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1. Brain volumetric deficits in MAPT mutation carriers: a multisite study

Author

Chu, S.A. (Stephanie A.), Flagan, T.M. (Taru M.), Staffaroni, A.M. (Adam M.), Jiskoot, L.C. (Lize), Deng, J. (Jersey), Spina, S. (Salvatore), Zhang, L. (Liwen), Sturm, V.E. (Virginia E.), Yokoyama, J.S. (Jennifer S.), Seeley, W.W. (William W.), Papma, J.M. (Janne), Geschwind, H., Rosen, H.J. (Howard J.), Boeve, B.F. (Bradley F.), Boxer, A.L. (Adam), Heuer, H.W. (Hilary W.), Forsberg, L.K. (Leah K.), Brushaber, D.E. (Danielle E.), Grossman, M. (Murray), Coppola, G. (Giovanni), Dickerson, F. (Faith), Bordelon, Y.M. (Yvette M.), Faber, K. (Kelley), Feldman, H.H. (Howard), Fields, J.A. (Julie A.), Fong, J.C. (Jamie C.), Foroud, T. (Tatiana), Gavrilova, R.H. (Ralitza H.), Ghoshal, N. (Nupur), Graff-Radford, N.R. (Neill), Hsiung, G.Y.R. (Ging-Yuek), Huey, E.D. (Edward), Irwin, D.J. (David J.), Kantarci, K. (Kejal), Kaufer, D.I. (Daniel I.), Karydas, A.M. (Anna M.), Knopman, D.S. (David), Kornak, J. (John), Kramer, J.H. (Joel), Kukull, W.A., Lapid, M.I. (Maria I.), Litvan, I., Mackenzie, I.R.A. (Ian), Mendez, M.F. (Mario), Miller, B.L. (Bruce Lars), Onyike, C.U. (Chiadi), Pantelyat, A.Y. (Alexander Y.), Rademakers, S. (Suzanne), Marisa Ramos, E. (Eliana), Roberson, E.D. (Erik D.), Carmela Tartaglia, M. (Maria), Tatton, N.A. (Nadine A.), Toga, A.W. (Arthur), Vetor, A. (Ashley), Weintraub, S. (Sandra), Wong, B. (Bonnie), Wszolek, Z.K. (Zbigniew), Swieten, J.C. (John) van, Lee, S.E. (Suzee E.), Chu, S.A. (Stephanie A.), Flagan, T.M. (Taru M.), Staffaroni, A.M. (Adam M.), Jiskoot, L.C. (Lize), Deng, J. (Jersey), Spina, S. (Salvatore), Zhang, L. (Liwen), Sturm, V.E. (Virginia E.), Yokoyama, J.S. (Jennifer S.), Seeley, W.W. (William W.), Papma, J.M. (Janne), Geschwind, H., Rosen, H.J. (Howard J.), Boeve, B.F. (Bradley F.), Boxer, A.L. (Adam), Heuer, H.W. (Hilary W.), Forsberg, L.K. (Leah K.), Brushaber, D.E. (Danielle E.), Grossman, M. (Murray), Coppola, G. (Giovanni), Dickerson, F. (Faith), Bordelon, Y.M. (Yvette M.), Faber, K. (Kelley), Feldman, H.H. (Howard), Fields, J.A. (Julie A.), Fong, J.C. (Jamie C.), Foroud, T. (Tatiana), Gavrilova, R.H. (Ralitza H.), Ghoshal, N. (Nupur), Graff-Radford, N.R. (Neill), Hsiung, G.Y.R. (Ging-Yuek), Huey, E.D. (Edward), Irwin, D.J. (David J.), Kantarci, K. (Kejal), Kaufer, D.I. (Daniel I.), Karydas, A.M. (Anna M.), Knopman, D.S. (David), Kornak, J. (John), Kramer, J.H. (Joel), Kukull, W.A., Lapid, M.I. (Maria I.), Litvan, I., Mackenzie, I.R.A. (Ian), Mendez, M.F. (Mario), Miller, B.L. (Bruce Lars), Onyike, C.U. (Chiadi), Pantelyat, A.Y. (Alexander Y.), Rademakers, S. (Suzanne), Marisa Ramos, E. (Eliana), Roberson, E.D. (Erik D.), Carmela Tartaglia, M. (Maria), Tatton, N.A. (Nadine A.), Toga, A.W. (Arthur), Vetor, A. (Ashley), Weintraub, S. (Sandra), Wong, B. (Bonnie), Wszolek, Z.K. (Zbigniew), Swieten, J.C. (John) van, and Lee, S.E. (Suzee E.)

Abstract

Objective: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach. Methods: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers’ clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson’s disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype. Results: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes

Published
2020
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2. Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

Author

Gao, Y. (Yixin), Wang, T. (Ting), Yu, X. (Xinghao), Ferrari, R. (Raffaele), Hernandez, D.G. (Dena), Nalls, M.A. (Michael), Rohrer, J.D. (Jonathan), Ramasamy, A. (Adaikalavan), Kwok, J.B.J. (John), Dobson-Stone, C. (Carol), Brooks, W.S. (William S.), Schofield, P.R. (Peter R.), Halliday, G.M. (Glenda Margaret), Hodges, J.R. (John R.), Piguet, O. (Olivier), Bartley, L. (Lauren), Thompson, E. (Elizabeth), Haan, E. (Eric), Hernández, I. (Isabel), Ruiz, A. (A.), Boada, M. (Mercè), Borroni, B. (Barbara), Padovani, A. (Alessandro), Crane, L.M.A., Cairns, N.J. (Nigel), Benussi, L. (Luisa), Binetti, G. (Giuliano), Ghidoni, R. (Roberta), Forloni, G. (Gianluigi), Albani, D. (Diego), Galimberti, D. (Daniela), Fenoglio, C. (Chiara), Serpente, M. (Maria), Scarpini, E. (Elio), Clarimón, J. (Jordi), Lleo, A. (Alberto), Blesa, R. (Rafael), Waldö, M.L. (Maria Landqvist), Nilsson, K. (Karin), Nilsson, C. (Christer), Mackenzie, I.R.A. (Ian), Hsiung, G.-Y.R. (Ging-Yuek R.), Mann, D.M.A. (David M. A.), Grafman, J. (Jordan), Morris, C.M. (Chris), Attems, J. (Johannes), Griffiths, T.D. (Timothy), McKeith, I.G. (Ian), Thomas, A.J. (Alan J.), Pietrini, P. (P.), Huey, E.D. (Edward), Wassermann, E.M. (Eric), Baborie, A. (Atik), Jaros, J.A.J. (Julian), Tierney, M.C. (Michael C.), Pastor, P. (Pau), Razquin, C. (Cristina), Ortega-Cubero, S. (Sara), Alonso, E. (Elena), Perneczky, R. (Robert), Diehl-Schmid, J. (Janine), Alexopoulos, E.C. (Evangelos), Kurz, A., Rainero, I. (Innocenzo), Rubino, M. (Maurizio), Pinessi, L. (Lorenzo), Rogaeva, E. (Ekaterina), George-Hyslop, P.S. (Peter St), Rossi, G. (Giacomina), Tagliavini, F. (Fabrizio), Giaccone, G. (Giuseppe), Rowe, J.B. (James), Schlachetzki, J.C.M. (Johannes C.), Uphill, J. (James), Collinge, J. (John), Mead, S. (Simon), Danek, A. (Adrian), Deerlin, V.M. (Vivianna), Grossman, M. (Murray), Trojanowski, J.Q. (John Q.), Zee, J. (Jill) van der, Cruts, M. (Marc), Broeckhoven, C. (Christine) van, Cappa, S.F. (Stefano), Leber, I. (Isabelle), Hannequin, D. (Didier), Golfier, V. (Véronique), Vercelletto, M. (Martine), Brice, A. (Alexis), Nacmias, B. (Benedetta), Sorbi, S. (Sandro), Bagnoli, S. (Silvia), Piaceri, I. (Irene), Nielsen, J.E. (Jørgen E.), Hjermind, L.E. (Lena), Riemenschneider, M. (Matthias), Mayhaus, M. (Manuel), Ibach, B. (Bernd), Gasparoni, G. (Gilles), Pichler, I. (Irene), Gu, W. (Wei), Rossor, M. (Martin), Fox, N.C. (Nick), Warren, J.D. (Jason), Spillantini, M.G., Morris, H.R. (Huw R.), Rizzu, P. (Patrizia), Heutink, P. (Peter), Snowden, J. (Julie), Rollinson, S. (Sara), Richardson, A. (Anna), Gerhard, A. (Alex), Bruni, A.C. (Amalia), Maletta, R. (Raffaele), Frangipane, F. (Francesca), Cupidi, C. (Chiara), Bernardi, L. (Livia), Anfossi, M. (Maria), Gallo, V. (Valentina), Conidi, A. (Andrea), Smirne, N. (Nicoletta), Rademakers, S. (Suzanne), Baker, M.C. (Matthew), Dickson, D. (Dennis), Graff-Radford, N.R. (Neill), Petersen, R.C. (Ronald C.), Knopman, D.S. (David), Josephs, K.A. (Keith), Boeve, B.F. (Bradley F.), Parisi, J.E. (Joseph), Seeley, W.W. (William W.), Miller, B.L. (Bruce L.), Karydas, A.M. (Anna M.), Rosen, H. (Howard), Swieten, J.C. (John) van, Dopper, E.G.P. (Elise), Seelaar, H. (Harro), Pijnenburg, Y.A.L. (Yolande), Scheltens, P. (Philip), Logroscino, G. (Giancarlo), Capozzo, R. (Rosa), Novelli, V. (Valeria), Puca, A.A. (Annibale), Franceschi, M. (Massimo), Postiglione, A. (Alfredo), Milan, D.J. (David), Sorrentino, D. (Dario), Kristiansen, M. (Mark), Chiang, Y.T., Graff, C. (Caroline), Pasquier, F. (Florence), Rollin, A. (Adeline), Deramecourt, V. (Vincent), Lebouvier, T. (Thibaud), Kapogiannis, D. (Dimitrios), Ferrucci, L. (Luigi), Pickering-Brown, S. (Stuart), Singleton, A. (Andrew), Hardy, J. (John), Momeni, P. (Parastoo), Zhao, H. (Huashuo), Zeng, P. (Ping), Gao, Y. (Yixin), Wang, T. (Ting), Yu, X. (Xinghao), Ferrari, R. (Raffaele), Hernandez, D.G. (Dena), Nalls, M.A. (Michael), Rohrer, J.D. (Jonathan), Ramasamy, A. (Adaikalavan), Kwok, J.B.J. (John), Dobson-Stone, C. (Carol), Brooks, W.S. (William S.), Schofield, P.R. (Peter R.), Halliday, G.M. (Glenda Margaret), Hodges, J.R. (John R.), Piguet, O. (Olivier), Bartley, L. (Lauren), Thompson, E. (Elizabeth), Haan, E. (Eric), Hernández, I. (Isabel), Ruiz, A. (A.), Boada, M. (Mercè), Borroni, B. (Barbara), Padovani, A. (Alessandro), Crane, L.M.A., Cairns, N.J. (Nigel), Benussi, L. (Luisa), Binetti, G. (Giuliano), Ghidoni, R. (Roberta), Forloni, G. (Gianluigi), Albani, D. (Diego), Galimberti, D. (Daniela), Fenoglio, C. (Chiara), Serpente, M. (Maria), Scarpini, E. (Elio), Clarimón, J. (Jordi), Lleo, A. (Alberto), Blesa, R. (Rafael), Waldö, M.L. (Maria Landqvist), Nilsson, K. (Karin), Nilsson, C. (Christer), Mackenzie, I.R.A. (Ian), Hsiung, G.-Y.R. (Ging-Yuek R.), Mann, D.M.A. (David M. A.), Grafman, J. (Jordan), Morris, C.M. (Chris), Attems, J. (Johannes), Griffiths, T.D. (Timothy), McKeith, I.G. (Ian), Thomas, A.J. (Alan J.), Pietrini, P. (P.), Huey, E.D. (Edward), Wassermann, E.M. (Eric), Baborie, A. (Atik), Jaros, J.A.J. (Julian), Tierney, M.C. (Michael C.), Pastor, P. (Pau), Razquin, C. (Cristina), Ortega-Cubero, S. (Sara), Alonso, E. (Elena), Perneczky, R. (Robert), Diehl-Schmid, J. (Janine), Alexopoulos, E.C. (Evangelos), Kurz, A., Rainero, I. (Innocenzo), Rubino, M. (Maurizio), Pinessi, L. (Lorenzo), Rogaeva, E. (Ekaterina), George-Hyslop, P.S. (Peter St), Rossi, G. (Giacomina), Tagliavini, F. (Fabrizio), Giaccone, G. (Giuseppe), Rowe, J.B. (James), Schlachetzki, J.C.M. (Johannes C.), Uphill, J. (James), Collinge, J. (John), Mead, S. (Simon), Danek, A. (Adrian), Deerlin, V.M. (Vivianna), Grossman, M. (Murray), Trojanowski, J.Q. (John Q.), Zee, J. (Jill) van der, Cruts, M. (Marc), Broeckhoven, C. (Christine) van, Cappa, S.F. (Stefano), Leber, I. (Isabelle), Hannequin, D. (Didier), Golfier, V. (Véronique), Vercelletto, M. (Martine), Brice, A. (Alexis), Nacmias, B. (Benedetta), Sorbi, S. (Sandro), Bagnoli, S. (Silvia), Piaceri, I. (Irene), Nielsen, J.E. (Jørgen E.), Hjermind, L.E. (Lena), Riemenschneider, M. (Matthias), Mayhaus, M. (Manuel), Ibach, B. (Bernd), Gasparoni, G. (Gilles), Pichler, I. (Irene), Gu, W. (Wei), Rossor, M. (Martin), Fox, N.C. (Nick), Warren, J.D. (Jason), Spillantini, M.G., Morris, H.R. (Huw R.), Rizzu, P. (Patrizia), Heutink, P. (Peter), Snowden, J. (Julie), Rollinson, S. (Sara), Richardson, A. (Anna), Gerhard, A. (Alex), Bruni, A.C. (Amalia), Maletta, R. (Raffaele), Frangipane, F. (Francesca), Cupidi, C. (Chiara), Bernardi, L. (Livia), Anfossi, M. (Maria), Gallo, V. (Valentina), Conidi, A. (Andrea), Smirne, N. (Nicoletta), Rademakers, S. (Suzanne), Baker, M.C. (Matthew), Dickson, D. (Dennis), Graff-Radford, N.R. (Neill), Petersen, R.C. (Ronald C.), Knopman, D.S. (David), Josephs, K.A. (Keith), Boeve, B.F. (Bradley F.), Parisi, J.E. (Joseph), Seeley, W.W. (William W.), Miller, B.L. (Bruce L.), Karydas, A.M. (Anna M.), Rosen, H. (Howard), Swieten, J.C. (John) van, Dopper, E.G.P. (Elise), Seelaar, H. (Harro), Pijnenburg, Y.A.L. (Yolande), Scheltens, P. (Philip), Logroscino, G. (Giancarlo), Capozzo, R. (Rosa), Novelli, V. (Valeria), Puca, A.A. (Annibale), Franceschi, M. (Massimo), Postiglione, A. (Alfredo), Milan, D.J. (David), Sorrentino, D. (Dario), Kristiansen, M. (Mark), Chiang, Y.T., Graff, C. (Caroline), Pasquier, F. (Florence), Rollin, A. (Adeline), Deramecourt, V. (Vincent), Lebouvier, T. (Thibaud), Kapogiannis, D. (Dimitrios), Ferrucci, L. (Luigi), Pickering-Brown, S. (Stuart), Singleton, A. (Andrew), Hardy, J. (John), Momeni, P. (Parastoo), Zhao, H. (Huashuo), and Zeng, P. (Ping)

Abstract

We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population.

Published
2020
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3. Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Author

Meeter, L.H.H. (Lieke), Gendron, T.F. (Tania F.), Sias, A.C. (Ana C.), Jiskoot, L.C. (Lize), Russo, S.P. (Silvia P.), Donker Kaat, L. (Laura), Papma, J.M. (Janne), Panman, J.L. (Jessica), Ende, E.L. (Emma) van der, Dopper, E.G.P. (Elise), Franzen, S. (Sanne), Graff, C. (Caroline), Boxer, A.L. (Adam), Rosen, H.J. (Howard J.), Sánchez-Valle, R. (Raquel), Galimberti, D. (Daniela), Pijnenburg, Y.A.L. (Yolande), Benussi, L. (Luisa), Ghidoni, R. (Roberta), Borroni, B. (Barbara), Laforce, R. (Robert), del Campo, M. (Marta), Teunissen, C.E. (Charlotte), Thornton, A.S. (Andrew), Rojas, J.C. (Julio C.), Coppola, D. (Domenico), Geschwind, H., Rademakers, S. (Suzanne), Karydas, A.M. (Anna M.), Öijerstedt, L. (Linn), Scarpini, E. (Elio), Binetti, G. (Giuliano), Padovani, A. (Alessandro), Cash, D.M. (David M.), Dick, K.M. (Katrina M.), Bocchetta, M. (Martina), Miller, B.L. (Bruce Lars), Rohrer, J.D. (Jonathan), Petrucelli, L. (Leonard), Swieten, J.C. (John) van, Lee, S.E. (Suzee E.), Meeter, L.H.H. (Lieke), Gendron, T.F. (Tania F.), Sias, A.C. (Ana C.), Jiskoot, L.C. (Lize), Russo, S.P. (Silvia P.), Donker Kaat, L. (Laura), Papma, J.M. (Janne), Panman, J.L. (Jessica), Ende, E.L. (Emma) van der, Dopper, E.G.P. (Elise), Franzen, S. (Sanne), Graff, C. (Caroline), Boxer, A.L. (Adam), Rosen, H.J. (Howard J.), Sánchez-Valle, R. (Raquel), Galimberti, D. (Daniela), Pijnenburg, Y.A.L. (Yolande), Benussi, L. (Luisa), Ghidoni, R. (Roberta), Borroni, B. (Barbara), Laforce, R. (Robert), del Campo, M. (Marta), Teunissen, C.E. (Charlotte), Thornton, A.S. (Andrew), Rojas, J.C. (Julio C.), Coppola, D. (Domenico), Geschwind, H., Rademakers, S. (Suzanne), Karydas, A.M. (Anna M.), Öijerstedt, L. (Linn), Scarpini, E. (Elio), Binetti, G. (Giuliano), Padovani, A. (Alessandro), Cash, D.M. (David M.), Dick, K.M. (Katrina M.), Bocchetta, M. (Martina), Miller, B.L. (Bruce Lars), Rohrer, J.D. (Jonathan), Petrucelli, L. (Leonard), Swieten, J.C. (John) van, and Lee, S.E. (Suzee E.)

Abstract

Objective: To evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72-associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume. Methods: We measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel-wise analyses. Results: Poly(GP) was present in C9orf72 expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus. Interpretation: This study of C9orf72 expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for C9orf72-associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression.

Published
2018
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