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2. 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

5. Using global team science to identify genetic parkinson's disease worldwide

Author

Vollstedt, E, Kasten, M, Klein, C, Aasly, J, Adler, C, Ahmad-Annuar, A, Albanese, A, Alcalay, R, Al-Mubarak, B, Alvarez, V, Andree-Munoz, B, Annesi, G, Appel-Cresswell, S, Arkadir, D, Armasu, S, Barber, T, Bardien, S, Barkhuizen, M, Barrett, M, Basak, A, Beach, T, Benitez, B, Berg, D, Bhatia, K, Binkofski, F, Blauwendraat, C, Bonifati, V, Borges, V, Bozi, M, Brice, A, Brighina, L, Brockmann, K, Brucke, T, Bruggemann, N, Camacho, M, Cardoso, F, Belin, A, Carr, J, Chan, P, Chang-Castello, J, Chase, B, Chen-Plotkin, A, Ju Chung, S, Cilia, R, Clarimon, J, Clark, L, Cornejo-Olivas, M, Corvol, J, Cosentino, C, Cras, P, Crosiers, D, Damasio, J, Das, P, de Carvalho Aguiar, P, De Michele, G, De Rosa, A, Dieguez, E, Dorszewska, J, Erer, S, Ertan, S, Farrer, M, Fedotova, E, Ferese, R, Ferrarese, C, Ferraz, H, Fiala, O, Foroud, T, Friedman, A, Frigerio, R, Funayama, M, Gambardella, S, Garraux, G, Gatto, E, Genc, G, Giladi, N, Goldwurm, S, Gomez-Esteban, J, Gomez-Garre, P, Gorostidi, A, Grosset, D, Hanagasi, H, Hardy, J, Hassan, A, Hattori, N, Hauser, R, Hedera, P, Hentati, F, Hertz, J, Holton, J, Houlden, H, Hutz, M, Ikeuchi, T, Illarioshkin, S, Inca-Martinez, M, Infante, J, Jankovic, J, Jeon, B, Jesus, S, Jimenez-Del-Rio, M, Kaasinen, V, Kataoka, H, Kawakami, H, Kim, Y, Klivenyi, P, Koks, S, Konig, I, Kostic, V, Koziorowski, D, Kruger, R, Krygowska-Wajs, A, Kulisevsky, J, Lai, D, Lang, A, Ledoux, M, Lesage, S, Lim, S, Lin, C, Lohmann, K, Lopera, F, Lopez, G, Lu, C, Lynch, T, Machaczka, M, Madoev, H, Magalhaes, M, Majamaa, K, Maraganore, D, Marder, K, Markopoulou, K, Martikainen, M, Mata, I, Mazzetti, P, Mellick, G, Menendez-Gonzalez, M, Micheli, F, Mirelman, A, Mir, P, Morino, H, Morris, H, Munhoz, R, Naito, A, Olszewska, D, Ozelius, L, Padmanabhan, S, Paisan-Ruiz, C, Payami, H, Peluso, S, Petkovic, S, Petrucci, S, Pezzoli, G, Pimentel, M, Pirker, W, Pramstaller, P, Pulkes, T, Puschmann, A, Quattrone, A, Raggio, V, Ransmayr, G, Rieder, C, Riess, O, Rodriguez-Porcel, F, Rogaeva, E, Ross, O, Ruiz-Martinez, J, Sammler, E, San Luciano, M, Satake, W, Saunders-Pullman, R, Sazci, A, Scherzer, C, Schrag, A, Schumacher-Schuh, A, Sharma, M, Sidransky, E, Singleton, A, Petersen, M, Smolders, S, Spitz, M, Stefanis, L, Struhal, W, Sue, C, Swan, M, Swanberg, M, Taba, P, Taipa, R, Tan, M, Tan, A, Tan, E, Tang, B, Tayebi, N, Thaler, A, Thomas, A, Toda, T, Toft, M, Torres, L, Tumas, V, Valente, E, Van Broeckhoven, C, Vecsei, L, Velez-Pardo, C, Vidailhet, M, Warner, T, Williams-Gray, C, Winkelmann, J, Woitalla, D, Wood, N, Wszolek, Z, Wu, R, Wu, Y, Xie, T, Yoshino, H, Zhang, B, Zimprich, A, Vollstedt E. -J., Kasten M., Klein C., Aasly J., Adler C., Ahmad-Annuar A., Albanese A., Alcalay R. N., Al-Mubarak B., Alvarez V., Andree-Munoz B., Annesi G., Appel-Cresswell S., Arkadir D., Armasu S., Barber T. R., Bardien S., Barkhuizen M., Barrett M. J., Basak A. N., Beach T., Benitez B. A., Berg D., Bhatia K., Binkofski F., Blauwendraat C., Bonifati V., Borges V., Bozi M., Brice A., Brighina L., Brockmann K., Brucke T., Bruggemann N., Camacho M., Cardoso F., Belin A. C., Carr J., Chan P., Chang-Castello J., Chase B., Chen-Plotkin A., Ju Chung S., Cilia R., Clarimon J., Clark L., Cornejo-Olivas M., Corvol J. -C., Cosentino C., Cras P., Crosiers D., Damasio J., Das P., de Carvalho Aguiar P., De Michele G., De Rosa A., Dieguez E., Dorszewska J., Erer S., Ertan S., Farrer M., Fedotova E., Ferese R., Ferrarese C., Ferraz H., Fiala O., Foroud T., Friedman A., Frigerio R., Funayama M., Gambardella S., Garraux G., Gatto E. M., Genc G., Giladi N., Goldwurm S., Gomez-Esteban J. C., Gomez-Garre P., Gorostidi A., Grosset D., Hanagasi H., Hardy J., Hassan A., Hattori N., Hauser R. A., Hedera P., Hentati F., Hertz J. M., Holton J. L., Houlden H., Hutz M. H., Ikeuchi T., Illarioshkin S., Inca-Martinez M., Infante J., Jankovic J., Jeon B. S., Jesus S., Jimenez-Del-Rio M., Kaasinen V., Kataoka H., Kawakami H., Kim Y. J., Klivenyi P., Koks S., Konig I. R., Kostic V., Koziorowski D., Kruger R., Krygowska-Wajs A., Kulisevsky J., Lai D., Lang A., LeDoux M., Lesage S., Lim S. -Y., Lin C. -H., Lohmann K., Lopera F., Lopez G., Lu C. -S., Lynch T., Machaczka M., Madoev H., Magalhaes M., Majamaa K., Maraganore D., Marder K., Markopoulou K., Martikainen M. H., Mata I., Mazzetti P., Mellick G., Menendez-Gonzalez M., Micheli F., Mirelman A., Mir P., Morino H., Morris H., Munhoz R. P., Naito A., Olszewska D. A., Ozelius L. J., Padmanabhan S., Paisan-Ruiz C., Payami H., Peluso S., Petkovic S., Petrucci S., Pezzoli G., Pimentel M., Pirker W., Pramstaller P. P., Pulkes T., Puschmann A., Quattrone A., Raggio V., Ransmayr G., Rieder C., Riess O., Rodriguez-Porcel F., Rogaeva E., Ross O. A., Ruiz-Martinez J., Sammler E., San Luciano M., Satake W., Saunders-Pullman R., Sazci A., Scherzer C., Schrag A., Schumacher-Schuh A., Sharma M., Sidransky E., Singleton A. B., Petersen M. S., Smolders S., Spitz M., Stefanis L., Struhal W., Sue C. M., Swan M., Swanberg M., Taba P., Taipa R., Tan M., Tan A. H., Tan E. -K., Tang B., Tayebi N., Thaler A., Thomas A., Toda T., Toft M., Torres L., Tumas V., Valente E. M., Van Broeckhoven C., Vecsei L., Velez-Pardo C., Vidailhet M., Warner T. T., Williams-Gray C. H., Winkelmann J., Woitalla D., Wood N. W., Wszolek Z. K., Wu R. -M., Wu Y. -R., Xie T., Yoshino H., Zhang B., Zimprich A., Vollstedt, E, Kasten, M, Klein, C, Aasly, J, Adler, C, Ahmad-Annuar, A, Albanese, A, Alcalay, R, Al-Mubarak, B, Alvarez, V, Andree-Munoz, B, Annesi, G, Appel-Cresswell, S, Arkadir, D, Armasu, S, Barber, T, Bardien, S, Barkhuizen, M, Barrett, M, Basak, A, Beach, T, Benitez, B, Berg, D, Bhatia, K, Binkofski, F, Blauwendraat, C, Bonifati, V, Borges, V, Bozi, M, Brice, A, Brighina, L, Brockmann, K, Brucke, T, Bruggemann, N, Camacho, M, Cardoso, F, Belin, A, Carr, J, Chan, P, Chang-Castello, J, Chase, B, Chen-Plotkin, A, Ju Chung, S, Cilia, R, Clarimon, J, Clark, L, Cornejo-Olivas, M, Corvol, J, Cosentino, C, Cras, P, Crosiers, D, Damasio, J, Das, P, de Carvalho Aguiar, P, De Michele, G, De Rosa, A, Dieguez, E, Dorszewska, J, Erer, S, Ertan, S, Farrer, M, Fedotova, E, Ferese, R, Ferrarese, C, Ferraz, H, Fiala, O, Foroud, T, Friedman, A, Frigerio, R, Funayama, M, Gambardella, S, Garraux, G, Gatto, E, Genc, G, Giladi, N, Goldwurm, S, Gomez-Esteban, J, Gomez-Garre, P, Gorostidi, A, Grosset, D, Hanagasi, H, Hardy, J, Hassan, A, Hattori, N, Hauser, R, Hedera, P, Hentati, F, Hertz, J, Holton, J, Houlden, H, Hutz, M, Ikeuchi, T, Illarioshkin, S, Inca-Martinez, M, Infante, J, Jankovic, J, Jeon, B, Jesus, S, Jimenez-Del-Rio, M, Kaasinen, V, Kataoka, H, Kawakami, H, Kim, Y, Klivenyi, P, Koks, S, Konig, I, Kostic, V, Koziorowski, D, Kruger, R, Krygowska-Wajs, A, Kulisevsky, J, Lai, D, Lang, A, Ledoux, M, Lesage, S, Lim, S, Lin, C, Lohmann, K, Lopera, F, Lopez, G, Lu, C, Lynch, T, Machaczka, M, Madoev, H, Magalhaes, M, Majamaa, K, Maraganore, D, Marder, K, Markopoulou, K, Martikainen, M, Mata, I, Mazzetti, P, Mellick, G, Menendez-Gonzalez, M, Micheli, F, Mirelman, A, Mir, P, Morino, H, Morris, H, Munhoz, R, Naito, A, Olszewska, D, Ozelius, L, Padmanabhan, S, Paisan-Ruiz, C, Payami, H, Peluso, S, Petkovic, S, Petrucci, S, Pezzoli, G, Pimentel, M, Pirker, W, Pramstaller, P, Pulkes, T, Puschmann, A, Quattrone, A, Raggio, V, Ransmayr, G, Rieder, C, Riess, O, Rodriguez-Porcel, F, Rogaeva, E, Ross, O, Ruiz-Martinez, J, Sammler, E, San Luciano, M, Satake, W, Saunders-Pullman, R, Sazci, A, Scherzer, C, Schrag, A, Schumacher-Schuh, A, Sharma, M, Sidransky, E, Singleton, A, Petersen, M, Smolders, S, Spitz, M, Stefanis, L, Struhal, W, Sue, C, Swan, M, Swanberg, M, Taba, P, Taipa, R, Tan, M, Tan, A, Tan, E, Tang, B, Tayebi, N, Thaler, A, Thomas, A, Toda, T, Toft, M, Torres, L, Tumas, V, Valente, E, Van Broeckhoven, C, Vecsei, L, Velez-Pardo, C, Vidailhet, M, Warner, T, Williams-Gray, C, Winkelmann, J, Woitalla, D, Wood, N, Wszolek, Z, Wu, R, Wu, Y, Xie, T, Yoshino, H, Zhang, B, Zimprich, A, Vollstedt E. -J., Kasten M., Klein C., Aasly J., Adler C., Ahmad-Annuar A., Albanese A., Alcalay R. N., Al-Mubarak B., Alvarez V., Andree-Munoz B., Annesi G., Appel-Cresswell S., Arkadir D., Armasu S., Barber T. R., Bardien S., Barkhuizen M., Barrett M. J., Basak A. N., Beach T., Benitez B. A., Berg D., Bhatia K., Binkofski F., Blauwendraat C., Bonifati V., Borges V., Bozi M., Brice A., Brighina L., Brockmann K., Brucke T., Bruggemann N., Camacho M., Cardoso F., Belin A. C., Carr J., Chan P., Chang-Castello J., Chase B., Chen-Plotkin A., Ju Chung S., Cilia R., Clarimon J., Clark L., Cornejo-Olivas M., Corvol J. -C., Cosentino C., Cras P., Crosiers D., Damasio J., Das P., de Carvalho Aguiar P., De Michele G., De Rosa A., Dieguez E., Dorszewska J., Erer S., Ertan S., Farrer M., Fedotova E., Ferese R., Ferrarese C., Ferraz H., Fiala O., Foroud T., Friedman A., Frigerio R., Funayama M., Gambardella S., Garraux G., Gatto E. M., Genc G., Giladi N., Goldwurm S., Gomez-Esteban J. C., Gomez-Garre P., Gorostidi A., Grosset D., Hanagasi H., Hardy J., Hassan A., Hattori N., Hauser R. A., Hedera P., Hentati F., Hertz J. M., Holton J. L., Houlden H., Hutz M. H., Ikeuchi T., Illarioshkin S., Inca-Martinez M., Infante J., Jankovic J., Jeon B. S., Jesus S., Jimenez-Del-Rio M., Kaasinen V., Kataoka H., Kawakami H., Kim Y. J., Klivenyi P., Koks S., Konig I. R., Kostic V., Koziorowski D., Kruger R., Krygowska-Wajs A., Kulisevsky J., Lai D., Lang A., LeDoux M., Lesage S., Lim S. -Y., Lin C. -H., Lohmann K., Lopera F., Lopez G., Lu C. -S., Lynch T., Machaczka M., Madoev H., Magalhaes M., Majamaa K., Maraganore D., Marder K., Markopoulou K., Martikainen M. H., Mata I., Mazzetti P., Mellick G., Menendez-Gonzalez M., Micheli F., Mirelman A., Mir P., Morino H., Morris H., Munhoz R. P., Naito A., Olszewska D. A., Ozelius L. J., Padmanabhan S., Paisan-Ruiz C., Payami H., Peluso S., Petkovic S., Petrucci S., Pezzoli G., Pimentel M., Pirker W., Pramstaller P. P., Pulkes T., Puschmann A., Quattrone A., Raggio V., Ransmayr G., Rieder C., Riess O., Rodriguez-Porcel F., Rogaeva E., Ross O. A., Ruiz-Martinez J., Sammler E., San Luciano M., Satake W., Saunders-Pullman R., Sazci A., Scherzer C., Schrag A., Schumacher-Schuh A., Sharma M., Sidransky E., Singleton A. B., Petersen M. S., Smolders S., Spitz M., Stefanis L., Struhal W., Sue C. M., Swan M., Swanberg M., Taba P., Taipa R., Tan M., Tan A. H., Tan E. -K., Tang B., Tayebi N., Thaler A., Thomas A., Toda T., Toft M., Torres L., Tumas V., Valente E. M., Van Broeckhoven C., Vecsei L., Velez-Pardo C., Vidailhet M., Warner T. T., Williams-Gray C. H., Winkelmann J., Woitalla D., Wood N. W., Wszolek Z. K., Wu R. -M., Wu Y. -R., Xie T., Yoshino H., Zhang B., and Zimprich A.

Published
2019

6. 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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7. 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

13. 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

14. 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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15. 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

18. Using global team science to identify genetic Parkinson's disease worldwide

Author

Vollstedt, E‐J, Kasten, M., Klein, C., Aasly, J., Adler, C., Ahmad‐Annuar, A., Albanese, A., Alcalay, R., Al‐Mubarak, B., Alvarez, V., Andree‐Muñoz, B., Annesi, G., Appel‐Cresswell, S., Arkadir, D., Armasu, S., Barber, T.R., Bardien, S., Barkhuizen, M., Barrett, M.J., BaŞak, A.N., Beach, T., Benitez, B.A., Berg, D., Bhatia, K., Binkofski, F., Blauwendraat, C., Bonifati, V., Borges, V., Bozi, M., Brice, A., Brighina, L., Brockmann, K., Brüggemann, N., Camacho, M., Cardoso, F., Belin, A.C., Carr, J., Chan, P., Chang‐Castello, J., Chase, B., Chen‐Plotkin, A., Chung, S.J., Cilia, R., Clarimon, J., Clark, L., Cornejo‐Olivas, M., Corvol, J‐C, Cosentino, C., Cras, P., Crosiers, D., Damásio, J., Das, P., Carvalho Aguiar, P., De Michele, G., De Rosa, A., Dieguez, E., Dorszewska, J., Erer, S., Ertan, S., Farrer, M., Fedotova, E., Ferese, R., Ferrarese, C., Ferraz, H., Fiala, O., Foroud, T., Friedman, A., Frigerio, R., Funayama, M., Gambardella, S., Garraux, G., Gatto, E.M., Genç, G., Goldwurm, S., Gomez‐Esteban, J.C., Gómez‐Garre, P., Gorostidi, A., Grosset, D., Hanagasi, H., Hardy, J., Hassan, A., Hattori, N., Hauser, R.A., Hedera, P., Hentati, F., Hertz, J.M., Holton, J.L., Houlden, H., Hutz, M.H., Ikeuchi, T., Illarioshkin, S., Inca‐Martinez, M., Infante, J., Jankovic, J., Jeon, B.S., Jesús, S., Jimenez‐Del‐Rio, M., Kataoka, H., Kawakami, H., Kim, Y.J., Klivényi, P., Kõks, S., König, I.R., KostiĆ, V., Koziorowski, D., Krüger, R., Krygowska‐Wajs, A., Kulisevsky, J., Lang, A., LeDoux, M., Lesage, S., Lim, S‐Y, Lin, C‐H, Lohmann, K., Lopera, F., Lopez, G., Lu, C‐S, Lynch, T., Machaczka, M., Madoev, H., Magalhães, M., Majamaa, K., Maraganore, D., Marder, K., Markopoulou, K., Martikainen, M.H., Mata, I., Mazzetti, P., Mellick, G., Menéndez‐González, M., Micheli, F., Mirelman, A., Mir, P., Morino, H., Morris, H., Munhoz, R.P., Naito, A., Olszewska, D.A., Ozelius, L.J., Padmanabhan, S., Paisán‐Ruiz, C., Payami, H., Peluso, S., Petkovic, S., Petrucci, S., Pezzoli, G., Pimentel, M., Pirker, W., Pramstaller, P.P., Pulkes, T., Puschmann, A., Quattrone, A., Raggio, V., Ransmayr, G., Rieder, C., Riess, O., Rodriguez‐Porcel, F., Rogaeva, E., Ross, O.A., Ruiz‐Martinez, J., Sammler, E., Luciano, M.S., Satake, W., Saunders‐Pullman, R., Sazci, A., Scherzer, C., Schrag, A., Schumacher‐Schuh, A., Sharma, M., Sidransky, E., Singleton, A.B., Petersen, M.S., Smolders, S., Spitz, M., Stefanis, L., Struhal, W., Sue, C., Swan, M., Swanberg, M., Taba, P., Taipa, R., Tan, M., Tan, A.H., Tan, E‐K, Tang, B., Tayebi, N., Thaler, A., Thomas, A., Toda, T., Toft, M., Torres, L., Tumas, V., Valente, E.M., Van Broeckhoven, C., Vecsei, L., Velez‐Pardo, C., Vidailhet, M., Warner, T.T., Williams‐Gray, C.H., Winkelmann, J., Woitalla, D., Wood, N.W., Wszolek, Z.K., Wu, R‐M, Wu, Y‐R, Xie, T., Yoshino, H., Zhang, B., Zimprich, A., Vollstedt, E‐J, Kasten, M., Klein, C., Aasly, J., Adler, C., Ahmad‐Annuar, A., Albanese, A., Alcalay, R., Al‐Mubarak, B., Alvarez, V., Andree‐Muñoz, B., Annesi, G., Appel‐Cresswell, S., Arkadir, D., Armasu, S., Barber, T.R., Bardien, S., Barkhuizen, M., Barrett, M.J., BaŞak, A.N., Beach, T., Benitez, B.A., Berg, D., Bhatia, K., Binkofski, F., Blauwendraat, C., Bonifati, V., Borges, V., Bozi, M., Brice, A., Brighina, L., Brockmann, K., Brüggemann, N., Camacho, M., Cardoso, F., Belin, A.C., Carr, J., Chan, P., Chang‐Castello, J., Chase, B., Chen‐Plotkin, A., Chung, S.J., Cilia, R., Clarimon, J., Clark, L., Cornejo‐Olivas, M., Corvol, J‐C, Cosentino, C., Cras, P., Crosiers, D., Damásio, J., Das, P., Carvalho Aguiar, P., De Michele, G., De Rosa, A., Dieguez, E., Dorszewska, J., Erer, S., Ertan, S., Farrer, M., Fedotova, E., Ferese, R., Ferrarese, C., Ferraz, H., Fiala, O., Foroud, T., Friedman, A., Frigerio, R., Funayama, M., Gambardella, S., Garraux, G., Gatto, E.M., Genç, G., Goldwurm, S., Gomez‐Esteban, J.C., Gómez‐Garre, P., Gorostidi, A., Grosset, D., Hanagasi, H., Hardy, J., Hassan, A., Hattori, N., Hauser, R.A., Hedera, P., Hentati, F., Hertz, J.M., Holton, J.L., Houlden, H., Hutz, M.H., Ikeuchi, T., Illarioshkin, S., Inca‐Martinez, M., Infante, J., Jankovic, J., Jeon, B.S., Jesús, S., Jimenez‐Del‐Rio, M., Kataoka, H., Kawakami, H., Kim, Y.J., Klivényi, P., Kõks, S., König, I.R., KostiĆ, V., Koziorowski, D., Krüger, R., Krygowska‐Wajs, A., Kulisevsky, J., Lang, A., LeDoux, M., Lesage, S., Lim, S‐Y, Lin, C‐H, Lohmann, K., Lopera, F., Lopez, G., Lu, C‐S, Lynch, T., Machaczka, M., Madoev, H., Magalhães, M., Majamaa, K., Maraganore, D., Marder, K., Markopoulou, K., Martikainen, M.H., Mata, I., Mazzetti, P., Mellick, G., Menéndez‐González, M., Micheli, F., Mirelman, A., Mir, P., Morino, H., Morris, H., Munhoz, R.P., Naito, A., Olszewska, D.A., Ozelius, L.J., Padmanabhan, S., Paisán‐Ruiz, C., Payami, H., Peluso, S., Petkovic, S., Petrucci, S., Pezzoli, G., Pimentel, M., Pirker, W., Pramstaller, P.P., Pulkes, T., Puschmann, A., Quattrone, A., Raggio, V., Ransmayr, G., Rieder, C., Riess, O., Rodriguez‐Porcel, F., Rogaeva, E., Ross, O.A., Ruiz‐Martinez, J., Sammler, E., Luciano, M.S., Satake, W., Saunders‐Pullman, R., Sazci, A., Scherzer, C., Schrag, A., Schumacher‐Schuh, A., Sharma, M., Sidransky, E., Singleton, A.B., Petersen, M.S., Smolders, S., Spitz, M., Stefanis, L., Struhal, W., Sue, C., Swan, M., Swanberg, M., Taba, P., Taipa, R., Tan, M., Tan, A.H., Tan, E‐K, Tang, B., Tayebi, N., Thaler, A., Thomas, A., Toda, T., Toft, M., Torres, L., Tumas, V., Valente, E.M., Van Broeckhoven, C., Vecsei, L., Velez‐Pardo, C., Vidailhet, M., Warner, T.T., Williams‐Gray, C.H., Winkelmann, J., Woitalla, D., Wood, N.W., Wszolek, Z.K., Wu, R‐M, Wu, Y‐R, Xie, T., Yoshino, H., Zhang, B., and Zimprich, A.

Abstract

Talks on rare diseases in the field of neurology often start with a statement like this: “About 80% of all rare diseases have a neurologic manifestation and about 80% of those are genetic in origin.” Although these numbers probably represent more of an estimate than well‐documented evidence, rapidly advancing and cost‐effective sequencing technologies have led to the quickly growing identification of patients with hereditary neurological diseases...

Published
2019

19. Using global team science to identify genetic parkinson's disease worldwide

Author

Vollstedt, E. -J., Kasten, M., Klein, C., Aasly, J., Adler, C., Ahmad-Annuar, A., Albanese, Alberto, Alcalay, R. N., Al-Mubarak, B., Alvarez, V., Andree-Munoz, B., Annesi, G., Appel-Cresswell, S., Arkadir, D., Armasu, S., Barber, T. R., Bardien, S., Barkhuizen, M., Barrett, M. J., Basak, A. N., Beach, T., Benitez, B. A., Berg, D., Bhatia, K., Binkofski, F., Blauwendraat, C., Bonifati, V., Borges, V., Bozi, M., Brice, A., Brighina, L., Brockmann, K., Brucke, T., Bruggemann, N., Camacho, M., Cardoso, F., Belin, A. C., Carr, J., Chan, P., Chang-Castello, J., Chase, B., Chen-Plotkin, A., Ju Chung, S., Cilia, R., Clarimon, J., Clark, L., Cornejo-Olivas, M., Corvol, J. -C., Cosentino, C., Cras, P., Crosiers, D., Damasio, J., Das, P., de Carvalho Aguiar, P., De Michele, G., De Rosa, A., Dieguez, E., Dorszewska, J., Erer, S., Ertan, S., Farrer, M., Fedotova, E., Ferese, R., Ferrarese, C., Ferraz, H., Fiala, O., Foroud, T., Friedman, A., Frigerio, R., Funayama, M., Gambardella, S., Garraux, G., Gatto, E. M., Genc, G., Giladi, N., Goldwurm, S., Gomez-Esteban, J. C., Gomez-Garre, P., Gorostidi, A., Grosset, D., Hanagasi, H., Hardy, J., Hassan, A., Hattori, N., Hauser, R. A., Hedera, P., Hentati, F., Hertz, J. M., Holton, J. L., Houlden, H., Hutz, M. H., Ikeuchi, T., Illarioshkin, S., Inca-Martinez, M., Infante, J., Jankovic, J., Jeon, B. S., Jesus, S., Jimenez-Del-Rio, M., Kaasinen, V., Kataoka, H., Kawakami, H., Kim, Y. J., Klivenyi, P., Koks, S., Konig, I. R., Kostic, V., Koziorowski, D., Kruger, R., Krygowska-Wajs, A., Kulisevsky, J., Lai, D., Lang, A., Ledoux, M., Lesage, S., Lim, S. -Y., Lin, C. -H., Lohmann, K., Lopera, F., Lopez, G., Lu, C. -S., Lynch, T., Machaczka, M., Madoev, H., Magalhaes, M., Majamaa, K., Maraganore, D., Marder, K., Markopoulou, K., Martikainen, M. H., Mata, I., Mazzetti, P., Mellick, G., Menendez-Gonzalez, M., Micheli, F., Mirelman, A., Mir, P., Morino, H., Morris, H., Munhoz, R. P., Naito, A., Olszewska, D. A., Ozelius, L. J., Padmanabhan, S., Paisan-Ruiz, C., Payami, H., Peluso, S., Petkovic, S., Petrucci, S., Pezzoli, G., Pimentel, M., Pirker, W., Pramstaller, P. P., Pulkes, T., Puschmann, A., Quattrone, A., Raggio, V., Ransmayr, G., Rieder, C., Riess, O., Rodriguez-Porcel, F., Rogaeva, E., Ross, O. A., Ruiz-Martinez, J., Sammler, E., San Luciano, M., Satake, W., Saunders-Pullman, R., Sazci, A., Scherzer, C., Schrag, A., Schumacher-Schuh, A., Sharma, M., Sidransky, E., Singleton, A. B., Petersen, M. S., Smolders, S., Spitz, M., Stefanis, L., Struhal, W., Sue, C. M., Swan, M., Swanberg, M., Taba, P., Taipa, R., Tan, M., Tan, A. H., Tan, E. -K., Tang, B., Tayebi, N., Thaler, A., Thomas, A., Toda, T., Toft, M., Torres, L., Tumas, V., Valente, E. M., Van Broeckhoven, C., Vecsei, L., Velez-Pardo, C., Vidailhet, M., Warner, T. T., Williams-Gray, C. H., Winkelmann, J., Woitalla, D., Wood, N. W., Wszolek, Z. K., Wu, R. -M., Wu, Y. -R., Xie, T., Yoshino, H., Zhang, B., Zimprich, A., Albanese A. (ORCID:0000-0002-5864-0006), Vollstedt, E. -J., Kasten, M., Klein, C., Aasly, J., Adler, C., Ahmad-Annuar, A., Albanese, Alberto, Alcalay, R. N., Al-Mubarak, B., Alvarez, V., Andree-Munoz, B., Annesi, G., Appel-Cresswell, S., Arkadir, D., Armasu, S., Barber, T. R., Bardien, S., Barkhuizen, M., Barrett, M. J., Basak, A. N., Beach, T., Benitez, B. A., Berg, D., Bhatia, K., Binkofski, F., Blauwendraat, C., Bonifati, V., Borges, V., Bozi, M., Brice, A., Brighina, L., Brockmann, K., Brucke, T., Bruggemann, N., Camacho, M., Cardoso, F., Belin, A. C., Carr, J., Chan, P., Chang-Castello, J., Chase, B., Chen-Plotkin, A., Ju Chung, S., Cilia, R., Clarimon, J., Clark, L., Cornejo-Olivas, M., Corvol, J. -C., Cosentino, C., Cras, P., Crosiers, D., Damasio, J., Das, P., de Carvalho Aguiar, P., De Michele, G., De Rosa, A., Dieguez, E., Dorszewska, J., Erer, S., Ertan, S., Farrer, M., Fedotova, E., Ferese, R., Ferrarese, C., Ferraz, H., Fiala, O., Foroud, T., Friedman, A., Frigerio, R., Funayama, M., Gambardella, S., Garraux, G., Gatto, E. M., Genc, G., Giladi, N., Goldwurm, S., Gomez-Esteban, J. C., Gomez-Garre, P., Gorostidi, A., Grosset, D., Hanagasi, H., Hardy, J., Hassan, A., Hattori, N., Hauser, R. A., Hedera, P., Hentati, F., Hertz, J. M., Holton, J. L., Houlden, H., Hutz, M. H., Ikeuchi, T., Illarioshkin, S., Inca-Martinez, M., Infante, J., Jankovic, J., Jeon, B. S., Jesus, S., Jimenez-Del-Rio, M., Kaasinen, V., Kataoka, H., Kawakami, H., Kim, Y. J., Klivenyi, P., Koks, S., Konig, I. R., Kostic, V., Koziorowski, D., Kruger, R., Krygowska-Wajs, A., Kulisevsky, J., Lai, D., Lang, A., Ledoux, M., Lesage, S., Lim, S. -Y., Lin, C. -H., Lohmann, K., Lopera, F., Lopez, G., Lu, C. -S., Lynch, T., Machaczka, M., Madoev, H., Magalhaes, M., Majamaa, K., Maraganore, D., Marder, K., Markopoulou, K., Martikainen, M. H., Mata, I., Mazzetti, P., Mellick, G., Menendez-Gonzalez, M., Micheli, F., Mirelman, A., Mir, P., Morino, H., Morris, H., Munhoz, R. P., Naito, A., Olszewska, D. A., Ozelius, L. J., Padmanabhan, S., Paisan-Ruiz, C., Payami, H., Peluso, S., Petkovic, S., Petrucci, S., Pezzoli, G., Pimentel, M., Pirker, W., Pramstaller, P. P., Pulkes, T., Puschmann, A., Quattrone, A., Raggio, V., Ransmayr, G., Rieder, C., Riess, O., Rodriguez-Porcel, F., Rogaeva, E., Ross, O. A., Ruiz-Martinez, J., Sammler, E., San Luciano, M., Satake, W., Saunders-Pullman, R., Sazci, A., Scherzer, C., Schrag, A., Schumacher-Schuh, A., Sharma, M., Sidransky, E., Singleton, A. B., Petersen, M. S., Smolders, S., Spitz, M., Stefanis, L., Struhal, W., Sue, C. M., Swan, M., Swanberg, M., Taba, P., Taipa, R., Tan, M., Tan, A. H., Tan, E. -K., Tang, B., Tayebi, N., Thaler, A., Thomas, A., Toda, T., Toft, M., Torres, L., Tumas, V., Valente, E. M., Van Broeckhoven, C., Vecsei, L., Velez-Pardo, C., Vidailhet, M., Warner, T. T., Williams-Gray, C. H., Winkelmann, J., Woitalla, D., Wood, N. W., Wszolek, Z. K., Wu, R. -M., Wu, Y. -R., Xie, T., Yoshino, H., Zhang, B., Zimprich, A., and Albanese A. (ORCID:0000-0002-5864-0006)

Abstract

Talks on rare diseases in the field of neurology often start with a statement like this: “About 80% of all rare diseases have a neurologic manifestation and about 80% of those are genetic in origin.” Although these numbers probably represent more of an estimate than well-documented evidence, rapidly advancing and cost-effective sequencing technologies have led to the quickly growing identification of patients with hereditary neurological diseases. Although the importance of genetics for diagnosis and genetic counseling is undisputed, the recent development of first genetargeted therapies entering clinical trial1,2 is adding an important new layer to the (re-)consideration of genetic testing in neurology. However, establishing accurate genotype– phenotype and genotype–treatment relationships requires large sample sizes. Systematic reviews can serve as instruments to combine information from several small samples, but unfortunately, this is often complicated by inconsistent and incomplete reporting of clinical and genetic data across studies. Thus, large multicenter approaches are necessary to systematically and uniformly characterize patients with genetic neurologic conditions and to eventually establish sizable clinical trial-ready cohorts.

Published
2019

24. Histopathological findings in brain tissue obtained during epilepsy surgery

Author

Blümcke, I., Spreafico, R., Haaker, G., Coras, R., Kobow, K., Bien, C.G., Pfäfflin, M., Elger, C., Widman, G., Schramm, J., Becker, A., Braun, K.P.J., Leijten, F.S.S., Baayen, J.C., Aronica, E., Chassoux, F., Hamer, H., Stefan, H., Rössler, K., Thom, M., Walker, M.C., Sisodiya, S.M., Duncan, J.S., McEvoy, A.W., Pieper, T., Holthausen, H., Kudernatsch, M., Meencke, H.J., Kahane, P., Schulze-Bonhage, A., Zentner, J., Heiland, D., Urbach, H., Steinhoff, B.J., Bast, T., Tassi, L., Lo Russo, G., Ozkara, C., Oz, B., Krsek, P., Vogelgesang, S., Runge, U., Lerche, H., Weber, Y., Honavar, M., Pimentel, J., Arzimanoglou, A., Ulate-Campos, A., Noachtar, S., Hartl, E., Schijns, O.E.M.G., Guerrini, R., Barba, C., Jacques, T.S., Cross, J.H., Feucht, M., Mühlebner, A., Grunwald, T., Trinka, E., Winkler, P.A., Gil-Nagel, A., Toledano Delgado, R., Mayer, T., Lutz, M., Zountsas, B., Garganis, K., Rosenow, F., Hermsen, A., Örtzen, T.J. von, Diepgen, T.L., Avanzini, G., Aparicio, J., Bento, C., Beckervordersandforth, J., Buccoliero, A.M., Cabral, P., Chamadoira, C., Colon, A.J., Chabardès, S., Carpenter, S., Czech, T., Dressler, A., Deleo, F., Dílio, A., Dings, J., Devaux, B., De Tisi, J., De Bellescize, J., Ebner, A., Franke, K., Groeppel, G., Giordano, F., Gozzo, F., Garbelli, R., Guenot, M., García‐Morales, I., Gómez‐Angulo, J.C., Garcia, G., Hainfellner, J.A., Höfler, J., Hoogland, G., Hendriks, M.P.H., Hofman, P., Harding, B., Huppertz, H.J., Herms, J., Hilkman, D.M.W., Hamelin, S., Idema, S., Jansen, F.E., Jahodova, A., Keeley, A., Kalss, G., Kudr, M., Kroell, J., Kokkinos, V., Keo Kosal, P., Kalbhenn, T., Leitinger, M., Landré, E., Melo Pires, M., Matas, A., Mann, M.W., Ostrowsky‐Coste, K., Prinz, M., Puttinger, G., Peraud, A., Rangel Pinho, R., Romero, C., Rego, R., Rouhl, R.P.W., Ryvlin, P., Rumia, J., Rampp, S., Scholl, T., Schulz, R., Stone, T.J., Streichenberger, N., Tisdall, M., Turak, B., Taipa, R., Uzan, M., Kranen‐Mastenbroek, V. van, Varlet, P., Vlooswijk, M.C.G., Wagner, L., Weis, S., Blümcke, I., Spreafico, R., Haaker, G., Coras, R., Kobow, K., Bien, C.G., Pfäfflin, M., Elger, C., Widman, G., Schramm, J., Becker, A., Braun, K.P.J., Leijten, F.S.S., Baayen, J.C., Aronica, E., Chassoux, F., Hamer, H., Stefan, H., Rössler, K., Thom, M., Walker, M.C., Sisodiya, S.M., Duncan, J.S., McEvoy, A.W., Pieper, T., Holthausen, H., Kudernatsch, M., Meencke, H.J., Kahane, P., Schulze-Bonhage, A., Zentner, J., Heiland, D., Urbach, H., Steinhoff, B.J., Bast, T., Tassi, L., Lo Russo, G., Ozkara, C., Oz, B., Krsek, P., Vogelgesang, S., Runge, U., Lerche, H., Weber, Y., Honavar, M., Pimentel, J., Arzimanoglou, A., Ulate-Campos, A., Noachtar, S., Hartl, E., Schijns, O.E.M.G., Guerrini, R., Barba, C., Jacques, T.S., Cross, J.H., Feucht, M., Mühlebner, A., Grunwald, T., Trinka, E., Winkler, P.A., Gil-Nagel, A., Toledano Delgado, R., Mayer, T., Lutz, M., Zountsas, B., Garganis, K., Rosenow, F., Hermsen, A., Örtzen, T.J. von, Diepgen, T.L., Avanzini, G., Aparicio, J., Bento, C., Beckervordersandforth, J., Buccoliero, A.M., Cabral, P., Chamadoira, C., Colon, A.J., Chabardès, S., Carpenter, S., Czech, T., Dressler, A., Deleo, F., Dílio, A., Dings, J., Devaux, B., De Tisi, J., De Bellescize, J., Ebner, A., Franke, K., Groeppel, G., Giordano, F., Gozzo, F., Garbelli, R., Guenot, M., García‐Morales, I., Gómez‐Angulo, J.C., Garcia, G., Hainfellner, J.A., Höfler, J., Hoogland, G., Hendriks, M.P.H., Hofman, P., Harding, B., Huppertz, H.J., Herms, J., Hilkman, D.M.W., Hamelin, S., Idema, S., Jansen, F.E., Jahodova, A., Keeley, A., Kalss, G., Kudr, M., Kroell, J., Kokkinos, V., Keo Kosal, P., Kalbhenn, T., Leitinger, M., Landré, E., Melo Pires, M., Matas, A., Mann, M.W., Ostrowsky‐Coste, K., Prinz, M., Puttinger, G., Peraud, A., Rangel Pinho, R., Romero, C., Rego, R., Rouhl, R.P.W., Ryvlin, P., Rumia, J., Rampp, S., Scholl, T., Schulz, R., Stone, T.J., Streichenberger, N., Tisdall, M., Turak, B., Taipa, R., Uzan, M., Kranen‐Mastenbroek, V. van, Varlet, P., Vlooswijk, M.C.G., Wagner, L., and Weis, S.

Abstract

Item does not contain fulltext, Background: Detailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy. Methods: We report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%). Results: The onset of seizures occurred before 18 years of age in 75.9% of patients overall, and 72.5% of the patients underwent surgery as adults. The mean duration of epilepsy before surgical resection was 20.1 years among adults and 5.3 years among children. The temporal lobe was involved in 71.9% of operations. There were 36 histopathological diagnoses in seven major disease categories. The most common categories were hippocampal sclerosis, found in 36.4% of the patients (88.7% of cases were in adults), tumors (mainly ganglioglioma) in 23.6%, and malformations of cortical development in 19.8% (focal cortical dysplasia was the most common type, 52.7% of cases of which were in children). No histopathological diagnosis could be established for 7.7% of the patients. Conclusions: In patients with drug-resistant focal epilepsy requiring surgery, hippocampal sclerosis was the most common histopathological diagnosis among adults, and focal cortical dysplasia was the most common diagnosis among children. Tumors were the second most common lesion in both groups. (Funded by the European Union and others.)

Published
2017

27. Intronic long interspersed nuclear element (LINE-1) insertion in the DMD gene as a cause of Becker Muscular Dystrophy

Author

Bronze da Rocha, E, Gonçalves A, Coelho T, Oliveira J, Vieira E, Taipa R, Melo Pires M, Santos R, and Faculdade de Farmácia

Abstract

Long interspersed nuclear elements (LINE-1 or L1) are the most abundant retrotransposable elements accounting for nearly 17% of the human genome. These elements can be randomly incorporated in the genome, therefore having an important role in its plasticity and in generating structural genetic variants. It has been demonstrated that L1 retrotransposon activity may occasionally cause genetic diseases. To date, only four disease-causing L1 elements have been described in the dystrophin (DMD) gene; three inserted in exons 44, 48 and 67, in patients with a Duchenne muscular dystrophy (DMD) phenotype, and one detected in the 5Žuntranslated region, in two apparently unrelated Japanese families with X-linked dilated cardiomyopathy. We report a 48 year old man with a clinical diagnosis of Becker muscular dystrophy (BMD), in 2001, without molecular confirmation by multiplex PCR and Southern-Blot analysis, and whose diagnosis was recently revisited because his daughter is considering pregnancy. A second molecular study, resorting to multiplex ligation-probe amplification (MLPA) analysis and genomic DMD gene sequencing, again failed to detect abnormalities. A new muscle biopsy showed dystrophic features with irregular labeling for dystrophin on immunohistochemical analysis, suggesting dystrophinopathy. With the intention of unveiling a genetic defect that might be refractory to the previous diagnostic techniques, muscle-derived DMD transcripts were sequenced in their entirety. Results revealed an insertion of 103 nucleotides between exons 51 and 52, which showed no homology to the genes reference sequence. Extensive bioinformatic analysis (homology search and splice-site/branch-point analysis) and sequential direct sequencing enabled the discovery of a deepintronic insertion of an L1 element, in intron 51. This extremely rare mutational event resulted in the partial exonization of the L1 plus 5 nucleotides of intron 51. In addition to the aberrant out-of-frame transcript, a residually expressed wild-type transcript was also detected, thereby explaining the milder phenotype in this patient. To our knowledge this is the first report ever of dystrophinopathy caused by an intronically placed L1 element. Besides representing an exceptional contribution towards widening the DMD gene mutation spectrum, this study highlights the importance of conducting mRNA studies in as yet uncharacterized BMD/DMD patients. This holds true even considering some of the most recent state-of-the-art screening approaches, based on next-generation sequencing technology, where this type of mutation may ultimately fail to be detected.

Published
2015

32. Inflammatory pathology markers (activated microglia and reactive astrocytes) in early and late onset Alzheimer disease: a <italic>post mortem</italic> study.

Author

Taipa, R., Ferreira, V., Brochado, P., Robinson, A., Reis, I., Marques, F., Mann, D. M., Melo‐Pires, M., and Sousa, N.

Subjects
*ALZHEIMER'S disease, *AMYLOID beta-protein, *COGNITION disorders, *PATHOLOGICAL physiology, *ASTROCYTES, *NEURODEGENERATION
Abstract

Aims: The association between the pathological features of AD and dementia is stronger in younger old persons than in older old persons suggesting that additional factors are involved in the clinical expression of dementia in the oldest old. Cumulative data suggests that neuroinflammation plays a prominent role in Alzheimer′s disease (AD) and different studies reported an age‐associated dysregulation of the neuroimmune system. Consequently, we sought to characterize the pattern of microglial cell activation and astrogliosis in brain post mortem tissue of pathologically confirmed cases of early and late onset AD (EOAD and LOAD) and determine their relation to age. Methods: Immunohistochemistry (CD68 and glial fibrillary acidic protein) with morphometric analysis of astroglial profiles in 36 cases of AD and 28 similarly aged controls. Results: Both EOAD and LOAD groups had higher microglial scores in CA1, entorhinal and temporal cortices, and higher astroglial response in CA1, dentate gyrus, entorhinal and temporal cortices, compared to aged matched controls. Additionally, EOAD had higher microglial scores in subiculum, entorhinal and temporal subcortical white matter, and LOAD higher astrogliosis in CA2 region. Conclusions: Overall, we found that the neuroinflammatory pathological markers in late stage AD human tissue to have a similar pattern in both EOAD and LOAD, though the severity of the pathological markers in the younger group was higher. Understanding the age effect in AD will be important when testing modifying agents that act on the neuroinflammation. [ABSTRACT FROM AUTHOR]

Published
2018
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33. Mitochondrial haplogroup H1 is protective for ischemic stroke in Portuguese patient

Author

Rosa, A, Fonseca, BV, Krug, T, Manso, H, Gouveia, L, Albergaria, I, Gaspar, G, Correia, M, Viana-Baptista, M, Simões, RM, Pinto, AN, Taipa, R, Ferreira, C, Fontes, JR, Gabriel, JP, Matos, I, Lopes, G, Ferro, JM, Vicente, AM, and Oliveira, SA

Subjects
Isquemia Cerebral, Acidente Vascular Cerebral, Haplótipos, Predisposição Genética para Doença, DNA Mitocondrial
Abstract

BACKGROUND: The genetic contribution to stroke is well established but it has proven difficult to identify the genes and the disease-associated alleles mediating this effect, possibly because only nuclear genes have been intensely investigated so far. Mitochondrial DNA (mtDNA) has been implicated in several disorders having stroke as one of its clinical manifestations. The aim of this case-control study was to assess the contribution of mtDNA polymorphisms and haplogroups to ischemic stroke risk. METHODS: We genotyped 19 mtDNA single nucleotide polymorphisms (SNPs) defining the major European haplogroups in 534 ischemic stroke patients and 499 controls collected in Portugal, and tested their allelic and haplogroup association with ischemic stroke risk. RESULTS: Haplogroup H1 was found to be significantly less frequent in stroke patients than in controls (OR = 0.61, 95% CI = 0.45-0.83, p = 0.001), when comparing each clade against all other haplogroups pooled together. Conversely, the pre-HV/HV and U mtDNA lineages emerge as potential genetic factors conferring risk for stroke (OR = 3.14, 95% CI = 1.41-7.01, p = 0.003, and OR = 2.87, 95% CI = 1.13-7.28, p = 0.021, respectively). SNPs m.3010G>A, m.7028C>T and m.11719G>A strongly influence ischemic stroke risk, their allelic state in haplogroup H1 corroborating its protective effect. CONCLUSION: Our data suggests that mitochondrial haplogroup H1 has an impact on ischemic stroke risk in a Portuguese sample.

Published
2010

35. Specific configuration of dendritic degeneration in pyramidal neurons of the medial prefrontal cortex induced by differing corticosteroid regimens

Author

Cerqueira, J., Taipa, R., Uylings, R., Osborne, F., Almeida, F., and Sousa, N.

Subjects
corticosteroid, stress, adrenalectomy, cingulate cortex, dendritic morphology
Abstract

We previously demonstrated that hypercorticalism induces pronounced volumetric reductions in the rat medial prefrontal cortex (mPFC) and that these structural changes correlate with deficits in executive function. By applying 3-dimensional analysis of Golgi- Cox--stained material, we now demonstrate that corticosteroids can exert differential effects on dendritic arborizations of pyramidal neurons in lamina II/III of the mPFC. Treatment with the glucocorticoid receptor--selective agonist dexamethasone and with the natural adrenosteroid, corticosterone (CORT), results in significant reductions in the total length of apical dendrites in the pyramidal neurons in lamina II/III of the anterior cingulate/prelimbic and infralimbic cortices. Interestingly, although these treatments do not affect the number of dendritic branches, they are associated with impoverished arborizations in their distal portions and, in CORTtreated animals, with increased branching in the middle portions of the apical dendritic tree. Deprivation of corticosteroids by adrenalectomy leads to decreases in total apical dendritic length and spine number, but in this case, dendritic impoverishment was restricted to the middle/proximal segments of the dendritic trees. None of the treatments influenced the architecture of the basal dendrites. These results add to our knowledge of the morphological substrates through which corticosteroids may disrupt mPFC-dependent behaviors.

Published
2007

46. Mucormicose disseminada com envolvimento cerebral em doente com possível linfocitopenia tcd4+ idiopática e distúrbio do metabolismo do ferro.

Author

Vale, A., Guimarães, P., Apolinário, D., Costa, A., Taipa, R., Pires, M. Melo, and Guimarães, F.

Abstract

Copyright of RPDI - Revista Portuguesa de Doenças Infecciosas is the property of Sociedade Portuguesa de Doencas Infecciosas e Microbiologia Clinica and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2015

47. Recurrent focal myositis: a rare inflammatory myopathy.

Author

Teixeira, F., Peixoto, D., Costa, J. A., Bogas, M., Taipa, R., Melo Pires, M., Afonso, C., and Araújo, D.

Abstract

Focal myositis is an acute and localized muscle inflammation of unknown aetiology. The clinical diagnosis is often difficult to obtain, since it can be confused with infections, vascular thrombosis or muscle tumours such as sarcomas. This leads to a significant delay in the diagnosis, resulting in the administration of inappropriate and potentially harmful treatments. We report here a case of recurrent focal myositis in a woman where the diagnosis was only obtained after 6 years, despite multiple hospital admissions. This case reinforces the importance of clinical knowledge and experience to tackle challenging medical scenarios. [ABSTRACT FROM AUTHOR]

Published
2014

48. Clinical, neuropathological, and genetic characteristics of the novel IVS9+1delG GRN mutation in a patient with frontotemporal dementia.

Author

Taipa R, Tuna A, Damásio J, Pinto PS, Cavaco S, Pereira S, Milterberger-Miltenyi G, Galimberti D, Melo-Pires M, Taipa, Ricardo, Tuna, Assunção, Damásio, Joana, Pinto, Pedro S, Cavaco, Sara, Pereira, Sonia, Milterberger-Miltenyi, Gabriel, Galimberti, Daniela, and Melo-Pires, Manuel

Abstract

Frontotemporal lobar degeneration (FTLD) refers to a clinically, pathologically, and genetically heterogeneous group of dementias that arises from the degeneration of the frontal and temporal lobes. Mutations in the progranulin gene (GRN) are a major cause of FTLD with TDP-43 inclusions. Herein, we describe the clinical, neuropathological, and genetic findings in a case of autosomal dominant behavioral variant of frontotemporal dementia (bvFTD) with asymmetrical parkinsonism and prominent visuospatial deficits that carries a novel GRN mutation. This case highlights important clinical characteristics that seem to be common in FTLD GRN-associated patients, such as asymmetrical parkinsonism and parietal symptoms, and that are correlated to the pathological involvement of striatum (rather than substantia nigra in our case) and parietal lobe. We also emphasize that plasma progranulin level can be useful to infer about the pathogenicity of new GRN mutations. [ABSTRACT FROM AUTHOR]

Published
2012
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