatography, High Pressure Liquid methods, Drug Monitoring methods, Pyridones blood, Tandem Mass Spectrometry methods
Abstract

Background: Perampanel is a novel noncompetitive selective antagonist at the postsynaptic ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) glutamate receptor, which is approved as an adjunctive agent for the treatment of partial-onset seizure with or without secondary generalization and for primary generalized tonic-clonic seizure in patients with epilepsy who are at least 12 years of age. Limited information is available about the clinical utility of therapeutic drug monitoring of perampanel and therapeutic ranges are so far not established. Therefore, perampanel titration should be performed especially in case of insufficient success of the drug., Methods: The authors developed a selective and sensitive LC-MS/MS (liquid chromatography-mass spectrometry) assay to monitor perampanel concentrations in plasma, which was compared to a commercially available high-performance liquid chromatography kit with fluorescent detection. Perampanel and the internal standard were extracted from plasma samples by a simple protein precipitation. The method allows the simultaneous quantification of perampanel and several other antiepileptic drugs (AEDs)., Results: Data were evaluated according to EMA guidelines for bioanalytical method validation. Extraction recovery of perampanel from human plasma was consistently above 98%. No matrix effect was found. Analytical interferences by other AEDs were not observed. The method was linear in the range from 2.5 to 2800 ng/mL. Intra-assay and interassay reproducibility analyses demonstrated accuracy and precision within acceptance criteria. Data collected from 95 patients, given perampanel as their maintenance antiepileptic therapy, showed a very strong correlation between the 2 methods., Conclusions: The assay allows for highly sensitive and selective quantification of perampanel and concomitant AEDs in patient plasma samples and can be easily implemented in clinical settings. Our findings are in agreement with previously published data in patients comedicated with enzyme inducer AEDs, but seem to indicate a possible interaction in patients treated with the enzyme inhibitor drug valproic acid.

Published
2018
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21. Anti-amyloid β autoantibodies in cerebral amyloid angiopathy-related inflammation: implications for amyloid-modifying therapies.

Author

Piazza F, Greenberg SM, Savoiardo M, Gardinetti M, Chiapparini L, Raicher I, Nitrini R, Sakaguchi H, Brioschi M, Billo G, Colombo A, Lanzani F, Piscosquito G, Carriero MR, Giaccone G, Tagliavini F, Ferrarese C, and DiFrancesco JC

Subjects
Adult, Aged, Amyloid beta-Peptides immunology, Apolipoproteins E genetics, Brain pathology, Case-Control Studies, Female, Humans, Male, Middle Aged, Peptide Fragments cerebrospinal fluid, Phosphorylation, Retrospective Studies, Steroids therapeutic use, tau Proteins cerebrospinal fluid, Amyloid beta-Peptides cerebrospinal fluid, Autoantibodies cerebrospinal fluid, Cerebral Amyloid Angiopathy cerebrospinal fluid, Cerebral Amyloid Angiopathy complications, Cerebral Amyloid Angiopathy immunology, Inflammation cerebrospinal fluid, Inflammation etiology, Inflammation immunology
Abstract

Objective: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is characterized by vasogenic edema and multiple cortical/subcortical microbleeds, sharing several aspects with the recently defined amyloid-related imaging abnormalities (ARIA) reported in Alzheimer's disease (AD) passive immunization therapies. Herein, we investigated the role of anti-amyloid β (Aβ) autoantibodies in the acute and remission phases of CAA-ri., Methods: We used a novel ultrasensitive technique on patients from a retrospective multicenter case-control study, and evaluated the anti-Aβ autoantibody concentration in the cerebrospinal fluid (CSF) of 10 CAA-ri, 8 CAA, 14 multiple sclerosis, and 25 control subjects. Levels of soluble Aβ40, Aβ42, tau, P-181 tau, and APOE genotype were also investigated., Results: During the acute phase of CAA-ri, anti-Aβ autoantibodies were specifically increased and directly correlated with Aβ mobilization, together with augmented tau and P-181 tau. Following clinical and radiological remission, autoantibodies progressively returned to control levels, and both soluble Aβ and axonal degeneration markers decreased in parallel., Interpretation: Our data support the hypothesis that the pathogenesis of CAA-ri may be mediated by a selective autoimmune reaction against cerebrovascular Aβ, directly related to autoantibody concentration and soluble Aβ. The CSF dosage of anti-Aβ autoantibodies with the technique here described can thus be proposed as a valid alternative tool for the diagnosis of CAA-ri. Moreover, given the similarities between ARIA developing spontaneously and those observed during immunization trials, anti-Aβ autoantibodies can be considered as novel potential biomarkers in future amyloid-modifying therapies for the treatment of AD and CAA., (Copyright © 2013 American Neurological Association.)

Published
2013
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22. Plasma cytokine levels in migraineurs and controls.

Author

Perini F, D'Andrea G, Galloni E, Pignatelli F, Billo G, Alba S, Bussone G, and Toso V

Subjects
Adult, Female, Humans, Male, Middle Aged, Interleukins blood, Migraine Disorders blood, Tumor Necrosis Factor-alpha analysis
Abstract

Background: The vasoactive peptide, calcitonin gene-related peptide (CGRP), is released from primary afferent neurons in the trigemino-vascular circulation during migraine headache. CGRP at physiological concentrations and possibly via stimulation of its selective receptors on T-cells, triggers the secretion of cytokines. Cytokines play an important role in several physiological and pathological settings such as immunology, inflammation, and pain., Objective: To investigate plasma levels of pro- and anti-inflammatory cytokines in migraineurs and healthy controls., Methods: We studied 25 migraine patients, during and outside attacks, and 18 healthy control subjects measuring plasma levels of IL-6, IL-10, tumor necrosis factor alpha (TNFalpha), IL-4, IL-1 beta, and IL-2 using ELISA., Results: Circulating levels of IL-10, TNFalpha, and IL-1 beta during attacks were significantly higher in comparison to their levels outside attacks (P=.0003, P=.03, and P=.05, respectively). IL-10 and TNF serum levels were higher in patients studied soon after headache onset and lower over time (P=.004 and P=.05)., Conclusion: Our results suggest that TNFalpha, IL-1 beta, and IL-10 may be involved in the pathogenesis of migraine attacks.

Published
2005
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