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1. FRONTotemporal dementia Incidence European Research Study—FRONTIERS:rationale and design

Author

Borroni, B. (Barbara), Graff, C. (Caroline), Hardiman, O. (Orla), Ludolph, A. C. (Albert C.), Moreno, F. (Fermin), Otto, M. (Markus), Piccininni, M. (Marco), Remes, A. M. (Anne M), Rowe, J. B. (James B), Seelaar, H. (Harro), Stefanova, E. (Elka), Traykov, L. (Latchezar), Logroscino, G. (Giancarlo), and F. (FRONTIERS)

Subjects
frontotemporal lobar degeneration, incidence, rare diseases, epidemiology, registry, frontotemporal dementia
Abstract

Introduction: The incidence of Frontotemporal Lobar Degeneration (FTLD)–related disorders and their characteristics are not well known. The “FRONTotemporal dementia Incidence European Research Study” (FRONTIERS) is designed to fill this gap. Methods: FRONTIERS is a European prospective, observational population study based on multinational registries. FRONTIERS comprises 11 tertiary referral centers across Europe with long-lasting experience in FTLD-related disorders and comprehensive regional referral networks, enabling incidence estimation over well-defined geographical areas. Endpoints: The primary endpoints are (1) the incidence of FTLD-related disorders across Europe; (2) geographic trends of FTLD-related disorders; (3) the distribution of FTLD phenotypes in different populations and ethnicities in Europe; (4) inheritance of FTLD-related disorders, including the frequencies of monogenic FTLD as compared to overall disease burden; and (5) implementation of data banking for clinical and biological material. Expected impacts: FRONTIERS will improve the understanding of FTLD-related disorders and their epidemiology, promoting appropriate public health service policies and treatment strategies.

Published
2021

2. Underlying genetic variation in familial frontotemporal dementia: sequencing of 198 patients

Author

Mol, M.O., Rooij, J.G.J. (Jeroen) van, Wong, T.H. (Tsz Hang), Melhem, S. (Shamiram), Verkerk, A., Kievit, A.J.A. (Anneke J.A.), Thornton, A.S. (Andrew), Rademakers, S. (Suzanne), Pottier, C. (Cyril), Donker Kaat, L. (Laura), Seelaar, H. (Harro), Swieten, J.C. (John) van, Dopper, E.G.P. (Elise), Mol, M.O., Rooij, J.G.J. (Jeroen) van, Wong, T.H. (Tsz Hang), Melhem, S. (Shamiram), Verkerk, A., Kievit, A.J.A. (Anneke J.A.), Thornton, A.S. (Andrew), Rademakers, S. (Suzanne), Pottier, C. (Cyril), Donker Kaat, L. (Laura), Seelaar, H. (Harro), Swieten, J.C. (John) van, and Dopper, E.G.P. (Elise)

Abstract

Frontotemporal dementia (FTD) presents with a wide variability in clinical syndromes, genetic etiologies, and underlying pathologies. Despite the discovery of pathogenic variants in several genes, many familial cases remain unsolved. In a large FTD cohort of 198 familial patients, we aimed to determine the types and frequencies of variants in genes related to FTD. Pathogenic or likely pathogenic variants were revealed in 74 (37%) patients, including 4 novel variants. The repeat expansion in C9orf72 was most common (21%), followed by variants in MAPT (6%), GRN (4.5%), and TARDBP (3.5%). Other pathogenic variants were found in VCP, TBK1, PSEN1, and a novel homozygous variant in OPTN. Furthermore, we identified 15 variants of uncertain significance, including a promising variant in TUBA4A and a frameshift in VCP, for which additional research is needed to confirm pathogenicity. The patients without identified genetic cause demonstrated a wide clinical and pathological variety. Our study contributes to the clinical characterization of the genetic subtypes and confirms the value of whole-exome sequencing in identifying novel genetic variants.

Published
2020
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3. Somatic TARDBP variants as a cause of semantic dementia

Author

Rooij, J.G.J. (Jeroen) van, Mol, M.O., Melhem, S. (Shamiram), van der Wal, P. (Pelle), Arp, P.P. (Pascal), Paron, F. (Francesca), Donker Kaat, L. (Laura), Seelaar, H. (Harro), Miedema, S.S.M. (Suzanne S M), Oshima, T. (Takuya), Eggen, B.J.L. (Bart J L), Uitterlinden, A.G. (André), van Meurs, J. (Joyce), Kesteren, R.E. (Ronald) van, Smit, A.B. (August), Buratti, E. (Emanuele), Swieten, J.C. (John) van, Rooij, J.G.J. (Jeroen) van, Mol, M.O., Melhem, S. (Shamiram), van der Wal, P. (Pelle), Arp, P.P. (Pascal), Paron, F. (Francesca), Donker Kaat, L. (Laura), Seelaar, H. (Harro), Miedema, S.S.M. (Suzanne S M), Oshima, T. (Takuya), Eggen, B.J.L. (Bart J L), Uitterlinden, A.G. (André), van Meurs, J. (Joyce), Kesteren, R.E. (Ronald) van, Smit, A.B. (August), Buratti, E. (Emanuele), and Swieten, J.C. (John) van

Abstract

The aetiology of late-onset neurodegenerative diseases is largely unknown. Here we investigated whether de novo somatic variants for semantic dementia can be detected, thereby arguing for a more general role of somatic variants in

Published
2020
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4. Unravelling the clinical spectrum and the role of repeat length in C9ORF72 repeat expansions

Author

Ende, E.L. (Emma) van der, Jackson, J.L. (Jazmyne L.), White, A. (Adrianna), Seelaar, H. (Harro), Van Blitterswijk, M. (Marka), Swieten, J.C. (John) van, Ende, E.L. (Emma) van der, Jackson, J.L. (Jazmyne L.), White, A. (Adrianna), Seelaar, H. (Harro), Van Blitterswijk, M. (Marka), and Swieten, J.C. (John) van

Abstract

Since the discovery of the C9orf72 repeat expansion as the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis, it has increasingly been associated with a wider spectrum of phenotypes, including other types of dementia, movement disorders, psychiatric symptoms and slowly progressive FTD. Prompt recognition of patients with C9orf72-associated diseases is essential in light of upcoming clinical trials. The striking clinical heterogeneity associated with C9orf72 repeat expansions remains largely unexplained. In contrast to other repeat expansion disorders, evidence for an effect of repeat length on phenotype is inconclusive. Patients with C9orf72-associated diseases typically have very long repeat expansions, containing hundreds to thousands of GGGGCC-repeats, but smaller expansions might also have clinical significance. The exact threshold at which repeat expansions lead to neurodegeneration is unknown, and discordant cut-offs between laboratories pose a challenge for genetic counselling. Accurate and large-scale measurement of repeat expansions has been severely hindered by technical difficulties in sizing long expansions and by variable repeat lengths across and within tissues. Novel long-read sequencing approaches have produced promising results and open up avenues to further investigate this enthralling repeat expansion, elucidating whether its length, purity, and methylation pattern might modulate clinical features of C9orf72-related diseases.

Published
2020
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5. Distinctive pattern of temporal atrophy in patients with frontotemporal dementia and the I383V variant in TARDBP

Author

Mol, M.O., Nijmeijer, S.W.R. (Sebastiaan W.R.), Rooij, J.G.J. (Jeroen) van, Van Spaendonk, R.M.L. (Resie M. L.), Pijnenburg, Y.A.L. (Yolande), Lee, S.J. (Sven) van der, Thornton, A.S. (Andrew), Donker Kaat, L. (Laura), Rozemuller, A.J.M. (Annemieke), Janse Van Mantgem, M.R. (Mark R.), Rheenen, W. (Wouter) van, Estrada Gil, K. (Karol), Veldink, J.H. (Jan), Hennekam, R.C.M. (Raoul), Vernooij, M.W. (Meike), Swieten, J.C. (John) van, Cohn-Hokke, P.E. (P.), Seelaar, H. (Harro), Dopper, E.G.P. (Elise), Mol, M.O., Nijmeijer, S.W.R. (Sebastiaan W.R.), Rooij, J.G.J. (Jeroen) van, Van Spaendonk, R.M.L. (Resie M. L.), Pijnenburg, Y.A.L. (Yolande), Lee, S.J. (Sven) van der, Thornton, A.S. (Andrew), Donker Kaat, L. (Laura), Rozemuller, A.J.M. (Annemieke), Janse Van Mantgem, M.R. (Mark R.), Rheenen, W. (Wouter) van, Estrada Gil, K. (Karol), Veldink, J.H. (Jan), Hennekam, R.C.M. (Raoul), Vernooij, M.W. (Meike), Swieten, J.C. (John) van, Cohn-Hokke, P.E. (P.), Seelaar, H. (Harro), and Dopper, E.G.P. (Elise)

Abstract

Introduction Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are closely related disorders, linked pathologically and ge

Published
2020
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6. Differences in Discriminability and Response Bias on Rey Auditory Verbal Learning Test Delayed Recognition in Behavioral Variant Frontotemporal Dementia and Alzheimer's Disease

Author

Berg, E. (Esther) van den, Poos, J.M. (Jackie), Jiskoot, L.C. (Lize), Heijnen, L.M., Franzen, S. (Sanne), Steketee, R.M.E., Meijboom, R., Jong, F.J. (Fransina) de, Seelaar, H. (Harro), Swieten, J.C. (John) van, Papma, J.M. (Janne), Berg, E. (Esther) van den, Poos, J.M. (Jackie), Jiskoot, L.C. (Lize), Heijnen, L.M., Franzen, S. (Sanne), Steketee, R.M.E., Meijboom, R., Jong, F.J. (Fransina) de, Seelaar, H. (Harro), Swieten, J.C. (John) van, and Papma, J.M. (Janne)

Abstract

Objective: Episodic memory is impaired in Alzheimer’s disease (AD) dementia but thought to be relatively spared in behavioral variant frontotemporal dementia (bvFTD). This view is challenged by evidence of memory impairment in bvFTD. This study investigated differences in recognition memory performance between bvFTD and AD. Method: We performed a retrospective analysis on the recognition trial of the Rey Auditory Verbal Learning Test in patients with bvFTD (n = 85), AD (n = 55), and control participants (n = 59). Age- and education-adjusted betweengroup analysis was performed on the total score and indices of discriminative ability and response bias. Correlations between recognition and measures of memory, language, executive functioning, and construction were examined. Results: Patients with AD had a significantly lower total recognition score than patients with bvFTD (control 28.8 ± 1.5; bvFTD 24.8 ± 4.5; AD 23.4 ± 3.6, p < .01). Both bvFTD and AD had worse discriminative ability than controls (A’ control 0.96 ± 0.03; bvFTD 0.87 ± 0.03; AD 0.84 ± 0.10, p < .01), but there was no difference in response

Published
2020
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7. Frontotemporal Dementia: Correlations Between Psychiatric Symptoms and Pathology

Author

Scarioni, M., Gami-Patel, P., Timar, Y., Seelaar, H. (Harro), Swieten, J.C. (John) van, Rozemuller, AJ, Dols, A., Scarpini, E. (Elio), Galimberti, D. (Daniela), Bank, N.B., Hoozemans, J.J., Pijnenburg, YA, Dijkstra, A.A. (Anke), Scarioni, M., Gami-Patel, P., Timar, Y., Seelaar, H. (Harro), Swieten, J.C. (John) van, Rozemuller, AJ, Dols, A., Scarpini, E. (Elio), Galimberti, D. (Daniela), Bank, N.B., Hoozemans, J.J., Pijnenburg, YA, and Dijkstra, A.A. (Anke)

Abstract

Objective: The pathology of frontotemporal dementia, termed frontotemporal lobar degeneration (FTLD), is characterized by distinct molecular classes of aggregated proteins, the most common being TAR DNA-binding protein-43 (TDP43), tau, and fused in sarcoma (FUS). With a few exceptions, it is currently not possible to predict the underlying pathology based on the clinical syndrome. In this study, we set out to investigate the relationship between pathological and clinical presentation at single symptom level, including neuropsychiatric features. Methods: The presence or absence of symptoms from the current clinical guidelines, together with neuropsychiatric features, such as hallucinations and delusions, were scored and compared across pathological groups in a cohort of 150 brain donors. Results: Our cohort consisted of 68.6% FTLD donors (35.3% TDP-43, 28% tau, and 5.3% FUS) and 31.3% non-FTLD donors with a clinical diagnosis of frontotemporal dementia and a different pathological substrate, such as Alzheimer’s disease (23%). The presence of hyperorality points to FTLD rather than non-FTLD pathology (p < 0.001). Within the FTLD group, hallucinations in the initial years of the disease were related to TDP-43 pathology (p = 0.02), including but not limited to chromosome 9 open reading frame 72 (C9orf72) repeat expansion carriers. The presence of perseverative or compulsive behavior was more common in the TDP-B and TDP-C histotypes (p = 0.002). Interpretation: Our findings indicate that neuropsychiatric features are common in FTLD and form an important indicator of underlying pathology. In order to allow better inclusion of patients in targeted molecular trials, the routine ev

Published
2020
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8. 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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9. Correction to: Cognitive profiles discriminate between genetic variants of behavioral frontotemporal dementia

Author

Poos, J.M. (Jackie), Jiskoot, L.C. (Lize), Leijdersdorff, S.M.J. (Sophie), Seelaar, H. (Harro), Panman, J.L. (Jessica), Ende, E.L. (Emma) van der, Mol, M.O., Meeter, L.H.H. (Lieke), Pijnenburg, Y.A.L. (Yolande), Donker Kaat, L. (Laura), De Jong, F.J. (Frank J.), Swieten, J.C. (John) van, Papma, J.M. (Janne), Berg, E. (Esther) van den, Poos, J.M. (Jackie), Jiskoot, L.C. (Lize), Leijdersdorff, S.M.J. (Sophie), Seelaar, H. (Harro), Panman, J.L. (Jessica), Ende, E.L. (Emma) van der, Mol, M.O., Meeter, L.H.H. (Lieke), Pijnenburg, Y.A.L. (Yolande), Donker Kaat, L. (Laura), De Jong, F.J. (Frank J.), Swieten, J.C. (John) van, Papma, J.M. (Janne), and Berg, E. (Esther) van den

Abstract

The original version of this article unfortunately contained a mistake. The presentation of Table 1 was incorrect. The original article has been corrected. The corrected Table 1 is given below. (Table presented.).

Published
2020
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10. Cognitive profiles discriminate between genetic variants of behavioral frontotemporal dementia

Author

Poos, J.M. (Jackie), Jiskoot, L.C. (Lize), Leijdersdorff, S.M.J. (Sophie), Seelaar, H. (Harro), Panman, J.L. (Jessica), Ende, E.L. (Emma) van der, Mol, M.O., Meeter, L.H.H. (Lieke), Pijnenburg, Y.A.L. (Yolande), Donker Kaat, L. (Laura), De Jong, F.J. (Frank J.), Swieten, J.C. (John) van, Papma, J.M. (Janne), Berg, E. (Esther) van den, Poos, J.M. (Jackie), Jiskoot, L.C. (Lize), Leijdersdorff, S.M.J. (Sophie), Seelaar, H. (Harro), Panman, J.L. (Jessica), Ende, E.L. (Emma) van der, Mol, M.O., Meeter, L.H.H. (Lieke), Pijnenburg, Y.A.L. (Yolande), Donker Kaat, L. (Laura), De Jong, F.J. (Frank J.), Swieten, J.C. (John) van, Papma, J.M. (Janne), and Berg, E. (Esther) van den

Abstract

Introduction: Trials to test disease-modifying treatments for frontotemporal dementia are eagerly awaited and sensitive instruments to assess potential treatment effects are increasingly urgent, yet lacking thus far. We aimed to identify gene-specific instruments assessing clinical onset and disease progression by comparing cognitive functioning between bvFTD patients across genetic mutations. Methods: We examined differences in 7 cognitive domains between bvFTD patients with GRN (n = 20), MAPT (n = 29) or C9orf72 (n = 31) mutations, and non-carriers (n = 24), and described

Published
2020
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11. Genetic screening in early-onset Alzheimer's disease identified three novel presenilin mutations

Author

Wong, T.H. (Tsz Hang), Seelaar, H. (Harro), Melhem, S. (Shamiram), Rozemuller, A.J.M. (Annemieke), van Swieten, J.C. (John C.), Wong, T.H. (Tsz Hang), Seelaar, H. (Harro), Melhem, S. (Shamiram), Rozemuller, A.J.M. (Annemieke), and van Swieten, J.C. (John C.)

Abstract

Mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) are major genetic causes of early-onset Alzheimer's disease (EOAD). Clinical heterogeneity is frequently observed in patients with PSEN1 and PSEN2 mutations. Using whole exome sequencing, we screened a Dutch cohort of 68 patients with EOAD for rare variants in Mendelian Alzheimer's disease, frontotemporal dementia, and prion disease genes. We identified 3 PSEN1 and 2 PSEN2 variants. Three variants, 1 in PSEN1 (p.H21Profs*2) and both PSEN2 (p.A415S and p.M174I), were novel and absent in control exomes. These novel variants can be classified as probable pathogenic, except for PSEN1 (p.H21Profs*2) in which the pathogenicity is uncertain. The initial clinical symptoms between mutation carriers varied from behavioral problems to memory impairment. Our findings extend the mutation spectrum of EOAD and underline the clinical heterogeneity among PSEN1 and PSEN2 mutation carriers. Screening for Alzheimer's disease–causing genes is indicated in presenile dementia with an overlapping clinical diagnosis.

Published
2019
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12. Clinical value of cerebrospinal fluid neurofilament light chain in semantic dementia

Author

Meeter, L.H.H. (Lieke), Steketee, R.M.E., Salkovic, D., Vos, M.E., Grossman, M. (Murray), McMillan, C.T., Irwin, D.J., Boxer, AL, Rojas, J.C., Olney, N.T., Karydas, A., Miller, BL, Pijnenburg, YA, Barkhof, F. (Frederik), Sánchez-Valle, R. (Raquel), Lladó, A. (Albert), Borrego-Ecija, S., Diehl-Schmid, J, Grimmer, T., Goldhardt, O., Santillo, A.F., Hansson, O. (Ola), Vestberg, S., Borroni, B. (Barbara), Padovani, A. (Alessandro), Galimberti, D. (Daniela), Scarpini, E. (Elio), Rohrer, JD, Woollacott, I.O.C., Synofzik, M., Wilke, C., Mendonça, A., Vandenberghe, R. (Rik), Benussi, L, Ghidoni, R, Binetti, G, Niessen, W.J. (Wiro), Papma, J.M. (Janne), Seelaar, H. (Harro), Jiskoot, L.C. (Lize), Jong, F.J. (Fransina) de, Kaat, L.D., Del Campo, M, Teunissen, C.E. (Charlotte), Bron, E.E. (Esther), Berg, E. (Esther) van den, Swieten, J.C. (John) van, Meeter, L.H.H. (Lieke), Steketee, R.M.E., Salkovic, D., Vos, M.E., Grossman, M. (Murray), McMillan, C.T., Irwin, D.J., Boxer, AL, Rojas, J.C., Olney, N.T., Karydas, A., Miller, BL, Pijnenburg, YA, Barkhof, F. (Frederik), Sánchez-Valle, R. (Raquel), Lladó, A. (Albert), Borrego-Ecija, S., Diehl-Schmid, J, Grimmer, T., Goldhardt, O., Santillo, A.F., Hansson, O. (Ola), Vestberg, S., Borroni, B. (Barbara), Padovani, A. (Alessandro), Galimberti, D. (Daniela), Scarpini, E. (Elio), Rohrer, JD, Woollacott, I.O.C., Synofzik, M., Wilke, C., Mendonça, A., Vandenberghe, R. (Rik), Benussi, L, Ghidoni, R, Binetti, G, Niessen, W.J. (Wiro), Papma, J.M. (Janne), Seelaar, H. (Harro), Jiskoot, L.C. (Lize), Jong, F.J. (Fransina) de, Kaat, L.D., Del Campo, M, Teunissen, C.E. (Charlotte), Bron, E.E. (Esther), Berg, E. (Esther) van den, and Swieten, J.C. (John) van

Abstract

Background Semantic dementia (SD) is a neurodegenerative disorder characterised by progressive language problems falling within the clinicopathological spectrum of frontotemporal lobar degeneration (FTLD). The development of diseasemodifying agents may be facilitated by the relative clinical and pathological homogeneity of SD, but we need robust monitoring biomarkers to measure their efficacy. In different FTLD subtypes, neurofilament light chain (NfL) is a promising marker, therefore we investigated the utility of cerebrospinal fluid (CSF) NfL in SD. Methods This large retrospective multicentre study compared cross-sectional CSF NfL levels of 162 patients with SD with 65 controls. CSF NfL levels of patients were correlated with clinical parameters (including survival), neuropsychological test scores and regional grey matter atrophy (including longitudinal data in a subset). Results CSF NfL levels were significantly higher in patients with SD (median: 2326 pg/mL, IQR: 1628– 3593) than in controls (577 (446–766), p<0.001). Higher CSF NfL levels were moderately associated with naming impairment as measured by the Boston Naming Test (r s =−0.32, p=0.002) and with smaller grey matter volume of the parahippocampal gyri (r s =−0.31, p=0.004). However, cross-sectional CSF NfL levels were not associated with progression of grey matter atrophy and did not predict survival. Conclusion CSF NfL is a promising biomarker in the diagnostic process of SD, although it has limited crosssectional monitoring or prognostic abilities.

Published
2019
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13. Novel CSF biomarkers in genetic frontotemporal dementia identified by proteomics

Author

van der Ende, E.L., Meeter, L.H.H. (Lieke), Stingl, C. (Christoph), van Rooij, J.G.J., Stoop, M.P., Nijholt, DAT, Sánchez-Valle, R. (Raquel), Graff, M.J. (Maud J.L.), Oijerstedt, L., Grossman, M. (Murray), McMillan, C., Pijnenburg, Y.A.L. (Yolande), Laforce, R, Binetti, G, Benussi, L, Ghidoni, R, Luider, T.M. (Theo), Seelaar, H. (Harro), Swieten, J.C. (John) van, van der Ende, E.L., Meeter, L.H.H. (Lieke), Stingl, C. (Christoph), van Rooij, J.G.J., Stoop, M.P., Nijholt, DAT, Sánchez-Valle, R. (Raquel), Graff, M.J. (Maud J.L.), Oijerstedt, L., Grossman, M. (Murray), McMillan, C., Pijnenburg, Y.A.L. (Yolande), Laforce, R, Binetti, G, Benussi, L, Ghidoni, R, Luider, T.M. (Theo), Seelaar, H. (Harro), and Swieten, J.C. (John) van

Abstract

Objective: To identify novel CSF biomarkers in GRN-associated frontotemporal dementia (FTD) by proteomics using mass spectrometry (MS). Methods: Unbiased MS was applied to CSF samples from 19 presymptomatic and 9 symptomatic GRN mutation carriers and 24 noncarriers. Protein abundances were compared between these groups. Proteins were then selected for validation if identified by ≥4 peptides and if fold change was ≤0.5 or ≥2.0. Validation and absolute quantification by parallel reaction monitoring (PRM), a high-resolution targeted MS method, was performed on an international cohort (n = 210) of presymptomatic and symptomatic GRN, C9orf72 and MAPT mutation carriers. Results: Unbiased MS revealed 20 differentially abundant proteins between symptomatic mutation carriers and noncarriers and nine between symptomatic and presymptomatic carriers. Seven of these proteins fulfilled our criteria for validation. PRM analyses revealed that symptomatic GRN mutation carriers had significantly lower levels of neuronal pentraxin receptor (NPTXR), receptortype tyrosine-protein phosphatase N2 (PTPRN2), neurosecretory protein VGF, chromogranin-A (CHGA), and V-set and transmembrane domain-containing protein 2B (VSTM2B) than presymptomatic carriers and noncarriers. Symptomatic C9orf72 mutation carriers had lower levels of NPTXR, PTPRN2, CHGA, and VSTM2B than noncarriers, while symptomatic MAPT mutation carriers had lower levels of NPTXR and CHGA than noncarriers. Interpretation: We identified and validated five novel CSF biomarkers in GRN-associated FTD. Our results show that synaptic, secretory vesicle, and inflammatory proteins are dysregulated in the symptomatic stage and may provide new insights into the pathophysiology of genetic FTD. Further validation is needed to investigate their clinical applicability as diagnostic or monitoring biomarkers.

Published
2019
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14. HR23B pathology preferentially co-localizes with p62, pTDP-43 and poly-GA in C9ORF72-linked frontotemporal dementia and amyotrophic lateral sclerosis

Author

Riemslagh, F.W., Lans, H. (Hannes), Seelaar, H. (Harro), Severijnen, L., Melhem, S., Vermeulen, W. (Wim), Aronica, E.M.A. (Eleonora), Pasterkamp, R.J. (Jeroen), Swieten, J.C. (John) van, Willemsen, R. (Rob), Riemslagh, F.W., Lans, H. (Hannes), Seelaar, H. (Harro), Severijnen, L., Melhem, S., Vermeulen, W. (Wim), Aronica, E.M.A. (Eleonora), Pasterkamp, R.J. (Jeroen), Swieten, J.C. (John) van, and Willemsen, R. (Rob)

Abstract

Human homologue of yeast UV excision repair protein Rad23b (HR23B) inclusions are found in a number of neurodegenerative diseases, including frontotemporal dementia (FTD), Huntington’s disease (HD), spinocerebellar ataxia type 3 and 7 (SCA3/7), fragile X associated tremor/ataxia syndrome (FXTAS) and Parkinson’s disease (PD). Here, we describe HR23B pathology in C9ORF72 linked FTD and amyotrophic lateral sclerosis (ALS) cases. HR23B presented in neuropils, intranuclear inclusions and cytoplasmic and perinuclear inclusions and was predominantly found in cortices (frontal, temporal and motor), spinal cord and hippocampal dentate gyrus. HR23B co-localized with poly-GA

Published
2019
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15. Cerebral blood flow in presymptomatic MAPT and GRN mutation carriers: A longitudinal arterial spin labeling study

Author

Dopper, E.G.P. (Elise), Chalos, V. (Vicky), Ghariq, E. (Eidrees), Heijer, T. (Tom) den, Hafkemeijer, A. (Anne), Jiskoot, L.C. (Lize), Koning, I. (Inge) de, Seelaar, H. (Harro), Thornton, A.S. (Andrew), Osch, M.J.P. (Matthias J.) van, Rombouts, S.A.R.B. (Serge), Swieten, J.C. (John) van, Dopper, E.G.P. (Elise), Chalos, V. (Vicky), Ghariq, E. (Eidrees), Heijer, T. (Tom) den, Hafkemeijer, A. (Anne), Jiskoot, L.C. (Lize), Koning, I. (Inge) de, Seelaar, H. (Harro), Thornton, A.S. (Andrew), Osch, M.J.P. (Matthias J.) van, Rombouts, S.A.R.B. (Serge), and Swieten, J.C. (John) van

Abstract

Objective Frontotemporal dementia (FTD) is characterized by behavioral disturbances and language problems. Familial forms can be caused by genetic defects in microtubule-associated protein tau (MAPT), progranulin (GRN), and C9orf72. In light of upcoming clinical trials with potential disease-modifying agents, the development of sensitive biomarkers to evaluate such agents in the earliest stage of FTD is crucial. In the current longitudinal study we used arterial spin labeling MRI (ASL) in presymptomatic carriers of MAPT and GRN mutations to investigate early changes in cerebral blood flow (CBF). Methods Healthy first-degree relatives of patients with a MAPT or GRN mutation underwent ASL at baseline and follow-up after two years. We investigated cross-sectional and longitudinal differences in CBF between mutation carriers (n = 34) and controls without a mutation (n = 31). Results GRN mutation carriers showed significant frontoparietal hypoperfusion compared with controls at follow-up, whereas we found no cross-sectional group differences in the total study group or the MAPT subgroup. Longitudinal analyses revealed a significantly stronger decrease in CBF in frontal, temporal, parietal, and subcortical areas in the total group of mutation carriers and the GRN subgroup, with the strongest decrease in two mutation carriers who converted to clinical FTD during follow-up. Interpretation We demonstrated longitudinal alterations in CBF in presymptomatic FTD independent of grey matter atrophy, with the strongest decrease in individuals that developed symptoms during follow-up. Therefore, ASL could have the potential to serve as a sensitive biomarker of disease progression in the presymptomatic stage of FTD in future clinical trials.

Published
2016
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16. Structural and functional brain connectivity in presymptomatic familial frontotemporal dementia

Author

Dopper, E.G.P. (Elise), Rombouts, S.A.R.B. (Serge), Jiskoot, L.C. (Lize), Heijer, T. (Tom) den, Graaf, J.R.A. (Joke) de, Koning, I. (Inge) de, Hammerschlag, M.R., Seelaar, H. (Harro), Seeley, W. (William), Veer, I.M. (Ilya), Buchem, M.A. (Mark) van, Rizzu, P. (Patrizia), Swieten, J.C. (John) van, Dopper, E.G.P. (Elise), Rombouts, S.A.R.B. (Serge), Jiskoot, L.C. (Lize), Heijer, T. (Tom) den, Graaf, J.R.A. (Joke) de, Koning, I. (Inge) de, Hammerschlag, M.R., Seelaar, H. (Harro), Seeley, W. (William), Veer, I.M. (Ilya), Buchem, M.A. (Mark) van, Rizzu, P. (Patrizia), and Swieten, J.C. (John) van

Abstract

Objective: We aimed to investigate whether cognitive deficits and structural and functional connectivity changes can be detected before symptom onset in a large cohort of carriers of MAPT (microtubule-associated protein tau) or GRN (progranulin) mutations. Methods: In this case-control study, 75 healthy individuals (aged 20-70 years) with 50% risk of frontotemporal dementia (FTD) underwent DNA screening, neuropsychological assessment, structural MRI, and fMRI. We used voxel-based morphometry and tract-based spatial statistics for voxel-wise analyses of gray matter volume and diffusion tensor imaging measures. Using resting-state fMRI scans, we assessed whole-brain functional connectivity to frontoinsular, anterior midcingulate, and posterior cingulate cortices. Results: Carriers (n = 39) and noncarriers (n = 36) had similar neuropsychological performance, except for lower Letter Digit Substitution Test scores in carriers. Worse performance on Stroop III, Rivermead Behavioral Memory Test, and Happé Cartoons correlated with higher age in carriers, but not controls. Reduced fractional anisotropy in the right uncinate fasciculus was found in carriers compared with controls. Reductions in functional connectivity between anterior midcingulate cortex and frontoinsula and several other brain regions were found in carriers compared with controls and correlated with higher age in carriers, but not controls. We found no significant differences or age correlations in posterior cingulate cortex connectivity. No differences in regional gray matter volume were found, except for a small cluster of higher volume in the precentral gyrus in carriers. Conclusions: This study demonstrates that alterations in structural and functional connectivity develop before the first symptoms of FTD arise. These findings suggest that diffusion tensor imaging and resting-state fMRI may have the potential to become sensitive biomarkers for early FTD in future clinical trials.

Published
2014
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17. Frontotemporal dementia and its subtypes: A genome-wide association study

Author

Ferrari, R. (Roberto), 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), Schofield, C.J. (Christopher), Halliday, G.M. (Glenda Margaret), Hodges, J. (John), Piguet, O. (Olivier), Bartley, L. (Lauren), Thompson, E. (Elizabeth), Haan, E. (Eric), Hernández, I. (Isabel), Ruiz, A. (Agustin), Boada, M. (Mercè), Borroni, B. (Barbara), Padovani, A. (Alessandro), Cruchaga, C. (Carlos), Cairns, N.J. (Nigel), Benussi, L. (Luisa), Binetti, G. (Giuliano), Ghidoni, R. (Roberta), Forloni, G. (Gianluigi), Galimberti, D. (Daniela), Fenoglio, C. (Chiara), Serpente, M. (Maria), Scarpini, E. (Elio), Clarimon, 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), Mann, D.M.A. (David), Grafman, J. (Jordan), Morris, C.M. (Chris), Attems, J. (Johannes), Griffiths, T.D. (Timothy), McKeith, I.G. (Ian), Thomas, A.W. (Alan), Pietrini, P. (P.), Huey, E.D. (Edward), Wassermann, E.M. (Eric), Baborie, A. (Atik), Jaros, J.A.J. (Julian), Tierney, M.C. (Michael), 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), St George-Hyslop, P.H. (Peter), Rossi, G. (Giulio) de, 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), Zee, J. (Jill) van der, Deschamps, J. (Jacqueline), Langenhove, T. (Tim) van, Cruts, M. (Marc), Broeckhoven, C. (Christine) van, Cappa, S.F. (Stefano), Le Ber, I. (Isabelle), Hannequin, D. (Didier), Golfier, V. (Véronique), Vercelletto, M. (Martine), Brice, A., Nacmias, B. (Benedetta), Sorbi, S. (Sandro), Bagnoli, S. (Silvia), Piaceri, I. (Irene), Nielsen, J.E. (Jorgen), 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. (Huw), 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.W. (Dennis), Graff-Radford, N.R. (Neill), Petersen, R.C. (Ronald), Knopman, D.S. (David), Josephs, K.A. (Keith), Boeve, B.F. (Bradley), Parisi, J.E. (Joseph), Seeley, W. (William), Miller, B.L. (Bruce Lars), Karydas, A. (Anna), 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, C. (Claudio), Postiglione, A. (Alfredo), Milan, D.J. (David), Sorrentino, D. (Dario), Kristiansen, M. (Mark), Chiang, Y.T., Graff, M.J. (Maud J.L.), Pasquier, F. (Florence), Rollin, P.E. (Pierre), Deramecourt, V. (Vincent), Lebert, F. (Florence), Kapogiannis, D. (Dimitrios), Ferrucci, L. (Luigi), Pickering-Brown, S. (Stuart), Singleton, A. (Andrew), Hardy, J. (John), Momeni, M. (Mona), Ferrari, R. (Roberto), 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), Schofield, C.J. (Christopher), Halliday, G.M. (Glenda Margaret), Hodges, J. (John), Piguet, O. (Olivier), Bartley, L. (Lauren), Thompson, E. (Elizabeth), Haan, E. (Eric), Hernández, I. (Isabel), Ruiz, A. (Agustin), Boada, M. (Mercè), Borroni, B. (Barbara), Padovani, A. (Alessandro), Cruchaga, C. (Carlos), Cairns, N.J. (Nigel), Benussi, L. (Luisa), Binetti, G. (Giuliano), Ghidoni, R. (Roberta), Forloni, G. (Gianluigi), Galimberti, D. (Daniela), Fenoglio, C. (Chiara), Serpente, M. (Maria), Scarpini, E. (Elio), Clarimon, 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), Mann, D.M.A. (David), Grafman, J. (Jordan), Morris, C.M. (Chris), Attems, J. (Johannes), Griffiths, T.D. (Timothy), McKeith, I.G. (Ian), Thomas, A.W. (Alan), Pietrini, P. (P.), Huey, E.D. (Edward), Wassermann, E.M. (Eric), Baborie, A. (Atik), Jaros, J.A.J. (Julian), Tierney, M.C. (Michael), 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), St George-Hyslop, P.H. (Peter), Rossi, G. (Giulio) de, 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), Zee, J. (Jill) van der, Deschamps, J. (Jacqueline), Langenhove, T. (Tim) van, Cruts, M. (Marc), Broeckhoven, C. (Christine) van, Cappa, S.F. (Stefano), Le Ber, I. (Isabelle), Hannequin, D. (Didier), Golfier, V. (Véronique), Vercelletto, M. (Martine), Brice, A., Nacmias, B. (Benedetta), Sorbi, S. (Sandro), Bagnoli, S. (Silvia), Piaceri, I. (Irene), Nielsen, J.E. (Jorgen), 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. (Huw), 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.W. (Dennis), Graff-Radford, N.R. (Neill), Petersen, R.C. (Ronald), Knopman, D.S. (David), Josephs, K.A. (Keith), Boeve, B.F. (Bradley), Parisi, J.E. (Joseph), Seeley, W. (William), Miller, B.L. (Bruce Lars), Karydas, A. (Anna), 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, C. (Claudio), Postiglione, A. (Alfredo), Milan, D.J. (David), Sorrentino, D. (Dario), Kristiansen, M. (Mark), Chiang, Y.T., Graff, M.J. (Maud J.L.), Pasquier, F. (Florence), Rollin, P.E. (Pierre), Deramecourt, V. (Vincent), Lebert, F. (Florence), Kapogiannis, D. (Dimitrios), Ferrucci, L. (Luigi), Pickering-Brown, S. (Stuart), Singleton, A. (Andrew), Hardy, J. (John), and Momeni, M. (Mona)

Abstract

Background: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 h

Published
2014
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18. Structural and functional brain connectivity in presymptomatic familial frontotemporal dementia

Author

Dopper, E.G.P. (Elise), Rombouts, S.A.R.B. (Serge), Jiskoot, L.C. (Lize), Heijer, T. (Tom) den, Graaf, J.R.A. (J. Roos) de, Koning, I. (Inge) de, Hammerschlag, M.R., Seelaar, H. (Harro), Seeley, W. (William), Veer, I.M. (Ilya), Buchem, M.A. (Mark) van, Rizzu, P. (Patrizia), Swieten, J.C. (John) van, Dopper, E.G.P. (Elise), Rombouts, S.A.R.B. (Serge), Jiskoot, L.C. (Lize), Heijer, T. (Tom) den, Graaf, J.R.A. (J. Roos) de, Koning, I. (Inge) de, Hammerschlag, M.R., Seelaar, H. (Harro), Seeley, W. (William), Veer, I.M. (Ilya), Buchem, M.A. (Mark) van, Rizzu, P. (Patrizia), and Swieten, J.C. (John) van

Abstract

Objective: We aimed to investigate whether cognitive deficits and structural and functional connectivity changes can be detected before symptom onset in a large cohort of carriers of microtubuleassociated protein tau and progranulin mutations. Methods: In this case-control study, 75 healthy individuals (aged 20-70 years) with 50%risk for frontotemporal dementia (FTD) underwent DNA screening, neuropsychological assessment, and structural and functional MRI. We used voxel-based morphometry and tract-based spatial statistics for voxelwise analyses of gray matter volume and diffusion tensor imaging measures. Using resting-state fMRI scans, we assessed whole-brain functional connectivity to frontoinsula, anterior midcingulate cortex (aMCC), and posterior cingulate cortex. Results: Although carriers (n 5 37) and noncarriers (n 5 38) had similar neuropsychological performance, worse performance on Stroop III, Ekman faces, and Happé cartoons correlated with higher age in carriers, but not controls. Reduced fractional anisotropy and increased radial diffusivity throughout frontotemporal white matter tracts were found in carriers and correlated with higher age. Reductions in functional aMCC connectivity were found in carriers compared with controls, and connectivity between frontoinsula and aMCC seeds and several brain regions significantly decreased with higher age in carriers but not controls. We found no significant differences or age correlations in posterior cingulate cortex connectivity. No differences in regional gray matter volume were found. Conclusions: This study convincingly demonstrates that alterations in structural and functional connectivity develop before the first symptoms of FTD arise. These findings suggest that diffusion tensor imaging and resting-state fMRI may have the potential to become sensitive biomarkers for early FTD in future clinical trials.

Published
2013
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19. Midcingulate involvement in progressive supranuclear palsy and tau positive frontotemporal dementia

Author

Chiu, W.Z. (Wang Zheng), Papma, J.M. (Janne), Koning, I. (Inge) de, Donker Kaat, L. (Laura), Seelaar, H. (Harro), Reijs, A.E.M. (Ambroos), Valkema, R. (Roelf), Hasan, D. (Djo), Boon, A.J.W. (Andrea), Swieten, J.C. (John) van, Chiu, W.Z. (Wang Zheng), Papma, J.M. (Janne), Koning, I. (Inge) de, Donker Kaat, L. (Laura), Seelaar, H. (Harro), Reijs, A.E.M. (Ambroos), Valkema, R. (Roelf), Hasan, D. (Djo), Boon, A.J.W. (Andrea), and Swieten, J.C. (John) van

Abstract

Background Progressive supranuclear palsy (PSP) patients often exhibit cognitive decline and behavioural changes during the disease course. In a subset, these symptoms may be the presenting manifestation and can be similar to those in frontotemporal dementia (FTD). However, correlation studies between quantitative imaging measures and detailed neuropsychological assessment are scarce. The aim of this study was to investigate the functional role of affected brain regions in cognition in PSP compared with controls and subsequently examine these regions in FTD patients with known tau pathology (FTD tau). Methods 21 PSP patients, 27 healthy controls and 11 FTD tau patients were enrolled. All participants underwent neuropsychological testing and technetium99m-hexamethyl-propylenamine-oxime single photon emission CT. Regression slope analyses were performed in statistical parametric mapping to find significant associations between neuropsychological test results and brain perfusion. Results PSP patients showed hypoperfusion in the midcingulate cortex (MCC) of which the posterior part correlated with Stroop III and Weigl. In FTD tau patients, MCC involvement was located more anterior and correlated with Stroop III and Wisconsin Card Sorting Test concepts. The degree of hypoperfusion in the anterior cortex and MCC in the disorders differed in the subgenual anterior cingulate cortex only. Conclusions Th

Published
2012
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20. Frontotemporal Dementia: clinical, genetic, and pathological heterogeneity

Author

Seelaar, H. (Harro) and Seelaar, H. (Harro)

Abstract

The current clinical syndrome frontotemporal dementia (FTD) was first described in 1892 by the Czech psychiatrist Arnold Pick. He described a patient with aphasia and behavioural changes with on macroscopic examination marked left frontotemporal atrophy. In 1911, Alois Alzheimer described the detailed microscopic changes, including argyrophilic neuronal inclusions, which are still known as Pick bodies. The term Pick’s disease was introduced in 1926 and was used till the early 90’s to describe the clinical and pathological entity. To date, Pick’s disease is used for a neuropathological subgroup of FTD patients. FTD encompasses distinct canonical syndromes: the behavioural variant of FTD (bvFTD), and two language variants, semantic dementia (SD), and progressive non-fluent aphasia (PNFA). FTD is accompanied by motor neuron disease (MND) in 5 – 15 % of the cases. FTD patients characteristically present at presenile age with variable behavioural changes and language disturbances. The clinical syndrome FTD is part of a wide clinicopathological spectrum designated by the term frontotemporal lobar degeneration (FTLD). The last few years have seen major advances in our understanding of FTD, its genetic causes and pathological substrates. In 1994, a genetic-epidemiological study on FTD was started at the Erasmus University Medical Center of Rotterdam. Since then, over 400 patients have been included in our FTD cohort. The aim of this thesis was to describe and determine the relationship between the clinical presentation, genetics and pathology of FTD, with emphasis on the hereditary form of FTD.

Published
2011

21. Symmetrical corticobasal syndrome caused by a novel c.314dup progranulin mutation

Author

Dopper, E.G.P. (Elise), Seelaar, H. (Harro), Chiu, W.Z. (Wang Zheng), Koning, I. (Inge) de, Minkelen, R. (Rick) van, Baker, M.C. (Matthew), Rozemuller, A.J.M. (Annemieke), Rademakers, R. (Rosa), Swieten, J.C. (John) van, Dopper, E.G.P. (Elise), Seelaar, H. (Harro), Chiu, W.Z. (Wang Zheng), Koning, I. (Inge) de, Minkelen, R. (Rick) van, Baker, M.C. (Matthew), Rozemuller, A.J.M. (Annemieke), Rademakers, R. (Rosa), and Swieten, J.C. (John) van

Abstract

Corticobasal syndrome (CBS) is characterised by asymmetrical parkinsonism and cognitive impairment. The underlying pathology varies between corticobasal degeneration, progressive supranuclear palsy, Alzheimer's disease, Creutzfeldt-Jakob disease and frontotemporal lobar degeneration sometimes in association with GRN mutations. A 61-year-old male underwent neurological examination, neuropsychological assessment, MRI, and HMPAO-SPECT at our medical centre. After his death at the age of 63, brain autopsy, genetic screening and mRNA expression analysis were performed. The patient presented with slow progressive walking disabilities, non-fluent language problems, behavioural changes and forgetfulness. His family history was negative. He had primitive reflexes, rigidity of his arms and postural instability. Later in the disease course he developed dystonia of his left leg, pathological crying, mutism and dysphagia. Neuropsychological assessment revealed prominent ideomotor and ideational apraxia, executive dysfunction, non-fluent aphasia and memory deficits. Neuroimaging showed symmetrical predominant frontoparietal atrophy and hypoperfusion. Frontotemporal lobar degeneration (FTLD)-TDP type 3 pathology was found at autopsy. GRN sequencing revealed a novel frameshift mutation c.314dup, p.Cys105fs and GRN mRNA levels showed a 50% decrease. We found a novel GRN mutation in a patient with an atypical (CBS) presentation with symmetric neuroimaging findings. GRN mutations are an important cause of CBS associated with FTLD-TDP type 3 pathology, sometimes in sporadic cases. Screening for GRN mutations should also be considered in CBS patients without a positive family history.

Published
2011
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22. Frequency of ubiquitin and FUS-positive, TDP-43-negative frontotemporal lobar degeneration

Author

Seelaar, H. (Harro), Klijnsma, K.Y. (Kirsten), Koning, I. (Inge) de, Lugt, A. (Aad) van der, Chiu, W.Z. (Wang Zheng), Azmani, A. (Asma), Rozemuller, A.J.M. (Annemieke), Swieten, J.C. (John) van, Seelaar, H. (Harro), Klijnsma, K.Y. (Kirsten), Koning, I. (Inge) de, Lugt, A. (Aad) van der, Chiu, W.Z. (Wang Zheng), Azmani, A. (Asma), Rozemuller, A.J.M. (Annemieke), and Swieten, J.C. (John) van

Abstract

Frontotemporal lobar degeneration (FTLD) is a clinically, genetically and pathologically heterogeneous disorder. Within FTLD with ubiquitin-positive inclusions (FTLD-U), a new pathological subtype named FTLD-FUS was recently found with fused in sarcoma (FUS) positive, TDP-43-negative inclusions, and striking atrophy of the caudate nucleus. The aim of this study was to determine the frequency of FTLD-FUS in our pathological FTLD series, and to describe the clinical, neuroimaging and neuropathological features of FTLD-FUS, especially caudate atrophy. Demographic and clinical data collected prospectively from 387 patients with frontotemporal dementia (FTD) yielded 74 brain specimens. Immunostaining was carried out using a panel of antibodies, including AT-8, ubiquitin, p62, FUS, and TDP-43. Cortical and caudate atrophy on MRI (n = 136) was rated as normal, mildmoderate or severe. Of the 37 FTLD-U cases, 33 were reclassified as FTLD-TDP and four (0.11, 95%: 0.00-0.21) as FTLD-FUS, with ubiquitin and FUS-positive, p62 and TDP-43-negative neuronal intranuclear inclusions (NII). All four FTLD-FUS cases had a negative family history, behavioural variant FTD (bvFTD), and three had an age at onset ≤40 years. MRI revealed mild-moderate or severe caudate atrophy in all, with a mean duration from onset till MRI of 63 months (range 16-119 months). In our total clinical FTD cohort, we found 11 pati

Published
2010
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23. FUS pathology defines the majority of tau-and TDP-43-negative frontotemporal lobar degeneration

Author

Urwin, H. (Hazel), Josephs, K.A. (Keith), Rohrer, J.D. (Jonathan), Mackenzie, I.R.A. (Ian), Neumann, H.A.M. (Martino), Authier, A. (Astrid), Seelaar, H. (Harro), Swieten, J.C. (John) van, Brown, J.M. (Jeremy), Johannsen, P. (Peter), Nielsen, J.E. (Jorgen), Holm, I.E. (Ida), Dickson, D. (Dennis), Rademakers, R. (Rosa), Graff-Radford, N.R. (Neill), Parisi, J.E. (Joseph), Petersen, R.C. (Ronald), Hatanpaa, K.J. (Kimmo), White III, C.L. (Charles), Geser, F. (Felix), Deerlin, V.M. (Vivianna), Weiner, M.F. (Myron), Trojanowski, J.Q. (John), Miller, B.L. (Bruce Lars), Seeley, W. (William), Zee, J. (Jill) van der, Kumar-Singh, S. (Samir), Engelborghs, S. (Sebastiaan), Deyn, P.P. (Peter) de, Broeckhoven, C. (Christine) van, Bigio, E.H. (Eileen), Deng, H-X. (Han-Xiang), Halliday, G.M. (Glenda Margaret), Kril, J.J. (Jillian), Munoz, D.G. (David), Mann, D. (David), Pickering-Brown, S. (Stuart), Doodeman, V. (Valerie), Adamson, G. (Gary), Ghazi-Noori, S. (Shabnam), Fisher, E.M.C. (Elizabeth), Holton, J.L. (Janice), Revesz, T. (Tamas), Rossor, M.N. (Martin), Collinge, J. (John), Mead, S. (Simon), Isaacs, A.M. (Adrian), Urwin, H. (Hazel), Josephs, K.A. (Keith), Rohrer, J.D. (Jonathan), Mackenzie, I.R.A. (Ian), Neumann, H.A.M. (Martino), Authier, A. (Astrid), Seelaar, H. (Harro), Swieten, J.C. (John) van, Brown, J.M. (Jeremy), Johannsen, P. (Peter), Nielsen, J.E. (Jorgen), Holm, I.E. (Ida), Dickson, D. (Dennis), Rademakers, R. (Rosa), Graff-Radford, N.R. (Neill), Parisi, J.E. (Joseph), Petersen, R.C. (Ronald), Hatanpaa, K.J. (Kimmo), White III, C.L. (Charles), Geser, F. (Felix), Deerlin, V.M. (Vivianna), Weiner, M.F. (Myron), Trojanowski, J.Q. (John), Miller, B.L. (Bruce Lars), Seeley, W. (William), Zee, J. (Jill) van der, Kumar-Singh, S. (Samir), Engelborghs, S. (Sebastiaan), Deyn, P.P. (Peter) de, Broeckhoven, C. (Christine) van, Bigio, E.H. (Eileen), Deng, H-X. (Han-Xiang), Halliday, G.M. (Glenda Margaret), Kril, J.J. (Jillian), Munoz, D.G. (David), Mann, D. (David), Pickering-Brown, S. (Stuart), Doodeman, V. (Valerie), Adamson, G. (Gary), Ghazi-Noori, S. (Shabnam), Fisher, E.M.C. (Elizabeth), Holton, J.L. (Janice), Revesz, T. (Tamas), Rossor, M.N. (Martin), Collinge, J. (John), Mead, S. (Simon), and Isaacs, A.M. (Adrian)

Abstract

Through an international consortium, we have collected 37 tau-and TAR DNA-binding protein 43 (TDP-43)-negative frontotemporal lobar degeneration (FTLD) cases, and present here the first comprehensive analysis of these cases in terms of neuropathology, genetics, demographics and clinical data. 92% (34/37) had fused in sarcoma (FUS) protein pathology, indicating that FTLD-FUS is an important FTLD subtype. This FTLD-FUS

Published
2010
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24. Variation at GRN3′-UTR rs5848 is not associated with a risk of frontotemporal lobar degenerationin Dutch population

Author

Simón-Sánchez, J. (Javier), Seelaar, H. (Harro), Bochdanovits, Z. (Zoltan), Deeg, D.J.H. (Dorly), Swieten, J.C. (John) van, Heutink, P. (Peter), Simón-Sánchez, J. (Javier), Seelaar, H. (Harro), Bochdanovits, Z. (Zoltan), Deeg, D.J.H. (Dorly), Swieten, J.C. (John) van, and Heutink, P. (Peter)

Abstract

Background: A single nucleotide polymorphism (rs5848) located in the 3′- untranslated region of GRN has recently been associated with a risk of frontotemporal lobar degeneration (FTLD) in North American population particularly in pathologically confirmed cases with neural inclusions immunoreactive for ubiquitin and TAR DNA-binding protein 43 (TDP-43), but negative for tau and alpha-synuclein (FTLD-TDP). Methodology/Principal Findings: In an effort to replicate these results in a different population, rs5848 was genotyped in 256 FTLD cases and 1695 controls from the Netherlands. Single SNP gender-adjusted logistic regression analysis revealed no significant association between variation at rs5848 and FTLD. Fisher's exact test, failed to find any significant association between rs5848 and a subset of 23 pathology confirmed FTLD-TDP cases. Conclusions/Significance: The evidence presented here suggests that variation at rs5848 does not contribute to the etiology of FTLD in the Dutch population.

Published
2009
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25. TDP-43 pathology in familial frontotemporal dementia and motor neuron disease without Progranulin mutations

Author

Seelaar, H. (Harro), Schelhaas, H.J. (Jurgen), Azmani, A. (Asma), Küsters, B. (Benno), Rosso, S.M. (Sonia), Majoor-Krakauer, D.F. (Danielle), Rijk, M.C. (Maarten) de, Rizzu, P. (Patrizia), Brummelhuis, M. (Ming) ten, Doorn, P.A. (Pieter) van, Kamphorst, W. (Wouter), Willemsen, R. (Rob), Swieten, J.C. (John) van, Seelaar, H. (Harro), Schelhaas, H.J. (Jurgen), Azmani, A. (Asma), Küsters, B. (Benno), Rosso, S.M. (Sonia), Majoor-Krakauer, D.F. (Danielle), Rijk, M.C. (Maarten) de, Rizzu, P. (Patrizia), Brummelhuis, M. (Ming) ten, Doorn, P.A. (Pieter) van, Kamphorst, W. (Wouter), Willemsen, R. (Rob), and Swieten, J.C. (John) van

Abstract

Frontotemporal dementia is accompanied by motor neuron disease (FTD + MND) in ∼10% of cases. There is accumulating evidence for a clinicopathological overlap between FTD and MND based on observations of familial aggregation and neuropathological findings of ubiquitin-positive neuronal cytoplasmatic inclusions (NCI) in lower motor neurons, hippocampus and neocortex in both conditions. Several familial forms exist with different genetic loci and defects. We investigated the familial aggregation and clinical presentation of FTD + MND cases in a large cohort of 368 FTD patients in the Netherlands. Immunohistochemistry of available brain tissue of deceased patients was investigated using a panel of antibodies including ubiquitin, p62 and TAR DNA-binding protein of 43kDa antibodies. A total of eight patients coming from six families had a family history positive for FTD + MND (mean age at onset 53.2 ± 8.4 years). Five patients presented with behavioural changes and cognitive changes followed by motor neuron disease, whereas symptoms of motor neuron disease were the presenting features in the remaining three patients. Other affected relatives in these families showed dementia/FTD, MND or FTD + MND reflecting the clini

Published
2007
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