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

Author

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

Abstract

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

Published
2020

3. 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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4. 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

5. Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis

Author

Rohrer, JD, Nicholas, JM, Cash, DM, van Swieten, J.C., Dopper, E, Jiskoot, L, van Minkelen, Rick, Rombouts, SA, Cardoso, MJ, Clegg, S, Espak, M, Mead, S, Thomas, DL, De Vita, E, Masellis, M, Black, SE, Freedman, M, Keren, R, MacIntosh, BJ, Rogaeva, E, Tang-Wai, D, Tartaglia, MC, Laforce, R, Tagliavini, F, Tiraboschi, P, Redaelli, V, Prioni, S, Grisoli, M, Borroni, B, Padovani, A, Galimberti, D, Scarpini, E, Arighi, A, Fumagalli, G, Rowe, JB, Coyle-Gilchrist, I, Graff, C, Fallstrom, M, Jelic, V, Stahlbom, AK, Andersson, C, Thonberg, H, Lilius, L, Frisoni, GB, Pievani, M, Bocchetta, M, Benussi, L, Ghidoni, R, Finger, E, Sorbi, S, Nacmias, B, Lombardi, G, Polito, C, Warren, JD, Ourselin, S, Fox, NC, Rossor, MN, Rohrer, JD, Nicholas, JM, Cash, DM, van Swieten, J.C., Dopper, E, Jiskoot, L, van Minkelen, Rick, Rombouts, SA, Cardoso, MJ, Clegg, S, Espak, M, Mead, S, Thomas, DL, De Vita, E, Masellis, M, Black, SE, Freedman, M, Keren, R, MacIntosh, BJ, Rogaeva, E, Tang-Wai, D, Tartaglia, MC, Laforce, R, Tagliavini, F, Tiraboschi, P, Redaelli, V, Prioni, S, Grisoli, M, Borroni, B, Padovani, A, Galimberti, D, Scarpini, E, Arighi, A, Fumagalli, G, Rowe, JB, Coyle-Gilchrist, I, Graff, C, Fallstrom, M, Jelic, V, Stahlbom, AK, Andersson, C, Thonberg, H, Lilius, L, Frisoni, GB, Pievani, M, Bocchetta, M, Benussi, L, Ghidoni, R, Finger, E, Sorbi, S, Nacmias, B, Lombardi, G, Polito, C, Warren, JD, Ourselin, S, Fox, NC, and Rossor, MN

Abstract

Background Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia. Methods We recruited participants to this multicentre study who either were known carriers of a pathogenic mutation in GRN, MAPT, or C9orf72, or were at risk of carrying a mutation because a first-degree relative was a known symptomatic carrier. We calculated time to expected onset as the difference between age at assessment and mean age at onset within the family. Participants underwent a standardised clinical assessment and neuropsychological battery. We did MRI and generated cortical and subcortical volumes using a parcellation of the volumetric T1-weighted scan. We used linear mixed-effects models to examine whether the association of neuropsychology and imaging measures with time to expected onset of symptoms differed between mutation carriers and non-carriers. Findings Between Jan 30,2012, and Sept 15,2013, we recruited participants from 11 research sites in the UK, Italy, the Netherlands, Sweden, and Canada. We analysed data from 220 participants: 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers. For neuropsychology measures, we noted the earliest significant differences between mutation carriers and non-carriers 5 years before expected onset, when differences were significant for all measures except for tests of immediate recall and verbal fluency. We noted the largest Z score differences between carriers and non-carriers 5 years before expected onset in tests of naming (Boston Naming Test -0.7; SE 0.3) and exec

Published
2015

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