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3. Atypical brain FDG-PET patterns increase the risk of long-term cognitive and motor progression in Parkinson's disease

Author

Imarisio, A, Pilotto, A, Premi, E, Caminiti, S, Presotto, L, Sala, A, Zatti, C, Lupini, A, Turrone, R, Paghera, B, Borroni, B, Perani, D, Padovani, A, Imarisio A., Pilotto A., Premi E., Caminiti S. P., Presotto L., Sala A., Zatti C., Lupini A., Turrone R., Paghera B., Borroni B., Perani D., Padovani A., Imarisio, A, Pilotto, A, Premi, E, Caminiti, S, Presotto, L, Sala, A, Zatti, C, Lupini, A, Turrone, R, Paghera, B, Borroni, B, Perani, D, Padovani, A, Imarisio A., Pilotto A., Premi E., Caminiti S. P., Presotto L., Sala A., Zatti C., Lupini A., Turrone R., Paghera B., Borroni B., Perani D., and Padovani A.

Abstract

Introduction: Brain hypometabolism patterns have been previously associated with cognitive decline in Parkinson's disease (PD). Our aim is to evaluate the impact of single-subject fluorodeoxyglucose (FDG)-PET brain hypometabolism on long-term cognitive and motor outcomes in PD. Methods: Forty-nine non-demented PD patients with baseline brain FDG-PET data underwent an extensive clinical follow-up for 8 years. The ability of FDG-PET to predict long-term cognitive and motor progression was evaluated using Cox regression and mixed ANCOVA models. Results: Participants were classified according to FDG-PET pattern in PD with typical (n = 26) and atypical cortical metabolism (n = 23). Patients with atypical brain hypometabolic patterns showed higher incidence of dementia (60% vs 3%; HR = 18.3), hallucinations (56% vs 7%, HR = 7.3) and faster motor decline compared to typical pattern group. Conclusion: This study argues for specific patterns of FDG-PET cortical hypometabolism in PD as a prognostic marker for long term cognitive and motor outcomes at single-subject level.

Published
2023

4. Cerebellar and subcortical atrophy contribute to psychiatric symptoms in frontotemporal dementia

Author

Bussy, A., Levy, J., Best, T., Patel, R., Cupo, L., Van Langenhove, T., Nielsen, J., Pijnenburg, Y., Waldö, M., Remes, A., Schroeter, M., Santana, I., Pasquier, F., Otto, M., Danek, A., Levin, J., Le Ber, I., Vandenberghe, R., Synofzik, M., Moreno, F., de Mendonça, A., Sanchez‐Valle, R., Laforce, R., Langheinrich, T., Gerhard, A., Graff, C., Butler, C., Sorbi, S., Jiskoot, L., Seelaar, H., van Swieten, J., Finger, E., Tartaglia, M., Masellis, M., Tiraboschi, P., Galimberti, D., Borroni, B., Rowe, J., Bocchetta, M., Rohrer, J., Devenyi, G., Chakravarty, M., Ducharme, S., Esteve, A., Nelson, A., Bouzigues, A., Heller, C., Greaves, C., Cash, D., Thomas, D., Todd, E., Benotmane, H., Zetterberg, H., Swift, I., Nicholas, J., Samra, K., Russell, L., Shafei, R., Convery, R., Timberlake, C., Cope, T., Rittman, T., Benussi, A., Premi, E., Gasparotti, R., Archetti, S., Gazzina, S., Cantoni, V., Arighi, A., Fenoglio, C., Scarpini, E., Fumagalli, G., Borracci, V., Rossi, G., Giaccone, G., Di Fede, G., Caroppo, P., Prioni, S., Redaelli, V., Tang‐Wai, D., Rogaeva, E., Castelo‐Branco, M., Freedman, M., Keren, R., Black, S., Mitchell, S., Shoesmith, C., Bartha, R., Rademakers, R., Poos, J., Papma, J., Giannini, L., van Minkelen, R., Nacmias, B., Ferrari, C., Polito, C., Lombardi, G., Bessi, V., Veldsman, M., Andersson, C., Thonberg, H., Öijerstedt, L., Jelic, V., Thompson, P., Lladó, A., Antonell, A., Olives, J., Balasa, M., Bargalló, N., Borrego‐Ecija, S., Verdelho, A., Maruta, C., Ferreira, C., Miltenberger, G., do Couto, F., Gabilondo, A., Gorostidi, A., Villanua, J., Cañada, M., Tainta, M., Zulaica, M., Barandiaran, M., Alves, P., Bender, B., Wilke, C., Graf, L., Vogels, A., Vandenbulcke, M., Van Damme, P., Bruffaerts, R., Poesen, K., Rosa‐Neto, P., Gauthier, S., Camuzat, A., Brice, A., Bertrand, A., Funkiewiez, A., Rinaldi, D., Saracino, D., Colliot, O., Sayah, S., Prix, C., Wlasich, E., Wagemann, O., Loosli, S., Schönecker, S., Hoegen, T., Lombardi, J., Anderl‐Straub, S., Rollin, A., Kuchcinski, G., Bertoux, M., Lebouvier, T., Deramecourt, V., Santiago, B., Duro, D., Leitão, M., Almeida, M., Tábuas‐Pereira, M., Afonso, S., Engel, A., Polyakova, M., Erasmus MC other, Neurology, Radiology & Nuclear Medicine, Clinical Genetics, GENetic Frontotemporal dementia Initiative (GENFI), Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Engel, Annerose, Polyakova, Maryna, Esteve, Aitana Sogorb, Nelson, Annabel, Bouzigues, Arabella, Heller, Carolin, Greaves, Caroline V, Cash, David, Thomas, David L, Todd, Emily, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J, Nicholas, Jennifer, Samra, Kiran, Russell, Lucy L, Bocchetta, Martina, Shafei, Rachelle, Convery, Rhian S, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Bussy, Aurélie [0000-0001-6695-9941], Nielsen, Jørgen E [0000-0003-0453-5582], Borroni, Barbara [0000-0001-9340-9814], Bocchetta, Martina [0000-0003-1814-5024], Devenyi, Gabriel A [0000-0002-7766-1187], Apollo - University of Cambridge Repository, and Amsterdam Neuroscience - Neurodegeneration

Subjects
C9orf72 Protein, Radiological and Ultrasound Technology, Medizin, frontotemporal dementia, Neurology, Frontotemporal Dementia, Cerebellum, Humans, magnetic resonance imaging, genetics, neuropsychiatry, Radiology, Nuclear Medicine and imaging, Human medicine, ddc:610, Neurology (clinical), Atrophy, Anatomy, genetics [Frontotemporal Dementia], genetics [C9orf72 Protein]
Abstract

Funder: Alzheimer Society of Canada; Id: http://dx.doi.org/10.13039/501100000143, Funder: Weston Brain Institute; Id: http://dx.doi.org/10.13039/100012479, Funder: Fonds de Recherche du Québec ‐ Santé, Funder: Canadian Institutes of Health Research; Id: http://dx.doi.org/10.13039/501100000024, Funder: NIHR Rare Diseases Translational Research Collaboration, Funder: Deutsche Forschungsgemeinschaft; Id: http://dx.doi.org/10.13039/501100001659, Recent studies have reported early cerebellar and subcortical impact in the disease progression of genetic frontotemporal dementia (FTD) due to microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72). However, the cerebello-subcortical circuitry in FTD has been understudied despite its essential role in cognition and behaviors related to FTD symptomatology. The present study aims to investigate the association between cerebellar and subcortical atrophy, and neuropsychiatric symptoms across genetic mutations. Our study included 983 participants from the Genetic Frontotemporal dementia Initiative including mutation carriers and noncarrier first-degree relatives of known symptomatic carriers. Voxel-wise analysis of the thalamus, striatum, globus pallidus, amygdala, and the cerebellum was performed, and partial least squares analyses (PLS) were used to link morphometry and behavior. In presymptomatic C9orf72 expansion carriers, thalamic atrophy was found compared to noncarriers, suggesting the importance of this structure in FTD prodromes. PLS analyses demonstrated that the cerebello-subcortical circuitry is related to neuropsychiatric symptoms, with significant overlap in brain/behavior patterns, but also specificity for each genetic mutation group. The largest differences were in the cerebellar atrophy (larger extent in C9orf72 expansion group) and more prominent amygdalar volume reduction in the MAPT group. Brain scores in the C9orf72 expansion carriers and MAPT carriers demonstrated covariation patterns concordant with atrophy patterns detectable up to 20 years before expected symptom onset. Overall, these results demonstrated the important role of the subcortical structures in genetic FTD symptom expression, particularly the cerebellum in C9orf72 and the amygdala in MAPT carriers.

Published
2023
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5. Motor symptoms in genetic frontotemporal dementia: developing a new module for clinical rating scales

Author

Samra, K, MacDougall, AM, Peakman, G, Bouzigues, A, Bocchetta, M, Cash, DM, Greaves, CV, Convery, RS, van Swieten, JC, Jiskoot, L, Seelaar, H, Butler, CR, Fenoglio, C, Rohrer, JD, Gerhard, A, Ducharme, S, Le Ber, I, Tiraboschi, P, Santana, I, Pasquier, F, Levin, J, Shoesmith, C, Otto, M, Russell, LL, Nelson, A, Cash, D, Thomas, DL, Todd, E, Ferrari, C, Benotmane, H, Timberlake, C, Gabilondo, A, Cope, T, Rittman, T, Benussi, A, Premi, E, Gasparotti, R, Thompson, P, Archetti, S, Fumagalli, G, do Couto, FS, Borracci, V, Polito, C, Rossi, G, Giaccone, G, Di Fede, G, Caroppo, P, Ferreira, CB, Prioni, S, Langheinrich, T, Redaelli, V, Lladó, A, Bartha, R, Tang-Wai, D, Rogaeva, E, Castelo-Branco, M, Freedman, M, Keren, R, Black, S, Mitchell, S, Miltenberger, G, Rademakers, R, Poos, J, Papma, JM, Giannini, L, van Minkelen, R, Pijnenburg, Y, Gauthier, S, Nacmias, B, Lombardi, G, Bessi, V, Veldsman, M, Andersson, C, Thonberg, H, Öijerstedt, L, Prix, C, Jelic, V, Antonell, A, Graff, C, Olives, J, Balasa, M, Bargalló, N, Borrego-Ecija, S, Verdelho, A, Kuchcinski, G, Maruta, C, Gorostidi, A, Laforce, R, Villanua, J, Wlasich, E, Cañada, M, Tainta, M, Zulaica, M, Barandiaran, M, Moreno, F, Alves, P, Bender, B, Bertoux, M, Wilke, C, Lebouvier, T, Camuzat, A, Graf, L, Vogels, A, Vandenbulcke, M, Van Damme, P, Bruffaerts, R, Poesen, K, Rosa-Neto, P, Sanchez-Valle, R, Brice, A, Bertrand, A, Funkiewiez, A, Rinaldi, D, Saracino, D, Colliot, O, Sorbi, S, Sayah, S, Wagemann, O, Loosli, S, Schönecker, S, Hoegen, T, Lombardi, J, Anderl-Straub, S, Nicholas, J, Rollin, A, Deramecourt, V, Arighi, A, Santiago, B, Duro, D, Leitão, MJ, Almeida, MR, Tábuas-Pereira, M, Gazzina, S, Afonso, S, Masellis, M, Tartaglia, C, Shafei, R, Rowe, JB, Borroni, B, Finger, E, Synofzik, M, Galimberti, D, Vandenberghe, R, de Mendonça, A, Cantoni, V, Genetic FTD Initiative (GENFI), Samra, Kiran [0000-0002-3105-7099], Apollo - University of Cambridge Repository, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Nelson, Annabel, Bocchetta, Martina, Cash, David, Thomas, David L, Todd, Emily, Benotmane, Hanya, Nicholas, Jennifer, Samra, Kiran, Shafei, Rachelle, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, and Verdelho, Ana

Subjects
Progranulin, Clinical Neurology, C9ORF72, tau Proteins, AMYOTROPHIC-LATERAL-SCLEROSIS, diagnosis [Frontotemporal Dementia], C9orf72, Tremor, Genetics, Humans, ddc:610, genetics [Frontotemporal Dementia], genetics [C9orf72 Protein], MUTATION, Science & Technology, C9orf72 Protein, HERITABILITY, Amyotrophic Lateral Sclerosis, PROGRESSIVE SUPRANUCLEAR PALSY, COGNITIVE IMPAIRMENT, REPEAT EXPANSION, genetics [tau Proteins], Motor, PATHOLOGICAL FEATURES, Neurology, FOS: Biological sciences, Frontotemporal Dementia, Mutation, Human medicine, Neurosciences & Neurology, Neurology (clinical), Tau, TAU, Life Sciences & Biomedicine, Frontotemporal dementia, PARKINSONISM
Abstract

Funder: CIBERNED, Funder: Canadian Institutes of Health Research; doi: http://dx.doi.org/10.13039/501100000024, Funder: Lemaire Family Foundation, Funder: Swedish Frontotemporal Dementia Initiative, Funder: Italian Ministry of Health, Funder: Weston Brain Institute; doi: http://dx.doi.org/10.13039/100012479, Funder: Mady Browaaeys Fund, Funder: Miriam Marks Brain Research UK, Funder: Bluefield Project, OBJECTIVE: To investigate the optimal method of adding motor features to a clinical rating scale for frontotemporal dementia (FTD). METHODS: Eight hundred and thirty-two participants from the international multicentre Genetic FTD Initiative (GENFI) study were recruited: 522 mutation carriers (with C9orf72, GRN and MAPT mutations) and 310 mutation-negative controls. A standardised clinical questionnaire was used to assess eight motor symptoms (dysarthria, dysphagia, tremor, slowness, weakness, gait disorder, falls and functional difficulties using hands). Frequency and severity of each motor symptom was assessed, and a principal component analysis (PCA) was performed to identify how the different motor symptoms loaded together. Finally, addition of a motor component to the CDR® plus NACC FTLD was investigated (CDR® plus NACC FTLD-M). RESULTS: 24.3% of mutation carriers had motor symptoms (31.7% C9orf72, 18.8% GRN, 19.3% MAPT) compared to 6.8% of controls. Slowness and gait disorder were the commonest in all genetic groups while tremor and falls were the least frequent. Symptom severity scores were similar to equivalent physical motor examination scores. PCA revealed that all motor symptoms loaded together so a single additional motor component was added to the CDR® plus NACC FTLD to form the CDR® plus NACC FTLD-M. Individual global scores were more severe with the CDR® plus NACC FTLD-M, and no patients with a clinically diagnosed motor disorder (ALS/FTD-ALS or parkinsonism) were classified anymore as asymptomatic (unlike the CDR® plus NACC FTLD alone). CONCLUSIONS: Motor features are present in mutation carriers at all disease stages across all three genetic groups. Inclusion of motor symptoms in a rating scale that can be used in future clinical trials will not only ensure a more accurate severity measure is recorded but that a wider spectrum of FTD phenotypes can be included in the same trial.

Published
2022
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6. SARS-CoV-2 infection and acute ischemic stroke in Lombardy, Italy

Author

Pezzini, A, Grassi, M, Silvestrelli, G, Locatelli, M, Rifino, N, Beretta, S, Gamba, M, Raimondi, E, Giussani, G, Carimati, F, Sangalli, D, Corato, M, Gerevini, S, Masciocchi, S, Cortinovis, M, La Gioia, S, Barbieri, F, Mazzoleni, V, Pezzini, D, Bonacina, S, Pilotto, A, Benussi, A, Magoni, M, Premi, E, Prelle, A, Agostoni, E, Palluzzi, F, De Giuli, V, Magherini, A, Roccatagliata, D, Vinciguerra, L, Puglisi, V, Fusi, L, Diamanti, S, Santangelo, F, Xhani, R, Pozzi, F, Grampa, G, Versino, M, Salmaggi, A, Marcheselli, S, Cavallini, A, Giossi, A, Censori, B, Ferrarese, C, Ciccone, A, Sessa, M, Padovani, A, Pezzini A., Grassi M., Silvestrelli G., Locatelli M., Rifino N., Beretta S., Gamba M., Raimondi E., Giussani G., Carimati F., Sangalli D., Corato M., Gerevini S., Masciocchi S., Cortinovis M., La Gioia S., Barbieri F., Mazzoleni V., Pezzini D., Bonacina S., Pilotto A., Benussi A., Magoni M., Premi E., Prelle A. C., Agostoni E. C., Palluzzi F., De Giuli V., Magherini A., Roccatagliata D. V., Vinciguerra L., Puglisi V., Fusi L., Diamanti S., Santangelo F., Xhani R., Pozzi F., Grampa G., Versino M., Salmaggi A., Marcheselli S., Cavallini A., Giossi A., Censori B., Ferrarese C., Ciccone A., Sessa M., Padovani A., Pezzini, A, Grassi, M, Silvestrelli, G, Locatelli, M, Rifino, N, Beretta, S, Gamba, M, Raimondi, E, Giussani, G, Carimati, F, Sangalli, D, Corato, M, Gerevini, S, Masciocchi, S, Cortinovis, M, La Gioia, S, Barbieri, F, Mazzoleni, V, Pezzini, D, Bonacina, S, Pilotto, A, Benussi, A, Magoni, M, Premi, E, Prelle, A, Agostoni, E, Palluzzi, F, De Giuli, V, Magherini, A, Roccatagliata, D, Vinciguerra, L, Puglisi, V, Fusi, L, Diamanti, S, Santangelo, F, Xhani, R, Pozzi, F, Grampa, G, Versino, M, Salmaggi, A, Marcheselli, S, Cavallini, A, Giossi, A, Censori, B, Ferrarese, C, Ciccone, A, Sessa, M, Padovani, A, Pezzini A., Grassi M., Silvestrelli G., Locatelli M., Rifino N., Beretta S., Gamba M., Raimondi E., Giussani G., Carimati F., Sangalli D., Corato M., Gerevini S., Masciocchi S., Cortinovis M., La Gioia S., Barbieri F., Mazzoleni V., Pezzini D., Bonacina S., Pilotto A., Benussi A., Magoni M., Premi E., Prelle A. C., Agostoni E. C., Palluzzi F., De Giuli V., Magherini A., Roccatagliata D. V., Vinciguerra L., Puglisi V., Fusi L., Diamanti S., Santangelo F., Xhani R., Pozzi F., Grampa G., Versino M., Salmaggi A., Marcheselli S., Cavallini A., Giossi A., Censori B., Ferrarese C., Ciccone A., Sessa M., and Padovani A.

Abstract

Objective: To characterize patients with acute ischemic stroke related to SARS-CoV-2 infection and assess the classification performance of clinical and laboratory parameters in predicting in-hospital outcome of these patients. Methods: In the setting of the STROKOVID study including patients with acute ischemic stroke consecutively admitted to the ten hub hospitals in Lombardy, Italy, between March 8 and April 30, 2020, we compared clinical features of patients with confirmed infection and non-infected patients by logistic regression models and survival analysis. Then, we trained and tested a random forest (RF) binary classifier for the prediction of in-hospital death among patients with COVID-19. Results: Among 1013 patients, 160 (15.8%) had SARS-CoV-2 infection. Male sex (OR 1.53; 95% CI 1.06–2.27) and atrial fibrillation (OR 1.60; 95% CI 1.05–2.43) were independently associated with COVID-19 status. Patients with COVID-19 had increased stroke severity at admission [median NIHSS score, 9 (25th to75th percentile, 13) vs 6 (25th to75th percentile, 9)] and increased risk of in-hospital death (38.1% deaths vs 7.2%; HR 3.30; 95% CI 2.17–5.02). The RF model based on six clinical and laboratory parameters exhibited high cross-validated classification accuracy (0.86) and precision (0.87), good recall (0.72) and F1-score (0.79) in predicting in-hospital death. Conclusions: Ischemic strokes in COVID-19 patients have distinctive risk factor profile and etiology, increased clinical severity and higher in-hospital mortality rate compared to non-COVID-19 patients. A simple model based on clinical and routine laboratory parameters may be useful in identifying ischemic stroke patients with SARS-CoV-2 infection who are unlikely to survive the acute phase.

Published
2022

8. Impact of SARS-CoV-2 on reperfusion therapies for acute ischemic stroke in Lombardy, Italy: the STROKOVID network

Author

Pezzini, A, Grassi, M, Silvestrelli, G, Locatelli, M, Rifino, N, Beretta, S, Gamba, M, Raimondi, E, Giussani, G, Carimati, F, Sangalli, D, Corato, M, Gerevini, S, Masciocchi, S, Cortinovis, M, La Gioia, S, Barbieri, F, Mazzoleni, V, Pezzini, D, Bonacina, S, Pilotto, A, Benussi, A, Magoni, M, Premi, E, Prelle, A, Agostoni, E, Palluzzi, F, De Giuli, V, Magherini, A, Roccatagliata, D, Vinciguerra, L, Puglisi, V, Fusi, L, Xhani, R, Pozzi, F, Diamanti, S, Santangelo, F, Grampa, G, Versino, M, Salmaggi, A, Marcheselli, S, Cavallini, A, Giossi, A, Censori, B, Ferrarese, C, Ciccone, A, Sessa, M, Padovani, A, Pezzini A., Grassi M., Silvestrelli G., Locatelli M., Rifino N., Beretta S., Gamba M., Raimondi E., Giussani G., Carimati F., Sangalli D., Corato M., Gerevini S., Masciocchi S., Cortinovis M., La Gioia S., Barbieri F., Mazzoleni V., Pezzini D., Bonacina S., Pilotto A., Benussi A., Magoni M., Premi E., Prelle A. C., Agostoni E. C., Palluzzi F., De Giuli V., Magherini A., Roccatagliata D. V., Vinciguerra L., Puglisi V., Fusi L., Xhani R., Pozzi F., Diamanti S., Santangelo F., Grampa G., Versino M., Salmaggi A., Marcheselli S., Cavallini A., Giossi A., Censori B., Ferrarese C., Ciccone A., Sessa M., Padovani A., Pezzini, A, Grassi, M, Silvestrelli, G, Locatelli, M, Rifino, N, Beretta, S, Gamba, M, Raimondi, E, Giussani, G, Carimati, F, Sangalli, D, Corato, M, Gerevini, S, Masciocchi, S, Cortinovis, M, La Gioia, S, Barbieri, F, Mazzoleni, V, Pezzini, D, Bonacina, S, Pilotto, A, Benussi, A, Magoni, M, Premi, E, Prelle, A, Agostoni, E, Palluzzi, F, De Giuli, V, Magherini, A, Roccatagliata, D, Vinciguerra, L, Puglisi, V, Fusi, L, Xhani, R, Pozzi, F, Diamanti, S, Santangelo, F, Grampa, G, Versino, M, Salmaggi, A, Marcheselli, S, Cavallini, A, Giossi, A, Censori, B, Ferrarese, C, Ciccone, A, Sessa, M, Padovani, A, Pezzini A., Grassi M., Silvestrelli G., Locatelli M., Rifino N., Beretta S., Gamba M., Raimondi E., Giussani G., Carimati F., Sangalli D., Corato M., Gerevini S., Masciocchi S., Cortinovis M., La Gioia S., Barbieri F., Mazzoleni V., Pezzini D., Bonacina S., Pilotto A., Benussi A., Magoni M., Premi E., Prelle A. C., Agostoni E. C., Palluzzi F., De Giuli V., Magherini A., Roccatagliata D. V., Vinciguerra L., Puglisi V., Fusi L., Xhani R., Pozzi F., Diamanti S., Santangelo F., Grampa G., Versino M., Salmaggi A., Marcheselli S., Cavallini A., Giossi A., Censori B., Ferrarese C., Ciccone A., Sessa M., and Padovani A.

Abstract

Whether and how SARS-CoV-2 outbreak affected in-hospital acute stroke care system is still matter of debate. In the setting of the STROKOVID network, a collaborative project between the ten centers designed as hubs for the treatment of acute stroke during SARS-CoV-2 outbreak in Lombardy, Italy, we retrospectively compared clinical features and process measures of patients with confirmed infection (COVID-19) and non-infected patients (non-COVID-19) who underwent reperfusion therapies for acute ischemic stroke. Between March 8 and April 30, 2020, 296 consecutive patients [median age, 74 years (interquartile range (IQR), 62–80.75); males, 154 (52.0%); 34 (11.5%) COVID-19] qualified for the analysis. Time from symptoms onset to treatment was longer in the COVID-19 group [230 (IQR 200.5–270) minutes vs. 190 (IQR 150–245) minutes; p = 0.007], especially in the first half of the study period. Patients with COVID-19 who underwent endovascular thrombectomy had more frequently absent collaterals or collaterals filling ≤ 50% of the occluded territory (50.0% vs. 16.6%; OR 5.05; 95% CI 1.82–13.80) and a lower rate of good/complete recanalization of the primary arterial occlusive lesion (55.6% vs. 81.0%; OR 0.29; 95% CI 0.10–0.80). Post-procedural intracranial hemorrhages were more frequent (35.3% vs. 19.5%; OR 2.24; 95% CI 1.04–4.83) and outcome was worse among COVID-19 patients (in-hospital death, 38.2% vs. 8.8%; OR 6.43; 95% CI 2.85–14.50). Our findings showed longer delays in the intra-hospital management of acute ischemic stroke in COVID-19 patients, especially in the early phase of the outbreak, that likely impacted patients outcome and should be the target of future interventions.

Published
2021

10. Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia

Author

Panman, J. L., Venkatraghavan, V., Van Der Ende, E. L., Steketee, R. M. E., Jiskoot, L. C., Poos, J. M., Dopper, E. G. P., Meeter, L. H. H., Kaat, L. D., Rombouts, S. A. R. B., Vernooij, M. W., Kievit, A. J. A., Premi, E., Cosseddu, M., Bonomi, E., Olives, J., Rohrer, J. D., Sanchez-Valle, R., Borroni, B., Bron, E. E., Van Swieten, J. C., Papma, J. M., Klein, S., Afonso, S., Almeida, M. R., Anderl-Straub, S., Andersson, C., Antonell, A., Archetti, S., Arighi, A., Balasa, M., Barandiaran, M., Bargallo, N., Bartha, R., Bender, B., Black, S., Butler, C., Bocchetta, M., Borrego-Ecija, S., Bras, J., Bruffaerts, R., Caroppo, P., Cash, D., Castelo-Branco, M., Convery, R., Cope, T., Danek, A., De Arriba, M., De Mendonca, A., Di Fede, G., Diaz, Z., Ducharme, S., Duro, D., Fenoglio, C., Ferreira, C. B., Finger, E., Flanagan, T., Fox, N., Freedman, M., Fumagalli, G., Gabilondo, A., Galimberti, D., Gasparotti, R., Gauthier, S., Gazzina, S., Gerhard, A., Giaccone, G., Gorostidi, A., Graff, C., Greaves, C., Guerreiro, R., Heller, C., Hoegen, T., Indakoetxea, B., Jelic, V., Karnath, H. -O., Keren, R., Laforce, R., Leitao, M. J., Levin, J., Llado, A., Loosli, S., Maruta, C., Masellis, M., Mead, S., Miltenberger, G., Van Minkelenm Sara Mitchell, R., Moore, K., Moreno, F., Nicholas, J., Oijerstedt, L., Otto, M., Ourselin, S., Padovani, A., Peakman, G., Pijnenburg, Y., Polito, C., Prioni, S., Prix, C., Rademakers, R., Redaelli, V., Rittman, T., Rogaeva, E., Rosa-Neto, P., Rossi, G., Rosser, M., Rowe, J., Santana, I., Santiago, B., Scarpini, E., Schonecker, S., Shafei, E. S. R., Shoesmith, C., Synofzik, M., Tabuas-Pereira, M., Tagliavini, F., Tartaglia, C., Tainta, M., Taipa, R., Tang-Wai, D., Thomas, D. L., Thonberg, H., Timberlake, C., Tiraboschi, P., Todd, E., Vandamme, P., Vandenberghe, R., Vandenbulcke, M., Veldsman, M., Verdelho, A., Villanua, J., Warren, J., Wilkeione, C., Elisabeth, W., Henrik, W., Zulaica, Z. M., Neurology, Physics and medical technology, Radiology & Nuclear Medicine, Clinical Genetics, and Medical Research Council

Subjects
Male, Oncology, Disease, Neuropsychological Tests, GENFI consortium investigators, Primary progressive aphasia, Cognition, Progranulins, 0302 clinical medicine, Neurofilament Proteins, BEHAVIORAL VARIANT, HETEROGENEITY, Gray Matter, 11 Medical and Health Sciences, Language, Psychiatry, 0303 health sciences, Brain, Middle Aged, Magnetic Resonance Imaging, White Matter, 17 Psychology and Cognitive Sciences, ALZHEIMERS-DISEASE, Psychiatry and Mental health, Phenotype, medicine.anatomical_structure, Frontotemporal Dementia, Disease Progression, Biomarker (medicine), Female, Life Sciences & Biomedicine, Frontotemporal dementia, medicine.medical_specialty, Clinical Neurology, EVENT-BASED MODEL, Grey matter, Lateralization of brain function, White matter, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, NEUROFILAMENT LIGHT-CHAIN, medicine, Humans, LOBAR DEGENERATION, PROGRANULIN, Aged, 030304 developmental biology, Science & Technology, Neurology & Neurosurgery, business.industry, DISEASE PROGRESSION, medicine.disease, Mutation, WHITE-MATTER INTEGRITY, Surgery, Neurosciences & Neurology, Neurology (clinical), business, GENFI, Biomarkers, 030217 neurology & neurosurgery, Progressive disease
Abstract

ObjectiveProgranulin-related frontotemporal dementia (FTD-GRN) is a fast progressive disease. Modelling the cascade of multimodal biomarker changes aids in understanding the aetiology of this disease and enables monitoring of individual mutation carriers. In this cross-sectional study, we estimated the temporal cascade of biomarker changes for FTD-GRN, in a data-driven way.MethodsWe included 56 presymptomatic and 35 symptomatic GRN mutation carriers, and 35 healthy non-carriers. Selected biomarkers were neurofilament light chain (NfL), grey matter volume, white matter microstructure and cognitive domains. We used discriminative event-based modelling to infer the cascade of biomarker changes in FTD-GRN and estimated individual disease severity through cross-validation. We derived the biomarker cascades in non-fluent variant primary progressive aphasia (nfvPPA) and behavioural variant FTD (bvFTD) to understand the differences between these phenotypes.ResultsLanguage functioning and NfL were the earliest abnormal biomarkers in FTD-GRN. White matter tracts were affected before grey matter volume, and the left hemisphere degenerated before the right. Based on individual disease severities, presymptomatic carriers could be delineated from symptomatic carriers with a sensitivity of 100% and specificity of 96.1%. The estimated disease severity strongly correlated with functional severity in nfvPPA, but not in bvFTD. In addition, the biomarker cascade in bvFTD showed more uncertainty than nfvPPA.ConclusionDegeneration of axons and language deficits are indicated to be the earliest biomarkers in FTD-GRN, with bvFTD being more heterogeneous in disease progression than nfvPPA. Our data-driven model could help identify presymptomatic GRN mutation carriers at risk of conversion to the clinical stage.

Published
2021
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11. Effect of COVID-19-related lockdown on ophthalmic practice in Italy: A report from 39 institutional centers

Author

Dell'Omo, Roberto, Filippelli, M., Virgili, Gianni, Bandello, F., Querques, G., Lanzetta, P., Avitabile, T., Viola, F., Reibaldi, M., Semeraro, F., Quaranta, L., Rizzo, Stanislao, Midena, E., Campagna, G., Costagliola, C., Marolo, P., Traverso, C. E., Iester, M., Cutolo, C. A., Azzolini, C., Donati, S., Premi, E., Nucci, P., Vujosevic, S., Staurenghi, G., Bottoni, F., Romano, Federica, Grosso, D., Borrelli, E., Sacconi, R., Milella, P., Ganci, S., Romano, M. R., Ricciardelli, G., Allegrini, D., Casaluci, M., Romano, D., Marchini, G., Chemello, F., Amantea, Carlotta, Frisina, R., Pilotto, E., Parrozzani, R., Veritti, D., Sarao, V., Daniele, T., Busin, M., Parmeggiani, F., De Nadai, K., Furiosi, L., Mastropasqua, R., Battaglia, B., Gironi, Marco, Gandolfi, S., Luciani, E., Mora, P., Schiavi, C., Bertaccini, Paolo Antonio, Finzi, A., Roda, M., Cagini, C., Lupidi, M., Giansanti, F., Bacherini, Daniela, Tosi, G., De Benedetto, E., Nardi, M., Figus, M., Posarelli, C., Mariotti, Cesare, Pirani, V., Nicolai, Massimo, Bonini, S., Coassin, M., Di Zazzo, A., Savastano, Maria Cristina, Savastano, Alfonso, Gambini, Gloria, Vico, U. D., Spadea, L., Iannaccone, A., Nucci, C., Ricci, F., Aiello, F., Afflitto, G. G., Mastropasqua, L., D'Onofio, G., Evangelista, F., Brescia, L., Napolitano, P., Polisena, P., Gianfrancesco, N., Trivisonno, D., Petti, F., Simonelli, F., Rossi, S., Tartaglione, A., Rosa, N., Bernardo, M. D., Iaculli, C., Valeria Bux, A., Maggiore, Giuseppe, Boscia, F., Sborgia, G., Grassi, M. O., Scorcia, V., Giannaccare, G., Parisi, Giuseppe, Cillino, S., Alaimo, F., Aragona, P., Meduri, A., Pinna, A., Sollazzo, A., Peiretti, E., Siotto, E., dell'Omo R., Virgili G., Rizzo S. (ORCID:0000-0001-6302-063X), Romano F., Amantea C., Gironi M., Bertaccini P., Bacherini D., Mariotti C., Nicolai M., Savastano M. (ORCID:0000-0003-1397-4333), Savastano A., Gambini G., Maggiore G., Parisi G., Dell'Omo, Roberto, Filippelli, M., Virgili, Gianni, Bandello, F., Querques, G., Lanzetta, P., Avitabile, T., Viola, F., Reibaldi, M., Semeraro, F., Quaranta, L., Rizzo, Stanislao, Midena, E., Campagna, G., Costagliola, C., Marolo, P., Traverso, C. E., Iester, M., Cutolo, C. A., Azzolini, C., Donati, S., Premi, E., Nucci, P., Vujosevic, S., Staurenghi, G., Bottoni, F., Romano, Federica, Grosso, D., Borrelli, E., Sacconi, R., Milella, P., Ganci, S., Romano, M. R., Ricciardelli, G., Allegrini, D., Casaluci, M., Romano, D., Marchini, G., Chemello, F., Amantea, Carlotta, Frisina, R., Pilotto, E., Parrozzani, R., Veritti, D., Sarao, V., Daniele, T., Busin, M., Parmeggiani, F., De Nadai, K., Furiosi, L., Mastropasqua, R., Battaglia, B., Gironi, Marco, Gandolfi, S., Luciani, E., Mora, P., Schiavi, C., Bertaccini, Paolo Antonio, Finzi, A., Roda, M., Cagini, C., Lupidi, M., Giansanti, F., Bacherini, Daniela, Tosi, G., De Benedetto, E., Nardi, M., Figus, M., Posarelli, C., Mariotti, Cesare, Pirani, V., Nicolai, Massimo, Bonini, S., Coassin, M., Di Zazzo, A., Savastano, Maria Cristina, Savastano, Alfonso, Gambini, Gloria, Vico, U. D., Spadea, L., Iannaccone, A., Nucci, C., Ricci, F., Aiello, F., Afflitto, G. G., Mastropasqua, L., D'Onofio, G., Evangelista, F., Brescia, L., Napolitano, P., Polisena, P., Gianfrancesco, N., Trivisonno, D., Petti, F., Simonelli, F., Rossi, S., Tartaglione, A., Rosa, N., Bernardo, M. D., Iaculli, C., Valeria Bux, A., Maggiore, Giuseppe, Boscia, F., Sborgia, G., Grassi, M. O., Scorcia, V., Giannaccare, G., Parisi, Giuseppe, Cillino, S., Alaimo, F., Aragona, P., Meduri, A., Pinna, A., Sollazzo, A., Peiretti, E., Siotto, E., dell'Omo R., Virgili G., Rizzo S. (ORCID:0000-0001-6302-063X), Romano F., Amantea C., Gironi M., Bertaccini P., Bacherini D., Mariotti C., Nicolai M., Savastano M. (ORCID:0000-0003-1397-4333), Savastano A., Gambini G., Maggiore G., and Parisi G.

Abstract

Background/objectives: To compare the number of eye surgical procedures performed in Italy in the 2 months following the beginning of lockdown (study period) because of COVID-19 epidemic with those performed in the two earlier months of the same year (intra-year control) and in the period of 2019 corresponding to the lockdown (inter-year control). Methods: Retrospective analysis of surgical procedures carried out at 39 Academic hospitals. A distinction was made between elective and urgent procedures. Intravitreal injections were also considered. Percentages for all surgical procedures and incidence rate ratios (IRR) for rhegmatogenous retinal detachment (RRD) events were calculated. A p value <0.05 was considered significant. Results: A total of 20,886 versus 55,259 and 56,640 patients underwent surgery during the lockdown versus intra-and inter-year control periods, respectively. During the lockdown, only 70% of patients for whom an operation/intravitreal injection was recommended, finally underwent surgery; the remaining patients did not attend because afraid of getting infected at the hospital (23%), taking public transportation (6.5%), or unavailable swabs (0.5%). Elective surgeries were reduced by 96.2% and 96.4%, urgent surgeries by 49.7% and 50.2%, and intravitreal injections by 48.5% and 48.6% in the lockdown period in comparison to intra-year and inter-year control periods, respectively. IRRs for RRDs during lockdown dropped significantly in comparison with intra- and inter-year control periods (CI: 0.65–0.80 and 0.61–0.75, respectively, p < 0.001 for both). Conclusion: This study provides a quantitative analysis of the reduction of eye surgical procedures performed in Italy because of the COVID-19 epidemic.

Published
2022

13. Correlación entre el metabolismo de la glucosa cerebral (18F-FDG) y el flujo sanguíneo cerebral con marcadores de amiloide (18F-florbetapir) en práctica clínica: evidencias preliminares

Author

Albano, D., primary, Premi, E., additional, Peli, A., additional, Luca, C., additional, Bertagna, F., additional, Turrone, R., additional, Borroni, B., additional, Calhoun, V.D., additional, Rodella, C., additional, Magoni, M., additional, Padovani, A., additional, Giubbini, R., additional, and Paghera, B., additional

Published
2021
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18. Abnormal pain perception is associated with thalamo-cortico-striatal atrophy in C9orf72 expansion carriers in the GENFI cohort

Author

Convery, Rhian S, Bocchetta, Martina, Masellis, Mario, Afonso, S., Taipa, R., Caroppo, P., Di Fede, G., Giaccone, G., Prioni, S., Redaelli, V., Rossi, G., Tiraboschi, P., Duro, D., Tartaglia, Maria Carmela, Almeida, M. R., Branco, M. C., Leitão, M. J., Tabuas-Pereira, M., Santiago, B., Gauthier, S., Rosa-Neto, P., Veldsman, M., Flanagan, T., Prix, C., Graff, Caroline, Hoegen, T., Wlasich, E., Loosli, S., Schonecker, S., Semler, E., Anderl-Straub, S., Galimberti, Daniela, Rowe, James B, Finger, Elizabeth, Synofzik, Matthis, Vandenberghe, Rik, de Mendonca, Alexandre, Tagliavini, Fabrizio, Greaves, Caroline V, Santana, Isabel, Ducharme, Simon, Butler, Christopher, Gerhard, Alex, Levin, Johannes, Danek, Adrian, Otto, Markus, Warren, Jason D, Rohrer, Jonathan D, Initiative, Genetic FTD, Moore, Katrina M, Rossor, M. N., Fox, N. C., Woollacott, I. O. C., Shafei, R., Heller, C., Peakman, G., Swift, I., Todd, E., Guerreiro, R., Bras, J., Cash, David M, Thomas, D. L., Nicholas, J., Mead, S., Jiskoot, L., Meeter, L., Panman, J., Papma, J., van Minkelen, R., Pijnenburg, Y., Barandiara, M., Van Swieten, John, Indakoetxea, B., Gabilondo, A., Tainta, M., de Arriba, M., Gorostidi, A., Zulaica, M., Villanua, J., Diaz, Z., Borrego-Ecija, S., Olives, J., Moreno, Fermin, Lladó, A., Balasa, M., Antonell, A., Bargallo, N., Premi, E., Cosseddu, M., Gazzina, S., Padovani, A., Gasparotti, R., Archetti, S., Sánchez-Valle, Raquel, Black, S., Mitchell, S., Rogaeva, E., Freedman, M., Keren, R., Tang-Wai, D., Öijerstedt, L., Andersson, C., Jelic, V., Thonberg, H., Borroni, Barbara, Arighi, A., Fenoglio, C., Scarpini, E., Fumagalli, G., Cope, T., Timberlake, C., Rittman, T., Shoesmith, C., Bartha, R., Rademakers, R., Laforce, Robert, Wilke, C., Karnarth, H-O, Bender, B., Bruffaerts, R., Vandamme, P., Vandenbulcke, M., Ferreira, C. B., Miltenberger, G., Maruta, C., Verdelho, A., Convery, Rhian S [0000-0002-9477-1812], Bocchetta, Martina [0000-0003-1814-5024], Greaves, Caroline V [0000-0002-6446-1960], Moore, Katrina M [0000-0002-4458-8390], Van Swieten, John [0000-0001-6278-6844], Borroni, Barbara [0000-0001-9340-9814], Rowe, James B [0000-0001-7216-8679], Finger, Elizabeth [0000-0003-4461-7427], Otto, Markus [0000-0002-6647-5944], Rohrer, Jonathan D [0000-0002-6155-8417], Apollo - University of Cambridge Repository, Neurology, and Repositório da Universidade de Lisboa

Subjects
Male, diagnostic imaging [Corpus Striatum], Medizin, Somatosensory system, physiopathology [Frontotemporal Dementia], frontotemporal dementia, Cohort Studies, genetics [Progranulins], 0302 clinical medicine, Progranulins, Thalamus, C9orf72, Cerebellum, diagnostic imaging [Cerebral Cortex], pathology [Cerebellum], Medicine, pain, genetics [Frontotemporal Dementia], Cerebral Cortex, 0303 health sciences, DNA Repeat Expansion, Pain Perception, Middle Aged, Magnetic Resonance Imaging, Temporal Lobe, Psychiatry and Mental health, Cohort, diagnostic imaging [Prefrontal Cortex], Female, Frontotemporal dementia, genetics [Atrophy], Adult, medicine.medical_specialty, pathology [Corpus Striatum], Pain, Prefrontal Cortex, genetics [Perceptual Disorders], MAPT protein, human, tau Proteins, diagnostic imaging [Frontotemporal Dementia], Temporal lobe, Perceptual Disorders, 03 medical and health sciences, Atrophy, pathology [Thalamus], Internal medicine, Humans, ddc:610, genetics [C9orf72 Protein], 030304 developmental biology, diagnostic imaging [Perceptual Disorders], Aged, diagnostic imaging [Thalamus], C9orf72 Protein, business.industry, pathology [Temporal Lobe], diagnostic imaging [Atrophy], physiopathology [Atrophy], medicine.disease, diagnostic imaging [Cerebellum], pathology [Prefrontal Cortex], Corpus Striatum, physiopathology [Perceptual Disorders], genetics [tau Proteins], diagnostic imaging [Temporal Lobe], Logistic Models, Asymptomatic Diseases, Mutation, GRN protein, human, Surgery, Orbitofrontal cortex, pathology [Cerebral Cortex], Neurology (clinical), C9orf72 protein, human, business, 030217 neurology & neurosurgery
Abstract

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. published by BMJ., Objective: Frontotemporal dementia (FTD) is typically associated with changes in behaviour, language and movement. However, recent studies have shown that patients can also develop an abnormal response to pain, either heightened or diminished. We aimed to investigate this symptom in mutation carriers within the Genetic FTD Initiative (GENFI). Methods: Abnormal responsiveness to pain was measured in 462 GENFI participants: 281 mutation carriers and 181 mutation-negative controls. Changes in responsiveness to pain were scored as absent (0), questionable or very mild (0.5), mild (1), moderate (2) or severe (3). Mutation carriers were classified into C9orf72 (104), GRN (128) and MAPT (49) groups, and into presymptomatic and symptomatic stages. An ordinal logistic regression model was used to compare groups, adjusting for age and sex. Voxel-based morphometry was performed to identify neuroanatomical correlates of abnormal pain perception. Results: Altered responsiveness to pain was present to a significantly greater extent in symptomatic C9orf72 expansion carriers than in controls: mean score 0.40 (SD 0.71) vs 0.00 (0.04), reported in 29% vs 1%. No significant differences were seen between the other symptomatic groups and controls, or any of the presymptomatic mutation carriers and controls. Neural correlates of altered pain perception in C9orf72 expansion carriers were the bilateral thalamus and striatum as well as a predominantly right-sided network of regions involving the orbitofrontal cortex, inferomedial temporal lobe and cerebellum. Conclusion: Changes in pain perception are a feature of C9orf72 expansion carriers, likely representing a disruption in somatosensory, homeostatic and semantic processing, underpinned by atrophy in a thalamo-cortico-striatal network.

Published
2020
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19. Progression of Behavioral Disturbances and Neuropsychiatric Symptoms in Patients With Genetic Frontotemporal Dementia

Author

Benussi, A. (Alberto), Premi, E. (Enrico), Gazzina, S. (Stefano), Brattini, C. (Chiara), Bonomi, E. (Elisa), Alberici, P. (Paola), Jiskoot, L.C. (Lize), Swieten, J.C. (John) van, Sánchez-Valle, R. (Raquel), Moreno, F. (Fermin), Laforce, R. (Robert), Graff, C. (Caroline), Synofzik, M. (Matthis), Galimberti, D. (Daniela), Masellis, M. (Mario), Tartaglia, C. (Carmela), Rowe, J.B. (James), Finger, E. (Elizabeth), Vandenberghe, R. (Rik), De Mendonça, A. (Alexandre), Tagliavini, F. (Fabrizio), Santana, I. (Isabel), Ducharme, S. (Simon), Butler, C.R. (Chris R.), Gerhard, A. (Alex), Levin, J. (Johannes), Danek, A. (Adrian), Otto, M. (Markus), Frisoni, G.B. (Giovanni B.), Ghidoni, R. (Roberta), Sorbi, S. (Sandro), Le Ber, I. (Isabelle), Pasquier, F. (Florence), Peakman, G. (Georgia), Todd, E. (Emily), Bocchetta, M. (Martina), Rohrer, J.D. (Jonathan), Borroni, B. (Barbara), Benussi, A. (Alberto), Premi, E. (Enrico), Gazzina, S. (Stefano), Brattini, C. (Chiara), Bonomi, E. (Elisa), Alberici, P. (Paola), Jiskoot, L.C. (Lize), Swieten, J.C. (John) van, Sánchez-Valle, R. (Raquel), Moreno, F. (Fermin), Laforce, R. (Robert), Graff, C. (Caroline), Synofzik, M. (Matthis), Galimberti, D. (Daniela), Masellis, M. (Mario), Tartaglia, C. (Carmela), Rowe, J.B. (James), Finger, E. (Elizabeth), Vandenberghe, R. (Rik), De Mendonça, A. (Alexandre), Tagliavini, F. (Fabrizio), Santana, I. (Isabel), Ducharme, S. (Simon), Butler, C.R. (Chris R.), Gerhard, A. (Alex), Levin, J. (Johannes), Danek, A. (Adrian), Otto, M. (Markus), Frisoni, G.B. (Giovanni B.), Ghidoni, R. (Roberta), Sorbi, S. (Sandro), Le Ber, I. (Isabelle), Pasquier, F. (Florence), Peakman, G. (Georgia), Todd, E. (Emily), Bocchetta, M. (Martina), Rohrer, J.D. (Jonathan), and Borroni, B. (Barbara)

Abstract

Importance: Behavioral disturbances are core features of frontotemporal dementia (FTD); however, symptom progression across the course of disease is not well characterized in genetic FTD. Objective: To investigate behavioral symptom frequency and severity and their evolution and progression in different forms of genetic FTD. Design, Setting, and Participants: This longitudinal cohort study, the international Genetic FTD Initiative (GENFI), was conducted from January 30, 2012, to May 31, 2019, at 23 multicenter specialist tertiary FTD research clinics in the United Kingdom, the Netherlands, Belgium, France, Spain, Portugal, Italy, Germany, Sweden, Finland, and Canada. Participants included a consecutive sample of 232 symptomatic FTD gene variation carriers comprising 115 with variations in C9orf72, 78 in GRN, and 39 in MAPT. A total of 101 carriers had at least 1 follow-up evaluation (for a total of 400 assessments). Gene variations were included only if considered pathogenetic. Main Outcomes and Measures: Behavioral and neuropsychiatric symptoms were assessed across disease duration and evaluated from symptom onset. Hierarchical generalized linear mixed models were used to model behavioral and neuropsychiatric measures as a function of

Published
2021
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20. Disease-related cortical thinning in presymptomatic granulin mutation carriers

Author

Borrego-Écija, S. (Sergi), Sala-Llonch, R. (Roser), Swieten, J.C. (John) van, Borroni, B. (Barbara), Moreno, F. (Fermin), Masellis, M. (Mario), Tartaglia, C. (Carmela), Graff, C. (Caroline), Galimberti, D. (Daniela), Laforce, R. (Robert), Rowe, J.B. (James), Finger, E. (Elizabeth), Vandenberghe, R. (Rik), Tagliavini, F. (Fabrizio), De Mendonça, A. (Alexandre), Santana, I. (Isabel), Synofzik, M. (Matthis), Ducharme, S. (Simon), Levin, J. (Johannes), Danek, A. (Adrian), Gerhard, A. (Alex), Otto, M. (Markus), Butler, C. (Chris), Frisoni, G.B. (Giovanni B.), Sorbi, S. (Sandro), Heller, C. (Carolin), Bocchetta, M. (Martina), Cash, D.M. (David M), Convery, R.S. (Rhian S), Moore, K.M. (Katrina M), Rohrer, J.D. (Jonathan), Sánchez-Valle, R. (Raquel), Rossor, M.N. (Martin N.), Fox, N.C. (Nick), Woollacott, I.O.C. (Ione O.C.), Shafei, R. (Rachelle), Greaves, C. (Caroline), Neason, M. (Mollie), Guerreiro, R. (Rita), Bras, J. (Jose), Thomas, D.L. (David L), Nicholas, J. (Jennifer), Mead, S. (Simon), Meeter, L.H.H. (Lieke), Panman, J.L. (Jessica), Papma, J.M. (Janne), Thornton, A.S. (Andrew), Pijnenburg, Y.A.L. (Yolande), Indakoetxea, B. (Begoña), Gabilondo, A. (Alazne), TaintaMD, M. (Mikel), de Arriba, M. (Maria), Gorostidi, A. (Ana), Zulaica, M. (Miren), Villanua, J. (Jorge), Diaz, Z. (Zigor), Olives, J. (Jaume), Lladó, A. (Albert), Balasa, M. (Mircea), Antonell, A. (Anna), Bargallo, N. (Nuria), Premi, E. (Enrico), Cosseddu, M. (Maura), Gazzina, S. (Stefano), Padovani, A. (Alessandro), Gasparotti, R. (Roberto), Archetti, S. (Silvana), Black, S. (Sandra), Mitchell, S. (Sara), Rogaeva, E. (Ekaterina), Freedman, M. (Morris), Keren, R. (Ron), Tang-Wai, D. (David), Öijerstedt, L. (Linn), Andersson, C. (Christin), Jelic, S. (Svetislav Svetislav), Thonberg, H. (Håkan), Arighi, A. (Andrea), Fenoglio, C. (Chiara), Scarpini MD, E. (Elio), Fumagalli, G. (Giorgio), Cope, T. (Thomas), Timberlake, C. (Carolyn), Rittman, T. (Timothy), Shoesmith, C. (Christen), Bartha, R. (Robart), Rademakers, S. (Suzanne), Wilke, C. (Carlo), Bender, B. (Benjamin), Bruffaerts, R. (Rose), Vandamme, P. (Philip), Vandenbulcke, M. (Mathieu), Maruta, C. (Carolina), Ferreira, C.B. (Catarina B.), Miltenberger, G. (Gabriel), Verdelho, A. (Ana), Afonso, S. (Sónia), Taipa, R. (Ricardo), Caroppo, P. (Paola), Di Fede, G. (Giuseppe), Giaccone, G. (Giorgio), Prioni, S. (Sara), Redaelli, V. (Veronica), Rossi, G. (Giacomina), Tiraboschi, P. (Pietro), Duro, D. (Diana), Rosario Almeida, M. (Maria), Castelo-Branco, M. (Miguel), João Leitão, M. (Maria), Tabuas-Pereira, M. (Miguel), Santiago, B. (Beatriz), Gauthier, S. (Serge), Rosa-Neto, P. (Pedro), Veldsman, M. (Michele), Flanagan, T. (Toby), Prix, C. (Catharina), Hoegen, T. (Tobias), Wlasich, E. (Elisabeth), Loosli, S. (Sandra), Schonecker, S. (Sonja), Semler, E. (Elisa), Anderl-Straub, S. (Sarah), Borrego-Écija, S. (Sergi), Sala-Llonch, R. (Roser), Swieten, J.C. (John) van, Borroni, B. (Barbara), Moreno, F. (Fermin), Masellis, M. (Mario), Tartaglia, C. (Carmela), Graff, C. (Caroline), Galimberti, D. (Daniela), Laforce, R. (Robert), Rowe, J.B. (James), Finger, E. (Elizabeth), Vandenberghe, R. (Rik), Tagliavini, F. (Fabrizio), De Mendonça, A. (Alexandre), Santana, I. (Isabel), Synofzik, M. (Matthis), Ducharme, S. (Simon), Levin, J. (Johannes), Danek, A. (Adrian), Gerhard, A. (Alex), Otto, M. (Markus), Butler, C. (Chris), Frisoni, G.B. (Giovanni B.), Sorbi, S. (Sandro), Heller, C. (Carolin), Bocchetta, M. (Martina), Cash, D.M. (David M), Convery, R.S. (Rhian S), Moore, K.M. (Katrina M), Rohrer, J.D. (Jonathan), Sánchez-Valle, R. (Raquel), Rossor, M.N. (Martin N.), Fox, N.C. (Nick), Woollacott, I.O.C. (Ione O.C.), Shafei, R. (Rachelle), Greaves, C. (Caroline), Neason, M. (Mollie), Guerreiro, R. (Rita), Bras, J. (Jose), Thomas, D.L. (David L), Nicholas, J. (Jennifer), Mead, S. (Simon), Meeter, L.H.H. (Lieke), Panman, J.L. (Jessica), Papma, J.M. (Janne), Thornton, A.S. (Andrew), Pijnenburg, Y.A.L. (Yolande), Indakoetxea, B. (Begoña), Gabilondo, A. (Alazne), TaintaMD, M. (Mikel), de Arriba, M. (Maria), Gorostidi, A. (Ana), Zulaica, M. (Miren), Villanua, J. (Jorge), Diaz, Z. (Zigor), Olives, J. (Jaume), Lladó, A. (Albert), Balasa, M. (Mircea), Antonell, A. (Anna), Bargallo, N. (Nuria), Premi, E. (Enrico), Cosseddu, M. (Maura), Gazzina, S. (Stefano), Padovani, A. (Alessandro), Gasparotti, R. (Roberto), Archetti, S. (Silvana), Black, S. (Sandra), Mitchell, S. (Sara), Rogaeva, E. (Ekaterina), Freedman, M. (Morris), Keren, R. (Ron), Tang-Wai, D. (David), Öijerstedt, L. (Linn), Andersson, C. (Christin), Jelic, S. (Svetislav Svetislav), Thonberg, H. (Håkan), Arighi, A. (Andrea), Fenoglio, C. (Chiara), Scarpini MD, E. (Elio), Fumagalli, G. (Giorgio), Cope, T. (Thomas), Timberlake, C. (Carolyn), Rittman, T. (Timothy), Shoesmith, C. (Christen), Bartha, R. (Robart), Rademakers, S. (Suzanne), Wilke, C. (Carlo), Bender, B. (Benjamin), Bruffaerts, R. (Rose), Vandamme, P. (Philip), Vandenbulcke, M. (Mathieu), Maruta, C. (Carolina), Ferreira, C.B. (Catarina B.), Miltenberger, G. (Gabriel), Verdelho, A. (Ana), Afonso, S. (Sónia), Taipa, R. (Ricardo), Caroppo, P. (Paola), Di Fede, G. (Giuseppe), Giaccone, G. (Giorgio), Prioni, S. (Sara), Redaelli, V. (Veronica), Rossi, G. (Giacomina), Tiraboschi, P. (Pietro), Duro, D. (Diana), Rosario Almeida, M. (Maria), Castelo-Branco, M. (Miguel), João Leitão, M. (Maria), Tabuas-Pereira, M. (Miguel), Santiago, B. (Beatriz), Gauthier, S. (Serge), Rosa-Neto, P. (Pedro), Veldsman, M. (Michele), Flanagan, T. (Toby), Prix, C. (Catharina), Hoegen, T. (Tobias), Wlasich, E. (Elisabeth), Loosli, S. (Sandra), Schonecker, S. (Sonja), Semler, E. (Elisa), and Anderl-Straub, S. (Sarah)

Abstract

Mutations in the granulin gene (GRN) cause familial frontotemporal dementia. Understanding the structural brain changes in presymptomatic GRN carriers would enforce the use of neuroimaging biomarkers for early diagnosis and monitoring. We studied 100 presymptomatic GRN mutation carriers and 94 noncarriers from the Genetic Frontotemporal dementia initiative (GENFI), with MRI structural images. We analyzed 3T MRI structural images using the FreeSurfer pipeline to calculate the whole brain cortical thickness (CTh) for each subject. We also perform a vertex-wise general linear model to assess differences between groups in the relationship between CTh and diverse covariables as gender, age, the estimated years to onset and education. We also explored differences according to TMEM106B genotype, a possible disease modifier. Whole brain CTh did not differ between carriers and noncarriers. Both groups showed age-related cortical thinning. The group-by-age interaction analysis showed that this age-related cortical thinning was significantly greater in GRN carriers in the left superior frontal cortex. TMEM106B did not significantly influence the age-related cortical thinning. Our results validate and expand previous findings suggesting an

Published
2021
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21. Clinical Presentation and Outcomes of Severe Acute Respiratory Syndrome Coronavirus 2-Related Encephalitis: The ENCOVID Multicenter Study

Author

Pilotto, A., Masciocchi, Sofia, Volonghi, I., Crabbio, M., Magni, Eugenio, De Giuli, V., Caprioli, Francesca, Rifino, N., Sessa, M., Gennuso, M., Cotelli, M. S., Turla, Mario, Balducci, U., Mariotto, S., Ferrari, S., Ciccone, A., Fiacco, F., Imarisio, A., Risi, B., Benussi, A., Premi, E., Foca, E., Caccuri, F., Leonardi, M., Gasparotti, Roberto, Castelli, F., Zanusso, G., Pezzini, A., Padovani, A., Del Zotto, E., Guindani, M., Poli, L., Gipponi, S., Filosto, M., Gamba, M., Caratozzolo, S., Cristillo, V., Libri, I., Cola, F. S. D., Piccinelli, S. C., Cortinovis, M., Scalvini, A., Baldelli, E., Locatelli, M., Benini, M., Gazzina, S., Chiari, E., Odolini, S., Caruso, A., Ambrosi, C., Pinelli, L., Gerevini, S., Ciceri, E. F. M., Ferraro, B., Volta, G. D., Masciocchi S. (ORCID:0000-0001-7714-0122), Magni E. (ORCID:0000-0002-2235-2280), Caprioli F., Turla M., Gasparotti R., Pilotto, A., Masciocchi, Sofia, Volonghi, I., Crabbio, M., Magni, Eugenio, De Giuli, V., Caprioli, Francesca, Rifino, N., Sessa, M., Gennuso, M., Cotelli, M. S., Turla, Mario, Balducci, U., Mariotto, S., Ferrari, S., Ciccone, A., Fiacco, F., Imarisio, A., Risi, B., Benussi, A., Premi, E., Foca, E., Caccuri, F., Leonardi, M., Gasparotti, Roberto, Castelli, F., Zanusso, G., Pezzini, A., Padovani, A., Del Zotto, E., Guindani, M., Poli, L., Gipponi, S., Filosto, M., Gamba, M., Caratozzolo, S., Cristillo, V., Libri, I., Cola, F. S. D., Piccinelli, S. C., Cortinovis, M., Scalvini, A., Baldelli, E., Locatelli, M., Benini, M., Gazzina, S., Chiari, E., Odolini, S., Caruso, A., Ambrosi, C., Pinelli, L., Gerevini, S., Ciceri, E. F. M., Ferraro, B., Volta, G. D., Masciocchi S. (ORCID:0000-0001-7714-0122), Magni E. (ORCID:0000-0002-2235-2280), Caprioli F., Turla M., and Gasparotti R.

Abstract

Background: Several preclinical and clinical investigations have argued for nervous system involvement in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Some sparse case reports have described various forms of encephalitis in coronavirus disease 2019 (COVID-19) disease, but very few data have focused on clinical presentations, clinical course, response to treatment, and outcomes. Methods: The SARS-CoV-2 related encephalopaties (ENCOVID) multicenter study included patients with encephalitis with full infectious screening, cerebrospinal fluid (CSF), electroencephalography (EEG), and magnetic resonance imaging (MRI) data and confirmed SARS-CoV-2 infection recruited from 13 centers in northern Italy. Clinical presentation and laboratory markers, severity of COVID-19 disease, response to treatment, and outcomes were recorded. Results: Twenty-five cases of encephalitis positive for SARS-CoV-2 infection were included. CSF showed hyperproteinorrachia and/or pleocytosis in 68% of cases whereas SARS-CoV-2 RNA by reverse-transcription polymerase chain reaction resulted negative. Based on MRI, cases were classified as acute demyelinating encephalomyelitis (ADEM; n = 3), limbic encephalitis (LE; n = 2), encephalitis with normal imaging (n = 13), and encephalitis with MRI alterations (n = 7). ADEM and LE cases showed a delayed onset compared to the other encephalitis cases (P = .001) and were associated with previous, more severe COVID-19 respiratory involvement. Patients with MRI alterations exhibited worse response to treatment and final outcomes compared to those with other encephalitis. Conclusions: SARS-CoV-2 infection is associated with a wide spectrum of encephalitis characterized by different clinical presentation, response to treatment, and outcomes.

Published
2021

22. Language training for oral and written naming impairment in primary progressive aphasia: a review

Author

Pagnoni, I., Gobbi, E., Premi, E., Borroni, B., Binetti, G., Cotelli, Maria, Manenti, Rosa, Cotelli M., Manenti R., Pagnoni, I., Gobbi, E., Premi, E., Borroni, B., Binetti, G., Cotelli, Maria, Manenti, Rosa, Cotelli M., and Manenti R.

Abstract

Background: Primary progressive aphasia (PPA) is a neurodegenerative disorder characterized by a gradual, insidious and progressive loss of language abilities, with naming difficulties being an early and persistent impairment common to all three variants. In the absence of effective pharmacological treatments and given the progressive nature of the disorder, in the past few decades, many studies have investigated the effectiveness of language training to minimize the functional impact of word-finding difficulties in daily life. Main body: We review language treatments most commonly used in clinical practice among patients with different variants of PPA, with a focus on the enhancement of spoken and written naming abilities. Generalization of gains to the ability to name untrained stimuli or to other language abilities and the maintenance of these results over time are also discussed. Forty-eight studies were included in this literature review, identifying four main types of language treatment: a) lexical retrieval treatment, b) phonological and/or orthographic treatment, c) semantic treatment, and d) a multimodality approach treatment. Overall, language training is able to induce immediate improvements of naming abilities in all variants of PPA. Moreover, despite the large variability among results, generalization and long-term effects can be recorded after the training. The reviewed studies also suggest that one factor that determines the choice of a particular approach is the compromised components of the lexical/semantic processing system. Conclusion: The majority of studies have demonstrated improvements of naming abilities following language treatments. Given the progressive nature of PPA, it is essential to apply language treatment in the early stages of the disease.

Published
2021

23. Progression of Behavioral Disturbances and Neuropsychiatric Symptoms in Patients With Genetic Frontotemporal Dementia

Author

Benussi, A, Premi, E, Gazzina, S, Brattini, C, Bonomi, E, Alberici, A, Jiskoot, Lize, van Swieten, J.C., Sanchez-Valle, R, Moreno, F, Laforce, R, Graff, C, Synofzik, M, Galimberti, D, Masellis, M, Tartaglia, C, Rowe, JB, Finger, E, Vandenberghe, R, De Mendonca, A, Tagliavini, F, Santana, I, Ducharme, S, Butler, CR, Gerhard, A, Levin, J, Danek, A, Otto, M, Frisoni, G, Ghidoni, R, Sorbi, S, Le Ber, I, Pasquier, F, Peakman, G, Todd, E, Bocchetta, M, Rohrer, JD, Borroni, B, Benussi, A, Premi, E, Gazzina, S, Brattini, C, Bonomi, E, Alberici, A, Jiskoot, Lize, van Swieten, J.C., Sanchez-Valle, R, Moreno, F, Laforce, R, Graff, C, Synofzik, M, Galimberti, D, Masellis, M, Tartaglia, C, Rowe, JB, Finger, E, Vandenberghe, R, De Mendonca, A, Tagliavini, F, Santana, I, Ducharme, S, Butler, CR, Gerhard, A, Levin, J, Danek, A, Otto, M, Frisoni, G, Ghidoni, R, Sorbi, S, Le Ber, I, Pasquier, F, Peakman, G, Todd, E, Bocchetta, M, Rohrer, JD, and Borroni, B

Abstract

Importance: Behavioral disturbances are core features of frontotemporal dementia (FTD); however, symptom progression across the course of disease is not well characterized in genetic FTD. Objective: To investigate behavioral symptom frequency and severity and their evolution and progression in different forms of genetic FTD. Design, Setting, and Participants: This longitudinal cohort study, the international Genetic FTD Initiative (GENFI), was conducted from January 30, 2012, to May 31, 2019, at 23 multicenter specialist tertiary FTD research clinics in the United Kingdom, the Netherlands, Belgium, France, Spain, Portugal, Italy, Germany, Sweden, Finland, and Canada. Participants included a consecutive sample of 232 symptomatic FTD gene variation carriers comprising 115 with variations in C9orf72, 78 in GRN, and 39 in MAPT. A total of 101 carriers had at least 1 follow-up evaluation (for a total of 400 assessments). Gene variations were included only if considered pathogenetic. Main Outcomes and Measures: Behavioral and neuropsychiatric symptoms were assessed across disease duration and evaluated from symptom onset. Hierarchical generalized linear mixed models were used to model behavioral and neuropsychiatric measures as a function of disease duration and variation. Results: Of 232 patients with FTD, 115 (49.6%) had a C9orf72 expansion (median [interquartile range (IQR)] age at evaluation, 64.3 [57.5-69.7] years; 72 men [62.6%]; 115 White patients [100%]), 78 (33.6%) had a GRN variant (median [IQR] age, 63.4 [58.3-68.8] years; 40 women [51.3%]; 77 White patients [98.7%]), and 39 (16.8%) had a MAPT variant (median [IQR] age, 56.3 [49.9-62.4] years; 25 men [64.1%]; 37 White patients [94.9%]). All core behavioral symptoms, including disinhibition, apathy, loss of empathy, perseverative behavior, and hyperorality, were highly expressed in all gene variant carriers (>50% patients), with apathy being one of the most common and severe symptoms throughout the disease

Published
2021

24. Classification accuracy of TMS for the diagnosis of mild cognitive impairment

Author

Benussi, A., Grassi, M., Palluzzi, F., Cantoni, V., Cotelli, M. S., Premi, E., Di Lorenzo, F., Pellicciari, M. C., Ranieri, F., Musumeci, G., Marra, Camillo, Manganotti, P., Nardone, R., Di Lazzaro, V., Koch, G., Borroni, B., Marra C. (ORCID:0000-0003-3994-4044), Benussi, A., Grassi, M., Palluzzi, F., Cantoni, V., Cotelli, M. S., Premi, E., Di Lorenzo, F., Pellicciari, M. C., Ranieri, F., Musumeci, G., Marra, Camillo, Manganotti, P., Nardone, R., Di Lazzaro, V., Koch, G., Borroni, B., and Marra C. (ORCID:0000-0003-3994-4044)

Abstract

Objective: To evaluate the performance of a Random Forest (RF) classifier on Transcranial Magnetic Stimulation (TMS) measures in patients with Mild Cognitive Impairment (MCI). Methods: We applied a RF classifier on TMS measures obtained from a multicenter cohort of patients with MCI, including MCI-Alzheimer's Disease (MCI-AD), MCI-frontotemporal dementia (MCI-FTD), MCI-dementia with Lewy bodies (MCI-DLB), and healthy controls (HC). All patients underwent TMS assessment at recruitment (index test), with application of reference clinical criteria, to predict different neurodegenerative disorders. The primary outcome measures were the classification accuracy, precision, recall and F1-score of TMS in differentiating each disorder. Results: 160 participants were included, namely 64 patients diagnosed as MCI-AD, 28 as MCI-FTD, 14 as MCI-DLB, and 47 as healthy controls (HC). A series of 3 binary classifiers was employed, and the prediction model exhibited high classification accuracy (ranging from 0.72 to 0.86), high precision (0.72–0.90), high recall (0.75–0.98), and high F1-scores (0.78–0.92), in differentiating each neurodegenerative disorder. By computing a new classifier, trained and validated on the current cohort of MCI patients, classification indices showed even higher accuracy (ranging from 0.83 to 0.93), precision (0.87–0.89), recall (0.83–1.00), and F1-scores (0.85–0.94). Conclusions: TMS may be considered a useful additional screening tool to be used in clinical practice in the prodromal stages of neurodegenerative dementias.

Published
2021

27. Single-subject SPM FDG-PET patterns predict risk of dementia progression in Parkinson disease

Author

Pilotto, A, Premi, E, Caminiti, S, Presotto, L, Turrone, R, Alberici, A, Paghera, B, Borroni, B, Padovani, A, Perani, D, Pilotto A., Premi E., Caminiti S. P., Presotto L., Turrone R., Alberici A., Paghera B., Borroni B., Padovani A., Perani D., Pilotto, A, Premi, E, Caminiti, S, Presotto, L, Turrone, R, Alberici, A, Paghera, B, Borroni, B, Padovani, A, Perani, D, Pilotto A., Premi E., Caminiti S. P., Presotto L., Turrone R., Alberici A., Paghera B., Borroni B., Padovani A., and Perani D.

Abstract

Objective To evaluate the statistical parametric mapping (SPM) procedure for fluorodeoxyglucose (FDG)-PET imaging as a possible single-subject marker of progression to dementia in Parkinson disease (PD). Methods Fifty-four consecutive patients with PD without dementia (age at onset of 59.9 ± 10.1 years, disease duration of 5.3 ± 3.4 years) entered the study. The patients underwent an extensive motor and cognitive assessment and a single-subject FDG-PET SPM evaluation at baseline. A 4-year follow-up provided disease progression and dementia diagnosis. Results The FDG-PET SPM was evaluated by 2 expert raters allowing the identification of a "typical PD pattern" in 29 patients, whereas 25 patients presented with "atypical patterns," namely, dementia with Lewy bodies (DLB)-like (n = 12), Alzheimer disease (AD)-like (n = 6), corticobasal syndrome (CBS)-like (n = 5), and frontotemporal dementia (FTD)-like (n = 2). At 4-year follow-up, 13 patients, all showing atypical brain metabolic patterns at baseline, progressed to dementia (PD dementia). The DLB-and AD-like SPM patterns were the best predictor for incident dementia (p < 0.005, sensitivity 85%, specificity 88%), independently from demographics or cognitive baseline classification. Conclusions This study suggests that FDG-PET SPM at the single-subject level might help in identifying patients with PD at risk of developing dementia.

Published
2018

29. 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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30. 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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31. Modelling the cascade of biomarker changes in GRN -related frontotemporal dementia

Author

Panman, J.L. (Jessica), Venkatraghavan, V. (Vikram), Ende, E.L. (Emma) van der, Steketee, R.M.E. (Rebecca), Jiskoot, L.C. (Lize), Poos, J.M. (Jackie), Dopper, E.G.P. (Elise), Meeter, L.H.H. (Lieke), Donker Kaat, L. (Laura), Rombouts, S.A.R.B. (Serge), Vernooij, M.W. (Meike), Kievit, A.J.A. (Anneke J.A.), Premi, E. (Enrico), Cosseddu, M. (Maura), Bonomi, E. (Elisa), Olives, J. (Jaume), Rohrer, J.D. (Jonathan), Sánchez-Valle, R. (Raquel), Borroni, B. (Barbara), Bron, E.E. (Esther), Swieten, J.C. (John) van, Papma, J.M. (Janne), Klein, S. (Stefan), Panman, J.L. (Jessica), Venkatraghavan, V. (Vikram), Ende, E.L. (Emma) van der, Steketee, R.M.E. (Rebecca), Jiskoot, L.C. (Lize), Poos, J.M. (Jackie), Dopper, E.G.P. (Elise), Meeter, L.H.H. (Lieke), Donker Kaat, L. (Laura), Rombouts, S.A.R.B. (Serge), Vernooij, M.W. (Meike), Kievit, A.J.A. (Anneke J.A.), Premi, E. (Enrico), Cosseddu, M. (Maura), Bonomi, E. (Elisa), Olives, J. (Jaume), Rohrer, J.D. (Jonathan), Sánchez-Valle, R. (Raquel), Borroni, B. (Barbara), Bron, E.E. (Esther), Swieten, J.C. (John) van, Papma, J.M. (Janne), and Klein, S. (Stefan)

Abstract

Objective: Progranulin-related frontotemporal dementia (FTD-GRN) is a fast progressive disease. Modelling the cascade of multimodal biomarker changes aids in understanding the aetiology of this disease and enables monitoring of individual mutation carriers. In this cross-sectional study, we estimated the temporal cascade of biomarker changes for FTD-GRN, in a data-driven way. Methods: We included 56 presymptomatic and 35 symptomatic GRN mutation carriers, and 35 healthy non-carriers. Selected biomarkers were neurofilament light chain (NfL), grey matter volume, white matter microstructure and cognitive domains. We used discriminative event-based modelling to infer the cascade of biomarker changes in FTD-GRN and estimated individual disease severity through cross-validation. We derived the biomarker cascades in non-fluent variant primary progressive aphasia (nfvPPA) and behavioural variant FTD (bvFTD) to understand the differences between these phenotypes. Results: Language functioning and NfL were the earliest abnormal biomarkers in FTD-GRN. White matter tracts were affected before grey matter volume, and the left hemisphere degenerated before the right. Based on individual disease severities, presymptomatic carriers could be delineated from symptomatic carriers with a sensitivity of 100% and specificity of 96.1%. The estimated dise

Published
2020
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32. Social cognition impairment in genetic frontotemporal dementia within the GENFI cohort

Author

Russell, L.L. (Lucy L.), Greaves, C.V. (Caroline V.), Bocchetta, M. (Martina), Nicholas, J.M. (Jennifer), Convery, R.S. (Rhian S.), Moore, K. (Katrina), Cash, D.M. (David M.), Swieten, J.C. (John) van, Jiskoot, L.C. (Lize), Moreno, F. (Fermin), Sánchez-Valle, R. (Raquel), Borroni, B. (Barbara), Laforce, R. (Robert), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Graff, C. (Caroline), Rotondo, E. (Emanuela), Galimberti, D. (Daniela), Rowe, J.B. (James), Finger, E. (Elizabeth), Synofzik, M. (Matthis), Vandenberghe, R. (Rik), De Mendonça, A. (Alexandre), Tagliavini, F. (Fabrizio), Santana, I. (Isabel), Ducharme, S. (Simon), Butler, C. (Chris), Gerhard, A. (Alex), Levin, J. (Johannes), Danek, A. (Adrian), Otto, M. (Markus), Warren, J.D. (Jason), Rohrer, J.D. (Jonathan), Rossor, M. (Martin), Fox, N.C. (Nick), Woollacott, I.O.C. (Ione O.C.), Shafei, R. (Rachelle), Heller, C. (Carolin), Guerreiro, R. (Rita), Bras, J. (Jose), Thomas, D.L. (David L), Mead, S. (Simon), Meeter, L.H.H. (Lieke), Panman, J.L. (Jessica), Papma, J.M. (Janne), Poos, J.M. (Jackie), Thornton, A.S. (Andrew), Pijnenburg, Y. (Yolanda), Barandiaran, M. (Myriam), Indakoetxea, B. (Begoña), Gabilondo, A. (Alazne), Tainta, M. (Mikel), de Arriba, M. (Maria), Gorostidi, A. (Ana), Zulaica, M. (Miren), Villanua, J. (Jorge), Diaz, Z. (Zigor), Borrego-Ecija, S. (Sergi), Olives, J. (Jaume), Lladó, A. (Albert), Balasa, M. (Mircea), Antonell, A. (Anna), Bargallo, N. (Nuria), Premi, E. (Enrico), Cosseddu MPsych, M. (Maura), Gazzina, S. (Stefano), Padovani, A. (Alessandro), Gasparotti, R. (Roberto), Archetti, S. (Silvana), Black, S.E. (Sandra), Mitchell, S. (Sara), Rogaeva, E. (Ekaterina), Freedman, M. (Morris), Keren, R. (Ron), Tang-Wai, D. (Daid), Öijerstedt, L. (Linn), Andersson, C. (Christin), Jelic, S. (Svetislav Svetislav), Thonberg, H. (Håkan), Arighi, A. (Andrea), Fenoglio, C. (Chiara), Scarpini, E. (Elio), Fumagalli, G. (Giorgio), Cope, T. (Thomas), Timberlake, C. (Carolyn), Rittman, T. (Timothy), Shoesmith, C. (Christen), Bartha, R. (Robart), Rademakers, S. (Suzanne), Wilke, C. (Carlo), Karnarth, H.-O. (Hans-Otto), Bender, B. (Benjamin), Bruffaerts, R. (Rose), Vandamme, P. (Philip), Vandenbulcke, M. (Mathieu), Ferreira, C.B. (Catarina B.), Miltenberger, G. (Gabriel), Maruta MPsych, C. (Carolina), Verdelho, A. (Ana), Afonso, S. (Sónia), Taipa, R. (Ricardo), Caroppo, P. (Paola), Di Fede, G. (Giuseppe), Giaccone, G. (Giuseppe), Muscio, C. (Cristina), Prioni, S. (Sara), Redaelli, V. (Veronica), Rossi, G. (Giacomina), Tiraboschi, P. (Pietro), Duro NPsych, D. (Diana), Almeida, M.R. (Maria R.), Castelo-Branco, M. (Miguel), Leitão, M.J. (Maria J.), Tabuas-Pereira, M. (Miguel), Santiago, B. (Beatriz), Gauthier, S. (Serge), Rosa-Neto, P. (Pedro), Veldsman, M. (Michele), Thompson, P.M. (Paul), Langheinrich, T. (Tobias), Prix, C. (Catharina), Hoegen, T. (Tobias), Wlasich, E. (Elisabeth), Loosli, S. (Sandra), Schonecker, S. (Sonja), Semler, E. (Elisa), Anderl-Straub, S. (Sarah), Russell, L.L. (Lucy L.), Greaves, C.V. (Caroline V.), Bocchetta, M. (Martina), Nicholas, J.M. (Jennifer), Convery, R.S. (Rhian S.), Moore, K. (Katrina), Cash, D.M. (David M.), Swieten, J.C. (John) van, Jiskoot, L.C. (Lize), Moreno, F. (Fermin), Sánchez-Valle, R. (Raquel), Borroni, B. (Barbara), Laforce, R. (Robert), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Graff, C. (Caroline), Rotondo, E. (Emanuela), Galimberti, D. (Daniela), Rowe, J.B. (James), Finger, E. (Elizabeth), Synofzik, M. (Matthis), Vandenberghe, R. (Rik), De Mendonça, A. (Alexandre), Tagliavini, F. (Fabrizio), Santana, I. (Isabel), Ducharme, S. (Simon), Butler, C. (Chris), Gerhard, A. (Alex), Levin, J. (Johannes), Danek, A. (Adrian), Otto, M. (Markus), Warren, J.D. (Jason), Rohrer, J.D. (Jonathan), Rossor, M. (Martin), Fox, N.C. (Nick), Woollacott, I.O.C. (Ione O.C.), Shafei, R. (Rachelle), Heller, C. (Carolin), Guerreiro, R. (Rita), Bras, J. (Jose), Thomas, D.L. (David L), Mead, S. (Simon), Meeter, L.H.H. (Lieke), Panman, J.L. (Jessica), Papma, J.M. (Janne), Poos, J.M. (Jackie), Thornton, A.S. (Andrew), Pijnenburg, Y. (Yolanda), Barandiaran, M. (Myriam), Indakoetxea, B. (Begoña), Gabilondo, A. (Alazne), Tainta, M. (Mikel), de Arriba, M. (Maria), Gorostidi, A. (Ana), Zulaica, M. (Miren), Villanua, J. (Jorge), Diaz, Z. (Zigor), Borrego-Ecija, S. (Sergi), Olives, J. (Jaume), Lladó, A. (Albert), Balasa, M. (Mircea), Antonell, A. (Anna), Bargallo, N. (Nuria), Premi, E. (Enrico), Cosseddu MPsych, M. (Maura), Gazzina, S. (Stefano), Padovani, A. (Alessandro), Gasparotti, R. (Roberto), Archetti, S. (Silvana), Black, S.E. (Sandra), Mitchell, S. (Sara), Rogaeva, E. (Ekaterina), Freedman, M. (Morris), Keren, R. (Ron), Tang-Wai, D. (Daid), Öijerstedt, L. (Linn), Andersson, C. (Christin), Jelic, S. (Svetislav Svetislav), Thonberg, H. (Håkan), Arighi, A. (Andrea), Fenoglio, C. (Chiara), Scarpini, E. (Elio), Fumagalli, G. (Giorgio), Cope, T. (Thomas), Timberlake, C. (Carolyn), Rittman, T. (Timothy), Shoesmith, C. (Christen), Bartha, R. (Robart), Rademakers, S. (Suzanne), Wilke, C. (Carlo), Karnarth, H.-O. (Hans-Otto), Bender, B. (Benjamin), Bruffaerts, R. (Rose), Vandamme, P. (Philip), Vandenbulcke, M. (Mathieu), Ferreira, C.B. (Catarina B.), Miltenberger, G. (Gabriel), Maruta MPsych, C. (Carolina), Verdelho, A. (Ana), Afonso, S. (Sónia), Taipa, R. (Ricardo), Caroppo, P. (Paola), Di Fede, G. (Giuseppe), Giaccone, G. (Giuseppe), Muscio, C. (Cristina), Prioni, S. (Sara), Redaelli, V. (Veronica), Rossi, G. (Giacomina), Tiraboschi, P. (Pietro), Duro NPsych, D. (Diana), Almeida, M.R. (Maria R.), Castelo-Branco, M. (Miguel), Leitão, M.J. (Maria J.), Tabuas-Pereira, M. (Miguel), Santiago, B. (Beatriz), Gauthier, S. (Serge), Rosa-Neto, P. (Pedro), Veldsman, M. (Michele), Thompson, P.M. (Paul), Langheinrich, T. (Tobias), Prix, C. (Catharina), Hoegen, T. (Tobias), Wlasich, E. (Elisabeth), Loosli, S. (Sandra), Schonecker, S. (Sonja), Semler, E. (Elisa), and Anderl-Straub, S. (Sarah)

Abstract

A key symptom of frontotemporal dementia (FTD) is difficulty interacting socially with others. Social cognition problems in FTD include impaired emotion processing and theory of mind difficulties, and whilst these have been studied extensively in sporadic FTD, few studies have investigated them in familial FTD. Facial Emotion Recognition (FER) and Faux Pas (FP) recognition tests were used to study social cognition within the Genetic Frontotemporal Dementia Initiative (GENFI), a large familial FTD cohort of C9orf72, GRN, and MAPT mutation carriers. 627 participants undertook at least one of the tasks, and were separated into mutation-negative healthy controls, presymptomatic mutation carriers (split into early and late groups) and symptomatic mutation carriers. Groups were compared using a linear regression model with bootstrapping, adjusting for age, sex, education, and for the FP recognition test, language. Neural correlates of social cognition deficits were explored using a voxel-based morphometry (VBM) study. All three of the symptomatic genetic groups were impaired on both tasks with no significant difference between them. However, prior to onset, only the late presymptomatic C9orf72 mutation carriers on the FER test were impaired compared to the control group, with a subanalysis showing differences particularly in fear and sadness. The VBM analysis revealed that impaired social cognition was mainly associated with a left hemisphere predominant network of regions involving particularly the striatum, orbitofrontal cortex and insula, and to a lesser extent the inferomedial temporal lobe and other areas of the frontal lobe. In conclusion, theory of mind and emotion processing abilities are impaired in familial FTD, with early changes occurring prior to symptom onset in C9orf72 presymptomatic mutation carriers. Future work should investigate how performance changes over time, in order to gain a clearer insight into social cognitive impairment over the course of the

Published
2020
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33. Social cognition impairment in genetic frontotemporal dementia within the GENFI cohort

Author

Russell, LL, Greaves, CV, Bocchetta, M, Nicholas, J, Convery, RS, Moore, K, Cash, DM, van Swieten, J.C., Jiskoot, Lize, Moreno, F, Sanchez-Valle, R, Borroni, B, Laforce, R, Jr, Masellis, M, Tartaglia, MC, Graff, C, Rotondo, E, Galimberti, D, Rowe, JB, Finger, E, Synofzik, M, Vandenberghe, R, Mendonça, A, Tagliavini, F, Santana, I, Ducharme, S, Butler, C, Gerhard, A, Levin, J, Danek, A, Otto, M, Warren, JD, Rohrer, JD, Rossor, MN, Fox, NC, Woollacott, IOC, Shafei, R, Heller, C, Guerreiro, R, Bras, J, Thomas, DL, Mead, S, Meeter, Lieke, Panman, J, Papma, J, Poos, J, van Minkelen, Rick, Al 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, Lladó, A, Balasa, M, Antonell, A, Bargallo, N, Premi, E, Cosseddu Mpsych, M, Gazzina, S, Padovani, A, Gasparotti, R, Archetti, S, Black, S, Mitchell, S, Rogaeva, E, Freedman, M, Keren, R, Tang-Wai, D, Öijerstedt, 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, HO, Bender, B, Bruffaerts, R, Vandamme, P, Vandenbulcke, M, Ferreira, CB, Miltenberger, G, Maruta Mpsych, C, Verdelho, A, Afonso, S, Taipa, R, Caroppo, P, Di Fede, G, Giaccone, G, Muscio, C, Prioni, S, Redaelli, V, Rossi, G, Tiraboschi, P, Duro Npsych, D, Almeida, M R, Castelo-Branco, M, Leitão, MJ, 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, Russell, LL, Greaves, CV, Bocchetta, M, Nicholas, J, Convery, RS, Moore, K, Cash, DM, van Swieten, J.C., Jiskoot, Lize, Moreno, F, Sanchez-Valle, R, Borroni, B, Laforce, R, Jr, Masellis, M, Tartaglia, MC, Graff, C, Rotondo, E, Galimberti, D, Rowe, JB, Finger, E, Synofzik, M, Vandenberghe, R, Mendonça, A, Tagliavini, F, Santana, I, Ducharme, S, Butler, C, Gerhard, A, Levin, J, Danek, A, Otto, M, Warren, JD, Rohrer, JD, Rossor, MN, Fox, NC, Woollacott, IOC, Shafei, R, Heller, C, Guerreiro, R, Bras, J, Thomas, DL, Mead, S, Meeter, Lieke, Panman, J, Papma, J, Poos, J, van Minkelen, Rick, Al 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, Lladó, A, Balasa, M, Antonell, A, Bargallo, N, Premi, E, Cosseddu Mpsych, M, Gazzina, S, Padovani, A, Gasparotti, R, Archetti, S, Black, S, Mitchell, S, Rogaeva, E, Freedman, M, Keren, R, Tang-Wai, D, Öijerstedt, 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, HO, Bender, B, Bruffaerts, R, Vandamme, P, Vandenbulcke, M, Ferreira, CB, Miltenberger, G, Maruta Mpsych, C, Verdelho, A, Afonso, S, Taipa, R, Caroppo, P, Di Fede, G, Giaccone, G, Muscio, C, Prioni, S, Redaelli, V, Rossi, G, Tiraboschi, P, Duro Npsych, D, Almeida, M R, Castelo-Branco, M, Leitão, MJ, 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, and Anderl-Straub, S

Published
2020

34. Expanding the role of education in frontotemporal dementia: a functional dynamic connectivity (the chronnectome) study

Author

Premi, E., Cristillo, V., Gazzina, S., Benussi, A., Alberici, A., Cotelli, M. S., Calhoun, V. D., Iraji, A., Magoni, M., Cotelli, Maria, Micheli, A., Gasparotti, R., Padovani, A., Borroni, B., Cotelli Maria, Premi, E., Cristillo, V., Gazzina, S., Benussi, A., Alberici, A., Cotelli, M. S., Calhoun, V. D., Iraji, A., Magoni, M., Cotelli, Maria, Micheli, A., Gasparotti, R., Padovani, A., Borroni, B., and Cotelli Maria

Abstract

In the present study, we aim at investigating whether education modulates dynamical properties of time-varying whole-brain network connectivity (the chronnectome) in frontotemporal dementia (FTD) at a given level of symptom severity. Dynamic connectivity parameters were evaluated in 128 patients with FTD using independent component analysis, sliding-time window correlation, and k-means approach to resting state–magnetic resonance imaging data. We evaluated the relationship between education, a proxy measure of cognitive reserve, and 4 indexes of metastate dynamic connectivity: (1) the number of distinct metastates a patient passes through, (2) the number of switches from one metastate to another, (3) the span of the realized metastates, and (4) the total distance traveled in the state space. We found a significant inverse correlation between years of education and the 4 indexes of metastate dynamic fluidity (all p-values ≤ 0.03, false discovery rate–corrected). This study suggests that patients with FTD with higher education but comparable clinical severity show more global functional brain impairment, suggesting that patients with higher cognitive reserve can cope with more global brain fluidity reduction.

Published
2020

35. 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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36. The inner fluctuations of the brain in presymptomatic Frontotemporal Dementia: The chronnectome fingerprint

Author

Premi, E., Calhoun, V.D. (Vince), Diano, M., Gazzina, S., Cosseddu, M., Alberici, A., Archetti, S., Paternico, D., Gasparotti, R., Swieten, J.C. (John) van, Galimberti, D. (Daniela), Sánchez-Valle, R. (Raquel), Laforce, R, Moreno, F, Synofzik, M., Graff, M.J. (Maud J.L.), Masellis, M, Tartaglia, MC, Rowe, J. (Jacob), Vandenberghe, R. (Rik), Finger, E, Tagliavini, F, Mendonça, A., Santana, I., Butler, C, Ducharme, S., Gerhard, A, Danek, A, Levin, J. (Jonathan), Otto, M., Frisoni, G. (Giuseppe), Cappa, S., Sorbi, S. (Sandro), Padovani, A. (Alessandro), Rohrer, JD, Borroni, B. (Barbara), Premi, E., Calhoun, V.D. (Vince), Diano, M., Gazzina, S., Cosseddu, M., Alberici, A., Archetti, S., Paternico, D., Gasparotti, R., Swieten, J.C. (John) van, Galimberti, D. (Daniela), Sánchez-Valle, R. (Raquel), Laforce, R, Moreno, F, Synofzik, M., Graff, M.J. (Maud J.L.), Masellis, M, Tartaglia, MC, Rowe, J. (Jacob), Vandenberghe, R. (Rik), Finger, E, Tagliavini, F, Mendonça, A., Santana, I., Butler, C, Ducharme, S., Gerhard, A, Danek, A, Levin, J. (Jonathan), Otto, M., Frisoni, G. (Giuseppe), Cappa, S., Sorbi, S. (Sandro), Padovani, A. (Alessandro), Rohrer, JD, and Borroni, B. (Barbara)

Abstract

Frontotemporal Dementia (FTD) is preceded by a long period of subtle brain changes, occurring in the absence of overt cognitive symptoms, that need to be still fully characterized. Dynamic network analysis based on restingstate magnetic resonance imaging (rs-fMRI) is a potentially powerful tool for the study of preclinical FTD. In the present study, we employed a "chronnectome" approach (recurring, time-varying patterns of connectivity) to evaluate measures of dynamic connectivity in 472 at-risk FTD subjects from the Genetic Frontotemporal dementia research Initiative (GENFI) cohort. We considered 249 subjects with FTD-related pathogenetic mutations and 223 mutation non-carriers (HC). Dynamic connectivity was evaluated using independent component analysis and sliding-time window correlation to rs-fMRI data, and meta-state measures of global brain flexibility were extracted. Results show that presymptomatic FTD exhibits diminished dynamic fluidity, visiting less meta-states, shifting less often across them, and travelling through a narrowed meta-state distance, as compared to HC. Dynamic connectivity changes characterize preclinical FTD, arguing for the desynchronization of the inner fluctuations of the brain. These changes antedate clinical symptoms, and might represent an early signature of FTD to be used as a biomarker in clinical trials.

Published
2019
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37. 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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38. The inner fluctuations of the brain in presymptomatic Frontotemporal Dementia: The chronnectome fingerprint

Author

Premi, E, Calhoun, VD, Diano, M, Gazzina, S, Cosseddu, M, Alberici, A, Archetti, S, Paternico, D, Gasparotti, R, van Swieten, J.C., Galimberti, D, Sanchez-Valle, R, Laforce, R, Moreno, F, Synofzik, M, Graff, C, Masellis, M, Tartaglia, MC, Rowe, J, Vandenberghe, R, Finger, E, Tagliavini, F, De Mendonca, A, Santana, I, Butler, C, Ducharme, S, Gerhard, A, Danek, A, Levin, J, Otto, M, Frisoni, G, Cappa, S, Sorbi, S, Padovani, A, Rohrer, JD, Borroni, B, Premi, E, Calhoun, VD, Diano, M, Gazzina, S, Cosseddu, M, Alberici, A, Archetti, S, Paternico, D, Gasparotti, R, van Swieten, J.C., Galimberti, D, Sanchez-Valle, R, Laforce, R, Moreno, F, Synofzik, M, Graff, C, Masellis, M, Tartaglia, MC, Rowe, J, Vandenberghe, R, Finger, E, Tagliavini, F, De Mendonca, A, Santana, I, Butler, C, Ducharme, S, Gerhard, A, Danek, A, Levin, J, Otto, M, Frisoni, G, Cappa, S, Sorbi, S, Padovani, A, Rohrer, JD, and Borroni, B

Published
2019

39. 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

40. 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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41. Clinical and radiological features of posterior cortical atrophy (PCA) in a GRN mutation carrier: a case report.

Author

Giunta, M., Libri, I., Premi, E., Brattini, C., Paghera, B., Archetti, S., Gasparotti, R., Padovani, A., Borroni, B., and Benussi, A.

Subjects
CEREBRAL atrophy, CEREBROSPINAL fluid examination, NEUROLOGIC examination, NEUROPSYCHOLOGICAL tests, ALZHEIMER'S disease, SPINOCEREBELLAR ataxia
Abstract

Background and purpose: Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome, defined by a distinctive clinical‐radiological profile, with Alzheimer's disease (AD) pathology accounting for the majority of cases. The aim of this report was to present the case of a patient with impairment of visual and constructional abilities as initial manifestations. Method: The patient underwent a multidimensional assessment, including neuropsychological evaluation, structural and functional imaging and genetic screening. Results: Neurological and neuropsychological assessment showed an impairment of constructive and visuo‐spatial skills, associated with dyscalculia, simultanagnosia, optic ataxia and oculomotor apraxia. In accordance with the latest consensus criteria, a diagnosis of PCA was made. Consistent with the clinical findings, structural and functional imaging showed a peculiar pattern of atrophy with primary involvement of right parieto‐occipital cortices, whereas cerebrospinal fluid biochemical analysis did not reveal a profile compatible with AD pathology. Genetic screening identified a known pathogenic GRN mutation. Conclusion: We present a case of PCA in a GRN mutation carrier in whom a concomitant AD pathological process was excluded. Consequently, although lacking histological data, our case suggests GRN‐related pathology causative of PCA. Through this report we provide further evidence for a new neurodegenerative pathway leading to PCA, extending the clinical spectrum of GRN‐associated phenotypes. [ABSTRACT FROM AUTHOR]

Published
2021
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43. Phenotypic heterogeneity of Niemann–Pick disease type C in monozygotic twins

Author

Benussi, A, Alberici, A, Premi, E, Bertasi, V, Cotelli, M, Turla, M, Dardis, A, Zampieri, S, Marchina, E, Paghera, B, Gallivanone, F, Castiglioni, I, Padovani, A, Borroni, B, Benussi A, Alberici A, Premi E, Bertasi V, Cotelli MS, Turla M, Dardis A, Zampieri S, Marchina E, Paghera B, Gallivanone F, CASTIGLIONI I, Padovani A, Borroni B, Benussi, A, Alberici, A, Premi, E, Bertasi, V, Cotelli, M, Turla, M, Dardis, A, Zampieri, S, Marchina, E, Paghera, B, Gallivanone, F, Castiglioni, I, Padovani, A, Borroni, B, Benussi A, Alberici A, Premi E, Bertasi V, Cotelli MS, Turla M, Dardis A, Zampieri S, Marchina E, Paghera B, Gallivanone F, CASTIGLIONI I, Padovani A, and Borroni B

Abstract

We report the case of Niemann–Pick disease type C with extensive phenotypic heterogeneity in two monozygotic twins. One of the twins presented with a history of obsessive–compulsive disorder and slowly progressive inferior limb clumsiness, dysphagia and dysarthria. Neurological examination revealed a broad-based ataxic gait, limb dysmetria, downward vertical gaze palsy, brisk lower limb reflexes and ankle clonus, while neuropsychological assessment revealed global cognitive deficits in multiple domains. Complete neurological and neuropsychological evaluation in the asymptomatic monozygotic twin brother only revealed mild neurological impairment. In the hypothesis of Niemann–Pick disease type C, Filipin test, measurement of plasma oxysterols levels and genetic analysis were carried out in both twins. Filipin staining showed massive intracellular accumulation of non-esterified cholesterol, plasma oxysterols levels were elevated and genetic analysis revealed a homozygous c.2662 C > T (p.P888S) mutation in the NPC1 gene (18q11.2) in both twins. 18F-FDG-PET imaging with single-subject analysis revealed a reduced frontal and temporal glucose metabolism, which correlated with disease progression. This case supports the phenotypic variability of Mendelian inherited disorders in monozygotic twins, likely due to epigenetic differences and post-zygotic mutagenesis.

Published
2015

45. Functional connectivity networks in asymptomatic and symptomatic DYT1 carriers

Author

Premi, E, Diano, Matteo, Gazzina, S, Cauda, Franco, Gualeni, V, Tinazzi, M, Fiorio, M, Liberini, P, Lazzarini, C, Archetti, S, Biasiotto, G, Turla, M, Bertasi, V, Cotelli, M, Gasparotti, R, Padovani, A, and Borroni, B.

Subjects
Adult, Cerebral Cortex, Male, Heterozygote, resting-state functional connectivity, Dystonia Musculorum Deformans, DYT1, Middle Aged, Magnetic Resonance Imaging, Connectome, Humans, Female, dystonia, dual regression, Molecular Chaperones
Abstract

DYT1 mutation is characterized by focal to generalized dystonia and incomplete penetrance. To explore the complex perturbations in the different neural networks and the mutual interactions among them, we studied symptomatic and asymptomatic DTY1 mutation carriers by resting-state functional MRI.A total of 7 symptomatic DYT1, 10 asymptomatic DYT1, and 26 healthy controls were considered. Resting-state functional MRI (Oxford Centre for Functional MRI of the Brain) [FMRIB] Software Library) (FSL) MELODIC, dual regression, (as a toolbox of FSL, with Nets is referred to "networks") (FSLNets) (http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/FSLNets) was performed on 9 resting-state neural networks.DYT1 mutation signature (symptomatic DYT1 and asymptomatic DYT1) was characterized by increased connectivity in the dorsal attention network and in the left fronto-parietal network. Functional correlates of symptomatic DYT1 patients (symptomatic DYT1 vs healthy controls) showed increased connectivity in the sensorimotor network.This study argues that DYT1 dystonia is a network disorder, with crucial nodes in sensory-motor integration of posterior parietal structures. A better characterization of cortical networks involved in dystonia is crucial for possible neurophysiological therapeutic interventions. © 2016 International Parkinson and Movement Disorder Society.

Published
2016

46. From Parkinson's disease to dementing alpha-synucleinopathies: subcortical 'matter'

Author

Gazzina, S., Premi, E., Turrone, R., Acosta-Cabronero, Julio, Alberici, A., Rizzetti, C., Gasparotti, R., Padovani, A., and Borroni, B.

Subjects
ddc:610
Abstract

Introduction: α-synucleinopathies, such as Parkinson’s Disease (PD) and Dementia with Lewy Bodies(DLB), are characterized by an ascending accumulation of α-synuclein extending from brainstem structures to the neocortex. Clinically, PD andDLB are clearly distinguished, while discriminationbetween Parkinson dementia (PDD) and DLB canbe subtle and actually based on temporal relationship between motor and cognitive symptoms. Studyof subcortical structures with MRI techniques couldprovide in-vivo information on the spread of pathology among these different clinical conditions.Objectives: To explore the patterns of atrophy atthe subcortical level in PD, PDD and DLB. In particular, we were interested in the markers of evolution from PD to PDD a

Published
2016

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

Author

Premi, E. (Enrico), Grassi, M. (Mario), Swieten, J.C. (John) van, Galimberti, D. (Daniela), Graff, C. (Caroline), Masellis, M. (Mario), Tartaglia, C. (Carmela), Tagliavini, F. (Fabrizio), Rowe, J.B. (James), Laforce, R. (Robert), Finger, E. (Elizabeth), Frisoni, G.B. (Giovanni B.), De Mendonça, A. (Alexandre), Sorbi, S. (Sandro), Gazzina, S. (Stefano), Cosseddu, M. (Maura), Archetti, S. (Silvana), Gasparotti, R. (Roberto), Manes, M. (Marta), Alberici, P. (Paola), Cardoso, M.J. (Manuel Jorge), Bocchetta, M. (Martina), Cash, D.M. (David M.), Ourselin, S. (Sebastien), Padovani, A. (Alessandro), Rohrer, J.D. (Jonathan), Borroni, B. (Barbara), Premi, E. (Enrico), Grassi, M. (Mario), Swieten, J.C. (John) van, Galimberti, D. (Daniela), Graff, C. (Caroline), Masellis, M. (Mario), Tartaglia, C. (Carmela), Tagliavini, F. (Fabrizio), Rowe, J.B. (James), Laforce, R. (Robert), Finger, E. (Elizabeth), Frisoni, G.B. (Giovanni B.), De Mendonça, A. (Alexandre), Sorbi, S. (Sandro), Gazzina, S. (Stefano), Cosseddu, M. (Maura), Archetti, S. (Silvana), Gasparotti, R. (Roberto), Manes, M. (Marta), Alberici, P. (Paola), Cardoso, M.J. (Manuel Jorge), Bocchetta, M. (Martina), Cash, D.M. (David M.), Ourselin, S. (Sebastien), Padovani, A. (Alessandro), Rohrer, J.D. (Jonathan), and Borroni, B. (Barbara)

Abstract

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 sl

Published
2017
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50. Subcortical and deep cortical atrophy in frontotemporal lobar degeneration

Author

Garibotto V. 1, 4, Borroni B. 2, Agosti C. 2, Premi E. 2, Alberici A. 2, Eickhoff S.B. 3, Brambati S.M. 5, Bellelli G. 6, Gasparotti R. 7, Perani D. 1, and Padovani A. 2

Subjects
Basal ganglia, Probabilistic atlases, Semantic Dementia, nervous system, Progressive Non-Fluent Aphasia, mental disorders, Frontotemporal Lobar Degeneration, Behavioral variant Frontotemporal Dementia
Abstract

Though neuroimaging, pathology and pathophysiology suggest a subcortical and deep cortical involvement in Frontotemporal Lobar Degeneration (FTLD), no studies have comprehensively assessed the associated gray matter (GM) volume changes. We measured caudate, putamen, thalamus, and amygdala GM volume using probabilistic a-priori regions of interest (ROIs) in 53 early FTLD patients (38 behavioral variant FTD [bvFTD], 9 Semantic Dementia [SD], 6 Progressive Non-Fluent Aphasia [PNFA]), and 25 age-matched healthy controls (HC). ANOVA showed significant (P

Published
2011

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