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3. Comparing Long-Acting Antipsychotic Discontinuation Rates Under Ordinary Clinical Circumstances: A Survival Analysis from an Observational, Pragmatic Study

Author

Bertolini, F, Ostuzzi, G, Pievani, M, Aguglia, A, Bartoli, F, Bortolaso, P, Callegari, C, Caroleo, M, Carra, G, Corbo, M, D'Agostino, A, De Fazio, P, Magliocco, F, Martinotti, G, Ostinelli, E, Piccinelli, M, Tedeschi, F, Barbui, C, Boschello, F, Gastaldon, C, Mazzi, M, Nose, M, Papola, D, Perini, G, Piccoli, A, Purgato, M, Ruggeri, M, Terlizzi, S, Turrini, G, Raffaele, G, Cavallotti, S, Chirico, M, Ferrato, F, Limosani, I, Mastromo, D, Monzani, E, Porcellana, M, Restaino, F, Annese, P, Bolognesi, S, Cerretini, M, De Capua, A, Debolini, S, Del Zanna, M, Fargnoli, F, Giannini, A, Luccarelli, L, Lucii, C, Pierantozzi, E, Tozzi, F, Bardicchia, F, Cardamone, G, Facchi, E, Magnani, N, Soscia, F, Biancosino, B, Zotos, S, Giacomin, M, Pompei, F, Spano, M, Zonta, F, Buzzi, A, Calzolari, R, Caselli, I, Diurni, M, Giana, E, Ielmini, M, Milano, A, Poloni, N, Sani, E, Zizolfi, D, Alberini, G, Cazzamalli, S, Costantini, C, Di Caro, A, Paronelli, C, Piantanida, S, Alessandro, P, Barbanti, S, D'Ippolito, C, Gozzi, M, Moretti, V, Campese, O, Di Capro, L, di Giannantonio, M, Fiori, F, Lorusso, M, Mancini, V, Viceconte, D, Calandra, C, Luca, M, Signorelli, M, Suraniti, F, Balzarro, B, Boncompagni, G, Caretto, V, Emiliani, R, Lupoli, P, Menchetti, M, Rossi, E, Storbini, V, Tarricone, I, Terzi, L, Boso, M, Catania, C, De Paoli, G, Risaro, P, Aspesi, F, Bava, M, Bono, A, Brambilla, G, Castagna, G, Lucchi, S, Nava, R, Provenzi, M, Tabacchi, T, Tremolada, M, Verrengia, E, Barchiesi, M, Oriani, M, Pacetti, M, Ferro, M, Ghio, L, Beneduce, R, Laffranchini, L, Magni, L, Rossi, G, Tura, G, Addeo, L, Balletta, G, De Vivo, E, Di Benedetto, R, Parise, V, Carpiniello, B, Pinna, F, Pecile, D, Mattei, C, Bonavigo, T, Fabrici, E, Panarello, S, Peresson, G, Vitucci, C, Gardellin, F, Strizzolo, S, Cossetta, E, Fizzotti, C, Moretti, D, Di Gregorio, L, Sozzi, F, Colli, G, La Barbera, D, Laurenzi, S, Bertolini F., Ostuzzi G., Pievani M., Aguglia A., Bartoli F., Bortolaso P., Callegari C., Caroleo M., Carra G., Corbo M., D'Agostino A., De Fazio P., Magliocco F., Martinotti G., Ostinelli E. G., Piccinelli M. P., Tedeschi F., Barbui C., Boschello F., Gastaldon C., Mazzi M. A., Nose M., Papola D., Perini G., Piccoli A., Purgato M., Ruggeri M., Terlizzi S., Turrini G., Raffaele G., Cavallotti S., Chirico M., Ferrato F., Limosani I., Mastromo D., Monzani E., Porcellana M., Restaino F., Annese P. M., Bolognesi S., Cerretini M., De Capua A., Debolini S., Del Zanna M., Fargnoli F., Giannini A., Luccarelli L., Lucii C., Pierantozzi E., Tozzi F., Bardicchia F., Cardamone G., Facchi E., Magnani N., Soscia F., Biancosino B., Zotos S., Giacomin M., Pompei F., Spano M., Zonta F., Buzzi A., Calzolari R., Caselli I., Diurni M., Giana E., Ielmini M., Milano A., Poloni N., Sani E., Zizolfi D., Alberini G., Cazzamalli S., Costantini C., Di Caro A., Paronelli C., Piantanida S., Piccinelli M., Alessandro P., Barbanti S. V., D'Ippolito C., Gozzi M., Moretti V., Campese O., Di Capro L., di Giannantonio M., Fiori F., Lorusso M., Mancini V., Viceconte D., Calandra C., Luca M., Signorelli M. S., Suraniti F., Balzarro B., Boncompagni G., Caretto V., Emiliani R., Lupoli P., Menchetti M., Rossi E., Storbini V., Tarricone I., Terzi L., Boso M., Catania C., De Paoli G., Risaro P., Aspesi F., Bava M., Bono A., Brambilla G., Castagna G., Lucchi S., Nava R., Provenzi M., Tabacchi T., Tremolada M., Verrengia E., Barchiesi M., Oriani M. G., Pacetti M., Ferro M., Ghio L., Beneduce R., Laffranchini L., Magni L. R., Rossi G., Tura G. B., Addeo L., Balletta G., De Vivo E., Di Benedetto R., Parise V. F., Carpiniello B., Pinna F., Pecile D., Mattei C., Bonavigo T., Fabrici E. P., Panarello S., Peresson G., Vitucci C., Gardellin F., Strizzolo S., Cossetta E., Fizzotti C., Moretti D., Di Gregorio L., Sozzi F., Colli G., La Barbera D., Laurenzi S., Bertolini, F, Ostuzzi, G, Pievani, M, Aguglia, A, Bartoli, F, Bortolaso, P, Callegari, C, Caroleo, M, Carra, G, Corbo, M, D'Agostino, A, De Fazio, P, Magliocco, F, Martinotti, G, Ostinelli, E, Piccinelli, M, Tedeschi, F, Barbui, C, Boschello, F, Gastaldon, C, Mazzi, M, Nose, M, Papola, D, Perini, G, Piccoli, A, Purgato, M, Ruggeri, M, Terlizzi, S, Turrini, G, Raffaele, G, Cavallotti, S, Chirico, M, Ferrato, F, Limosani, I, Mastromo, D, Monzani, E, Porcellana, M, Restaino, F, Annese, P, Bolognesi, S, Cerretini, M, De Capua, A, Debolini, S, Del Zanna, M, Fargnoli, F, Giannini, A, Luccarelli, L, Lucii, C, Pierantozzi, E, Tozzi, F, Bardicchia, F, Cardamone, G, Facchi, E, Magnani, N, Soscia, F, Biancosino, B, Zotos, S, Giacomin, M, Pompei, F, Spano, M, Zonta, F, Buzzi, A, Calzolari, R, Caselli, I, Diurni, M, Giana, E, Ielmini, M, Milano, A, Poloni, N, Sani, E, Zizolfi, D, Alberini, G, Cazzamalli, S, Costantini, C, Di Caro, A, Paronelli, C, Piantanida, S, Alessandro, P, Barbanti, S, D'Ippolito, C, Gozzi, M, Moretti, V, Campese, O, Di Capro, L, di Giannantonio, M, Fiori, F, Lorusso, M, Mancini, V, Viceconte, D, Calandra, C, Luca, M, Signorelli, M, Suraniti, F, Balzarro, B, Boncompagni, G, Caretto, V, Emiliani, R, Lupoli, P, Menchetti, M, Rossi, E, Storbini, V, Tarricone, I, Terzi, L, Boso, M, Catania, C, De Paoli, G, Risaro, P, Aspesi, F, Bava, M, Bono, A, Brambilla, G, Castagna, G, Lucchi, S, Nava, R, Provenzi, M, Tabacchi, T, Tremolada, M, Verrengia, E, Barchiesi, M, Oriani, M, Pacetti, M, Ferro, M, Ghio, L, Beneduce, R, Laffranchini, L, Magni, L, Rossi, G, Tura, G, Addeo, L, Balletta, G, De Vivo, E, Di Benedetto, R, Parise, V, Carpiniello, B, Pinna, F, Pecile, D, Mattei, C, Bonavigo, T, Fabrici, E, Panarello, S, Peresson, G, Vitucci, C, Gardellin, F, Strizzolo, S, Cossetta, E, Fizzotti, C, Moretti, D, Di Gregorio, L, Sozzi, F, Colli, G, La Barbera, D, Laurenzi, S, Bertolini F., Ostuzzi G., Pievani M., Aguglia A., Bartoli F., Bortolaso P., Callegari C., Caroleo M., Carra G., Corbo M., D'Agostino A., De Fazio P., Magliocco F., Martinotti G., Ostinelli E. G., Piccinelli M. P., Tedeschi F., Barbui C., Boschello F., Gastaldon C., Mazzi M. A., Nose M., Papola D., Perini G., Piccoli A., Purgato M., Ruggeri M., Terlizzi S., Turrini G., Raffaele G., Cavallotti S., Chirico M., Ferrato F., Limosani I., Mastromo D., Monzani E., Porcellana M., Restaino F., Annese P. M., Bolognesi S., Cerretini M., De Capua A., Debolini S., Del Zanna M., Fargnoli F., Giannini A., Luccarelli L., Lucii C., Pierantozzi E., Tozzi F., Bardicchia F., Cardamone G., Facchi E., Magnani N., Soscia F., Biancosino B., Zotos S., Giacomin M., Pompei F., Spano M., Zonta F., Buzzi A., Calzolari R., Caselli I., Diurni M., Giana E., Ielmini M., Milano A., Poloni N., Sani E., Zizolfi D., Alberini G., Cazzamalli S., Costantini C., Di Caro A., Paronelli C., Piantanida S., Piccinelli M., Alessandro P., Barbanti S. V., D'Ippolito C., Gozzi M., Moretti V., Campese O., Di Capro L., di Giannantonio M., Fiori F., Lorusso M., Mancini V., Viceconte D., Calandra C., Luca M., Signorelli M. S., Suraniti F., Balzarro B., Boncompagni G., Caretto V., Emiliani R., Lupoli P., Menchetti M., Rossi E., Storbini V., Tarricone I., Terzi L., Boso M., Catania C., De Paoli G., Risaro P., Aspesi F., Bava M., Bono A., Brambilla G., Castagna G., Lucchi S., Nava R., Provenzi M., Tabacchi T., Tremolada M., Verrengia E., Barchiesi M., Oriani M. G., Pacetti M., Ferro M., Ghio L., Beneduce R., Laffranchini L., Magni L. R., Rossi G., Tura G. B., Addeo L., Balletta G., De Vivo E., Di Benedetto R., Parise V. F., Carpiniello B., Pinna F., Pecile D., Mattei C., Bonavigo T., Fabrici E. P., Panarello S., Peresson G., Vitucci C., Gardellin F., Strizzolo S., Cossetta E., Fizzotti C., Moretti D., Di Gregorio L., Sozzi F., Colli G., La Barbera D., and Laurenzi S.

Abstract

Background: Recent guidelines suggested a wider use of long-acting injectable antipsychotics (LAI) than previously, but naturalistic data on the consequences of LAI use in terms of discontinuation rates and associated factors are still sparse, making it hard for clinicians to be informed on plausible treatment courses. Objective: Our objective was to assess, under real-world clinical circumstances, LAI discontinuation rates over a period of 12 months after a first prescription, reasons for discontinuation, and associated factors. Methods: The STAR Network ‘Depot Study’ was a naturalistic, multicentre, observational prospective study that enrolled subjects initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centres were assessed at baseline and at 6 and 12 months of follow-up. Psychopathology, drug attitude and treatment adherence were measured using the Brief Psychiatric Rating Scale, the Drug Attitude Inventory and the Kemp scale, respectively. Results: The study followed 394 participants for 12 months. The overall discontinuation rate at 12 months was 39.3% (95% confidence interval [CI] 34.4–44.3), with paliperidone LAI being the least discontinued LAI (33.9%; 95% CI 25.3–43.5) and olanzapine LAI the most discontinued (62.5%; 95% CI 35.4–84.8). The most frequent reason for discontinuation was onset of adverse events (32.9%; 95% CI 25.6–40.9) followed by participant refusal of the medication (20.6%; 95% CI 14.6–27.9). Medication adherence at baseline was negatively associated with discontinuation risk (hazard ratio [HR] 0.853; 95% CI 0.742–0.981; p = 0.026), whereas being prescribed olanzapine LAI was associated with increased discontinuation risk compared with being prescribed paliperidone LAI (HR 2.156; 95% CI 1.003–4.634; p = 0.049). Conclusions: Clinicians should be aware that LAI discontinuation is a frequent occurrence. LAI choice should be carefully discussed with the patient, tak

Published
2021

4. Comparing Long-Acting Antipsychotic Discontinuation Rates Under Ordinary Clinical Circumstances: A Survival Analysis from an Observational, Pragmatic Study

Author

Bertolini, F., Ostuzzi, G., Pievani, M., Aguglia, A., Bartoli, F., Bortolaso, P., Callegari, C., Caroleo, M., Carra, G., Corbo, M., D'Agostino, A., De Fazio, P., Magliocco, F., Martinotti, G., Ostinelli, E. G., Piccinelli, M. P., Tedeschi, F., Barbui, C., Boschello, F., Gastaldon, C., Mazzi, M. A., Nose, M., Papola, D., Perini, G., Piccoli, A., Purgato, M., Ruggeri, M., Terlizzi, S., Turrini, G., Raffaele, G., Cavallotti, S., Chirico, M., Ferrato, F., Limosani, I., Mastromo, D., Monzani, E., Porcellana, M., Restaino, F., Annese, P. M., Bolognesi, S., Cerretini, M., De Capua, A., Debolini, S., Del Zanna, M., Fargnoli, F., Giannini, A., Luccarelli, L., Lucii, C., Pierantozzi, E., Tozzi, F., Bardicchia, F., Cardamone, G., Facchi, E., Magnani, N., Soscia, F., Biancosino, B., Zotos, S., Giacomin, M., Pompei, F., Spano, M., Zonta, F., Buzzi, A., Callegred, C., Calzolari, R., Caselli, I., Diurni, M., Giana, E., Ielmini, M., Milano, A., Poloni, N., Sani, E., Zizolfi, D., Alberini, G., Cazzamalli, S., Costantini, C., Di Caro, A., Paronelli, C., Piantanida, S., Piccinelli, M., Alessandro, P., Barbanti, S. V., D'Ippolito, C., Gozzi, M., Moretti, V., Campese, O., Di Capro, L., di Giannantonio, M., Fiori, F., Lorusso, M., Mancini, V., Viceconte, D., Calandra, C., Luca, M., Signorelli, M. S., Suraniti, F., Balzarro, B., Boncompagni, G., Caretto, V., Emiliani, R., Lupoli, P., Menchetti, M., Rossi, E., Storbini, V., Tarricone, I., Terzi, L., Boso, M., Catania, C., De Paoli, G., Risaro, P., Aspesi, F., Bava, M., Bono, A., Brambilla, G., Castagna, G., Lucchi, S., Nava, R., Provenzi, M., Tabacchi, T., Tremolada, M., Verrengia, E., Barchiesi, M., Oriani, M. G., Pacetti, M., Ferro, M., Ghio, L., Beneduce, R., Laffranchini, L., Magni, L. R., Rossi, G., Tura, G. B., Addeo, L., Balletta, G., De Vivo, E., Di Benedetto, R., Parise, V. F., Carpiniello, B., Pinna, F., Pecile, D., Mattei, C., Bonavigo, T., Fabrici, E. P., Panarello, S., Peresson, G., Vitucci, C., Gardellin, F., Strizzolo, S., Cossetta, E., Fizzotti, C., Moretti, D., Di Gregorio, L., Sozzi, F., Colli, G., La Barbera, D., Laurenzi, S., Bertolini, F, Ostuzzi, G, Pievani, M, Aguglia, A, Bartoli, F, Bortolaso, P, Callegari, C, Caroleo, M, Carra, G, Corbo, M, D'Agostino, A, De Fazio, P, Magliocco, F, Martinotti, G, Ostinelli, E, Piccinelli, M, Tedeschi, F, Barbui, C, Boschello, F, Gastaldon, C, Mazzi, M, Nose, M, Papola, D, Perini, G, Piccoli, A, Purgato, M, Ruggeri, M, Terlizzi, S, Turrini, G, Raffaele, G, Cavallotti, S, Chirico, M, Ferrato, F, Limosani, I, Mastromo, D, Monzani, E, Porcellana, M, Restaino, F, Annese, P, Bolognesi, S, Cerretini, M, De Capua, A, Debolini, S, Del Zanna, M, Fargnoli, F, Giannini, A, Luccarelli, L, Lucii, C, Pierantozzi, E, Tozzi, F, Bardicchia, F, Cardamone, G, Facchi, E, Magnani, N, Soscia, F, Biancosino, B, Zotos, S, Giacomin, M, Pompei, F, Spano, M, Zonta, F, Buzzi, A, Calzolari, R, Caselli, I, Diurni, M, Giana, E, Ielmini, M, Milano, A, Poloni, N, Sani, E, Zizolfi, D, Alberini, G, Cazzamalli, S, Costantini, C, Di Caro, A, Paronelli, C, Piantanida, S, Alessandro, P, Barbanti, S, D'Ippolito, C, Gozzi, M, Moretti, V, Campese, O, Di Capro, L, di Giannantonio, M, Fiori, F, Lorusso, M, Mancini, V, Viceconte, D, Calandra, C, Luca, M, Signorelli, M, Suraniti, F, Balzarro, B, Boncompagni, G, Caretto, V, Emiliani, R, Lupoli, P, Menchetti, M, Rossi, E, Storbini, V, Tarricone, I, Terzi, L, Boso, M, Catania, C, De Paoli, G, Risaro, P, Aspesi, F, Bava, M, Bono, A, Brambilla, G, Castagna, G, Lucchi, S, Nava, R, Provenzi, M, Tabacchi, T, Tremolada, M, Verrengia, E, Barchiesi, M, Oriani, M, Pacetti, M, Ferro, M, Ghio, L, Beneduce, R, Laffranchini, L, Magni, L, Rossi, G, Tura, G, Addeo, L, Balletta, G, De Vivo, E, Di Benedetto, R, Parise, V, Carpiniello, B, Pinna, F, Pecile, D, Mattei, C, Bonavigo, T, Fabrici, E, Panarello, S, Peresson, G, Vitucci, C, Gardellin, F, Strizzolo, S, Cossetta, E, Fizzotti, C, Moretti, D, Di Gregorio, L, Sozzi, F, Colli, G, La Barbera, D, Laurenzi, S, Bertolini F., Ostuzzi G., Pievani M., Aguglia A., Bartoli F., Bortolaso P., Callegari C., Caroleo M., Carra G., Corbo M., D'Agostino A., De Fazio P., Magliocco F., Martinotti G., Ostinelli E.G., Piccinelli M.P., Tedeschi F., Barbui C., Boschello F., Gastaldon C., Mazzi M.A., Nose M., Papola D., Perini G., Piccoli A., Purgato M., Ruggeri M., Terlizzi S., Turrini G., Raffaele G., Cavallotti S., Chirico M., Ferrato F., Limosani I., Mastromo D., Monzani E., Porcellana M., Restaino F., Annese P.M., Bolognesi S., Cerretini M., De Capua A., Debolini S., Del Zanna M., Fargnoli F., Giannini A., Luccarelli L., Lucii C., Pierantozzi E., Tozzi F., Bardicchia F., Cardamone G., Facchi E., Magnani N., Soscia F., Biancosino B., Zotos S., Giacomin M., Pompei F., Spano M., Zonta F., Buzzi A., Callegred C., Calzolari R., Caselli I., Diurni M., Giana E., Ielmini M., Milano A., Poloni N., Sani E., Zizolfi D., Alberini G., Cazzamalli S., Costantini C., Di Caro A., Paronelli C., Piantanida S., Piccinelli M., Alessandro P., Barbanti S.V., D'Ippolito C., Gozzi M., Moretti V., Campese O., Di Capro L., di Giannantonio M., Fiori F., Lorusso M., Mancini V., Viceconte D., Calandra C., Luca M., Signorelli M.S., Suraniti F., Balzarro B., Boncompagni G., Caretto V., Emiliani R., Lupoli P., Menchetti M., Rossi E., Storbini V., Tarricone I., Terzi L., Boso M., Catania C., De Paoli G., Risaro P., Aspesi F., Bava M., Bono A., Brambilla G., Castagna G., Lucchi S., Nava R., Provenzi M., Tabacchi T., Tremolada M., Verrengia E., Barchiesi M., Oriani M.G., Pacetti M., Ferro M., Ghio L., Beneduce R., Laffranchini L., Magni L.R., Rossi G., Tura G.B., Addeo L., Balletta G., De Vivo E., Di Benedetto R., Parise V.F., Carpiniello B., Pinna F., Pecile D., Mattei C., Bonavigo T., Fabrici E.P., Panarello S., Peresson G., Vitucci C., Gardellin F., Strizzolo S., Cossetta E., Fizzotti C., Moretti D., Di Gregorio L., Sozzi F., Colli G., La Barbera D., and Laurenzi S.

Subjects
Male, Pediatrics, respectively), 0302 clinical medicine, Delayed-Action Preparation, Brief Psychiatric Rating Scale, Pharmacology (medical), he STAR Network ‘Depot Study’ prospectively followed 394 subjects initiating treatment with long-acting injections (LAIs) of antipsychotics under naturalistic conditions for 12 months. LAI discontinuation was frequent in everyday clinical practice in Italy, Original Research Article, Prospective Studies, Prospective cohort study, treatment, Mental Disorders, Hazard ratio, whereas more than half of participants initiating risperidone LAI and olanzapine LAI discontinued during the 12 months of follow-up (51.4 and 62.5%, Psychiatric Status Rating Scale, Middle Aged, side efects, Psychiatry and Mental health, Italy, Mental Disorder, Female, he STAR Network ‘Depot Study’ prospectively followed 394 subjects initiating treatment with long-acting injections (LAIs) of antipsychotics under naturalistic conditions for 12 months. LAI discontinuation was frequent in everyday clinical practice in Italy, occurring in almost 40% of the entire sample, side efects, participant refusal to continue LAIs and LAIs no longer being required were the most frequently reported reasons for discontinuation. Paliperidone LAI and aripiprazole LAI were the least discontinued medications (33.9 and 35.4%, respectively), whereas more than half of participants initiating risperidone LAI and olanzapine LAI discontinued during the 12 months of follow-up (51.4 and 62.5%, respectively). In multivariate analysis, being prescribed olanzapine LAI and poor medication adherence at baseline were signifcantly associated with higher discontinuation risk, Human, Antipsychotic Agents, medicine.drug, Psychopathology, Adult, medicine.medical_specialty, Discontinuation, Follow-Up Studie, Medication Adherence, 03 medical and health sciences, medicine, Humans, Paliperidone, Adverse effect, Settore MED/25 - Psichiatria, discontinuation rates, Psychiatric Status Rating Scales, respectively). In multivariate analysis, business.industry, Long-Acting Antipsychotic, long-acting injectable antipsychotics, Survival Analysis, Confidence interval, participant refusal to continue LAIs and LAIs no longer being required were the most frequently reported reasons for discontinuation. Paliperidone LAI and aripiprazole LAI were the least discontinued medications (33.9 and 35.4%, 030227 psychiatry, Prospective Studie, Antipsychotic Agent, occurring in almost 40% of the entire sample, Delayed-Action Preparations, Neurology (clinical), business, 030217 neurology & neurosurgery, being prescribed olanzapine LAI and poor medication adherence at baseline were signifcantly associated with higher discontinuation risk, Follow-Up Studies
Abstract

Background Recent guidelines suggested a wider use of long-acting injectable antipsychotics (LAI) than previously, but naturalistic data on the consequences of LAI use in terms of discontinuation rates and associated factors are still sparse, making it hard for clinicians to be informed on plausible treatment courses. Objective Our objective was to assess, under real-world clinical circumstances, LAI discontinuation rates over a period of 12 months after a first prescription, reasons for discontinuation, and associated factors. Methods The STAR Network ‘Depot Study’ was a naturalistic, multicentre, observational prospective study that enrolled subjects initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centres were assessed at baseline and at 6 and 12 months of follow-up. Psychopathology, drug attitude and treatment adherence were measured using the Brief Psychiatric Rating Scale, the Drug Attitude Inventory and the Kemp scale, respectively. Results The study followed 394 participants for 12 months. The overall discontinuation rate at 12 months was 39.3% (95% confidence interval [CI] 34.4–44.3), with paliperidone LAI being the least discontinued LAI (33.9%; 95% CI 25.3–43.5) and olanzapine LAI the most discontinued (62.5%; 95% CI 35.4–84.8). The most frequent reason for discontinuation was onset of adverse events (32.9%; 95% CI 25.6–40.9) followed by participant refusal of the medication (20.6%; 95% CI 14.6–27.9). Medication adherence at baseline was negatively associated with discontinuation risk (hazard ratio [HR] 0.853; 95% CI 0.742–0.981; p = 0.026), whereas being prescribed olanzapine LAI was associated with increased discontinuation risk compared with being prescribed paliperidone LAI (HR 2.156; 95% CI 1.003–4.634; p = 0.049). Conclusions Clinicians should be aware that LAI discontinuation is a frequent occurrence. LAI choice should be carefully discussed with the patient, taking into account individual characteristics and possible obstacles related to the practicalities of each formulation. Supplementary Information The online version contains supplementary material available at 10.1007/s40263-021-00809-w.

Published
2021

5. A low-dimensional cognitive-network space in Alzheimer’s disease and frontotemporal dementia

Author

Pini, L., de Lange, S. C., Pizzini, F. B., Boscolo Galazzo, I., Manenti, R., Cotelli, Maria, Galluzzi, S., Cotelli, M. S., Corbetta, M., van den Heuvel, M. P., Pievani, M., Cotelli M., Pini, L., de Lange, S. C., Pizzini, F. B., Boscolo Galazzo, I., Manenti, R., Cotelli, Maria, Galluzzi, S., Cotelli, M. S., Corbetta, M., van den Heuvel, M. P., Pievani, M., and Cotelli M.

Abstract

Background: Alzheimer’s disease (AD) and frontotemporal dementia (FTD) show network dysfunctions linked with cognitive deficits. Within this framework, network abnormalities between AD and FTD show both convergent and divergent patterns. However, these functional patterns are far from being established and their relevance to cognitive processes remains to be elucidated. Methods: We investigated the relationship between cognition and functional connectivity of major cognitive networks in these diseases. Twenty-three bvFTD (age: 71±10), 22 AD (age: 72±6), and 20 controls (age: 72±6) underwent cognitive evaluation and resting-state functional MRI. Principal component analysis was used to describe cognitive variance across participants. Brain network connectivity was estimated with connectome analysis. Connectivity matrices were created assessing correlations between parcels within each functional network. The following cognitive networks were considered: default mode (DMN), dorsal attention (DAN), ventral attention (VAN), and frontoparietal (FPN) networks. The relationship between cognition and connectivity was assessed using a bootstrapping correlation and interaction analyses. Results: Three principal cognitive components explained more than 80% of the cognitive variance: the first component (cogPC1) loaded on memory, the second component (cogPC2) loaded on emotion and language, and the third component (cogPC3) loaded on the visuo-spatial and attentional domains. Compared to HC, AD and bvFTD showed impairment in all cogPCs (p<0.002), and bvFTD scored worse than AD in cogPC2 (p=0.031). At the network level, the DMN showed a significant association in the whole group with cogPC1 and cogPC2 and the VAN with cogPC2. By contrast, DAN and FPN showed a divergent pattern between diagnosis and connectivity for cogPC2. We confirmed these results by means of a multivariate analysis (canonical correlation). Conclusions: A low-dimensional representation can account for a large

Published
2022

6. Brain network modulation in Alzheimer's and frontotemporal dementia with transcranial electrical stimulation

Author

Pini, L., Pizzini, F. B., Boscolo-Galazzo, I., Ferrari, C., Galluzzi, S., Cotelli, Maria, Gobbi, E., Cattaneo, A., Cotelli, M. S., Geroldi, C., Zanetti, O., Corbetta, M., van den Heuvel, M., Frisoni, G. B., Manenti, Rosa, Pievani, M., Cotelli M., Manenti R., Pini, L., Pizzini, F. B., Boscolo-Galazzo, I., Ferrari, C., Galluzzi, S., Cotelli, Maria, Gobbi, E., Cattaneo, A., Cotelli, M. S., Geroldi, C., Zanetti, O., Corbetta, M., van den Heuvel, M., Frisoni, G. B., Manenti, Rosa, Pievani, M., Cotelli M., and Manenti R.

Abstract

The default mode (DMN) and the salience (SN) networks show functional hypo-connectivity in Alzheimer's disease (AD) and the behavioral variant of frontotemporal dementia (bvFTD), respectively, along with patterns of hyper-connectivity. We tested the clinical and neurobiological effects of noninvasive stimulation over these networks in 45 patients (AD and bvFTD) who received either anodal (target network: DMN in AD, SN in bvFTD) or cathodal stimulation (target network: SN in AD, DMN in bvFTD). We evaluated changes in clinical, cognitive, functional and structural connectivity, and perfusion measures. In both patient groups, cathodal stimulation was followed by behavioral improvement, whereas anodal stimulation led to cognitive improvement. Neither functional connectivity nor perfusion showed significant effects. A significant interaction between DMN and SN functional connectivity changes and stimulation protocol was reported in AD. These results suggest a protocol-dependent response, whereby the protocols studied show divergent effects on cognitive and clinical measures, along with a divergent modulatory pattern of connectivity in AD.

Published
2022

15. Cognitive reserve and TMEM106B genotype modulate brain damage in presymptomatic frontotemporal dementia: a GENFI study

Author

Premi, Enrico, Grassi, Mario, van Swieten John, Galimberti, Daniela, Graff, Caroline, Masellis, Mario, Tartaglia, Carmela, Tagliavini, Fabrizio, Rowe James, B, Laforce, Robert, Finger, Elizabeth, Frisoni Giovanni, B, de Mendonça Alexandre, Sorbi, Sandro, Gazzina, Stefano, Cosseddu, Maura, Archetti, Silvana, Gasparotti, Roberto, Manes, Marta, Alberici, Antonella, Cardoso Manuel, J, Bocchetta, Martina, Cash David, M, Ourselin, Sebastian, Padovani, Alessandro, Rohrer Jonathan, D, Andersson, C, Arighi, A, Benussi, L, Binetti, G, Black, S, Dick, K, Fallström, M, Ferreira, C, Fenoglio, C, Fox, N, Freedman, M, Fumagalli, G, Ghidoni, R, Grisoli, M, Jelic, V, Jiskoot, L, Keren, R, Lombardi, G, Maruta, C, Meeter, L, Miltenberger-Miltényi, G, Nacmias, B, Öijerstedt, L, Panman, J, Pievani, M, Polito, C, Prioni, S, Rademakers, R, Redaelli, V, Rogaeva, E, Rossi, G, Rossor, M, Scarpini, E, Tang-Wai, D, Thomas, D, Thonberg, H, Tiraboschi, P, van Minkelen, R, Verdelho, A, Warren, J, Borroni, Barbara, Rowe, James [0000-0001-7216-8679], Apollo - University of Cambridge Repository, and Neurology

Subjects
Male, 0301 basic medicine, Oncology, frontotemporal dementia, Cognitive reserve, Frontotemporal dementia, Genetics, Structural MRI, TMEM106b, Cohort Studies, ddc:616.89, 0302 clinical medicine, C9orf72, genetics, Gray Matter, 10. No inequality, medicine.diagnostic_test, Middle Aged, cognitive reserve, Magnetic Resonance Imaging, medicine.anatomical_structure, structural MRI, Brain size, Educational Status, Female, Psychology, Adult, medicine.medical_specialty, Genotype, Prodromal Symptoms, Nerve Tissue Proteins, Grey matter, 03 medical and health sciences, Internal medicine, mental disorders, medicine, Humans, Dementia, Cerebral atrophy, Polymorphism, Genetic, Mini–Mental State Examination, Membrane Proteins, Original Articles, medicine.disease, Editor's Choice, 030104 developmental biology, Neurology (clinical), Atrophy, Neuroscience, 030217 neurology & neurosurgery
Abstract

Frontotemporal dementia (FTD) shows substantial phenotypic variability. In a multicentre study, Premi et al. explore the effect of cognitive reserve and TMEM106B genotype in modulating grey matter volume in presymptomatic FTD. Environmental as well as genetic factors affect rates of brain atrophy, suggesting a possible strategy for delaying disease onset., Frontotemporal dementia is a heterogeneous neurodegenerative disorder with around a third of cases having autosomal dominant inheritance. There is wide variability in phenotype even within affected families, raising questions about the determinants of the progression of disease and age at onset. It has been recently demonstrated that cognitive reserve, as measured by years of formal schooling, can counteract the ongoing pathological process. The TMEM106B genotype has also been found to be a modifier of the age at disease onset in frontotemporal dementia patients with TDP-43 pathology. This study therefore aimed to elucidate the modulating effect of environment (i.e. cognitive reserve as measured by educational attainment) and genetic background (i.e. TMEM106B polymorphism, rs1990622 T/C) on grey matter volume in a large cohort of presymptomatic subjects bearing frontotemporal dementia-related pathogenic mutations. Two hundred and thirty-one participants from the GENFI study were included: 108 presymptomatic MAPT, GRN, and C9orf72 mutation carriers and 123 non-carriers. For each subject, cortical and subcortical grey matter volumes were generated using a parcellation of the volumetric T1-weighted magnetic resonance imaging brain scan. TMEM106B genotyping was carried out, and years of education recorded. First, we obtained a composite measure of grey matter volume by graph-Laplacian principal component analysis, and then fitted a linear mixed-effect interaction model, considering the role of (i) genetic status; (ii) educational attainment; and (iii) TMEM106B genotype on grey matter volume. The presence of a mutation was associated with a lower grey matter volume (P = 0.002), even in presymptomatic subjects. Education directly affected grey matter volume in all the samples (P = 0.02) with lower education attainment being associated with lower volumes. TMEM106B genotype did not influence grey matter volume directly on its own but in mutation carriers it modulated the slope of the correlation between education and grey matter volume (P = 0.007). Together, these results indicate that brain atrophy in presymptomatic carriers of common frontotemporal dementia mutations is affected by both genetic and environmental factors such that TMEM106B enhances the benefit of cognitive reserve on brain structure. These findings should be considered in evaluating outcomes in future disease-modifying trials, and support the search for protective mechanisms in people at risk of dementia that might facilitate new therapeutic strategies.

Published
2017
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17. Analysis of brain atrophy and local gene expression in genetic frontotemporal dementia

Author

Altmann, A., Cash, D. M., Bocchetta, M., Heller, C., Reynolds, R., Moore, K., Convery, R. S., Thomas, D. L., Van Swieten, J. C., Moreno, F., Sanchez-Valle, R., Borroni, B., Laforce, R., Masellis, M., Tartaglia, M. C., Graff, C., Galimberti, D., Rowe, J. B., Finger, E., Synofzik, M., Vandenberghe, R., De Mendonca, A., Tagliavini, F., Santana, I., Ducharme, S., Butler, C. R., Gerhard, A., Levin, J., Danek, A., Frisoni, G., Ghidoni, R., Sorbi, S., Otto, M., Ryten, M., Rohrer, J. D., Greaves, C., Peakman, G., Shafei, R., Todd, E., Rossor, M. N., Warren, J. D., Fox, N. C., Zetterberg, H., Guerreiro, R., Bras, J., Nicholas, J., Mead, S., Jiskoot, L., Meeter, L., Panman, J., Papma, J. M., Van Minkelen, R., Pijnenburg, Y., Barandiaran, M., Indakoetxea, B., Gabilondo, A., Tainta, M., De Arriba, M., Gorostidi, A., Zulaica, M., Villanua, J., Diaz, Z., Borrego-Ecija, S., Olives, J., Llado, A., Balasa, M., Antonell, A., Bargallo, N., Premi, E., Cosseddu, M., Gazzina, S., Padovani, A., Gasparotti, R., Archetti, S., Black, S., Mitchell, S., Rogaeva, E., Freedman, M., Keren, R., Tang-Wai, D., Oijerstedt, L., Andersson, C., Jelic, V., Thonberg, H., Arighi, A., Fenoglio, C., Scarpini, E., Fumagalli, G., Cope, T., Timberlake, C., Rittman, T., Shoesmith, C., Bartha, R., Rademakers, R., Wilke, C., Karnarth, H. -O., Bender, B., Bruffaerts, R., Van Damme, P., Vandenbulcke, M., Ferreira, C. B., Miltenberger, G., Maruta, C., Verdelho, A., Afonso, S., Taipa, R., Caroppo, P., Di Fede, G., Giaccone, G., Prioni, S., Redaelli, V., Rossi, G., Tiraboschi, P., Duro, D., Almeida, M. R., Castelo-Branco, M., Leitao, M. J., Tabuas-Pereira, M., Santiago, B., Gauthier, S., Rosa-Neto, P., Veldsman, M., Thompson, P., Langheinrich, T., Prix, C., Hoegen, T., Wlasich, E., Loosli, S., Schonecker, S., Semler, E., Anderl-Straub, S., Benussi, L., Binetti, G., Pievani, M., Lombardi, G., Nacmias, B., Ferrari, C., Bessi, V., Polito, C., Rowe, James [0000-0001-7216-8679], Apollo - University of Cambridge Repository, Medical Research Council, and Genetic FTD Initiative, GENFI

Subjects
0301 basic medicine, Cell type, Imaging genetics, Clinical Neurology, Medizin, Biology, Article, DISEASE, 03 medical and health sciences, 0302 clinical medicine, Atrophy, atrophy, C9orf72, Gene expression, medicine, Astrocytes, Frontotemporal dementia, ddc:610, 10. No inequality, Gene, 030304 developmental biology, Genetics, 0303 health sciences, Science & Technology, TREM2, AcademicSubjects/SCI01870, Neurodegeneration, General Engineering, C9orf72 Gene, Neurosciences, astrocytes, Genetic FTD Initiative, GENFI, medicine.disease, C9orf72 Protein, 030104 developmental biology, gene expression, imaging genetics, Original Article, AcademicSubjects/MED00310, Human medicine, Neurosciences & Neurology, Life Sciences & Biomedicine, 030217 neurology & neurosurgery
Abstract

Frontotemporal dementia is a heterogeneous neurodegenerative disorder characterized by neuronal loss in the frontal and temporal lobes. Despite progress in understanding which genes are associated with the aetiology of frontotemporal dementia, the biological basis of how mutations in these genes lead to cell loss in specific cortical regions remains unclear. In this work, we combined gene expression data for 16 772 genes from the Allen Institute for Brain Science atlas with brain maps of grey matter atrophy in symptomatic C9orf72, GRN and MAPT mutation carriers obtained from the Genetic Frontotemporal dementia Initiative study. No significant association was seen between C9orf72, GRN and MAPT expression and the atrophy patterns in the respective genetic groups. After adjusting for spatial autocorrelation, between 1000 and 5000 genes showed a negative or positive association with the atrophy pattern within each individual genetic group, with the most significantly associated genes being TREM2, SSBP3 and GPR158 (negative association in C9Orf72, GRN and MAPT respectively) and RELN, MXRA8 and LPA (positive association in C9Orf72, GRN and MAPT respectively). An overrepresentation analysis identified a negative association with genes involved in mitochondrial function, and a positive association with genes involved in vascular and glial cell function in each of the genetic groups. A set of 423 and 700 genes showed significant positive and negative association, respectively, with atrophy patterns in all three maps. The gene set with increased expression in spared cortical regions was enriched for neuronal and microglial genes, while the gene set with increased expression in atrophied regions was enriched for astrocyte and endothelial cell genes. Our analysis suggests that these cell types may play a more active role in the onset of neurodegeneration in frontotemporal dementia than previously assumed, and in the case of the positively associated cell marker genes, potentially through emergence of neurotoxic astrocytes and alteration in the blood–brain barrier, respectively., Altmann et al. investigated the concordance between spatial cortical gene expression in healthy subjects and atrophy patterns in genetic frontotemporal dementia. They found that elevated gene expression of endothelial cell and astrocyte-related genes in regions with atrophy, suggesting a role of these cell types in the aetiology of frontotemporal dementia., Graphical Abstract Graphical Abstract

Published
2020
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18. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study

Author

Moore, K.M. Nicholas, J. Grossman, M. McMillan, C.T. Irwin, D.J. Massimo, L. Van Deerlin, V.M. Warren, J.D. Fox, N.C. Rossor, M.N. Mead, S. Bocchetta, M. Boeve, B.F. Knopman, D.S. Graff-Radford, N.R. Forsberg, L.K. Rademakers, R. Wszolek, Z.K. van Swieten, J.C. Jiskoot, L.C. Meeter, L.H. Dopper, E.G. Papma, J.M. Snowden, J.S. Saxon, J. Jones, M. Pickering-Brown, S. Le Ber, I. Camuzat, A. Brice, A. Caroppo, P. Ghidoni, R. Pievani, M. Benussi, L. Binetti, G. Dickerson, B.C. Lucente, D. Krivensky, S. Graff, C. Öijerstedt, L. Fallström, M. Thonberg, H. Ghoshal, N. Morris, J.C. Borroni, B. Benussi, A. Padovani, A. Galimberti, D. Scarpini, E. Fumagalli, G.G. Mackenzie, I.R. Hsiung, G.-Y.R. Sengdy, P. Boxer, A.L. Rosen, H. Taylor, J.B. Synofzik, M. Wilke, C. Sulzer, P. Hodges, J.R. Halliday, G. Kwok, J. Sanchez-Valle, R. Lladó, A. Borrego-Ecija, S. Santana, I. Almeida, M.R. Tábuas-Pereira, M. Moreno, F. Barandiaran, M. Indakoetxea, B. Levin, J. Danek, A. Rowe, J.B. Cope, T.E. Otto, M. Anderl-Straub, S. de Mendonça, A. Maruta, C. Masellis, M. Black, S.E. Couratier, P. Lautrette, G. Huey, E.D. Sorbi, S. Nacmias, B. Laforce, R., Jr Tremblay, M.-P.L. Vandenberghe, R. Damme, P.V. Rogalski, E.J. Weintraub, S. Gerhard, A. Onyike, C.U. Ducharme, S. Papageorgiou, S.G. Ng, A.S.L. Brodtmann, A. Finger, E. Guerreiro, R. Bras, J. Rohrer, J.D. Heller, C. Convery, R.S. Woollacott, I.O. Shafei, R.M. Graff-Radford, J. Jones, D.T. Dheel, C.M. Savica, R. Lapid, M.I. Baker, M. Fields, J.A. Gavrilova, R. Domoto-Reilly, K. Poos, J.M. Van der Ende, E.L. Panman, J.L. Donker Kaat, L. Seelaar, H. Richardson, A. Frisoni, G. Mega, A. Fostinelli, S. Chiang, H.-H. Alberici, A. Arighi, A. Fenoglio, C. Heuer, H. Miller, B. Karydas, A. Fong, J. João Leitão, M. Santiago, B. Duro, D. Ferreira, C. Gabilondo, A. De Arriba, M. Tainta, M. Zulaica, M. Ferreira, C. Semler, E. Ludolph, A. Landwehrmeyer, B. Volk, A.E. Miltenberger, G. Verdelho, A. Afonso, S. Tartaglia, M.C. Freedman, M. Rogaeva, E. Ferrari, C. Piaceri, I. Bessi, V. Lombardi, G. St-Onge, F. Doré, M.-C. Bruffaerts, R. Vandenbulcke, M. Van den Stock, J. Mesulam, M.M. Bigio, E. Koros, C. Papatriantafyllou, J. Kroupis, C. Stefanis, L. Shoesmith, C. Robertson, E. Coppola, G. Da Silva Ramos, E.M. Geschwind, D.

Abstract

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0·45 between individual and parental age at onset, r=0·63 between individual and mean family age at onset, r=0·58 between individual and parental age at death, and r=0·69 between individual and mean family age at death) than in either the C9orf72 group (r=0·32 individual and parental age at onset, r=0·36 individual and mean family age at onset, r=0·38 individual and parental age at death, and r=0·40 individual and mean family age at death) or the GRN group (r=0·22 individual and parental age at onset, r=0·18 individual and mean family age at onset, r=0·22 individual and parental age at death, and r=0·32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35–62, for age at onset; 61%, 47–73, for age at death), and even more by family membership (66%, 56–75, for age at onset; 74%, 65–82, for age at death). In the GRN group, only 2% (0–10) of the variability of age at onset and 9% (3–21) of that of age of death was explained by the specific mutation, whereas 14% (9–22) of the variability of age at onset and 20% (12–30) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11–26) of the variability of age at onset and 19% (12–29) of that of age at death. Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates. Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society. © 2020 Elsevier Ltd

Published
2020

19. Neurobiological and clinical effect of metacognitive interpersonal therapy vs structured clinical model: study protocol for a randomized controlled trial

Author

Magni, LAURA ROSA, Carcione, Antonino, Ferrari, Clarissa, Semerari, Antonio, Riccardi, Ilaria, Nicolo', Giuseppe, Lanfredi, Mariangela, Pedrini, Laura, Cotelli, Maria, Bocchio, Luisella, Pievani, Michela, Gasparotti, Roberto, Rossi, Roberta, Rossi, R, Magni, Lr, Lanfredi, M, Pedrini, L, Carcione, A, Semerari, A, Riccardi, I, Nicolo', G, Almici, M, Beneduce, R, Borsci, G, Caprioli, C, Nodari, M, Vita, A, Barlati, S, Laffranchini, L, Rillosi, L, Rossi, G, Bocchio, L, Cattaneo, A, Cattane, N, Tura, Gb, Bignotti, S, Speziali, M, Cotelli, M, Rosini, S, Gasparotti, R, Ambrosi, C, Mascaro, L, Corbo, D, Pievani, M, Quattrini, G, Bilotta, E, Colle, L, Conti, L, Fiore, D, Micheloni, A, Procacci, M, and Silvestre, V.

Subjects
Adult, Male, Adolescent, lcsh:RC435-571, Settore M-PSI/02 - PSICOBIOLOGIA E PSICOLOGIA FISIOLOGICA, medicine.medical_treatment, Neuroimaging, Impulsivity, law.invention, Study Protocol, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Alexithymia, law, Emotionality, lcsh:Psychiatry, mental disorders, medicine, Humans, 030212 general & internal medicine, Borderline personality disorder, Interpersonal Psychotherapy, Emotion dysregulation, Metacognition, Psychotherapy, business.industry, Borderline Personality Disorder, Female, Middle Aged, Treatment Outcome, medicine.disease, 030227 psychiatry, Clinical trial, Cognitive behavioral therapy, Psychiatry and Mental health, Adjunctive treatment, medicine.symptom, business, Clinical psychology
Abstract

Background Borderline Personality Disorder (BPD) is a complex and debilitating disorder, characterized by deficits in metacognition and emotion dysregulation. The “gold standard” treatment for this disorder is psychotherapy with pharmacotherapy as an adjunctive treatment to target state symptoms. The present randomized clinical trial aims to assess the clinical and neurobiological changes following Metacognitive Interpersonal Therapy (MIT) compared with Structured Clinical Management (SCM) derived from specific recommendations in APA (American Psychiatric Association) guidelines for BPD. Methods The study design is a randomized parallel controlled clinical trial and will include 80 BPD outpatients, aged 18–45 enrolled at 2 recruitment centers. Primary outcome will be the clinical change in emotion regulation capacities assessed with the Difficulties in Emotion Regulation Scale (DERS). We will also investigated the effect of psychotherapy on metacognitive abilities and several clinical features such as BPD symptomatology, general psychopathology, depression, personal functioning, and trait dimensions (anger, impulsivity, alexithymia). We will evaluate changes in brain connectivity patterns and during the view of emotional pictures. A multidimensional assessment will be performed at the baseline, at 6, 12, 18 months. We will obtain structural and functional Magnetic Resonance Images (MRIs) in MIT-Treated BPD (N = 30) and SCM-treated BPD (N = 30) at baseline and after treatment, as well as in a group of 30 healthy and unrelated volunteers that will be scanned once for comparison. Discussion The present study could contribute to elucidate the neurobiological mechanisms underlying psychotherapy efficacy. The inclusion of a multidisciplinary study protocol will allow to study BPD considering different features that can affect the treatment response and their reciprocal relationships. Trial registration NCT02370316. Registered 02/24/2015. Electronic supplementary material The online version of this article (10.1186/s12888-019-2127-2) contains supplementary material, which is available to authorized users.

Published
2019
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20. Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia: a GENFI study

Author

Mutsaerts, H. J. M. M., Mirza, S. S., Petr, J., Thomas, D. L., Cash, D. M., Bocchetta, M., De Vita, E., Metcalfe, A. W. S., Shirzadi, Z., Robertson, A. D., Tartaglia, M. C., Mitchell, S. B., Black, S. E., Freedman, M., Tang-Wai, D., Keren, R., Rogaeva, E., Van Swieten, J., Laforce, R., Tagliavini, F., Borroni, B., Galimberti, D., Rowe, J. B., Graff, C., Frisoni, G. B., Finger, E., Sorbi, S., De Mendonca, A., Rohrer, J. D., Macintosh, B. J., Masellis, M., Andersson, C., Archetti, S., Arighi, A., Benussi, L., Binetti, G., Cosseddu, M., Dick, K. M., Fallstrom, M., Ferreira, C., Fenoglio, C., Fox, N. C., Fumagalli, G., Gazzina, S., Ghidoni, R., Grisoli, M., Jelic, V., Jiskoot, L., Lombardi, G., Maruta, C., Mead, S., Meeter, L., Van Minkelen, R., Nacmias, B., Oijerstedt, L., Ourselin, S., Padovani, A., Panman, J., Pievani, M., Polito, C., Premi, E., Prioni, S., Rademakers, R., Redaelli, V., Rossi, G., Rossor, M. N., Scarpini, E., Thonberg, H., Tiraboschi, P., Verdelho, A., Warren, J. D., Rowe, James [0000-0001-7216-8679], Apollo - University of Cambridge Repository, Neurology, Amsterdam Neuroscience - Neurodegeneration, and Radiology and Nuclear Medicine

Subjects
0301 basic medicine, Male, Pathology, Tau Proteins/genetics, cerebral blood flow, Gene mutation, Neuropsychological Tests, Arterial spin labelling, Frontotemporal Dementia/genetics, 0302 clinical medicine, Progranulins, C9orf72, Brain, Middle Aged, Corrigenda, Magnetic Resonance Imaging, Cerebral blood flow, Cerebrovascular Circulation, Frontotemporal Dementia, Female, arterial spin labelling, Frontotemporal dementia, Adult, medicine.medical_specialty, Heterozygote, genetic frontotemporal dementia, presymptomatic biomarker, C9orf72 Protein/genetics, tau Proteins, Progranulins/genetics, 03 medical and health sciences, Neuroimaging, mental disorders, medicine, Brain/metabolism, Dementia, Humans, Cerebral perfusion pressure, Aged, C9orf72 Protein, business.industry, Original Articles, Voxel-based morphometry, medicine.disease, arterial spin labeling, ddc:616.8, Genetic frontotemporal dementia, Presymptomatic biomarker, 030104 developmental biology, Cross-Sectional Studies, Mutation, Neurology (clinical), business, 030217 neurology & neurosurgery, Cerebrovascular Circulation/genetics
Abstract

Imaging biomarkers are needed to detect early brain changes in presymptomatic carriers harbouring FTD mutations. Using arterial spin labelling-MRI, Mutsaerts, Mirza et al. identify an inverse association between cerebral perfusion in frontotemporoparietal regions and expected age of onset. Cerebral perfusion may be a promising imaging biomarker for presymptomatic genetic FTD., Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-sectional differences in arterial spin labelling MRI-based cerebral blood flow between presymptomatic C9orf72, GRN or MAPT mutation carriers (n = 107) and non-carriers (n = 113), using general linear mixed-effects models and voxel-based analyses. Cerebral blood flow within regions of interest derived from this model was then explored to identify differences between individual gene carrier groups and to estimate a timeframe for the expression of these differences. The voxel-based analysis revealed a significant inverse association between cerebral blood flow and the expected age of symptom onset in carriers, but not non-carriers. Regions included the bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, and inferior parietal cortices, as well as the left middle temporal gyrus. For all bilateral regions, associations were greater on the right side. After correction for partial volume effects in a region of interest analysis, the results were found to be largely driven by the C9orf72 genetic subgroup. These cerebral blood flow differences first appeared approximately 12.5 years before the expected symptom onset determined on an individual basis. Cerebral blood flow was lower in presymptomatic mutation carriers closer to and beyond their expected age of symptom onset in key frontotemporal dementia signature regions. These results suggest that arterial spin labelling MRI may be a promising non-invasive imaging biomarker for the presymptomatic stages of genetic frontotemporal dementia.

Published
2019
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21. Amygdalar nuclei and hippocampal subfields on MRI: Test-retest reliability of automated volumetry across different MRI sites and vendors

Author

Quattrini, G., Pievani, M., Jovicich, J., Aiello, M., Bargallo, N., Barkhof, F., Bartres-Faz, D., Beltramello, A., Pizzini, F. B., Blin, O., Bordet, R., Caulo, M., Constantinides, M., Didic, M., Drevelegas, A., Ferretti, A., Fiedler, U., Floridi, P., Gros-Dagnac, H., Hensch, T., Hoffmann, K. -T., Kuijer, J. P., Lopes, R., Marra, Camillo, Muller, B. W., Nobili, F., Parnetti, L., Payoux, P., Picco, A., Ranjeva, J. -P., Roccatagliata, L., Rossini, Paolo Maria, Salvatore, M., Schonknecht, P., Schott, B. H., Sein, J., Soricelli, A., Tarducci, R., Tsolaki, M., Visser, P. J., Wiltfang, J., Richardson, J. C., Frisoni, G. B., Marizzoni, M., Marra C. (ORCID:0000-0003-3994-4044), Rossini P. M. (ORCID:0000-0003-2665-534X), Quattrini, G., Pievani, M., Jovicich, J., Aiello, M., Bargallo, N., Barkhof, F., Bartres-Faz, D., Beltramello, A., Pizzini, F. B., Blin, O., Bordet, R., Caulo, M., Constantinides, M., Didic, M., Drevelegas, A., Ferretti, A., Fiedler, U., Floridi, P., Gros-Dagnac, H., Hensch, T., Hoffmann, K. -T., Kuijer, J. P., Lopes, R., Marra, Camillo, Muller, B. W., Nobili, F., Parnetti, L., Payoux, P., Picco, A., Ranjeva, J. -P., Roccatagliata, L., Rossini, Paolo Maria, Salvatore, M., Schonknecht, P., Schott, B. H., Sein, J., Soricelli, A., Tarducci, R., Tsolaki, M., Visser, P. J., Wiltfang, J., Richardson, J. C., Frisoni, G. B., Marizzoni, M., Marra C. (ORCID:0000-0003-3994-4044), and Rossini P. M. (ORCID:0000-0003-2665-534X)

Published
2020

22. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study

Author

Moore, K.M. Nicholas, J. Grossman, M. McMillan, C.T. Irwin, D.J. Massimo, L. Van Deerlin, V.M. Warren, J.D. Fox, N.C. Rossor, M.N. Mead, S. Bocchetta, M. Boeve, B.F. Knopman, D.S. Graff-Radford, N.R. Forsberg, L.K. Rademakers, R. Wszolek, Z.K. van Swieten, J.C. Jiskoot, L.C. Meeter, L.H. Dopper, E.G. Papma, J.M. Snowden, J.S. Saxon, J. Jones, M. Pickering-Brown, S. Le Ber, I. Camuzat, A. Brice, A. Caroppo, P. Ghidoni, R. Pievani, M. Benussi, L. Binetti, G. Dickerson, B.C. Lucente, D. Krivensky, S. Graff, C. Öijerstedt, L. Fallström, M. Thonberg, H. Ghoshal, N. Morris, J.C. Borroni, B. Benussi, A. Padovani, A. Galimberti, D. Scarpini, E. Fumagalli, G.G. Mackenzie, I.R. Hsiung, G.-Y.R. Sengdy, P. Boxer, A.L. Rosen, H. Taylor, J.B. Synofzik, M. Wilke, C. Sulzer, P. Hodges, J.R. Halliday, G. Kwok, J. Sanchez-Valle, R. Lladó, A. Borrego-Ecija, S. Santana, I. Almeida, M.R. Tábuas-Pereira, M. Moreno, F. Barandiaran, M. Indakoetxea, B. Levin, J. Danek, A. Rowe, J.B. Cope, T.E. Otto, M. Anderl-Straub, S. de Mendonça, A. Maruta, C. Masellis, M. Black, S.E. Couratier, P. Lautrette, G. Huey, E.D. Sorbi, S. Nacmias, B. Laforce, R., Jr Tremblay, M.-P.L. Vandenberghe, R. Damme, P.V. Rogalski, E.J. Weintraub, S. Gerhard, A. Onyike, C.U. Ducharme, S. Papageorgiou, S.G. Ng, A.S.L. Brodtmann, A. Finger, E. Guerreiro, R. Bras, J. Rohrer, J.D. Heller, C. Convery, R.S. Woollacott, I.O. Shafei, R.M. Graff-Radford, J. Jones, D.T. Dheel, C.M. Savica, R. Lapid, M.I. Baker, M. Fields, J.A. Gavrilova, R. Domoto-Reilly, K. Poos, J.M. Van der Ende, E.L. Panman, J.L. Donker Kaat, L. Seelaar, H. Richardson, A. Frisoni, G. Mega, A. Fostinelli, S. Chiang, H.-H. Alberici, A. Arighi, A. Fenoglio, C. Heuer, H. Miller, B. Karydas, A. Fong, J. João Leitão, M. Santiago, B. Duro, D. Ferreira, C. Gabilondo, A. De Arriba, M. Tainta, M. Zulaica, M. Ferreira, C. Semler, E. Ludolph, A. Landwehrmeyer, B. Volk, A.E. Miltenberger, G. Verdelho, A. Afonso, S. Tartaglia, M.C. Freedman, M. Rogaeva, E. Ferrari, C. Piac and Moore, K.M. Nicholas, J. Grossman, M. McMillan, C.T. Irwin, D.J. Massimo, L. Van Deerlin, V.M. Warren, J.D. Fox, N.C. Rossor, M.N. Mead, S. Bocchetta, M. Boeve, B.F. Knopman, D.S. Graff-Radford, N.R. Forsberg, L.K. Rademakers, R. Wszolek, Z.K. van Swieten, J.C. Jiskoot, L.C. Meeter, L.H. Dopper, E.G. Papma, J.M. Snowden, J.S. Saxon, J. Jones, M. Pickering-Brown, S. Le Ber, I. Camuzat, A. Brice, A. Caroppo, P. Ghidoni, R. Pievani, M. Benussi, L. Binetti, G. Dickerson, B.C. Lucente, D. Krivensky, S. Graff, C. Öijerstedt, L. Fallström, M. Thonberg, H. Ghoshal, N. Morris, J.C. Borroni, B. Benussi, A. Padovani, A. Galimberti, D. Scarpini, E. Fumagalli, G.G. Mackenzie, I.R. Hsiung, G.-Y.R. Sengdy, P. Boxer, A.L. Rosen, H. Taylor, J.B. Synofzik, M. Wilke, C. Sulzer, P. Hodges, J.R. Halliday, G. Kwok, J. Sanchez-Valle, R. Lladó, A. Borrego-Ecija, S. Santana, I. Almeida, M.R. Tábuas-Pereira, M. Moreno, F. Barandiaran, M. Indakoetxea, B. Levin, J. Danek, A. Rowe, J.B. Cope, T.E. Otto, M. Anderl-Straub, S. de Mendonça, A. Maruta, C. Masellis, M. Black, S.E. Couratier, P. Lautrette, G. Huey, E.D. Sorbi, S. Nacmias, B. Laforce, R., Jr Tremblay, M.-P.L. Vandenberghe, R. Damme, P.V. Rogalski, E.J. Weintraub, S. Gerhard, A. Onyike, C.U. Ducharme, S. Papageorgiou, S.G. Ng, A.S.L. Brodtmann, A. Finger, E. Guerreiro, R. Bras, J. Rohrer, J.D. Heller, C. Convery, R.S. Woollacott, I.O. Shafei, R.M. Graff-Radford, J. Jones, D.T. Dheel, C.M. Savica, R. Lapid, M.I. Baker, M. Fields, J.A. Gavrilova, R. Domoto-Reilly, K. Poos, J.M. Van der Ende, E.L. Panman, J.L. Donker Kaat, L. Seelaar, H. Richardson, A. Frisoni, G. Mega, A. Fostinelli, S. Chiang, H.-H. Alberici, A. Arighi, A. Fenoglio, C. Heuer, H. Miller, B. Karydas, A. Fong, J. João Leitão, M. Santiago, B. Duro, D. Ferreira, C. Gabilondo, A. De Arriba, M. Tainta, M. Zulaica, M. Ferreira, C. Semler, E. Ludolph, A. Landwehrmeyer, B. Volk, A.E. Miltenberger, G. Verdelho, A. Afonso, S. Tartaglia, M.C. Freedman, M. Rogaeva, E. Ferrari, C. Piac

Abstract

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at

Published
2020

23. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study

Author

Moore, KM, Nicholas, J, Grossman, M, McMillan, CT, Irwin, DJ, Massimo, L, Van Deerlin, VM, Warren, JD, Fox, NC, Rossor, MN, Mead, S, Bocchetta, M, Boeve, BF, Knopman, DS, Graff-Radford, NR, Forsberg, LK, Rademakers, R, Wszolek, ZK, van Swieten, JC, Jiskoot, LC, Meeter, LH, Dopper, EGP, Papma, JM, Snowden, JS, Saxon, J, Jones, M, Pickering-Brown, S, Le Ber, I, Camuzat, A, Brice, A, Caroppo, P, Ghidoni, R, Pievani, M, Benussi, L, Binetti, G, Dickerson, BC, Lucente, D, Krivensky, S, Graff, C, Oijerstedt, L, Fallstrom, M, Thonberg, H, Ghoshal, N, Morris, JC, Borroni, B, Benussi, A, Padovani, A, Galimberti, D, Scarpini, E, Fumagalli, GG, Mackenzie, IR, Hsiung, G-YR, Sengdy, P, Boxer, AL, Rosen, H, Taylor, JB, Synofzik, M, Wilke, C, Sulzer, P, Hodges, JR, Halliday, G, Kwok, J, Sanchez-Valle, R, Llado, A, Borrego-Ecija, S, Santana, I, Almeida, MR, Tabuas-Pereira, M, Moreno, F, Barandiaran, M, Indakoetxea, B, Levin, J, Danek, A, Rowe, JB, Cope, TE, Otto, M, Anderl-Straub, S, de Mendonca, A, Maruta, C, Masellis, M, Black, SE, Couratier, P, Lautrette, G, Huey, ED, Sorbi, S, Nacmias, B, Laforce, R, Tremblay, M-PL, Vandenberghe, R, Van Damme, P, Rogalski, EJ, Weintraub, S, Gerhard, A, Onyike, CU, Ducharme, S, Papageorgiou, SG, Ng, ASL, Brodtmann, A, Finger, E, Guerreiro, R, Bras, J, Rohrer, JD, Heller, C, Convery, R, Woollacott, IOC, Shafei, R, Graff-Radford, J, Jones, DT, Dheel, CM, Savica, R, Lapid, MI, Baker, M, Fields, JA, Gavrilova, R, Domoto-Reilly, K, Poos, JM, van der Ende, EL, Panman, JL, Kaat, LD, Seelaar, H, Richardson, A, Frisoni, G, Mega, A, Fostinelli, S, Chiang, H-H, Alberici, A, Arighi, A, Fenoglio, C, Heuer, H, Miller, B, Karydas, A, Fong, J, Leitao, MJ, Santiago, B, Duro, D, Ferreira, C, Gabilondo, A, de Arriba, M, Tainta, M, Zulaica, M, Ferreira, CB, Semler, E, Ludolph, A, Landwehrmeyer, B, Volk, AE, Miltenberger, G, Verdelho, A, Afonso, S, Tartaglia, MC, Freedman, M, Rogaeva, E, Ferrari, C, Piaceri, I, Bessi, V, Lombardi, G, St-Onge, F, Dore, M-C, Bruffaerts, R, Vandenbulcke, M, Van den Stock, J, Mesulam, MM, Bigio, E, Koros, C, Papatriantafyllou, J, Kroupis, C, Stefanis, L, Shoesmith, C, Roberson, E, Coppola, G, Ramos, EMDS, Geschwind, D, Moore, KM, Nicholas, J, Grossman, M, McMillan, CT, Irwin, DJ, Massimo, L, Van Deerlin, VM, Warren, JD, Fox, NC, Rossor, MN, Mead, S, Bocchetta, M, Boeve, BF, Knopman, DS, Graff-Radford, NR, Forsberg, LK, Rademakers, R, Wszolek, ZK, van Swieten, JC, Jiskoot, LC, Meeter, LH, Dopper, EGP, Papma, JM, Snowden, JS, Saxon, J, Jones, M, Pickering-Brown, S, Le Ber, I, Camuzat, A, Brice, A, Caroppo, P, Ghidoni, R, Pievani, M, Benussi, L, Binetti, G, Dickerson, BC, Lucente, D, Krivensky, S, Graff, C, Oijerstedt, L, Fallstrom, M, Thonberg, H, Ghoshal, N, Morris, JC, Borroni, B, Benussi, A, Padovani, A, Galimberti, D, Scarpini, E, Fumagalli, GG, Mackenzie, IR, Hsiung, G-YR, Sengdy, P, Boxer, AL, Rosen, H, Taylor, JB, Synofzik, M, Wilke, C, Sulzer, P, Hodges, JR, Halliday, G, Kwok, J, Sanchez-Valle, R, Llado, A, Borrego-Ecija, S, Santana, I, Almeida, MR, Tabuas-Pereira, M, Moreno, F, Barandiaran, M, Indakoetxea, B, Levin, J, Danek, A, Rowe, JB, Cope, TE, Otto, M, Anderl-Straub, S, de Mendonca, A, Maruta, C, Masellis, M, Black, SE, Couratier, P, Lautrette, G, Huey, ED, Sorbi, S, Nacmias, B, Laforce, R, Tremblay, M-PL, Vandenberghe, R, Van Damme, P, Rogalski, EJ, Weintraub, S, Gerhard, A, Onyike, CU, Ducharme, S, Papageorgiou, SG, Ng, ASL, Brodtmann, A, Finger, E, Guerreiro, R, Bras, J, Rohrer, JD, Heller, C, Convery, R, Woollacott, IOC, Shafei, R, Graff-Radford, J, Jones, DT, Dheel, CM, Savica, R, Lapid, MI, Baker, M, Fields, JA, Gavrilova, R, Domoto-Reilly, K, Poos, JM, van der Ende, EL, Panman, JL, Kaat, LD, Seelaar, H, Richardson, A, Frisoni, G, Mega, A, Fostinelli, S, Chiang, H-H, Alberici, A, Arighi, A, Fenoglio, C, Heuer, H, Miller, B, Karydas, A, Fong, J, Leitao, MJ, Santiago, B, Duro, D, Ferreira, C, Gabilondo, A, de Arriba, M, Tainta, M, Zulaica, M, Ferreira, CB, Semler, E, Ludolph, A, Landwehrmeyer, B, Volk, AE, Miltenberger, G, Verdelho, A, Afonso, S, Tartaglia, MC, Freedman, M, Rogaeva, E, Ferrari, C, Piaceri, I, Bessi, V, Lombardi, G, St-Onge, F, Dore, M-C, Bruffaerts, R, Vandenbulcke, M, Van den Stock, J, Mesulam, MM, Bigio, E, Koros, C, Papatriantafyllou, J, Kroupis, C, Stefanis, L, Shoesmith, C, Roberson, E, Coppola, G, Ramos, EMDS, and Geschwind, D

Abstract

BACKGROUND: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. METHODS: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. FINDINGS: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at

Published
2020

24. Age at onset reveals different functional connectivity abnormalities in prodromal Alzheimer’s disease

Author

Pini, L., Geroldi, C., Galluzzi, S., Baruzzi, R., Bertocchi, M., Chito, E., Orini, S., Romano, M., Cotelli, Maria, Rosini, S., Magnaldi, S., Morassi, M., Cobelli, M., Bonvicini, C., Archetti, S., Zanetti, O., Frisoni, G. B., Pievani, M., Cotelli M., Pini, L., Geroldi, C., Galluzzi, S., Baruzzi, R., Bertocchi, M., Chito, E., Orini, S., Romano, M., Cotelli, Maria, Rosini, S., Magnaldi, S., Morassi, M., Cobelli, M., Bonvicini, C., Archetti, S., Zanetti, O., Frisoni, G. B., Pievani, M., and Cotelli M.

Abstract

Age at symptom onset (AAO) underlies different Alzheimer’s disease (AD) clinical variants: late-onset AD (LOAD) is characterized by memory deficits, while early-onset AD (EOAD) presents predominantly with non-memory symptoms. The involvement of different neural networks may explain these distinct clinical phenotypes. In this study, we tested the hypothesis of an early and selective involvement of neural networks based on AAO in AD. Twenty memory clinic patients with prodromal AD (i.e., mild cognitive impairment with an AD-like cerebrospinal fluid profile) and 30 healthy controls underwent a cognitive evaluation and a resting state functional MRI exam. Independent component analysis was performed to assess functional connectivity (FC) in the following networks: default mode, frontoparietal, limbic, visual, and sensorimotor. Patients were stratified into late-onset (pLOAD) and early-onset (pEOAD) prodromal AD according to the AAO and controls were stratified into younger and older groups accordingly. Decreased FC within the default mode and the limbic networks was observed in pLOAD, while pEOAD showed lower FC in the frontoparietal and visual networks. The sensorimotor network did not show differences between groups. A significant association was found between memory and limbic network FC in pLOAD, and between executive functions and frontoparietal network FC in pEOAD, although the latter association did not survive multiple comparison correction. Our findings indicate that aberrant connectivity in memory networks is associated with pLOAD, while networks underlying executive and visuo-spatial functions are affected in pEOAD. These findings are in line with the hypothesis that the pathophysiological mechanisms underlying EOAD and LOAD are distinct.

Published
2020

25. Corrigendum to ?Functional cortical source connectivity of resting state electroencephalographic alpha rhythms shows similar abnormalities in patients with mild cognitive impairment due to Alzheimer{'}s and Parkinson{'}s diseases? [Clin. Neurophysiol. 129 (2018) 766?782] (Clinical Neurophysiology (2018) 129(4) (766?782), (S1388245718300245), (10.1016/j.clinph.2018.01.009))

Author

Babiloni, C., Percio, C. D., Lizio, R., Noce, G., Lopez, S., Soricelli, A., Ferri, R., Pascarelli, M. T., Catania, V., Nobili, F., Arnaldi, D., Famà, F., Orzi, F., Buttinelli, C., Giubilei, F., Bonanni, L., Franciotti, R., Onofrj, M., Stirpe, P., Fuhr, P., Gschwandtner, U., Ransmayr, G., Garn, H., Fraioli, L., Pievani, M., D(')Antonio, F., De Lena, C., and G

Published
2019

26. Comparison of arterial spin labeling registration strategies in the multi-center GENetic frontotemporal dementia initiative (GENFI)

Author

Mutsaerts, H. J. M. M., Petr, J., Thomas, D. L., De Vita, E., Cash, D. M., van Osch, M. J. P., Golay, X., Groot, P. F. C., Ourselin, S., van Swieten, J., Laforce, R., Tagliavini, F., Borroni, B., Galimberti, D., Rowe, J. B., Graff, C., Pizzini, F. B., Finger, E., Sorbi, S., Castelo Branco, M., Rohrer, J. D., Masellis, M., Macintosh, B. J., Rossor, M., Fox, N., Warren, J., Bocchetta, M., Dick, K., Pievani, M., Ghidoni, R., Benussi, L., Padovani, A., Cosseddu, M., Mendonca, A., Frisoni, G., Premi, E., Archetti, S., Scarpini, E., Fumagalli, G., Arighi, A., Fenoglio, C., Prioni, S., Redaelii, V., Grisoli, M., Tiraboschi, P., Black, S., Rogaeva, E., Freedman, M., Tartaglia, M. C., Tang-Wai, D., Keren, R., Panman, J., Meeter, L., Jiskoot, L., van Minkelen, R., Lombardi, G., Polito, C., Nacmias, B., Jelic, V., Andersson, C., Oijerstedt, L., Fallstrom, M., Thonberg, H., Verdelho, A., Maruta, C., Neurology, Mutsaerts, Henri JMM [0000-0003-0894-0307], Apollo - University of Cambridge Repository, and Other departments

Subjects
Adult, Male, cerebral blood flow, Brain, Reproducibility of Results, Arteries, Middle Aged, arterial spin labeling, Magnetic Resonance Imaging, Article, Perfusion, image registration, Young Adult, Imaging, Three-Dimensional, Cerebrovascular Circulation, Frontotemporal Dementia, Image Processing, Computer-Assisted, Humans, Female, Spin Labels, Gray Matter
Abstract

PURPOSE: To compare registration strategies to align arterial spin labeling (ASL) with 3D T1-weighted (T1w) images, with the goal of reducing the between-subject variability of cerebral blood flow (CBF) images. MATERIALS AND METHODS: Multi-center 3T ASL data were collected at eight sites with four different sequences in the multi-center GENetic Frontotemporal dementia Initiative (GENFI) study. In a total of 48 healthy controls, we compared the following image registration options: (I) which images to use for registration (perfusion-weighted images [PWI] to the segmented gray matter (GM) probability map (pGM) (CBF-pGM) or M0 to T1w (M0-T1w); (II) which transformation to use (rigid-body or non-rigid); and (III) whether to mask or not (no masking, M0-based FMRIB software library Brain Extraction Tool [BET] masking). In addition to visual comparison, we quantified image similarity using the Pearson correlation coefficient (CC), and used the Mann-Whitney U rank sum test. RESULTS: CBF-pGM outperformed M0-T1w (CC improvement 47.2% ± 22.0%; P < 0.001), and the non-rigid transformation outperformed rigid-body (20.6% ± 5.3%; P < 0.001). Masking only improved the M0-T1w rigid-body registration (14.5% ± 15.5%; P = 0.007). CONCLUSION: The choice of image registration strategy impacts ASL group analyses. The non-rigid transformation is promising but requires validation. CBF-pGM rigid-body registration without masking can be used as a default strategy. In patients with expansive perfusion deficits, M0-T1w may outperform CBF-pGM in sequences with high effective spatial resolution. BET-masking only improves M0-T1w registration when the M0 image has sufficient contrast. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:131-140.

Published
2018
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27. Spatiotemporal analysis for detection of pre-symptomatic shape changes in neurodegenerative diseases: Initial application to the GENFI cohort

Author

Cury, C. (Claire), Durrleman, S. (Stanley), Cash, D.M. (David M.), Lorenzi, M. (Marco), Nicholas, J.M. (Jennifer M.), Bocchetta, M. (Martina), Swieten, J.C. (John) van, Borroni, B. (Barbara), Galimberti, D. (Daniela), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Rowe, J.B. (James), Graff, C. (Caroline), Tagliavini, F. (Fabrizio), Frisoni, G.B. (Giovanni B.), Laforce, R. (Robert), Finger, E. (Elizabeth), De Mendonça, A. (Alexandre), Sorbi, S. (Sandro), Ourselin, S. (Sebastien), Rohrer, J.D. (Jonathan D.), Modat, M. (Marc), Andersson, C. (Christin), Archetti, S. (Silvana), Arighi, A. (Andrea), Benussi, L. (Luisa), Black, S. (Sandra), Cosseddu, M. (Maura), Fallstrm, M. (Marie), Ferreira, C. (Carlos), Fenoglio, C. (Chiara), Fox, N. (Nick), Freedman, M. (Morris), Fumagalli, G. (Giorgio), Gazzina, S. (Stefano), Ghidoni, R. (Roberta), Grisoli, M. (Marina), Jelic, V. (Vesna), Jiskoot, L.C. (Lize), Keren, R. (Ron), Lombardi, G. (Gemma), Maruta, C. (Carolina), Meeter, L.H.H. (Lieke), Thornton, A.S. (Andrew), Nacmias, B. (Benedetta), ijerstedt, L. (Linn), Padovani, A. (Alessandro), Panman, J. (Jessica), Pievani, M. (Michela), Polito, C. (Cristina), Premi, E. (Enrico), Prioni, S. (Sara), Rademakers, S. (Suzanne), Redaelli, V. (Veronica), Rogaeva, E. (Ekaterina), Rossi, G. (Giacomina), Rossor, M. (Martin), Scarpini, E. (Elio), Tang-Wai, D. (David), Tartaglia, C. (Carmela), Thonberg, H. (Håkan), Tiraboschi, P. (Pietro), Verdelho, A. (Ana), Warren, J. (Jason), Cury, C. (Claire), Durrleman, S. (Stanley), Cash, D.M. (David M.), Lorenzi, M. (Marco), Nicholas, J.M. (Jennifer M.), Bocchetta, M. (Martina), Swieten, J.C. (John) van, Borroni, B. (Barbara), Galimberti, D. (Daniela), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Rowe, J.B. (James), Graff, C. (Caroline), Tagliavini, F. (Fabrizio), Frisoni, G.B. (Giovanni B.), Laforce, R. (Robert), Finger, E. (Elizabeth), De Mendonça, A. (Alexandre), Sorbi, S. (Sandro), Ourselin, S. (Sebastien), Rohrer, J.D. (Jonathan D.), Modat, M. (Marc), Andersson, C. (Christin), Archetti, S. (Silvana), Arighi, A. (Andrea), Benussi, L. (Luisa), Black, S. (Sandra), Cosseddu, M. (Maura), Fallstrm, M. (Marie), Ferreira, C. (Carlos), Fenoglio, C. (Chiara), Fox, N. (Nick), Freedman, M. (Morris), Fumagalli, G. (Giorgio), Gazzina, S. (Stefano), Ghidoni, R. (Roberta), Grisoli, M. (Marina), Jelic, V. (Vesna), Jiskoot, L.C. (Lize), Keren, R. (Ron), Lombardi, G. (Gemma), Maruta, C. (Carolina), Meeter, L.H.H. (Lieke), Thornton, A.S. (Andrew), Nacmias, B. (Benedetta), ijerstedt, L. (Linn), Padovani, A. (Alessandro), Panman, J. (Jessica), Pievani, M. (Michela), Polito, C. (Cristina), Premi, E. (Enrico), Prioni, S. (Sara), Rademakers, S. (Suzanne), Redaelli, V. (Veronica), Rogaeva, E. (Ekaterina), Rossi, G. (Giacomina), Rossor, M. (Martin), Scarpini, E. (Elio), Tang-Wai, D. (David), Tartaglia, C. (Carmela), Thonberg, H. (Håkan), Tiraboschi, P. (Pietro), Verdelho, A. (Ana), and Warren, J. (Jason)

Abstract

Brain atrophy as measured from structural MR images, is one of the primary imaging biomarkers used to track neurodegenerative disease progression. In diseases such as frontotemporal dementia or Alzheimer's disease, atrophy can be observed in key brain structures years before any clinical symptoms are present. Atrophy is most commonly captured as volume change of key structures and the shape changes of these structures are typically not analysed despite being potentially more sensitive than summary volume statistics over the entire structure. In this paper we propose a spatiotemporal analysis pipeline based on Large Diffeomorphic Deformation Metric Mapping (LDDMM) to detect shape changes from volumetric MRI scans. We applied our framework to a cohort of individuals with genetic variants of frontotemporal dementia and healthy controls from the Genetic FTD Initiative (GENFI) study. Our method, take full advantage of the LDDMM framework, and relies on the creation of a population specific average spatiotemporal trajectory of a relevant brain structure of interest, the thalamus in our case. The residuals from each patient data to the average spatiotemporal trajectory are then clustered and studied to assess when presymptomatic mutation carriers differ from healthy control subjects. We found statistical differences in shape in the anterior region of the thalamus at least five years before the mutation carrier subjects develop any clinical symptoms. This region of the thalamus has been shown to be predominantly connected to the frontal lobe, consistent with the pattern of cortical atrophy seen in the disease.

Published
2019
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28. Neurobiological and clinical effect of metacognitive interpersonal therapy vs structured clinical model: study protocol for a randomized controlled trial

Author

Magni, L. R., Carcione, A., Ferrari, C., Semerari, A., Riccardi, I., Nicolo, G., Lanfredi, M., Pedrini, L., Cotelli, M., Bocchio, L., Pievani, M., Gasparotti, R., Rossi, R., Almici, M., Beneduce, R., Borsci, G., Caprioli, C., Nodari, M., Vita, A., Barlati, S., Laffranchini, L., Rillosi, L., Rossi, G., Cattaneo, A., Cattane, N., Tura, G. B., Bignotti, S., Speziali, M., Rosini, S., Ambrosi, C., Mascaro, L., Corbo, D., Quattrini, G., Bilotta, E., Colle, L., Conti, L., Fiore, D., Micheloni, A., Procacci, M., Silvestre, V., Cotelli M., Magni, L. R., Carcione, A., Ferrari, C., Semerari, A., Riccardi, I., Nicolo, G., Lanfredi, M., Pedrini, L., Cotelli, M., Bocchio, L., Pievani, M., Gasparotti, R., Rossi, R., Almici, M., Beneduce, R., Borsci, G., Caprioli, C., Nodari, M., Vita, A., Barlati, S., Laffranchini, L., Rillosi, L., Rossi, G., Cattaneo, A., Cattane, N., Tura, G. B., Bignotti, S., Speziali, M., Rosini, S., Ambrosi, C., Mascaro, L., Corbo, D., Quattrini, G., Bilotta, E., Colle, L., Conti, L., Fiore, D., Micheloni, A., Procacci, M., Silvestre, V., and Cotelli M.

Abstract

Background: Borderline Personality Disorder (BPD) is a complex and debilitating disorder, characterized by deficits in metacognition and emotion dysregulation. The "gold standard" treatment for this disorder is psychotherapy with pharmacotherapy as an adjunctive treatment to target state symptoms. The present randomized clinical trial aims to assess the clinical and neurobiological changes following Metacognitive Interpersonal Therapy (MIT) compared with Structured Clinical Management (SCM) derived from specific recommendations in APA (American Psychiatric Association) guidelines for BPD. Methods: The study design is a randomized parallel controlled clinical trial and will include 80 BPD outpatients, aged 18-45 enrolled at 2 recruitment centers. Primary outcome will be the clinical change in emotion regulation capacities assessed with the Difficulties in Emotion Regulation Scale (DERS). We will also investigated the effect of psychotherapy on metacognitive abilities and several clinical features such as BPD symptomatology, general psychopathology, depression, personal functioning, and trait dimensions (anger, impulsivity, alexithymia). We will evaluate changes in brain connectivity patterns and during the view of emotional pictures. A multidimensional assessment will be performed at the baseline, at 6, 12, 18 months. We will obtain structural and functional Magnetic Resonance Images (MRIs) in MIT-Treated BPD (N = 30) and SCM-treated BPD (N = 30) at baseline and after treatment, as well as in a group of 30 healthy and unrelated volunteers that will be scanned once for comparison. Discussion: The present study could contribute to elucidate the neurobiological mechanisms underlying psychotherapy efficacy. The inclusion of a multidisciplinary study protocol will allow to study BPD considering different features that can affect the treatment response and their reciprocal relationships. Trial registration: NCT02370316. Registered 02/24/2015.

Published
2019

29. Do beliefs about the pathogenetic role of amyloid affect the interpretation of amyloid PET in the clinic?

Author

Boccardi, M, Altomare, D, Ferrari, C, Festari, C, Antelmi, L, Pievani, M, Tarallo, A, Muscio, C, Guerra, U, Paghera, B, Padovani, A, Frisoni, G, Zanetti, O, Anzola, G, Bertocchi, M, Chito, E, Galluzzi, S, Geroldi, C, Lussignoli, G, Mattioli, F, Moretti, D, Pizzocaro, C, Borroni, B, Rozzini, L, Prelle, A, Gennuso, M, Villani, D, Raimondi, M, Gentile, S, Bellelli, G, Morandi, A, Turco, R, Bellandi, D, Carbone, P, Abruzzi, L, Bettoni, L, Bianchetti, A, Facchi, E, Di Fazio, I, Turla, M, Cotelli, M, Volta, G, Bigni, B, Bilotti, G, Vollaro, S, Rozzini, R, Boffelli, S, Cappuccio, M, Conti, M, Guizzetti, G, Defanti, C, Mirabile, D, Fascendini, S, Manzoni, L, Salvi, G, Belotti, G, Cavaliere, S, Fiacco, F, Valente, L, Ciccone, A, Lanari, A, Selletti, L, Palmerini, F, Avanzi, S, Vezzadini, G, Boccardi M., Altomare D., Ferrari C., Festari C., Antelmi L., Pievani M., Tarallo A., Muscio C., Guerra U. P., Paghera B., Padovani A., Frisoni G. B., Zanetti O., Anzola G. P., Bertocchi M., Chito E., Galluzzi S., Geroldi C., Lussignoli G., Mattioli F., Moretti D., Pizzocaro C., Borroni B., Rozzini L., Prelle A., Gennuso M., Villani D., Raimondi M. C., Gentile S., Bellelli G., Morandi A., Turco R., Bellandi D., Carbone P., Abruzzi L., Bettoni L., Bianchetti A., Facchi E., Di Fazio I., Turla M., Cotelli M. S., Volta G. D., Bigni B., Bilotti G., Vollaro S., Rozzini R., Boffelli S., Cappuccio M., Conti M. Z., Guizzetti G., Defanti C., Mirabile D., Fascendini S., Manzoni L., Salvi G. P., Belotti G., Cavaliere S., Fiacco F., Valente L., Ciccone A., Lanari A., Selletti L., Palmerini F., Avanzi S., Vezzadini G., Boccardi, M, Altomare, D, Ferrari, C, Festari, C, Antelmi, L, Pievani, M, Tarallo, A, Muscio, C, Guerra, U, Paghera, B, Padovani, A, Frisoni, G, Zanetti, O, Anzola, G, Bertocchi, M, Chito, E, Galluzzi, S, Geroldi, C, Lussignoli, G, Mattioli, F, Moretti, D, Pizzocaro, C, Borroni, B, Rozzini, L, Prelle, A, Gennuso, M, Villani, D, Raimondi, M, Gentile, S, Bellelli, G, Morandi, A, Turco, R, Bellandi, D, Carbone, P, Abruzzi, L, Bettoni, L, Bianchetti, A, Facchi, E, Di Fazio, I, Turla, M, Cotelli, M, Volta, G, Bigni, B, Bilotti, G, Vollaro, S, Rozzini, R, Boffelli, S, Cappuccio, M, Conti, M, Guizzetti, G, Defanti, C, Mirabile, D, Fascendini, S, Manzoni, L, Salvi, G, Belotti, G, Cavaliere, S, Fiacco, F, Valente, L, Ciccone, A, Lanari, A, Selletti, L, Palmerini, F, Avanzi, S, Vezzadini, G, Boccardi M., Altomare D., Ferrari C., Festari C., Antelmi L., Pievani M., Tarallo A., Muscio C., Guerra U. P., Paghera B., Padovani A., Frisoni G. B., Zanetti O., Anzola G. P., Bertocchi M., Chito E., Galluzzi S., Geroldi C., Lussignoli G., Mattioli F., Moretti D., Pizzocaro C., Borroni B., Rozzini L., Prelle A., Gennuso M., Villani D., Raimondi M. C., Gentile S., Bellelli G., Morandi A., Turco R., Bellandi D., Carbone P., Abruzzi L., Bettoni L., Bianchetti A., Facchi E., Di Fazio I., Turla M., Cotelli M. S., Volta G. D., Bigni B., Bilotti G., Vollaro S., Rozzini R., Boffelli S., Cappuccio M., Conti M. Z., Guizzetti G., Defanti C., Mirabile D., Fascendini S., Manzoni L., Salvi G. P., Belotti G., Cavaliere S., Fiacco F., Valente L., Ciccone A., Lanari A., Selletti L., Palmerini F., Avanzi S., and Vezzadini G.

Abstract

Background: Beliefs of dementia experts about the pathogenic role of amyloid in Alzheimer's disease (AD) may affect the use of amyloid positron emission tomography (PET). Objective:To assess the role attributed to amyloid in AD pathogenesis by Italian dementia experts, and whether this modulates the impact of amyloid PET results in their diagnostic workup. Methods: 22 dementia experts rated their beliefs about the pathogenic role of amyloid. Then, we asked them to rate the probability of change in diagnosis based on the result of amyloid PET for 7 case vignettes, depicting patients who initially received a diagnosis based on a comprehensive workup and later received amyloid PET results consistent or inconsistent with the clinical picture. Results: 55% of the experts assigned a dominant role to amyloid, and 32% attributed a similar role to amyloid and tau in AD pathogenesis. The probability of change in diagnosis ranged from 17% (SD = 21.6) for cases with consistent to 51% (SD = 34) for cases with inconsistent PET versus clinical data. Diagnostic change was not biased by the clinicians' beliefs about AD pathogenesis. Conclusions: This work supports an unbiased interpretation of amyloid PET across different beliefs about the pathogenic role of amyloid, and a belief -independent reluctance to change diagnosis in cases where change is expected and recommended. (C) 2015 S. Karger AG, Basel

Published
2016

30. Assessment of the incremental diagnostic value of florbetapir F 18 imaging in patients with cognitive impairment: The incremental diagnostic value of amyloid PET with [18F]-florbetapir (INDIA-FBP) study

Author

Boccardi, M, Altomare, D, Ferrari, C, Festari, C, Guerra, U, Paghera, B, Pizzocaro, C, Lussignoli, G, Geroldi, C, Zanetti, O, Cotelli, M, Turla, M, Borroni, B, Rozzini, L, Mirabile, D, Defanti, C, Gennuso, M, Prelle, A, Gentile, S, Morandi, A, Vollaro, S, Volta, G, Bianchetti, A, Conti, M, Cappuccio, M, Carbone, P, Bellandi, D, Abruzzi, L, Bettoni, L, Villani, D, Raimondi, M, Lanari, A, Ciccone, A, Facchi, E, Di Fazio, I, Rozzini, R, Boffelli, S, Manzoni, L, Salvi, G, Cavaliere, S, Belotti, G, Avanzi, S, Pasqualetti, P, Muscio, C, Padovani, A, Frisoni, G, Antelmi, L, Galluzzi, S, Pievani, M, Redolfi, A, Tarallo, A, Arora, A, Bertocchi, M, Chito, E, Moretti, D, Giubbini, R, Rodella, C, Camoni, L, Massetti, V, Andreoli, M, Bellelli, G, Fascendini, S, Mattioli, F, Turco, R, Vezzadini, G, Raimondi, V, Mondini, S, Zanacchi, E, Grigolo, M, Pezzini, A, Bilotti, G, Bigni, B, Zavarise, P, Ngonga, G, Anzola, G, Turrone, R, Guizzetti, G, Zanetti, M, Boccardi M., Altomare D., Ferrari C., Festari C., Guerra U. P., Paghera B., Pizzocaro C., Lussignoli G., Geroldi C., Zanetti O., Cotelli M. S., Turla M., Borroni B., Rozzini L., Mirabile D., Defanti C., Gennuso M., Prelle A., Gentile S., Morandi A., Vollaro S., Volta G. D., Bianchetti A., Conti M. Z., Cappuccio M., Carbone P., Bellandi D., Abruzzi L., Bettoni L., Villani D., Raimondi M. C., Lanari A., Ciccone A., Facchi E., Di Fazio I., Rozzini R., Boffelli S., Manzoni L., Salvi G. P., Cavaliere S., Belotti G., Avanzi S., Pasqualetti P., Muscio C., Padovani A., Frisoni G. B., Antelmi L., Galluzzi S., Pievani M., Redolfi A., Tarallo A., Arora A., Bertocchi M., Chito E., Moretti D. V., Giubbini R., Rodella C., Camoni L., Massetti V., Andreoli M., Bellelli G., Fascendini S., Mattioli F., Turco R., Vezzadini G., Raimondi V., Mondini S., Zanacchi E. C., Grigolo M., Pezzini A., Bilotti G., Bigni B., Zavarise P., Ngonga G., Anzola G. P., Turrone R., Guizzetti G., Zanetti M., Boccardi, M, Altomare, D, Ferrari, C, Festari, C, Guerra, U, Paghera, B, Pizzocaro, C, Lussignoli, G, Geroldi, C, Zanetti, O, Cotelli, M, Turla, M, Borroni, B, Rozzini, L, Mirabile, D, Defanti, C, Gennuso, M, Prelle, A, Gentile, S, Morandi, A, Vollaro, S, Volta, G, Bianchetti, A, Conti, M, Cappuccio, M, Carbone, P, Bellandi, D, Abruzzi, L, Bettoni, L, Villani, D, Raimondi, M, Lanari, A, Ciccone, A, Facchi, E, Di Fazio, I, Rozzini, R, Boffelli, S, Manzoni, L, Salvi, G, Cavaliere, S, Belotti, G, Avanzi, S, Pasqualetti, P, Muscio, C, Padovani, A, Frisoni, G, Antelmi, L, Galluzzi, S, Pievani, M, Redolfi, A, Tarallo, A, Arora, A, Bertocchi, M, Chito, E, Moretti, D, Giubbini, R, Rodella, C, Camoni, L, Massetti, V, Andreoli, M, Bellelli, G, Fascendini, S, Mattioli, F, Turco, R, Vezzadini, G, Raimondi, V, Mondini, S, Zanacchi, E, Grigolo, M, Pezzini, A, Bilotti, G, Bigni, B, Zavarise, P, Ngonga, G, Anzola, G, Turrone, R, Guizzetti, G, Zanetti, M, Boccardi M., Altomare D., Ferrari C., Festari C., Guerra U. P., Paghera B., Pizzocaro C., Lussignoli G., Geroldi C., Zanetti O., Cotelli M. S., Turla M., Borroni B., Rozzini L., Mirabile D., Defanti C., Gennuso M., Prelle A., Gentile S., Morandi A., Vollaro S., Volta G. D., Bianchetti A., Conti M. Z., Cappuccio M., Carbone P., Bellandi D., Abruzzi L., Bettoni L., Villani D., Raimondi M. C., Lanari A., Ciccone A., Facchi E., Di Fazio I., Rozzini R., Boffelli S., Manzoni L., Salvi G. P., Cavaliere S., Belotti G., Avanzi S., Pasqualetti P., Muscio C., Padovani A., Frisoni G. B., Antelmi L., Galluzzi S., Pievani M., Redolfi A., Tarallo A., Arora A., Bertocchi M., Chito E., Moretti D. V., Giubbini R., Rodella C., Camoni L., Massetti V., Andreoli M., Bellelli G., Fascendini S., Mattioli F., Turco R., Vezzadini G., Raimondi V., Mondini S., Zanacchi E. C., Grigolo M., Pezzini A., Bilotti G., Bigni B., Zavarise P., Ngonga G., Anzola G. P., Turrone R., Guizzetti G., and Zanetti M.

Abstract

IMPORTANCE Cerebral amyloidosis is a key abnormality in Alzheimer disease (AD) and can be detected in vivo with positron emission tomography (PET) ligands. Although amyloid PET has clearly demonstrated analytical validity, its clinical utility is debated. OBJECTIVE To evaluate the incremental diagnostic value of amyloid PET with florbetapir F 18 in addition to the routine clinical diagnostic assessment of patients evaluated for cognitive impairment. DESIGN, SETTING, AND PARTICIPANTS The Incremental Diagnostic Value ofAmyloid PET With [18F]-Florbetapir (INDIA-FBP) Study is a multicenter study involving 18 AD evaluation units from eastern Lombardy, Northern Italy, 228 consecutive adults with cognitive impairmentwere evaluated for AD and other causes of cognitive decline, with a prescan diagnostic confidence of AD between 15%and 85%. Participants underwent routine clinical and instrumental diagnostic assessment. A prescan diagnosiswas made, diagnostic confidencewas estimated, and drug treatmentwas provided. At the time of thisworkup, an amyloid PET/computed tomographic scanwas performed, and the resultwas communicated to physicians afterworkup completion. Physicianswere asked to review the diagnosis, diagnostic confidence, and treatment after the scan. The studywas conducted from August 5, 2013, to December 31, 2014. MAIN OUTCOMES AND MEASURES Primary outcomeswere prescan to postscan changes of diagnosis, diagnostic confidence, and treatment. RESULTS Of the 228 participants, 107 (46%) were male; mean (SD) age was 70.5 (7) years. Diagnostic change occurred in 46 patients (79%) having both a previous diagnosis of AD and an amyloid-negative scan (P < .001) and in 16 (53%) of those with non-AD diagnoses and an amyloid-positive scan (P < .001). Diagnostic confidence in AD diagnosis increased by 15.2%in amyloid-positive (P < .001; effect size Cohen d = 1.04) and decreased by 29.9%in amyloid-negative (P < .001; d = -1.19) scans. Acetylcholinesterase inhibitors and

Published
2016

31. Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

Author

Young, A. L., Marinescu, R. V., Oxtoby, N. P., Bocchetta, M., Yong, K., Firth, N. C., Cash, D. M., Thomas, D. L., Dick, K. M., Cardoso, J., van Swieten, J., Borroni, B., Galimberti, D., Masellis, M., Tartaglia, M. C., Rowe, J. B., Graff, C., Tagliavini, F., Frisoni, G. B., Laforce, R., Finger, E., de Mendonca, A., Sorbi, S., Warren, J. D., Crutch, S., Fox, N. C., Ourselin, S., Schott, J. M., Rohrer, J. D., Alexander, D. C., Andersson, C., Archetti, S., Arighi, A., Benussi, L., Binetti, G., Black, S., Cosseddu, M., Fallstrom, M., Ferreira, C., Fenoglio, C., Freedman, M., Fumagalli, G. G., Gazzina, S., Ghidoni, R., Grisoli, M., Jelic, V., Jiskoot, L., Keren, R., Lombardi, G., Maruta, C., Meeter, L., Mead, S., van Minkelen, R., Nacmias, B., Oijerstedt, L., Padovani, A., Panman, J., Pievani, M., Polito, C., Premi, E., Prioni, S., Rademakers, R., Redaelli, V., Rogaeva, E., Rossi, G., Rossor, M., Scarpini, E., Tang-Wai, D., Thonberg, H., Tiraboschi, P., Verdelho, A., Weiner, M. W., Aisen, P., Petersen, R., Jack, C. R., Jagust, W., Trojanowki, J. Q., Toga, A. W., Beckett, L., Green, R. C., Saykin, A. J., Morris, J., Shaw, L. M., Khachaturian, Z., Sorensen, G., Kuller, L., Raichle, M., Paul, S., Davies, P., Fillit, H., Hefti, F., Holtzman, D., Mesulam, M. M., Potter, W., Snyder, P., Schwartz, A., Montine, T., Thomas, R. G., Donohue, M., Walter, S., Gessert, D., Sather, T., Jiminez, G., Harvey, D., Bernstein, M., Thompson, P., Schuff, N., Borowski, B., Gunter, J., Senjem, M., Vemuri, P., Jones, D., Kantarci, K., Ward, C., Koeppe, R. A., Foster, N., Reiman, E. M., Chen, K., Mathis, C., Landau, S., Cairns, N. J., Householder, E., Taylor-Reinwald, L., Lee, V., Korecka, M., Figurski, M., Crawford, K., Neu, S., Foroud, T. M., Potkin, S., Shen, L., Faber, K., Kim, S., Nho, K., Thal, L., Buckholtz, N., Albert, M., Frank, R., Hsiao, J., Kaye, J., Quinn, J., Lind, B., Carter, R., Dolen, S., Schneider, L. S., Pawluczyk, S., Beccera, M., Teodoro, L., Spann, B. M., Brewer, J., Vanderswag, H., Fleisher, A., Heidebrink, J. L., Lord, J. L., Mason, S. S., Albers, C. S., Knopman, D., Johnson, K., Doody, R. S., Villanueva-Meyer, J., Chowdhury, M., Rountree, S., Dang, M., Stern, Y., Honig, L. S., Bell, K. L., Ances, B., Carroll, M., Leon, S., Mintun, M. A., Schneider, S., Oliver, A., Marson, D., Griffith, R., Clark, D., Geldmacher, D., Brockington, J., Roberson, E., Grossman, H., Mitsis, E., de Toledo-Morrell, L., Shah, R. C., Duara, R., Varon, D., Greig, M. T., Roberts, P., Onyike, C., D'Agostino, D., Kielb, S., Galvin, J. E., Cerbone, B., Michel, C. A., Rusinek, H., de Leon, M. J., Glodzik, L., De Santi, S., Doraiswamy, P. M., Petrella, J. R., Wong, T. Z., Arnold, S. E., Karlawish, J. H., Wolk, D., Smith, C. D., Jicha, G., Hardy, P., Sinha, P., Oates, E., Conrad, G., Lopez, O. L., Oakley, M. A., Simpson, D. M., Porsteinsson, A. P., Goldstein, B. S., Martin, K., Makino, K. M., Ismail, M. S., Brand, C., Mulnard, R. A., Thai, G., Mc-Adams-Ortiz, C., Womack, K., Mathews, D., Quiceno, M., Diaz-Arrastia, R., King, R., Weiner, M., Martin-Cook, K., Devous, M., Levey, A. I., Lah, J. J., Cellar, J. S., Burns, J. M., Anderson, H. S., Swerdlow, R. H., Apostolova, L., Tingus, K., Woo, E., Silverman, D. H., P. H., Lu, Bartzokis, G., Graff-Radford, N. R., Parfitt, F., Kendall, T., Johnson, H., Farlow, M. R., Hake, A. M., Matthews, B. R., Herring, S., Hunt, C., van Dyck, C. H., Carson, R. E., Macavoy, M. G., Chertkow, H., Bergman, H., Hosein, C., Stefanovic, B., Caldwell, C., Hsiung, G. -Y. R., Feldman, H., Mudge, B., Assaly, M., Kertesz, A., Rogers, J., Bernick, C., Munic, D., Kerwin, D., Mesulam, M. -M., Lipowski, K., C. -K., Wu, Johnson, N., Sadowsky, C., Martinez, W., Villena, T., Turner, R. S., Reynolds, B., Sperling, R. A., Johnson, K. A., Marshall, G., Frey, M., Lane, B., Rosen, A., Tinklenberg, J., Sabbagh, M. N., Belden, C. M., Jacobson, S. A., Sirrel, S. A., Kowall, N., Killiany, R., Budson, A. E., Norbash, A., Johnson, P. L., Allard, J., Lerner, A., Ogrocki, P., Hudson, L., Fletcher, E., Carmichael, O., Olichney, J., Decarli, C., Kittur, S., Borrie, M., Lee, T. -Y., Bartha, R., Johnson, S., Asthana, S., Carlsson, C. M., Potkin, S. G., Preda, A., Nguyen, D., Tariot, P., Reeder, S., Bates, V., Capote, H., Rainka, M., Scharre, D. W., Kataki, M., Adeli, A., Zimmerman, E. A., Celmins, D., Brown, A. D., Pearlson, G. D., Blank, K., Anderson, K., Santulli, R. B., Kitzmiller, T. J., Schwartz, E. S., Sink, K. M., Williamson, J. D., Garg, P., Watkins, F., Ott, B. R., Querfurth, H., Tremont, G., Salloway, S., Malloy, P., Correia, S., Rosen, H. J., Miller, B. L., Mintzer, J., Spicer, K., Bachman, D., Pasternak, S., Rachinsky, I., Drost, D., Pomara, N., Hernando, R., Sarrael, A., Schultz, S. K., Ponto, L. L. B., Shim, H., Smith, K. E., Relkin, N., Chaing, G., Raudin, L., Smith, A., Fargher, K., Raj, B. A., Neylan, T., Grafman, J., Davis, M., Morrison, R., Hayes, J., Finley, S., Friedl, K., Fleischman, D., Arfanakis, K., James, O., Massoglia, D., Fruehling, J. J., Harding, S., Peskind, E. R., Petrie, E. C., Li, G., Yesavage, J. A., Taylor, J. L., and Furst, A. J.

Published
2018

33. Downregulation of exosomal miR-204-5p and miR-632 as a biomarker for FTD: a GENFI study

Author

Schneider, R., Mckeever, P., Kim, T., Graff, C., Van Swieten, J. C., Karydas, A., Boxer, A., Rosen, H., Miller, B. L., Laforce, R., Galimberti, D., Masellis, M., Borroni, B., Zhang, Z., Zinman, L., Rohrer, J. D., Tartaglia, M. C., Robertson, J., Andersson, C., Archetti, S., Arighi, A., Benussi, L., Binetti, G., Black, S., Bocchetta, M., Cash, D., Cosseddu, M., Dick, K., Fallström, M., Ferreira, C., Fenoglio, C., Fox, N., Freedman, M., Frisoni, G., Fumagalli, G., Gazzina, S., Ghidoni, R., Grisoli, M., Jelic, V., Jiskoot, L., Keren, R., Lombardi, G., Maruta, C., Meeter, L., van Minkelen, M., Nacmias, B., Öijerstedt, L., Ourselin, S., Padovani, A., Panman, J., Pievani, M., Polito, C., Premi, E., Prioni, S., Rademakers, R. Redaelli V., Rogaeva, E., Rossi, G., Rossor, M., Row, J., Scarpini, E., Tagliavini, F., Sorbi, S., Tang-Wai, D., Thomas, D., Thonberg, H., Tiraboschi, P., Verdelho, A., Warren, J., Neurology, Schneider, Raphael [0000-0003-1776-2418], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, Male, Aging, Neurodegenerative, Alzheimer's Disease, medicine.disease_cause, Exosomes, Medical and Health Sciences, 0302 clinical medicine, Mutation Carrier, Alzheimer's Disease Related Dementias (ADRD), screening and diagnosis, Mutation, biology, Cognitive Neurology, 3. Good health, Detection, Psychiatry and Mental health, Real-time polymerase chain reaction, Frontotemporal Dementia, Neurological, Cohort, Biomarker (medicine), Female, Biotechnology, Frontotemporal dementia, medicine.medical_specialty, Tau protein, Down-Regulation, Chromosome 9, tau Proteins, 03 medical and health sciences, Rare Diseases, Internal medicine, mental disorders, Acquired Cognitive Impairment, Genetics, medicine, Humans, Neurology & Neurosurgery, business.industry, Prevention, Psychology and Cognitive Sciences, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Genetic FTD Initiative, medicine.disease, Brain Disorders, 4.1 Discovery and preclinical testing of markers and technologies, MicroRNAs, 030104 developmental biology, biology.protein, Dementia, Surgery, Neurology (clinical), business, 030217 neurology & neurosurgery, Biomarkers
Abstract

ObjectiveTo determine whether exosomal microRNAs (miRNAs) in cerebrospinal fluid (CSF) of patients with frontotemporal dementia (FTD) can serve as diagnostic biomarkers, we assessed miRNA expression in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort and in sporadic FTD.MethodsGENFI participants were either carriers of a pathogenic mutation in progranulin, chromosome 9 open reading frame 72 or microtubule-associated protein tau or were at risk of carrying a mutation because a first-degree relative was a known symptomatic mutation carrier. Exosomes were isolated from CSF of 23 presymptomatic and 15 symptomatic mutation carriers and 11 healthy non-mutation carriers. Expression of 752 miRNAs was measured using quantitative PCR (qPCR) arrays and validated by qPCR using individual primers. MiRNAs found differentially expressed in symptomatic compared with presymptomatic mutation carriers were further evaluated in a cohort of 17 patients with sporadic FTD, 13 patients with sporadic Alzheimer’s disease (AD) and 10 healthy controls (HCs) of similar age.ResultsIn the GENFI cohort, miR-204-5p and miR-632 were significantly decreased in symptomatic compared with presymptomatic mutation carriers. Decrease of miR-204-5p and miR-632 revealed receiver operator characteristics with an area of 0.89 (90% CI 0.79 to 0.98) and 0.81 (90% CI 0.68 to 0.93), respectively, and when combined an area of 0.93 (90% CI 0.87 to 0.99). In sporadic FTD, only miR-632 was significantly decreased compared with AD and HCs. Decrease of miR-632 revealed an area of 0.90 (90% CI 0.81 to 0.98).ConclusionsExosomal miR-204-5p and miR-632 have potential as diagnostic biomarkers for genetic FTD and miR-632 also for sporadic FTD.

Published
2017
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34. Do Beliefs about the Pathogenetic Role of Amyloid Affect the Interpretation of Amyloid PET in the Clinic

Author

Boccardi M., Altomare D., Ferrari C., Festari C., Antelmi L., Pievani M., Tarallo A., Muscio C., Guerra U. P., Paghera B., Padovani A., Frisoni G. B., Zanetti O., Anzola G. P., Bertocchi M., Chito E., Galluzzi S., Geroldi C., Lussignoli G., Mattioli F., Moretti D., Pizzocaro C., Borroni B., Rozzini L., Prelle A., Gennuso M., Villani D., Raimondi M. C., Gentile S., Bellelli G., Morandi A., Turco R., Bellandi D., Carbone P., Abruzzi L., Bettoni L., Bianchetti A., Facchi E., Di Fazio I., Turla M., Cotelli M. S., Volta G. D., Bigni B., Bilotti G., Vollaro S., Rozzini R., Boffelli S., Cappuccio M., Conti M. Z., Guizzetti G., Defanti C., Mirabile D., Fascendini S., Manzoni L., Salvi G. P., Belotti G., Cavaliere S., Fiacco F., Valente L., Ciccone A., Lanari A., Selletti L., Palmerini F., Avanzi S., Vezzadini G., Boccardi, M, Altomare, D, Ferrari, C, Festari, C, Antelmi, L, Pievani, M, Tarallo, A, Muscio, C, Guerra, U, Paghera, B, Padovani, A, Frisoni, G, Zanetti, O, Anzola, G, Bertocchi, M, Chito, E, Galluzzi, S, Geroldi, C, Lussignoli, G, Mattioli, F, Moretti, D, Pizzocaro, C, Borroni, B, Rozzini, L, Prelle, A, Gennuso, M, Villani, D, Raimondi, M, Gentile, S, Bellelli, G, Morandi, A, Turco, R, Bellandi, D, Carbone, P, Abruzzi, L, Bettoni, L, Bianchetti, A, Facchi, E, Di Fazio, I, Turla, M, Cotelli, M, Volta, G, Bigni, B, Bilotti, G, Vollaro, S, Rozzini, R, Boffelli, S, Cappuccio, M, Conti, M, Guizzetti, G, Defanti, C, Mirabile, D, Fascendini, S, Manzoni, L, Salvi, G, Belotti, G, Cavaliere, S, Fiacco, F, Valente, L, Ciccone, A, Lanari, A, Selletti, L, Palmerini, F, Avanzi, S, and Vezzadini, G

Subjects
0301 basic medicine, Amyloid, Attitude of Health Personnel, Tau Proteins/metabolism, Amyloid pet, tau Proteins, Pilot Projects, Disease, Affect (psychology), Amyloid/metabolism, Diagnosis, Differential, 03 medical and health sciences, ddc:616.89, Alzheimer's disease pathogenesis, Amyloid positron emission tomography, Differential diagnosis, Incremental diagnostic value, 0302 clinical medicine, Neuroimaging, Positron-Emission Tomography/psychology, Alzheimer Disease, Physicians, Physicians/psychology, mental disorders, Diagnosis, Medicine, Dementia, Humans, business.industry, Alzheimer Disease/diagnosis/diagnostic imaging/metabolism, medicine.disease, eye diseases, 030104 developmental biology, Neurology, Italy, Positron-Emission Tomography, Differential, sense organs, Neurology (clinical), Alzheimer's disease, business, Neuroscience, 030217 neurology & neurosurgery
Abstract

Background: Beliefs of dementia experts about the pathogenic role of amyloid in Alzheimer's disease (AD) may affect the use of amyloid positron emission tomography (PET). Objective: To assess the role attributed to amyloid in AD pathogenesis by Italian dementia experts, and whether this modulates the impact of amyloid PET results in their diagnostic workup. Methods: 22 dementia experts rated their beliefs about the pathogenic role of amyloid. Then, we asked them to rate the probability of change in diagnosis based on the result of amyloid PET for 7 case vignettes, depicting patients who initially received a diagnosis based on a comprehensive workup and later received amyloid PET results consistent or inconsistent with the clinical picture. Results: 55% of the experts assigned a dominant role to amyloid, and 32% attributed a similar role to amyloid and tau in AD pathogenesis. The probability of change in diagnosis ranged from 17% (SD = 21.6) for cases with consistent to 51% (SD = 34) for cases with inconsistent PET versus clinical data. Diagnostic change was not biased by the clinicians' beliefs about AD pathogenesis. Conclusions: This work supports an unbiased interpretation of amyloid PET across different beliefs about the pathogenic role of amyloid, and a belief-independent reluctance to change diagnosis in cases where change is expected and recommended.

Published
2016

35. Association of postoperative delirium with markers of neurodegeneration and brain amyloidosis: a pilot study

Author

Rolandi, E, Cavedo, E, Pievani, M, Galluzzi, S, Ribaldi, F, Buckley, C, Cunningham, C, Guerra, U, Musarra, M, Morzenti, S, Magnaldi, S, Patassini, M, Terragnoli, F, Matascioli, L, Franzoni, S, Annoni, G, Carnevali, L, Bellelli, G, Frisoni, G, Rolandi, E, Cavedo, E, Pievani, M, Galluzzi, S, Ribaldi, F, Buckley, C, Cunningham, C, Guerra, U, Musarra, M, Morzenti, S, Magnaldi, S, Patassini, M, Terragnoli, F, Matascioli, L, Franzoni, S, Annoni, G, Carnevali, L, Bellelli, G, and Frisoni, G

Abstract

The aim of the study was to investigate the association between postoperative delirium (POD) and in vivo markers of Alzheimer's disease pathology in nondemented hip fracture surgery patients. POD was assessed with the Confusion Assessment Method. Amyloid load was quantified on 18F-Flutemetamol positron emission tomography images as standardized uptake value ratio. Secondary outcome measures were gray matter volumes, white matter integrity, and functional connectivity at rest. All the patients with POD (POD+, N = 5) were amyloid negative (standardized uptake value ratio <0.59), whereas 6 out of 11 patients without POD (POD−) showed brain amyloid positivity. POD+ compared to POD− displayed: lower gray matter volumes in the amygdala (p = 0.003), in the middle temporal gyrus and in the anterior cingulate cortex (p < 0.001), increased diffusivity in the genu of the corpus callosum and in the anterior corona radiata (p < 0.05), and higher functional connectivity within the default mode network (p < 0.001). POD patients showed altered gray and white matter integrity in the fronto-limbic regions in absence of brain amyloidosis. Based on this preliminary investigation, delirium pathophysiology might be independent of Alzheimer's disease. Future studies on larger samples are needed to confirm this hypothesis.

Published
2018

36. Hippocampal atrophy in people with memory deficits: results from the population-based IPREA study

Author

Ferrarini L, van Lew B, Reiber JH, Gandin C, Galluzzo L, Scafato E, FrisoniGB, Milles J, Pievani M, IPREA Working Group: Scafato E, Farchi G, Giampaoli S, Mariotti S, Ghirini S, Martire S, Di Pasquale L, Maggi S, Crepaldi G, Enzi G, Gallina P, Inzitari D, Baldereschi M, Di Carlo A, Frisoni GB, Galluzzi S, Gandolfo C, Conti M, Postacchini D, Cruciani G, Giuli C, Capurso A, Solfrizzi V, Panza F, Rengo F, ABETE, PASQUALE, Motta M, Negrini R, Forti P, Tabanelli P, Cocchi A, Zuccal G, Cacciatore F, Calabrese C, Sica G, Estraneo A, Foundation SM, Consoli D, Naso F, Torcasio G, Valentia V, Mecocci P, Rinaldi P, Serafini V, Senin U., Ferrarini, L, van Lew, B, Reiber, Jh, Gandin, C, Galluzzo, L, Scafato, E, Frisonigb, Milles, J, Pievani, M, IPREA Working Group: Scafato, E, Farchi, G, Giampaoli, S, Mariotti, S, Ghirini, S, Martire, S, Di Pasquale, L, Maggi, S, Crepaldi, G, Enzi, G, Gallina, P, Inzitari, D, Baldereschi, M, Di Carlo, A, Frisoni, Gb, Galluzzi, S, Gandolfo, C, Conti, M, Postacchini, D, Cruciani, G, Giuli, C, Capurso, A, Solfrizzi, V, Panza, F, Rengo, F, Abete, Pasquale, Motta, M, Negrini, R, Forti, P, Tabanelli, P, Cocchi, A, Zuccal, G, Cacciatore, F, Calabrese, C, Sica, G, Estraneo, A, Foundation, Sm, Consoli, D, Naso, F, Torcasio, G, Valentia, V, Mecocci, P, Rinaldi, P, Serafini, V, and Senin, U.

Subjects
medicine.medical_specialty, education.field_of_study, business.industry, Population, Not Otherwise Specified, Hippocampus, Audiology, Hippocampal formation, medicine.disease, population-based, memory, Psychiatry and Mental health, Clinical Psychology, Atrophy, hippocampal atrophy, medicine, Dementia, Memory impairment, Geriatrics and Gerontology, Alzheimer's disease, business, education, Gerontology, MRI
Abstract

Background:Clinical studies have shown that hippocampal atrophy is present before dementia in people with memory deficits and can predict dementia development. The question remains whether this association holds in the general population. This is of interest for the possible use of hippocampal atrophy to screen population for preventive interventions. The aim of this study was to assess hippocampal volume and shape abnormalities in elderly adults with memory deficits in a cross-sectional population-based study.Methods:We included individuals participating in the Italian Project on the Epidemiology of Alzheimer Disease (IPREA) study: 75 cognitively normal individuals (HC), 31 individuals with memory deficits (MEM), and 31 individuals with memory deficits not otherwise specified (MEMnos). Hippocampal volumes and shape were extracted through manual tracing and the growing and adaptive meshes (GAMEs) shape-modeling algorithm. We investigated between-group differences in hippocampal volume and shape, and correlations with memory deficits.Results:In MEM participants, hippocampal volumes were significantly smaller than in HC and were mildly associated with worse memory scores. Memory-associated shape changes mapped to the anterior hippocampus. Shape-based analysis detected no significant difference between MEM and HC, while MEMnos showed shape changes in the posterior hippocampus compared with HC and MEM groups.Conclusions:These findings support the discriminant validity of hippocampal volumetry as a biomarker of memory impairment in the general population. The detection of shape changes in MEMnos but not in MEM participants suggests that shape-based biomarkers might lack sensitivity to detect Alzheimer's-like pathology in the general population.

Published
2014

37. The ε4 genotype of apolipoprotein E and white matter integrity in Alzheimer's disease

Author

Kljajevic, V, Meyer, P, Holzmann, C, Dyrba, M, Kasper, E, Bokde, Al, Fellgiebel, A, Meindl, T, Hampel, H, Teipel, S, EDSD study group, Agosta, F, Barkhof, F, Blautzik, J, Ewers, M, Filippi, M, Fischer, F, Frisoni, Gb, Frolich, L, Hauenstein, K, Hausner, L, Hentschel, F, Hull, M, Jessen, F, Kloppel, S, O'Dwyer, L, Pievani, M, Pouwels, Pj, Teipel, Sj, Kljajevic, V, Meyer, P, Holzmann, C, Dyrba, M, Kasper, E, Bokde, Al, Fellgiebel, A, Meindl, T, Hampel, H, Teipel, S, EDSD study, Group, Agosta, F, Barkhof, F, Blautzik, J, Ewers, M, Filippi, M, Fischer, F, Frisoni, Gb, Frolich, L, Hauenstein, K, Hausner, L, Hentschel, F, Hull, M, Jessen, F, Kloppel, S, O'Dwyer, L, Pievani, M, Pouwels, Pj, and Teipel, Sj

Subjects
Apolipoprotein E, Male, medicine.medical_specialty, Heterozygote, Genotype, Epidemiology, Apolipoprotein E4, genetics [Alzheimer Disease], Disease, White matter, Age and gender, Cellular and Molecular Neuroscience, pathology [Alzheimer Disease], Developmental Neuroscience, pathology [Brain], Alzheimer Disease, Internal medicine, pathology [White Matter], Fractional anisotropy, medicine, Humans, ddc:610, Allele, genetics [Apolipoprotein E4], Aged, Aged, 80 and over, Health Policy, Brain, Middle Aged, White Matter, Psychiatry and Mental health, Endocrinology, medicine.anatomical_structure, Diffusion Magnetic Resonance Imaging, Diffusion Tensor Imaging, Anisotropy, Female, Neurology (clinical), Geriatrics and Gerontology, Psychology, Neuroscience, Diffusion MRI
Abstract

In this multicenter study, we investigated a possible association between the APOE ε4 allele and white matter (WM) integrity in Alzheimer's disease (AD) using diffusion tensor imaging (DTI).We analyzed fractional anisotropy (FA) and mean diffusivity (MD) as indices of WM integrity in 70 AD patients (35 APOE ε4 carriers, 35 noncarriers) and 56 healthy control (HC) subjects (28 APOE ε4 carriers, 28 noncarriers). APOE ε4 carriers and noncarriers were matched for age and gender within each diagnostic group.We found significant effects of diagnosis (Pcorrected.05 [FWE]; i.e., smaller FA values and larger MD values in AD patients compared with HCs) and significant effects (P.001) of APOE ε4 carrier status on MD in HCs but not in AD subjects.The results indicate that APOE ε4 has a moderate effect on WM integrity in HCs, but no effect on WM integrity in manifest AD.

Published
2014
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38. Fractional anisotropy changes in Alzheimer's disease depend on the underlying fiber tract architecture: a multiparametric DTI study using joint independent component analysis

Author

Teipel SJ, Grothe MJ, Filippi M, Fellgiebel A, Dyrba M, Frisoni GB, Meindl T, Bokde ALW, Hampel H, Klöppel S, Hauenstein K, the EDSD study group, Agosta F, Barkhof F, Blautzik J, Bokde AL, Ewers M, Fischer F, Frolich L, Hausner L, Hentschel F, Hull M, Jessen F, Kljajevic V, Kloppel S, O'Dwyer L, Pievani M, Pouwels PJ, Teipel, Sj, Grothe, Mj, Filippi, M, Fellgiebel, A, Dyrba, M, Frisoni, Gb, Meindl, T, Bokde, Alw, Hampel, H, Klöppel, S, Hauenstein, K, the EDSD study, Group, Agosta, F, Barkhof, F, Blautzik, J, Bokde, Al, Ewers, M, Fischer, F, Frolich, L, Hausner, L, Hentschel, F, Hull, M, Jessen, F, Kljajevic, V, Kloppel, S, O'Dwyer, L, Pievani, M, and Pouwels, Pj

Subjects
Male, White Matter/pathology, pathology [Cognitive Dysfunction], pathology [Pyramidal Tracts], Alzheimer Disease/diagnosis/pathology, Pyramidal Tracts, Nerve Fibers, Myelinated, methods [Diffusion Tensor Imaging], pathology [Alzheimer Disease], ddc:616.89, pathology [Brain], methods [Image Processing, Computer-Assisted], pathology [White Matter], methods [Diffusion Magnetic Resonance Imaging], Image Processing, Computer-Assisted, Anisotropy, Nerve Degeneration/pathology, pathology [Axons], General Neuroscience, diagnosis [Alzheimer Disease], pathology [Nerve Degeneration], Brain, General Medicine, White Matter, Pyramidal Tracts/pathology, Diffusion Magnetic Resonance Imaging/methods, Europe, Psychiatry and Mental health, Clinical Psychology, medicine.anatomical_structure, Diffusion Tensor Imaging, Disease Progression, Female, Psychology, Image Processing, Computer-Assisted/methods, Fiber tract, White matter, Alzheimer Disease, Diffusion Tensor Imaging/methods, Fractional anisotropy, mental disorders, medicine, Dementia, Humans, Cognitive Dysfunction, Brain/pathology, ddc:610, Aged, Nerve Fibers, Myelinated/pathology, pathology [Nerve Fibers, Myelinated], Mild Cognitive Impairment/diagnosis/pathology, medicine.disease, Independent component analysis, Axons, Diffusion Magnetic Resonance Imaging, Axons/pathology, Early Diagnosis, diagnosis [Cognitive Dysfunction], Corticospinal tract, Nerve Degeneration, Geriatrics and Gerontology, Neuroscience, Diffusion MRI
Abstract

Diffusion tensor imaging (DTI) allows the simultaneous measurement of several diffusion indices that provide complementary information on the substrate of white matter alterations in neurodegenerative diseases. These indices include fractional anisotropy (FA) as measure of fiber tract integrity, and the mode of anisotropy (Mode) reflecting differences in the shape of the diffusion tensor. We used a multivariate approach based on joint independent component analysis of FA and Mode in a large sample of 138 subjects with Alzheimer's disease (AD) dementia, 37 subjects with cerebrospinal fluid biomarker positive mild cognitive impairment (MCI-AD), and 153 healthy elderly controls from the European DTI Study on Dementia to comprehensively study alterations of microstructural white matter integrity in AD dementia and predementia AD. We found a parallel decrease of FA and Mode in intracortically projecting fiber tracts, and a parallel increase of FA and Mode in the corticospinal tract in AD patients compared to controls. Subjects with MCI-AD showed a similar, but spatially more restricted pattern of diffusion changes. Our findings suggest an early axonal degeneration in intracortical projecting fiber tracts in dementia and predementia stages of AD. An increase of Mode, parallel to an increase of FA, in the corticospinal tract suggests a more linear shape of diffusion due to loss of crossing fibers along relatively preserved cortico-petal and cortico-fugal fiber tracts in AD. Supporting this interpretation, we found three populations of fiber tracts, namely cortico-petal and cortico-fugal, commissural, and intrahemispherically projecting fiber tracts, in the peak area of parallel FA and Mode increase.

Published
2014
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40. The topography of brain damage at different stages of Parkinson's disease

Author

Agosta F, Canu E, Stojković T, Pievani M, Tomić A, Sarro L, Dragašević N, Copetti M, Comi G, Kostić VS, Filippi M, Agosta, F, Canu, E, Stojkovic, T, Pievani, M, Tomic, A, Sarro, L, Dragasevic, N, Copetti, M, Comi, G, Kostic, V., Filippi, Massimo, Stojković, T, Tomić, A, Dragašević, N, Kostić, V, and Filippi, M

Subjects
Aged, 80 and over, Male, Brain Mapping, Echo-Planar Imaging, Brain, Parkinson Disease, Middle Aged, Neuropsychological Tests, Magnetic Resonance Imaging, Neural Pathways, Disease Progression, Image Processing, Computer-Assisted, Educational Status, Humans, Brain Damage, Chronic, Female, Age of Onset, Atrophy, Cognition Disorders, Biomarkers, Research Articles, Aged
Abstract

This study investigated gray matter (GM) and white matter (WM) damage in 89 patients at different clinical stages of Parkinson's disease (PD) (17 early, 46 mild, 14 moderate, and 12 severe) to differentiate the trajectories of tissue injury in this condition. PD patients had a very little GM atrophy even at the more advanced stages of the disease. Microstructural damage to the WM occurs with increasing PD severity and involves the brainstem, thalamocortical pathways, olfactory tracts, as well as the major interhemispheric, limbic, and extramotor association tracts. The most marked WM damage was found in moderate vs. mild cases. WM damage correlated with the degree of global cognitive deficits. WM abnormalities beyond the nigrostriatal system accumulate with increasing PD severity. WM damage is likely to contribute to the more severe motor and nonmotor dysfunctions occurring in patients at the later stages. Hum Brain Mapp 34:2798–2807, 2013. © 2012 Wiley Periodicals, Inc.

Published
2011

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