370 results on '"Ekaterina, Rogaeva"'
Search Results
2. Early neurotransmitters changes in prodromal frontotemporal dementia: A GENFI study
- Author
-
Enrico Premi, Marta Pengo, Irene Mattioli, Valentina Cantoni, Juergen Dukart, Roberto Gasparotti, Emanuele Buratti, Alessandro Padovani, Martina Bocchetta, Emily G. Todd, Arabella Bouzigues, David M. Cash, Rhian S. Convery, Lucy L. Russell, Phoebe Foster, David L. Thomas, John C. van Swieten, Lize C. Jiskoot, Harro Seelaar, Daniela Galimberti, Raquel Sanchez-Valle, Robert Laforce, Jr, Fermin Moreno, Matthis Synofzik, Caroline Graff, Mario Masellis, Maria Carmela Tartaglia, James B. Rowe, Kamen A. Tsvetanov, Rik Vandenberghe, Elizabeth Finger, Pietro Tiraboschi, Alexandre de Mendonça, Isabel Santana, Chris R. Butler, Simon Ducharme, Alexander Gerhard, Johannes Levin, Markus Otto, Sandro Sorbi, Isabelle Le Ber, Florence Pasquier, Jonathan D. Rohrer, Barbara Borroni, Aitana Sogorb Esteve, Carolin Heller, Caroline V. Greaves, Henrik Zetterberg, Imogen J. Swift, Kiran Samra, Rachelle Shafei, Carolyn Timberlake, Thomas Cope, Timothy Rittman, Andrea Arighi, Chiara Fenoglio, Elio Scarpini, Giorgio Fumagalli, Vittoria Borracci, Giacomina Rossi, Giorgio Giaccone, Giuseppe Di Fede, Paola Caroppo, Sara Prioni, Veronica Redaelli, David Tang-Wai, Ekaterina Rogaeva, Miguel Castelo-Branco, Morris Freedman, Ron Keren, Sandra Black, Sara Mitchell, Christen Shoesmith, Robart Bartha, Rosa Rademakers, Jackie Poos, Janne M. Papma, Lucia Giannini, Rick van Minkelen, Yolande Pijnenburg, Benedetta Nacmias, Camilla Ferrari, Cristina Polito, Gemma Lombardi, Valentina Bessi, Michele Veldsman, Christin Andersson, Hakan Thonberg, Linn Öijerstedt, Vesna Jelic, Paul Thompson, Tobias Langheinrich, Albert Lladó, Anna Antonell, Jaume Olives, Mircea Balasa, Nuria Bargalló, Sergi Borrego-Ecija, Ana Verdelho, Carolina Maruta, Catarina B. Ferreira, Gabriel Miltenberger, Frederico Simões do Couto, Alazne Gabilondo, Ana Gorostidi, Jorge Villanua, Marta Cañada, Mikel Tainta, Miren Zulaica, Myriam Barandiaran, Patricia Alves, Benjamin Bender, Carlo Wilke, Lisa Graf, Annick Vogels, Mathieu Vandenbulcke, Philip Van Damme, Rose Bruffaerts, Koen Poesen, Pedro Rosa-Neto, Serge Gauthier, Agnès Camuzat, Alexis Brice, Anne Bertrand, Aurélie Funkiewiez, Daisy Rinaldi, Dario Saracino, Olivier Colliot, Sabrina Sayah, Catharina Prix, Elisabeth Wlasich, Olivia Wagemann, Sandra Loosli, Sonja Schönecker, Tobias Hoegen, Jolina Lombardi, Sarah Anderl-Straub, Adeline Rollin, Gregory Kuchcinski, Maxime Bertoux, Thibaud Lebouvier, Vincent Deramecourt, Beatriz Santiago, Diana Duro, Maria João Leitão, Maria Rosario Almeida, Miguel Tábuas-Pereira, and Sónia Afonso
- Subjects
Frontotemporal dementia ,Frontotemporal lobar degeneration ,Genes ,Magnetic resonance imaging ,Positron emission tomography ,Neurotransmitters ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Background: Neurotransmitters deficits in Frontotemporal Dementia (FTD) are still poorly understood. Better knowledge of neurotransmitters impairment, especially in prodromal disease stages, might tailor symptomatic treatment approaches. Methods: In the present study, we applied JuSpace toolbox, which allowed for cross-modal correlation of Magnetic Resonance Imaging (MRI)-based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, GABAergic and glutamatergic neurotransmission.We included 392 mutation carriers (157 GRN, 164 C9orf72, 71 MAPT), together with 276 non-carrier cognitively healthy controls (HC). We tested if the spatial patterns of grey matter volume (GMV) alterations in mutation carriers (relative to HC) are correlated with specific neurotransmitter systems in prodromal (CDR® plus NACC FTLD = 0.5) and in symptomatic (CDR® plus NACC FTLD≥1) FTD. Results: In prodromal stages of C9orf72 disease, voxel-based brain changes were significantly associated with spatial distribution of dopamine and acetylcholine pathways; in prodromal MAPT disease with dopamine and serotonin pathways, while in prodromal GRN disease no significant findings were reported (p
- Published
- 2023
- Full Text
- View/download PDF
3. Letter to the editor on a paper by Kaivola et al. (2020): carriership of two copies of C9orf72 hexanucleotide repeat intermediate-length alleles is not associated with amyotrophic lateral sclerosis or frontotemporal dementia
- Author
-
Sterre C. M. de Boer, Lauren Woolley, Merel O. Mol, Maria Serpente, Lianne M. Reus, Rick van Minkelen, Joke F. A. van Vugt, Federica Sorrentino, Jan H. Veldink, Harro Seelaar, Daniela Galimberti, Fred van Ruissen, Simon Mead, Ekaterina Rogaeva, Yolande A. L. Pijnenburg, and Sven J. van der Lee
- Subjects
Neurology. Diseases of the nervous system ,RC346-429 - Published
- 2022
- Full Text
- View/download PDF
4. Generation of five induced pluripotent stem cells lines from four members of the same family carrying a C9orf72 repeat expansion and one wild-type member
- Author
-
Chiara Lattuada, Serena Santangelo, Silvia Peverelli, Philip McGoldrick, Ekaterina Rogaeva, Lorne Zinman, Georg Haase, Vincent Géli, Vincenzo Silani, Janice Robertson, Antonia Ratti, and Patrizia Bossolasco
- Subjects
Biology (General) ,QH301-705.5 - Abstract
The most common genetic cause of Amyotrophic Lateral Sclerosis (ALS) is the expansion of a G4C2 hexanucleotide repeat in the C9orf72 gene. The size of the repeat expansion is highly variable and a cut-off of 30 repeats has been suggested as the lower pathological limit. Repeat size variability has been observed intergenerationally and intraindividually in tissues from different organs and within the same tissue, suggesting instability of the pathological repeat expansion. In order to study this genomic instability, we established iPSCs from five members of the same family of which four carried a C9orf72 repeat expansion and one was wild-type.
- Published
- 2023
- Full Text
- View/download PDF
5. Establishing an online resource to facilitate global collaboration and inclusion of underrepresented populations: Experience from the MJFF Global Genetic Parkinson's Disease Project.
- Author
-
Eva-Juliane Vollstedt, Harutyun Madoev, Anna Aasly, Azlina Ahmad-Annuar, Bashayer Al-Mubarak, Roy N Alcalay, Victoria Alvarez, Ignacio Amorin, Grazia Annesi, David Arkadir, Soraya Bardien, Roger A Barker, Melinda Barkhuizen, A Nazli Basak, Vincenzo Bonifati, Agnita Boon, Laura Brighina, Kathrin Brockmann, Andrea Carmine Belin, Jonathan Carr, Jordi Clarimon, Mario Cornejo-Olivas, Leonor Correia Guedes, Jean-Christophe Corvol, David Crosiers, Joana Damásio, Parimal Das, Patricia de Carvalho Aguiar, Anna De Rosa, Jolanta Dorszewska, Sibel Ertan, Rosangela Ferese, Joaquim Ferreira, Emilia Gatto, Gençer Genç, Nir Giladi, Pilar Gómez-Garre, Hasmet Hanagasi, Nobutaka Hattori, Faycal Hentati, Dorota Hoffman-Zacharska, Sergey N Illarioshkin, Joseph Jankovic, Silvia Jesús, Valtteri Kaasinen, Anneke Kievit, Peter Klivenyi, Vladimir Kostic, Dariusz Koziorowski, Andrea A Kühn, Anthony E Lang, Shen-Yang Lim, Chin-Hsien Lin, Katja Lohmann, Vladana Markovic, Mika Henrik Martikainen, George Mellick, Marcelo Merello, Lukasz Milanowski, Pablo Mir, Özgür Öztop-Çakmak, Márcia Mattos Gonçalves Pimentel, Teeratorn Pulkes, Andreas Puschmann, Ekaterina Rogaeva, Esther M Sammler, Maria Skaalum Petersen, Matej Skorvanek, Mariana Spitz, Oksana Suchowersky, Ai Huey Tan, Pichet Termsarasab, Avner Thaler, Vitor Tumas, Enza Maria Valente, Bart van de Warrenburg, Caroline H Williams-Gray, Ruey-Mei Wu, Baorong Zhang, Alexander Zimprich, Justin Solle, Shalini Padmanabhan, and Christine Klein
- Subjects
Medicine ,Science - Abstract
Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.
- Published
- 2023
- Full Text
- View/download PDF
6. Contribution of rare variant associations to neurodegenerative disease presentation
- Author
-
Allison A. Dilliott, Abdalla Abdelhady, Kelly M. Sunderland, Sali M. K. Farhan, Agessandro Abrahao, Malcolm A. Binns, Sandra E. Black, Michael Borrie, Leanne K. Casaubon, Dar Dowlatshahi, Elizabeth Finger, Corinne E. Fischer, Andrew Frank, Morris Freedman, David Grimes, Ayman Hassan, Mandar Jog, Sanjeev Kumar, Donna Kwan, Anthony E. Lang, Jennifer Mandzia, Mario Masellis, Adam D. McIntyre, Stephen H. Pasternak, Bruce G. Pollock, Tarek K. Rajji, Ekaterina Rogaeva, Demetrios J. Sahlas, Gustavo Saposnik, Christine Sato, Dallas Seitz, Christen Shoesmith, Thomas D. L. Steeves, Richard H. Swartz, Brian Tan, David F. Tang-Wai, Maria C. Tartaglia, John Turnbull, Lorne Zinman, ONDRI Investigators, and Robert A. Hegele
- Subjects
Medicine ,Genetics ,QH426-470 - Abstract
Abstract Genetic factors contribute to neurodegenerative diseases, with high heritability estimates across diagnoses; however, a large portion of the genetic influence remains poorly understood. Many previous studies have attempted to fill the gaps by performing linkage analyses and association studies in individual disease cohorts, but have failed to consider the clinical and pathological overlap observed across neurodegenerative diseases and the potential for genetic overlap between the phenotypes. Here, we leveraged rare variant association analyses (RVAAs) to elucidate the genetic overlap among multiple neurodegenerative diagnoses, including Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), mild cognitive impairment, and Parkinson’s disease (PD), as well as cerebrovascular disease, using the data generated with a custom-designed neurodegenerative disease gene panel in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). As expected, only ~3% of ONDRI participants harboured a monogenic variant likely driving their disease presentation. Yet, when genes were binned based on previous disease associations, we observed an enrichment of putative loss of function variants in PD genes across all ONDRI cohorts. Further, individual gene-based RVAA identified significant enrichment of rare, nonsynonymous variants in PARK2 in the FTD cohort, and in NOTCH3 in the PD cohort. The results indicate that there may be greater heterogeneity in the genetic factors contributing to neurodegeneration than previously appreciated. Although the mechanisms by which these genes contribute to disease presentation must be further explored, we hypothesize they may be a result of rare variants of moderate phenotypic effect contributing to overlapping pathology and clinical features observed across neurodegenerative diagnoses.
- Published
- 2021
- Full Text
- View/download PDF
7. White matter hyperintensities in autopsy-confirmed frontotemporal lobar degeneration and Alzheimer’s disease
- Author
-
Philippe Desmarais, Andrew F. Gao, Krista Lanctôt, Ekaterina Rogaeva, Joel Ramirez, Nathan Herrmann, Donald T. Stuss, Sandra E. Black, Julia Keith, and Mario Masellis
- Subjects
Alzheimer’s disease ,Frontotemporal lobar degeneration ,White matter hyperintensity ,Magnetic resonance imaging ,Neuropsychiatric symptoms ,Neuropathology ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background We aimed to systematically describe the burden and distribution of white matter hyperintensities (WMH) and investigate correlations with neuropsychiatric symptoms in pathologically proven Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD). Methods Autopsy-confirmed cases were identified from the Sunnybrook Dementia Study, including 15 cases of AD and 58 cases of FTLD (22 FTLD-TDP cases; 10 FTLD-Tau [Pick’s] cases; 11 FTLD-Tau Corticobasal Degeneration cases; and 15 FTLD-Tau Progressive Supranuclear Palsy cases). Healthy matched controls (n = 35) were included for comparison purposes. Data analyses included ANCOVA to compare the burden of WMH on antemortem brain MRI between groups, adjusted linear regression models to identify associations between WMH burden and neuropsychiatric symptoms, and image-guided pathology review of selected areas of WMH from each pathologic group. Results Burden and regional distribution of WMH differed significantly between neuropathological groups (F 5,77 = 2.67, P’ = 0.029), with the FTLD-TDP group having the highest mean volume globally (8032 ± 8889 mm3) and in frontal regions (4897 ± 6163 mm3). The AD group had the highest mean volume in occipital regions (468 ± 420 mm3). Total score on the Neuropsychiatric Inventory correlated with bilateral frontal WMH volume (β = 0.330, P = 0.006), depression correlated with bilateral occipital WMH volume (β = 0.401, P < 0.001), and apathy correlated with bilateral frontal WMH volume (β = 0.311, P = 0.009), all corrected for the false discovery rate. Image-guided neuropathological assessment of selected cases with the highest burden of WMH in each pathologic group revealed presence of severe gliosis, myelin pallor, and axonal loss, but with no distinguishing features indicative of the underlying proteinopathy. Conclusions These findings suggest that WMH are associated with neuropsychiatric manifestations in AD and FTLD and that WMH burden and regional distribution in neurodegenerative disorders differ according to the underlying neuropathological processes.
- Published
- 2021
- Full Text
- View/download PDF
8. Targeted copy number variant identification across the neurodegenerative disease spectrum
- Author
-
Allison A. Dilliott, Kristina K. Zhang, Jian Wang, Agessandro Abrahao, Malcolm A. Binns, Sandra E. Black, Michael Borrie, Dar Dowlatshahi, Elizabeth Finger, Corinne E. Fischer, Andrew Frank, Morris Freedman, David Grimes, Ayman Hassan, Mandar Jog, Sanjeev Kumar, Anthony E. Lang, Jennifer Mandzia, Mario Masellis, Stephen H. Pasternak, Bruce G. Pollock, Tarek K. Rajji, Ekaterina Rogaeva, Demetrios J. Sahlas, Gustavo Saposnik, Christine Sato, Dallas Seitz, Christen Shoesmith, Thomas D. L. Steeves, Richard H. Swartz, Brian Tan, David F. Tang‐Wai, Maria C. Tartaglia, John Turnbull, Lorne Zinman, ONDRI Investigators, and Robert A. Hegele
- Subjects
cerebrovascular disease ,copy number variants ,neurodegenerative disease ,next‐generation sequencing ,Genetics ,QH426-470 - Abstract
Abstract Background Although genetic factors are known to contribute to neurodegenerative disease susceptibility, there remains a large amount of heritability unaccounted for across the diagnoses. Copy number variants (CNVs) contribute to these phenotypes, but their presence and influence on disease state remains relatively understudied. Methods Here, we applied a depth of coverage approach to detect CNVs in 80 genes previously associated with neurodegenerative disease within participants of the Ontario Neurodegenerative Disease Research Initiative (n = 519). Results In total, we identified and validated four CNVs in the cohort, including: (1) a heterozygous deletion of exon 5 in OPTN in an Alzheimer's disease participant; (2) a duplication of exons 1–5 in PARK7 in an amyotrophic lateral sclerosis participant; (3) a duplication of >3 Mb, which encompassed ABCC6, in a cerebrovascular disease (CVD) participant; and (4) a duplication of exons 7–11 in SAMHD1 in a mild cognitive impairment participant. We also identified 43 additional CNVs that may be candidates for future replication studies. Conclusion The identification of the CNVs suggests a portion of the apparent missing heritability of the phenotypes may be due to these structural variants, and their assessment is imperative for a thorough understanding of the genetic spectrum of neurodegeneration.
- Published
- 2022
- Full Text
- View/download PDF
9. Combined epigenetic/genetic study identified an ALS age of onset modifier
- Author
-
Ming Zhang, Zhengrui Xi, Sara Saez-Atienzar, Ruth Chia, Danielle Moreno, Christine Sato, Mahdi Montazer Haghighi, Bryan J. Traynor, Lorne Zinman, and Ekaterina Rogaeva
- Subjects
ALS ,Age of onset ,Modifier ,DNA methylation ,CpG-SNPs ,Genetic association ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Age at onset of amyotrophic lateral sclerosis (ALS) is highly variable (eg, 27–74 years in carriers of the G4C2-expansion in C9orf72). It might be influenced by environmental and genetic factors via the modulation of DNA methylation (DNAm) at CpG-sites. Hence, we combined an epigenetic and genetic approach to test the hypothesis that some common single nucleotide polymorphisms (SNPs) at CpG-sites (CpG-SNPs) could modify ALS age of onset. Our genome-wide DNAm analysis suggested three CpG-SNPs whose DNAm levels are significantly associated with age of onset in 249 ALS patients (q
- Published
- 2021
- Full Text
- View/download PDF
10. Genetic and Epigenetic Study of Monozygotic Twins Affected by Parkinson’s Disease
- Author
-
Yi-Min Sun, Wan-Li Yang, Ekaterina Rogaeva, Anthony E. Lang, Jian Wang, and Ming Zhang
- Subjects
monozygotic twins ,Parkinson’s disease ,genetics ,epigenetics ,age at onset ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Background: Genetic and epigenetic modifiers of age at onset of Parkinson’s disease (PD) are largely unknown. It remains unclear whether DNA methylation (DNAm) age acceleration is linked to age at onset in PD patients of different ethnicities with a similar genetic background. We aim to characterize the clinical, genomic and epigenomic features of three pairs of Chinese monozygotic twins discordant for PD onset by up to 10 years. Methods: We conducted whole genome sequencing, multiplex ligation-dependent probe amplification and genome-wide DNAm array to evaluate the three pairs of Chinese monozygotic twins discordant for age at onset of PD (families A–C). Results: We identified two heterozygous PRKN mutations (exon 2–4 deletion and p.Met1Thr) in PD affected members of one family. Somatic mutation analyses of investigated families did not reveal any variants that could explain the phenotypic discordance in the twin pairs. Of note, our epigenetic study revealed that the twins with earlier-onset had a trend of faster DNAm age acceleration than the later-onset/asymptomatic twins, but without statistical significance. Conclusion: The link between DNAm age acceleration and PD onset in Chinese patients should be interpreted with cautious, and need to be further verified in an extended PD cohort with similar genetic background.
- Published
- 2023
- Full Text
- View/download PDF
11. Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies
- Author
-
Tatiana Orme, Dena Hernandez, Owen A. Ross, Celia Kun-Rodrigues, Lee Darwent, Claire E. Shepherd, Laura Parkkinen, Olaf Ansorge, Lorraine Clark, Lawrence S. Honig, Karen Marder, Afina Lemstra, Ekaterina Rogaeva, Peter St. George-Hyslop, Elisabet Londos, Henrik Zetterberg, Kevin Morgan, Claire Troakes, Safa Al-Sarraj, Tammaryn Lashley, Janice Holton, Yaroslau Compta, Vivianna Van Deerlin, John Q. Trojanowski, Geidy E. Serrano, Thomas G. Beach, Suzanne Lesage, Douglas Galasko, Eliezer Masliah, Isabel Santana, Pau Pastor, Pentti J. Tienari, Liisa Myllykangas, Minna Oinas, Tamas Revesz, Andrew Lees, Brad F. Boeve, Ronald C. Petersen, Tanis J. Ferman, Valentina Escott-Price, Neill Graff-Radford, Nigel J. Cairns, John C. Morris, Stuart Pickering-Brown, David Mann, Glenda Halliday, David J. Stone, Dennis W. Dickson, John Hardy, Andrew Singleton, Rita Guerreiro, and Jose Bras
- Subjects
Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, and also describe variants reported as pathogenic which remain of unknown clinical significance, as well as variants associated with strong risk. Rare missense variants of unknown significance were found in APP, CHCHD2, DCTN1, GRN, MAPT, NOTCH3, SQSTM1, TBK1 and TIA1. Additionally, we identified a pathogenic GRN p.Arg493* mutation, potentially adding to the diversity of phenotypes associated with this mutation. The rarity of previously reported pathogenic mutations in this cohort suggests that the genetic overlap of other neurodegenerative diseases with DLB is not substantial. Since it is now clear that genetics plays a role in DLB, these data suggest that other genetic loci play a role in this disease.
- Published
- 2020
- Full Text
- View/download PDF
12. Heritability and genetic variance of dementia with Lewy bodies
- Author
-
Rita Guerreiro, Valentina Escott-Price, Dena G. Hernandez, Celia Kun-Rodrigues, Owen A. Ross, Tatiana Orme, Joao Luis Neto, Susana Carmona, Nadia Dehghani, John D. Eicher, Claire Shepherd, Laura Parkkinen, Lee Darwent, Michael G. Heckman, Sonja W. Scholz, Juan C. Troncoso, Olga Pletnikova, Ted Dawson, Liana Rosenthal, Olaf Ansorge, Jordi Clarimon, Alberto Lleo, Estrella Morenas-Rodriguez, Lorraine Clark, Lawrence S. Honig, Karen Marder, Afina Lemstra, Ekaterina Rogaeva, Peter St. George-Hyslop, Elisabet Londos, Henrik Zetterberg, Imelda Barber, Anne Braae, Kristelle Brown, Kevin Morgan, Claire Troakes, Safa Al-Sarraj, Tammaryn Lashley, Janice Holton, Yaroslau Compta, Vivianna Van Deerlin, Geidy E. Serrano, Thomas G. Beach, Suzanne Lesage, Douglas Galasko, Eliezer Masliah, Isabel Santana, Pau Pastor, Monica Diez-Fairen, Miquel Aguilar, Pentti J. Tienari, Liisa Myllykangas, Minna Oinas, Tamas Revesz, Andrew Lees, Brad F. Boeve, Ronald C. Petersen, Tanis J. Ferman, Neill Graff-Radford, Nigel J. Cairns, John C. Morris, Stuart Pickering-Brown, David Mann, Glenda M. Halliday, John Hardy, John Q. Trojanowski, Dennis W. Dickson, Andrew Singleton, David J. Stone, and Jose Bras
- Subjects
Genetic variance ,Dementia ,Lewy bodies ,Genetic correlation ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.
- Published
- 2019
- Full Text
- View/download PDF
13. Disease-related cortical thinning in presymptomatic granulin mutation carriers
- Author
-
Sergi Borrego-Écija, Roser Sala-Llonch, John van Swieten, Barbara Borroni, Fermín Moreno, Mario Masellis, Carmela Tartaglia, Caroline Graff, Daniela Galimberti, Robert Laforce, Jr, James B Rowe, Elizabeth Finger, Rik Vandenberghe, Fabrizio Tagliavini, Alexandre de Mendonça, Isabel Santana, Matthis Synofzik, Simon Ducharme, Johannes Levin, Adrian Danek, Alex Gerhard, Markus Otto, Chris Butler, Giovanni Frisoni, Sandro Sorbi, Carolin Heller, Martina Bocchetta, David M Cash, Rhian S Convery, Katrina M Moore, Jonathan D Rohrer, Raquel Sanchez-Valle, Martin N. Rossor, Nick C. Fox, Ione O.C. Woollacott, Rachelle Shafei, Caroline Greaves, Mollie Neason, Rita Guerreiro, Jose Bras, David L. Thomas, Jennifer Nicholas, Simon Mead, Lieke Meeter, Jessica Panman, Janne Papma, Rick van Minkelen, Yolande Pijnenburg, Begoña Indakoetxea, Alazne Gabilondo, Mikel TaintaMD, Maria de Arriba, Ana Gorostidi, Miren Zulaica, Jorge Villanua, Zigor Diaz, Jaume Olives, Albert Lladó, Mircea Balasa, Anna Antonell, Nuria Bargallo, Enrico Premi, Maura Cosseddu, Stefano Gazzina, Alessandro Padovani, Roberto Gasparotti, Silvana Archetti, Sandra Black, Sara Mitchell, Ekaterina Rogaeva, Morris Freedman, Ron Keren, David Tang-Wai, Linn Öijerstedt, Christin Andersson, Vesna Jelic, Hakan Thonberg, Andrea Arighi, Chiara Fenoglio, Elio Scarpini MD, Giorgio Fumagalli, Thomas Cope, Carolyn Timberlake, Timothy Rittman, Christen Shoesmith, Robart Bartha, Rosa Rademakers, Carlo Wilke, Benjamin Bender, Rose Bruffaerts, Philip Vandamme, Mathieu Vandenbulcke, Carolina Maruta, Catarina B. Ferreira, Gabriel Miltenberger, Ana Verdelho, Sónia Afonso, Ricardo Taipa, Paola Caroppo, Giuseppe Di Fede, Giorgio Giaccone, Sara Prioni, Veronica Redaelli, Giacomina Rossi, Pietro Tiraboschi, Diana Duro, Maria Rosario Almeida, Miguel Castelo-Branco, Maria João Leitão, Miguel Tabuas-Pereira, Beatriz Santiago, Serge Gauthier, Pedro Rosa-Neto, Michele Veldsman, Toby Flanagan, Catharina Prix, Tobias Hoegen, Elisabeth Wlasich, Sandra Loosli, Sonja Schonecker, Elisa Semler, and Sarah Anderl-Straub
- Subjects
Frontotemporal dementia ,Cortical thickness ,GRN ,Presymptomatic ,Genetic mutations ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Mutations in the granulin gene (GRN) cause familial frontotemporal dementia. Understanding the structural brain changes in presymptomatic GRN carriers would enforce the use of neuroimaging biomarkers for early diagnosis and monitoring. We studied 100 presymptomatic GRN mutation carriers and 94 noncarriers from the Genetic Frontotemporal dementia initiative (GENFI), with MRI structural images. We analyzed 3T MRI structural images using the FreeSurfer pipeline to calculate the whole brain cortical thickness (CTh) for each subject. We also perform a vertex-wise general linear model to assess differences between groups in the relationship between CTh and diverse covariables as gender, age, the estimated years to onset and education. We also explored differences according to TMEM106B genotype, a possible disease modifier. Whole brain CTh did not differ between carriers and noncarriers. Both groups showed age-related cortical thinning. The group-by-age interaction analysis showed that this age-related cortical thinning was significantly greater in GRN carriers in the left superior frontal cortex. TMEM106B did not significantly influence the age-related cortical thinning. Our results validate and expand previous findings suggesting an increased CTh loss associated with age and estimated proximity to symptoms onset in GRN carriers, even before the disease onset.
- Published
- 2021
- Full Text
- View/download PDF
14. Differential early subcortical involvement in genetic FTD within the GENFI cohort
- Author
-
Martina Bocchetta, Emily G. Todd, Georgia Peakman, David M. Cash, Rhian S. Convery, Lucy L. Russell, David L. Thomas, Juan Eugenio Iglesias, John C. van Swieten, Lize C. Jiskoot, Harro Seelaar, Barbara Borroni, Daniela Galimberti, Raquel Sanchez-Valle, Robert Laforce, Fermin Moreno, Matthis Synofzik, Caroline Graff, Mario Masellis, Maria Carmela Tartaglia, James B. Rowe, Rik Vandenberghe, Elizabeth Finger, Fabrizio Tagliavini, Alexandre de Mendonça, Isabel Santana, Chris R. Butler, Simon Ducharme, Alexander Gerhard, Adrian Danek, Johannes Levin, Markus Otto, Sandro Sorbi, Isabelle Le Ber, Florence Pasquier, Jonathan D. Rohrer, Sónia Afonso, Maria Rosario Almeida, Sarah Anderl-Straub, Christin Andersson, Anna Antonell, Silvana Archetti, Andrea Arighi, Mircea Balasa, Myriam Barandiaran, Nuria Bargalló, Robart Bartha, Benjamin Bender, Alberto Benussi, Maxime Bertoux, Anne Bertrand, Valentina Bessi, Sandra Black, Sergi Borrego-Ecija, Jose Bras, Alexis Brice, Rose Bruffaerts, Agnès Camuzat, Marta Cañada, Valentina Cantoni, Paola Caroppo, Miguel Castelo-Branco, Olivier Colliot, Thomas Cope, Vincent Deramecourt, María de Arriba, Giuseppe Di Fede, Alina Díez, Diana Duro, Chiara Fenoglio, Camilla Ferrari, Catarina B. Ferreira, Nick Fox, Morris Freedman, Giorgio Fumagalli, Aurélie Funkiewiez, Alazne Gabilondo, Roberto Gasparotti, Serge Gauthier, Stefano Gazzina, Giorgio Giaccone, Ana Gorostidi, Caroline Greaves, Rita Guerreiro, Carolin Heller, Tobias Hoegen, Begoña Indakoetxea, Vesna Jelic, Hans-Otto Karnath, Ron Keren, Gregory Kuchcinski, Tobias Langheinrich, Thibaud Lebouvier, Maria João Leitão, Albert Lladó, Gemma Lombardi, Sandra Loosli, Carolina Maruta, Simon Mead, Lieke Meeter, Gabriel Miltenberger, Rick van Minkelen, Sara Mitchell, Katrina Moore, Benedetta Nacmias, Annabel Nelson, Jennifer Nicholas, Linn Öijerstedt, Jaume Olives, Sebastien Ourselin, Alessandro Padovani, Jessica Panman, Janne M. Papma, Yolande Pijnenburg, Cristina Polito, Enrico Premi, Sara Prioni, Catharina Prix, Rosa Rademakers, Veronica Redaelli, Daisy Rinaldi, Tim Rittman, Ekaterina Rogaeva, Adeline Rollin, Pedro Rosa-Neto, Giacomina Rossi, Martin Rossor, Beatriz Santiago, Dario Saracino, Sabrina Sayah, Elio Scarpini, Sonja Schönecker, Elisa Semler, Rachelle Shafei, Christen Shoesmith, Imogen Swift, Miguel Tábuas-Pereira, Mikel Tainta, Ricardo Taipa, David Tang-Wai, Paul Thompson, Hakan Thonberg, Carolyn Timberlake, Pietro Tiraboschi, Philip Van Damme, Mathieu Vandenbulcke, Michele Veldsman, Ana Verdelho, Jorge Villanua, Jason Warren, Carlo Wilke, Ione Woollacott, Elisabeth Wlasich, Henrik Zetterberg, and Miren Zulaica
- Subjects
Genetic frontotemporal dementia ,MRI imaging ,Brain volumetry ,Presymptomatic stage ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Background: Studies have previously shown evidence for presymptomatic cortical atrophy in genetic FTD. Whilst initial investigations have also identified early deep grey matter volume loss, little is known about the extent of subcortical involvement, particularly within subregions, and how this differs between genetic groups. Methods: 480 mutation carriers from the Genetic FTD Initiative (GENFI) were included (198 GRN, 202 C9orf72, 80 MAPT), together with 298 non-carrier cognitively normal controls. Cortical and subcortical volumes of interest were generated using automated parcellation methods on volumetric 3 T T1-weighted MRI scans. Mutation carriers were divided into three disease stages based on their global CDR® plus NACC FTLD score: asymptomatic (0), possibly or mildly symptomatic (0.5) and fully symptomatic (1 or more). Results: In all three groups, subcortical involvement was seen at the CDR 0.5 stage prior to phenoconversion, whereas in the C9orf72 and MAPT mutation carriers there was also involvement at the CDR 0 stage. In the C9orf72 expansion carriers the earliest volume changes were in thalamic subnuclei (particularly pulvinar and lateral geniculate, 9–10%) cerebellum (lobules VIIa-Crus II and VIIIb, 2–3%), hippocampus (particularly presubiculum and CA1, 2–3%), amygdala (all subregions, 2–6%) and hypothalamus (superior tuberal region, 1%). In MAPT mutation carriers changes were seen at CDR 0 in the hippocampus (subiculum, presubiculum and tail, 3–4%) and amygdala (accessory basal and superficial nuclei, 2–4%). GRN mutation carriers showed subcortical differences at CDR 0.5 in the presubiculum of the hippocampus (8%). Conclusions: C9orf72 expansion carriers show the earliest and most widespread changes including the thalamus, basal ganglia and medial temporal lobe. By investigating individual subregions, changes can also be seen at CDR 0 in MAPT mutation carriers within the limbic system. Our results suggest that subcortical brain volumes may be used as markers of neurodegeneration even prior to the onset of prodromal symptoms.
- Published
- 2021
- Full Text
- View/download PDF
15. The Intersection between COVID-19, the Gene Family of ACE2 and Alzheimer’s Disease
- Author
-
Mahdi Montazer Haghighi, Erfan Ghani Kakhki, Christine Sato, Mahdi Ghani, and Ekaterina Rogaeva
- Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
We reviewed factors that might influence COVID-19 outcomes (eg, neurological symptoms), including the link to Alzheimer’s disease. Since the virus triggers COVID-19 infection through binding to ACE2, we focused on the ACE2 gene family, including ACE . Both ACE2 and ACE are involved in the renin–angiotensin system (RAS). In general, ACE causes inflammation and vasoconstriction, while ACE2 leads to anti-inflammation activity and vasodilation. The disturbed balance between these counter-regulatory pathways could influence susceptibility to COVID-19. Notably, dysregulation of the RAS-equilibrium contributes to Alzheimer’s disease. Differences in the incidence and symptoms of COVID-19 in diverse populations could be attributed to variability in the human genome. For example, ACE and ACE2 variations could modify the outcome of COVID-19 in different populations. It would be important to conduct genome-wide studies to detect variants influencing COVID-19 presentation, with a special focus on variants affecting immune-related pathways and expression of RAS-related genes.
- Published
- 2020
- Full Text
- View/download PDF
16. DNA Methylation Clocks and Their Predictive Capacity for Aging Phenotypes and Healthspan
- Author
-
Tessa Bergsma and Ekaterina Rogaeva
- Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The number of age predictors based on DNA methylation (DNAm) profile is rising due to their potential in predicting healthspan and application in age-related illnesses, such as neurodegenerative diseases. The cumulative assessment of DNAm levels at age-related CpGs (DNAm clock) may reflect biological aging. Such DNAm clocks have been developed using various training models and could mirror different aspects of disease/aging mechanisms. Hence, evaluating several DNAm clocks together may be the most effective strategy in capturing the complexity of the aging process. However, various confounders may influence the outcome of these age predictors, including genetic and environmental factors, as well as technical differences in the selected DNAm arrays. These factors should be taken into consideration when interpreting DNAm clock predictions. In the current review, we discuss 15 reported DNAm clocks with consideration for their utility in investigating neurodegenerative diseases and suggest research directions towards developing a more optimal measure for biological aging.
- Published
- 2020
- Full Text
- View/download PDF
17. Interaction of APOE4 alleles and PET tau imaging in former contact sport athletes
- Author
-
Anna Vasilevskaya, Foad Taghdiri, Charles Burke, Apameh Tarazi, Seyed Ali Naeimi, Mozghan Khodadadi, Ruma Goswami, Christine Sato, Mark Grinberg, Danielle Moreno, Richard Wennberg, David Mikulis, Robin Green, Brenda Colella, Karen D. Davis, Pablo Rusjan, Sylvain Houle, Charles Tator, Ekaterina Rogaeva, and Maria C. Tartaglia
- Subjects
Concussion ,Apoe4 ,Positron emission tomography ,Tau ,Chronic traumatic encephalopathy ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Background: Genetic polymorphisms like apolipoprotein E (APOE) and microtubule-associated protein tau (MAPT) genes increase the risk of neurodegeneration. Methods: 38 former players (age 52.63±14.02) of contact sports underwent neuroimaging, biofluid collection, and comprehensive neuropsychological assessment. The [F-18]AV-1451 tracer signal was compared in the cortical grey matter between APOE4 allele carriers and non-carriers as well as carriers of MAPT H1H1 vs non-H1H1. Participants were then divided into the high (N = 13) and low (N = 13) groups based on cortical PET tau standard uptake value ratios (SUVRs) for comparison. Findings: Cortical grey matter PET tau SUVR values were significantly higher in APOE4 carriers compared to non-carriers (p = 0.020). In contrast, there was no significant difference in SUVR between MAPT H1H1 vs non-H1H1 carrier genes (p = 1.00). There was a significantly higher APOE4 allele frequency in the high cortical grey matter PET tau group, comparing to low cortical grey matter PET tau group (p = 0.048). No significant difference in neuropsychological function was found between APOE4 allele carriers and non-carriers. Interpretation: There is an association between higher cortical grey matter tau burden as seen with [F-18]AV-1451 PET tracer SUVR, and the APOE4 allele in former professional and semi-professional players at high risk of concussions. APOE4 allele may be a risk factor for tau accumulation in former contact sports athletes at high risk of neurodegeneration. Funding: Toronto General and Western Hospital Foundations; Weston Brain Institute; Canadian Consortium on Neurodegeneration in ageing; Krembil Research Institute. There was no role of the funders in this study.
- Published
- 2020
- Full Text
- View/download PDF
18. A complex of C9ORF72 and p62 uses arginine methylation to eliminate stress granules by autophagy
- Author
-
Maneka Chitiprolu, Chantal Jagow, Veronique Tremblay, Emma Bondy-Chorney, Geneviève Paris, Alexandre Savard, Gareth Palidwor, Francesca A. Barry, Lorne Zinman, Julia Keith, Ekaterina Rogaeva, Janice Robertson, Mathieu Lavallée-Adam, John Woulfe, Jean-François Couture, Jocelyn Côté, and Derrick Gibbings
- Subjects
Science - Abstract
Many Amyotrophic Lateral Sclerosis (ALS)-linked mutations cause accumulation of stress granules, and most ALS cases are caused by repeat expansions in C9ORF72. Here the authors show that C9ORF72 and the autophagy receptor p62 interact to associate with proteins symmetrically dimethylated on arginines such as FUS, to eliminate stress granules by autophagy.
- Published
- 2018
- Full Text
- View/download PDF
19. The relationship between brain atrophy and cognitive-behavioural symptoms in retired Canadian football players with multiple concussions
- Author
-
Karen Misquitta, Mahsa Dadar, Apameh Tarazi, Mohammed W. Hussain, Mohammed K. Alatwi, Ahmed Ebraheem, Namita Multani, Mozhgan Khodadadi, Ruma Goswami, Richard Wennberg, Charles Tator, Robin Green, Brenda Colella, Karen Deborah Davis, David Mikulis, Mark Grinberg, Christine Sato, Ekaterina Rogaeva, D. Louis Collins, and Maria Carmela Tartaglia
- Subjects
Computer applications to medicine. Medical informatics ,R858-859.7 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Multiple concussions, particularly in contact sports, have been associated with cognitive deficits, psychiatric impairment and neurodegenerative diseases like chronic traumatic encephalopathy. We used volumetric and deformation-based morphometric analyses to test the hypothesis that repeated concussions may be associated with smaller regional brain volumes, poorer cognitive performance and behavioural symptoms among former professional football players compared to healthy controls. This study included fifty-three retired Canadian Football League players, 25 age- and education-matched healthy controls, and controls from the Cambridge Centre for Aging and Neuroscience database for validation. Volumetric analyses revealed greater hippocampal atrophy than expected for age in former athletes with multiple concussions than controls and smaller left hippocampal volume was associated with poorer verbal memory performance in the former athletes. Deformation-based morphometry confirmed smaller bilateral hippocampal volume that was associated with poorer verbal memory performance in athletes. Repeated concussions may lead to greater regional atrophy than expected for age. Keywords: Sport-related concussion, Mild traumatic brain injury, Deformation based morphometry, Aging
- Published
- 2018
- Full Text
- View/download PDF
20. Clinical and neuropathological features of ALS/FTD with TIA1 mutations
- Author
-
Veronica Hirsch-Reinshagen, Cyril Pottier, Alexandra M. Nicholson, Matt Baker, Ging-Yuek R. Hsiung, Charles Krieger, Pheth Sengdy, Kevin B. Boylan, Dennis W. Dickson, Marsel Mesulam, Sandra Weintraub, Eileen Bigio, Lorne Zinman, Julia Keith, Ekaterina Rogaeva, Sasha A. Zivkovic, David Lacomis, J. Paul Taylor, Rosa Rademakers, and Ian R. A. Mackenzie
- Subjects
Amyotrophic lateral sclerosis ,Frontotemporal dementia ,Frontotemporal lobar degeneration ,T-cell restricted intracellular antigen-1 ,TDP-43 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Mutations in the stress granule protein T-cell restricted intracellular antigen 1 (TIA1) were recently shown to cause amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). Here, we provide detailed clinical and neuropathological descriptions of nine cases with TIA1 mutations, together with comparisons to sporadic ALS (sALS) and ALS due to repeat expansions in C9orf72 (C9orf72+). All nine patients with confirmed mutations in TIA1 were female. The clinical phenotype was heterogeneous with a range in the age at onset from late twenties to the eighth decade (mean = 60 years) and disease duration from one to 6 years (mean = 3 years). Initial presentation was either focal weakness or language impairment. All affected individuals received a final diagnosis of ALS with or without FTD. No psychosis or parkinsonism was described. Neuropathological examination on five patients found typical features of ALS and frontotemporal lobar degeneration (FTLD-TDP, type B) with anatomically widespread TDP-43 proteinopathy. In contrast to C9orf72+ cases, caudate atrophy and hippocampal sclerosis were not prominent. Detailed evaluation of the pyramidal motor system found a similar degree of neurodegeneration and TDP-43 pathology as in sALS and C9orf72+ cases; however, cases with TIA1 mutations had increased numbers of lower motor neurons containing round eosinophilic and Lewy body-like inclusions on HE stain and round compact cytoplasmic inclusions with TDP-43 immunohistochemistry. Immunohistochemistry and immunofluorescence failed to demonstrate any labeling of inclusions with antibodies against TIA1. In summary, our TIA1 mutation carriers developed ALS with or without FTD, with a wide range in age at onset, but without other neurological or psychiatric features. The neuropathology was characterized by widespread TDP-43 pathology, but a more restricted pattern of neurodegeneration than C9orf72+ cases. Increased numbers of round eosinophilic and Lewy-body like inclusions in lower motor neurons may be a distinctive feature of ALS caused by TIA1 mutations.
- Published
- 2017
- Full Text
- View/download PDF
21. White matter hyperintensities are seen only in GRN mutation carriers in the GENFI cohort
- Author
-
Carole H. Sudre, Martina Bocchetta, David Cash, David L. Thomas, Ione Woollacott, Katrina M. Dick, John van Swieten, Barbara Borroni, Daniela Galimberti, Mario Masellis, Maria Carmela Tartaglia, James B. Rowe, Caroline Graff, Fabrizio Tagliavini, Giovanni Frisoni, Robert Laforce, Jr, Elizabeth Finger, Alexandre de Mendonça, Sandro Sorbi, Sébastien Ourselin, M. Jorge Cardoso, Jonathan D. Rohrer, Christin Andersson, Silvana Archetti, Andrea Arighi, Luisa Benussi, Giuliano Binetti, Sandra Black, Maura Cosseddu, Marie Fallström, Carlos Ferreira, Chiara Fenoglio, Nick C. Fox, Morris Freedman, Giorgio Fumagalli, Stefano Gazzina, Roberta Ghidoni, Marina Grisoli, Vesna Jelic, Lize Jiskoot, Ron Keren, Gemma Lombardi, Carolina Maruta, Simon Mead, Lieke Meeter, Rick van Minkelen, Benedetta Nacmias, Linn Öijerstedt, Alessandro Padovani, Jessica Panman, Michela Pievani, Cristina Polito, Enrico Premi, Sara Prioni, Rosa Rademakers, Veronica Redaelli, Ekaterina Rogaeva, Giacomina Rossi, Martin N. Rossor, Elio Scarpini, David Tang-Wai, Hakan Thonberg, Pietro Tiraboschi, Ana Verdelho, and Jason D. Warren
- Subjects
Computer applications to medicine. Medical informatics ,R858-859.7 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Genetic frontotemporal dementia is most commonly caused by mutations in the progranulin (GRN), microtubule-associated protein tau (MAPT) and chromosome 9 open reading frame 72 (C9orf72) genes. Previous small studies have reported the presence of cerebral white matter hyperintensities (WMH) in genetic FTD but this has not been systematically studied across the different mutations. In this study WMH were assessed in 180 participants from the Genetic FTD Initiative (GENFI) with 3D T1- and T2-weighed magnetic resonance images: 43 symptomatic (7 GRN, 13 MAPT and 23 C9orf72), 61 presymptomatic mutation carriers (25 GRN, 8 MAPT and 28 C9orf72) and 76 mutation negative non-carrier family members. An automatic detection and quantification algorithm was developed for determining load, location and appearance of WMH. Significant differences were seen only in the symptomatic GRN group compared with the other groups with no differences in the MAPT or C9orf72 groups: increased global load of WMH was seen, with WMH located in the frontal and occipital lobes more so than the parietal lobes, and nearer to the ventricles rather than juxtacortical. Although no differences were seen in the presymptomatic group as a whole, in the GRN cohort only there was an association of increased WMH volume with expected years from symptom onset. The appearance of the WMH was also different in the GRN group compared with the other groups, with the lesions in the GRN group being more similar to each other. The presence of WMH in those with progranulin deficiency may be related to the known role of progranulin in neuroinflammation, although other roles are also proposed including an effect on blood-brain barrier permeability and the cerebral vasculature. Future studies will be useful to investigate the longitudinal evolution of WMH and their potential use as a biomarker as well as post-mortem studies investigating the histopathological nature of the lesions.
- Published
- 2017
- Full Text
- View/download PDF
22. Epigenetic Clock Acceleration Is Linked to Age at Onset of Parkinson's Disease
- Author
-
Xuelin Tang, Paulina Gonzalez‐Latapi, Connie Marras, Naomi P. Visanji, Wanli Yang, Christine Sato, Anthony E. Lang, Ekaterina Rogaeva, and Ming Zhang
- Subjects
Adult ,Epigenomics ,Neurology ,Acceleration ,Mutation ,Humans ,Parkinson Disease ,Neurology (clinical) ,Age of Onset ,Middle Aged ,Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ,Aged ,Epigenesis, Genetic - Abstract
Aging is the strongest risk factor for Parkinson's disease (PD), which is a clinically heterogeneous movement disorder with highly variable age at onset. DNA methylation age (DNAm age) is an epigenetic clock that could reflect biological aging.The aim was to evaluate whether PD age at onset is associated with DNAm-age acceleration (difference between DNAm age and chronological age).We used the genome-wide Infinium MethylationEPIC array to assess DNAm age in discovery (n = 96) and replication (n = 182) idiopathic PD cohorts and a unique longitudinal LRRK2 cohort (n = 220) at four time points over a 3-year period, comprising 91 manifesting and 129 nonmanifesting G2019S carriers at baseline. Cox proportional hazard regression and multivariate linear regression were used to evaluate the relation between DNAm-age acceleration and PD age at onset, which was highly variable in manifesting G2019S carriers (36-75 years) and both idiopathic PD cohorts (26-77 and 35-81 years).DNAm-age acceleration remained steady over the 3-year period in most G2019S carriers. It was strongly associated with age at onset in the LRRK2 cohort (P = 2.25 × 10This study is the first to demonstrate that DNAm-age acceleration is related to PD age at onset, which could be considered in disease-modifying clinical trials. Future studies should evaluate the stability of DNAm-age acceleration over longer time periods, especially for phenoconverters from nonmanifesting to manifesting individuals. © 2022 International Parkinson and Movement Disorder Society.
- Published
- 2022
23. Epigenetic clock acceleration is linked to earlier onset and phenoconversion age in REM sleep behavior disorder
- Author
-
Konstantin Senkevich, Amélie Pelletier, Christine Sato, Allison Keil, Ziv Gan-Or, Anthony E. Lang, Ronald Postuma, and Ekaterina Rogaeva
- Abstract
Rapid-eye movement sleep behavior disorder (RBD) is the strongest prodromal marker for α-synucleinopathies. The Horvath DNA-methylation-age (DNAm-age) is an epigenetic clock that could reflect biological aging. We evaluated whether RBD age-at-onset/phenoconversion are associated with DNAm-age-acceleration in 162 RBD patients. We found an association of DNAm-age-acceleration with RBD age-at-onset at baseline (P=2.59e-08) and at follow-up (N=45; P=9.73e-06). RBD patients with faster aging had 4.6 years earlier onset than patients with slow/normal aging. Similarly, earlier age-at-phenoconversion was associated with DNAm-age-acceleration (N=53; P=1.26e-04). We demonstrated that epigenetic clock acceleration is linked with an earlier RBD age-at-onset and, hence with earlier phenoconversion.
- Published
- 2023
24. <scp>MicroRNA</scp> ‐128 suppresses tau phosphorylation and reduces amyloid‐beta accumulation by inhibiting the expression of <scp>GSK3β</scp> , <scp>APPBP2</scp> , and <scp>mTOR</scp> in Alzheimer's disease
- Author
-
Siwen Li, Chi Him Poon, Zhigang Zhang, Ming Yue, Ruijun Chen, Yalun Zhang, Md. Farhad Hossain, Yining Pan, Jun Zhao, Lei Rong, Leung Wing Chu, Yat Fung Shea, Ekaterina Rogaeva, Jie Tu, Peter St George‐Hyslop, Lee Wei Lim, and You‐Qiang Song
- Subjects
Pharmacology ,Psychiatry and Mental health ,Physiology (medical) ,Pharmacology (medical) - Published
- 2023
25. A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia
- Author
-
Ione O.C. Woollacott, Cristina Polito, Philip Van Damme, Mathieu Vandenbulcke, Rose Bruffaerts, Diana Duro, Chiara Fenoglio, David M. Cash, Maria Rosário Almeida, Sonja Schönecker, C. Ferreira, Sónia Afonso, Matthis Synofzik, Sara Prioni, Marta Cañada, Mikel Tainta, Miguel Tábuas-Pereira, Christin Andersson, Caroline Graff, Miguel Castelo-Branco, Enrico Premi, Håkan Thonberg, Fabrizio Tagliavini, Rachelle Shafei, Benjamin Bender, Ana Gorostidi, Maria João Leitão, Jennifer M. Nicholas, Elise G.P. Dopper, Silvana Archetti, Esther E. Bron, Ana Verdelho, Ron Keren, Isabel Santana, Christen Shoesmith, Pietro Tiraboschi, Sergi Borrego-Écija, Michela Pievani, Sandro Sorbi, Rick van Minkelen, Hans-Otto Karnath, Albert Lladó, Caroline V. Greaves, Jaume Olives, Alessandro Padovani, Miren Zulaica, Giuliano Binetti, Martin Rosser, Pedro Rosa-Neto, Vesna Jelic, Alexander Gerhard, Rosa Rademakers, Sandra E. Black, Wiro J. Niessen, Tobias Hoegen, Rhian S Convery, Janne M. Papma, Maria Carmela Tartaglia, Emily Todd, Adrian Danek, Rita Guerreiro, Robart Bartha, Linn Öijerstedt, Giuseppe Di Fede, Sebastien Ourselin, Núria Bargalló, James B. Rowe, Christopher C Butler, Giorgio G. Fumagalli, Valentina Bessi, Alberto Benussi, Nick C. Fox, Beatriz Santiago, Ekaterina Rogaeva, Alazne Gabilondo, Giacomina Rossi, Mircea Balasa, David L. Thomas, Benedetta Nacmias, Veronica Redaelli, Anna Antonell, Vikram Venkatraghavan, Jonathan D. Rohrer, Jackie M. Poos, Yolande A.L. Pijnenburg, Lieke H.H. Meeter, Carlo Wilke, Sandra V. Loosli, Elio Scarpini, Tobias Langheinrich, Alina Díez, Elisa Semler, Elizabeth Finger, Begoña Indakoetxea, Jessica L. Panman, Carolyn Timberlake, Gemma Lombardi, Luisa Benussi, Morris Freedman, Barbara Borroni, Ricardo Taipa, Johannes Levin, Thomas E. Cope, Paul M. Thompson, Giorgio Giaccone, Valentina Cantoni, Arabella Bouzigues, Jose Bras, Serge Gauthier, Andrea Arighi, Stefan Klein, Fermin Moreno, Markus Otto, Georgia Peakman, Emma L. van der Ende, David F. Tang-Wai, Sarah Anderl-Straub, Jason D. Warren, Alexandre de Mendonça, Camilla Ferrari, Elisabeth Wlasich, Catharina Prix, Michele Veldsman, Raquel Sánchez-Valle, Sara Mitchell, Carolina Maruta, Robert Laforce, Paola Caroppo, Jorge Villanua, Imogen J Swift, Harro Seelaar, Henrik Zetterberg, Simon Mead, Simon Ducharme, Myriam Barandiaran, Katrina M. Moore, John C. van Swieten, Gabriel Miltenberger, Mario Masellis, Timothy Rittman, Lize C. Jiskoot, Daniela Galimberti, Rik Vandenberghe, Carolin Heller, Stefano Gazzina, Aitana Sogorb-Esteve, Roberto Gasparotti, Martina Bocchetta, Neurology, Amsterdam Neuroscience - Neurodegeneration, Repositório da Universidade de Lisboa, Radiology & Nuclear Medicine, and Neurosurgery
- Subjects
Oncology ,medicine.medical_specialty ,Medizin ,tau Proteins ,Disease ,medicine.disease_cause ,frontotemporal dementia ,biomarker ,disease progression model ,event-based modelling ,neurofilament light chain ,Biomarkers ,C9orf72 Protein ,Complement C1q ,Cross-Sectional Studies ,Disease Progression ,Glial Fibrillary Acidic Protein ,Humans ,Longitudinal Studies ,Mutation ,Frontotemporal Dementia ,diagnosis [Frontotemporal Dementia] ,Settore BIO/13 - Biologia Applicata ,C9orf72 ,Internal medicine ,Medicine ,ddc:610 ,genetics [C9orf72 Protein] ,genetics [Frontotemporal Dementia] ,business.industry ,medicine.disease ,Astrogliosis ,genetics [tau Proteins] ,Cohort ,Biomarker (medicine) ,Neurology (clinical) ,Sample collection ,business ,Frontotemporal dementia - Abstract
© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com, Several CSF and blood biomarkers for genetic frontotemporal dementia have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain and phosphorylated neurofilament heavy chain), synapse dysfunction [neuronal pentraxin 2 (NPTX2)], astrogliosis (glial fibrillary acidic protein) and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage frontotemporal dementia, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic frontotemporal dementia using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. Two-hundred and seventy-five presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection ('converters'). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialized DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on previous diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF neurofilament light chain, blood phosphorylated neurofilament heavy chain, blood glial fibrillary acidic protein and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The areas under the curve to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic frontotemporal dementia revealed that NPTX2 and neurofilament light chain are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model's ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions., This study was supported in the Netherlands by two Memorabel grants from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland; grant numbers 733050813,733050103 and 733050513), the Bluefield Project to Cure Frontotemporal Dementia, the Dioraphte foundation (grant number 1402 1300), the European Joint Programme—Neurodegenerative Disease Research and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD: 733051024); V.V. and S.K. have received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 666992 (EuroPOND). E.B. was supported by the Hartstichting (PPP Allowance, 2018B011); in Belgium by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie; in the UK by the MRC UK GENFI grant (MR/M023664/1); J.D.R. is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH); I.J.S. is supported by the Alzheimer’s Association; J.B.R. is supported by the Wellcome Trust (103838); in Spain by the Fundació Marató de TV3 (20143810 to R.S.V.); in Germany by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and by grant 779357 ‘Solve-RD’ from the Horizon 2020 Research and Innovation Programme (to MS); in Sweden by grants from the Swedish FTD Initiative funded by the Schörling Foundation, grants from JPND PreFrontALS Swedish Research Council (VR) 529–2014-7504, Swedish Research Council (VR) 2015–02926, Swedish Research Council (VR) 2018–02754, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Swedish Demensfonden, Stohnes foundation, Gamla Tjänarinnor, Karolinska Institutet Doctoral Funding and StratNeuro. H.Z. is a Wallenberg Scholar.
- Published
- 2022
26. Protracted course progressive supranuclear palsy
- Author
-
Blas Couto, Ivan Martinez‐Valbuena, Seojin Lee, Isabel Alfradique‐Dunham, Richard J. Perrin, Joel S. Perlmutter, Carlos Cruchaga, Ain Kim, Naomi Visanji, Christine Sato, Ekaterina Rogaeva, Anthony E. Lang, and Gabor G. Kovacs
- Subjects
Ubiquitin-Protein Ligases ,Glucose Transport Proteins, Facilitative ,tau Proteins ,Polymorphism, Single Nucleotide ,Article ,Tripartite Motif Proteins ,Parkinsonian Disorders ,Tauopathies ,Neurology ,Disease Progression ,Humans ,Supranuclear Palsy, Progressive ,Neurology (clinical) ,Retrospective Studies - Abstract
BACKGROUND AND PURPOSE: Progressive supranuclear palsy (PSP) encompasses a broader range of disease courses than previously appreciated. The most frequent clinical presentations of PSP are Richardson syndrome (RS) and PSP with a predominant Parkinsonism phenotype (PSP-P). Time to reach gait dependence and cognitive impairment have been proposed as prognostic disease milestones. Genetic polymorphisms in TRIM11 and SLC2A13 genes have been associated with longer disease duration (DD). METHODS: Methods used include retrospective chart review, genetic single nucleotide polymorphism analyses (in three cases), and neuropathology. RESULTS: We identified four cases with long (>10–15 years) or very long (>15 years) DD. Stage 1 PSP tau pathology was present in two cases (one PSP-P and one undifferentiated phenotype), whereas pallidonigroluysian atrophy (PSP-RS) and Stage 4/6 (PSP-P) PSP pathology were found in the other two cases. Three cases were homozygous for the rs564309-C allele of the TRIM11 gene and the H1 MAPT haplotype. Two were heterozygous for rs2242367 (G/A) in SLC2A13, whereas the third was homozygous for the G-allele. CONCLUSIONS: We propose a protracted course subtype of PSP (PC-PSP) based on clinical or neuropathological criteria in two cases with anatomically restricted PSP pathology, and very long DD and slower clinical progression in the other two cases. The presence of the rs564309-C allele may influence the protracted disease course. Crystallizing the concept of PC-PSP is important to further understand the pathobiology of tauopathies in line with current hypotheses of protein misfolding, seeding activity, and propagation.
- Published
- 2022
27. New insights into the genetic etiology of Alzheimer's disease and related dementias
- Author
-
Bellenguez, C., Küçükali, F., Jansen, I. E., Kleineidam, L., Moreno-Grau, S., Amin, N., Naj, A. C., Campos-Martin, R., Grenier-Boley, B., Andrade, V., Holmans, P. A., Boland, A., Damotte, V., van der Lee, S. J., Costa, M. R., Kuulasmaa, T., Yang, Q., de Rojas, I., Bis, J. C., Yaqub, A., Prokic, I., Chapuis, J., Ahmad, S., Giedraitis, V., Aarsland, D., Garcia-Gonzalez, P., Abdelnour, C., Alarcón-Martín, E., Alcolea, D., Alegret, M., Alvarez, I., Álvarez, V., Armstrong, N. J., Tsolaki, A., Antúnez, C., Appollonio, I., Arcaro, M., Archetti, S., Pastor, A. A., Arosio, B., Athanasiu, L., Bailly, H., Banaj, N., Baquero, M., Barral, S., Beiser, A., Pastor, A. B., Below, J. E., Benchek, P., Benussi, L., Berr, C., Besse, C., Bessi, V., Binetti, G., Bizarro, A., Blesa, R., Boada, M., Boerwinkle, E., Borroni, B., Boschi, S., Bossù, P., Bråthen, G., Bressler, J., Bresner, C., Brodaty, H., Brookes, K. J., Brusco, L. I., Buiza-Rueda, D., Bûrger, K., Burholt, V., Bush, W. S., Calero, M., Cantwell, L. B., Chene, G., Chung, J., Cuccaro, M. L., Carracedo, Á., Cecchetti, R., Cervera-Carles, L., Charbonnier, C., Chen, H. -H., Chillotti, C., Ciccone, S., Claassen, J. A. H. R., Clark, C., Conti, E., Corma-Gómez, A., Costantini, E., Custodero, C., Daian, D., Dalmasso, M. C., Daniele, A., Dardiotis, E., Dartigues, J. -F., de Deyn, P. P., de Paiva Lopes, K., de Witte, L. D., Debette, S., Deckert, J., del Ser, T., Denning, N., Destefano, A., Dichgans, M., Diehl-Schmid, J., Diez-Fairen, M., Rossi, P. D., Djurovic, S., Duron, E., Düzel, E., Dufouil, C., Eiriksdottir, G., Engelborghs, S., Escott-Price, V., Espinosa, A., Ewers, M., Faber, K. M., Fabrizio, T., Nielsen, S. F., Fardo, D. W., Farotti, L., Fenoglio, C., Fernández-Fuertes, M., Ferrari, R., Ferreira, C. B., Ferri, E., Fin, B., Fischer, P., Fladby, T., Fließbach, K., Fongang, B., Fornage, M., Fortea, J., Foroud, T. M., Fostinelli, S., Fox, N. C., Franco-Macías, E., Bullido, M. J., Frank-García, A., Froelich, L., Fulton-Howard, B., Galimberti, D., García-Alberca, J. M., García-González, P., Garcia-Madrona, S., Garcia-Ribas, G., Ghidoni, R., Giegling, I., Giorgio, G., Goate, A. M., Goldhardt, O., Gomez-Fonseca, D., González-Pérez, A., Graff, C., Grande, G., Green, E., Grimmer, T., Grünblatt, E., Grunin, M., Gudnason, V., Guetta-Baranes, T., Haapasalo, A., Hadjigeorgiou, G., Haines, J. L., Hamilton-Nelson, K. L., Hampel, H., Hanon, O., Hardy, J., Hartmann, A. M., Hausner, L., Harwood, J., Heilmann-Heimbach, S., Helisalmi, S., Heneka, M. T., Hernández, I., Herrmann, M. J., Hoffmann, P., Holmes, C., Holstege, H., Vilas, R. H., Hulsman, M., Humphrey, J., Biessels, G. J., Jian, X., Johansson, C., Jun, G. R., Kastumata, Y., Kauwe, J., Kehoe, P. G., Kilander, L., Ståhlbom, A. K., Kivipelto, M., Koivisto, A., Kornhuber, J., Kosmidis, M. H., Kukull, W. A., Kuksa, P. P., Kunkle, B. W., Kuzma, A. B., Lage, C., Laukka, E. J., Launer, L., Lauria, A., Lee, C. -Y., Lehtisalo, J., Lerch, O., Lleó, A., Longstreth, W., Lopez, O., de Munain, A. L., Love, S., Löwemark, M., Luckcuck, L., Lunetta, K. L., Ma, Y., Macías, J., Macleod, C. A., Maier, W., Mangialasche, F., Spallazzi, M., Marquié, M., Marshall, R., Martin, E. R., Montes, A. M., Rodríguez, C. M., Masullo, C., Mayeux, R., Mead, S., Mecocci, P., Medina, M., Meggy, A., Mehrabian, S., Mendoza, S., Menéndez-González, M., Mir, P., Moebus, S., Mol, M., Molina-Porcel, L., Montrreal, L., Morelli, L., Moreno, F., Morgan, K., Mosley, T., Nöthen, M. M., Muchnik, C., Mukherjee, S., Nacmias, B., Ngandu, T., Nicolas, G., Nordestgaard, B. G., Olaso, R., Orellana, A., Orsini, M., Ortega, G., Padovani, A., Paolo, C., Papenberg, G., Parnetti, L., Pasquier, F., Pastor, P., Peloso, G., Pérez-Cordón, A., Pérez-Tur, J., Pericard, P., Peters, O., Pijnenburg, Y. A. L., Pineda, J. A., Piñol-Ripoll, G., Pisanu, C., Polak, T., Popp, J., Posthuma, D., Priller, J., Puerta, R., Quenez, O., Quintela, I., Thomassen, J. Q., Rábano, A., Rainero, I., Rajabli, F., Ramakers, I., Real, L. M., Reinders, M. J. T., Reitz, C., Reyes-Dumeyer, D., Ridge, P., Riedel-Heller, S., Riederer, P., Roberto, N., Rodriguez-Rodriguez, E., Rongve, A., Allende, I. R., Rosende-Roca, M., Royo, J. L., Rubino, E., Rujescu, D., Sáez, M. E., Sakka, P., Saltvedt, I., Sanabria, Á., Sánchez-Arjona, M. B., Sanchez-Garcia, F., Juan, P. S., Sánchez-Valle, R., Sando, S. B., Sarnowski, C., Satizabal, C. L., Scamosci, M., Scarmeas, N., Scarpini, E., Scheltens, P., Scherbaum, N., Scherer, M., Schmid, M., Schneider, A., Schott, J. M., Selbæk, G., Seripa, D., Serrano, M., Sha, J., Shadrin, A. A., Skrobot, O., Slifer, S., Snijders, G. J. L., Soininen, H., Solfrizzi, V., Solomon, A., Song, Y. E., Sorbi, S., Sotolongo-Grau, O., Spalletta, G., Spottke, A., Squassina, A., Stordal, E., Tartan, J. P., Tárraga, L., Tesí, N., Thalamuthu, A., Thomas, T., Tosto, G., Traykov, L., Tremolizzo, L., Tybjærg-Hansen, A., Uitterlinden, A., Ullgren, A., Ulstein, I., Valero, S., Valladares, O., Broeckhoven, C. V., Vance, J., Vardarajan, B. N., van der Lugt, A., Dongen, J. V., van Rooij, J., van Swieten, J., Vandenberghe, R., Verhey, F., Vidal, J. -S., Vogelgsang, J., Vyhnalek, M., Wagner, M., Wallon, D., Wang, L. -S., Wang, R., Weinhold, L., Wiltfang, J., Windle, G., Woods, B., Yannakoulia, M., Zare, H., Zhao, Y., Zhang, X., Zhu, C., Zulaica, M., Laczo, J., Matoska, V., Serpente, M., Assogna, F., Piras, F., Ciullo, V., Shofany, J., Ferrarese, C., Andreoni, S., Sala, G., Zoia, C. P., Zompo, M. D., Benussi, A., Bastiani, P., Takalo, M., Natunen, T., Laatikainen, T., Tuomilehto, J., Antikainen, R., Strandberg, T., Lindström, J., Peltonen, M., Abraham, R., Al-Chalabi, A., Bass, N. J., Brayne, C., Brown, K. S., Collinge, J., Craig, D., Deloukas, P., Fox, N., Gerrish, A., Gill, M., Gwilliam, R., Harold, D., Hollingworth, P., Johnston, J. A., Jones, L., Lawlor, B., Livingston, G., Lovestone, S., Lupton, M., Lynch, A., Mann, D., Mcguinness, B., Mcquillin, A., O’Donovan, M. C., Owen, M. J., Passmore, P., Powell, J. F., Proitsi, P., Rossor, M., Shaw, C. E., Smith, A. D., Gurling, H., Todd, S., Mummery, C., Ryan, N., Lacidogna, G., Adarmes-Gómez, A., Mauleón, A., Pancho, A., Gailhajenet, A., Lafuente, A., Macias-García, D., Martín, E., Pelejà, E., Carrillo, F., Merlín, I. S., Garrote-Espina, L., Vargas, L., Carrion-Claro, M., Marín, M., Labrador, M., Buendia, M., Alonso, M. D., Guitart, M., Moreno, M., Ibarria, M., Periñán, M., Aguilera, N., Gómez-Garre, P., Cañabate, P., Escuela, R., Pineda-Sánchez, R., Vigo-Ortega, R., Jesús, S., Preckler, S., Rodrigo-Herrero, S., Diego, S., Vacca, A., Roveta, F., Salvadori, N., Chipi, E., Boecker, H., Laske, C., Perneczky, R., Anastasiou, C., Janowitz, D., Malik, R., Anastasiou, A., Parveen, K., López-García, S., Antonell, A., Mihova, K. Y., Belezhanska, D., Weber, H., Kochen, S., Solis, P., Medel, N., Lisso, J., Sevillano, Z., Politis, D. G., Cores, V., Cuesta, C., Ortiz, C., Bacha, J. I., Rios, M., Saenz, A., Abalos, M. S., Kohler, E., Palacio, D. L., Etchepareborda, I., Kohler, M., Novack, G., Prestia, F. A., Galeano, P., Castaño, E. M., Germani, S., Toso, C. R., Rojo, M., Ingino, C., Mangone, C., Rubinsztein, D. C., Teipel, S., Fievet, N., Deramerourt, V., Forsell, C., Thonberg, H., Bjerke, M., Roeck, E. D., Martínez-Larrad, M. T., Olivar, N., Cano, A., Macias, J., Maroñas, O., Nuñez-Llaves, R., Olivé, C., Adarmes-Gómez, A. D., Amer-Ferrer, G., Antequera, M., Burguera, J. A., Casajeros, M. J., Martinez de Pancorbo, M., Hevilla, S., Espinosa, M. A. L., Legaz, A., Manzanares, S., Marín-Muñoz, J., Marín, T., Martínez, B., Martínez, V., Martínez-Lage Álvarez, P., Iriarte, M. M., Periñán-Tocino, M. T., Real de Asúa, D., Rodrigo, S., Sastre, I., Vicente, M. P., Vivancos, L., Epelbaum, J., Hannequin, D., Campion, D., Deramecourt, V., Tzourio, C., Brice, A., Dubois, B., Williams, A., Thomas, C., Davies, C., Nash, W., Dowzell, K., Morales, A. C., Bernardo-Harrington, M., Turton, J., Lord, J., Brown, K., Vardy, E., Fisher, E., Warren, J. D., Ryan, N. S., Guerreiro, R., Uphill, J., Bass, N., Heun, R., Kölsch, H., Schürmann, B., Lacour, A., Herold, C., Powell, J., Patel, Y., Hodges, A., Becker, T., Warden, D., Wilcock, G., Clarke, R., Ben-Shlomo, Y., Hooper, N. M., Pickering-Brown, S., Sussams, R., Warner, N., Bayer, A., Heuser, I., Drichel, D., Klopp, N., Mayhaus, M., Riemenschneider, M., Pinchler, S., Feulner, T., Gu, W., van den Bussche, H., Hüll, M., Frölich, L., Wichmann, H. -E., Jöckel, K. -H., O’Donovan, M., Owen, M., Bahrami, S., Bosnes, I., Selnes, P., Bergh, S., Palotie, A., Daly, M., Jacob, H., Matakidou, A., Runz, H., John, S., Plenge, R., Mccarthy, M., Hunkapiller, J., Ehm, M., Waterworth, D., Fox, C., Malarstig, A., Klinger, K., Call, K., Behrens, T., Loerch, P., Mäkelä, T., Kaprio, J., Virolainen, P., Pulkki, K., Kilpi, T., Perola, M., Partanen, J., Pitkäranta, A., Kaarteenaho, R., Vainio, S., Turpeinen, M., Serpi, R., Laitinen, T., Mäkelä, J., Kosma, V. -M., Kujala, U., Tuovila, O., Hendolin, M., Pakkanen, R., Waring, J., Riley-Gillis, B., Liu, J., Biswas, S., Diogo, D., Marshall, C., Hu, X., Gossel, M., Graham, R., Cummings, B., Ripatti, S., Schleutker, J., Arvas, M., Carpén, O., Hinttala, R., Kettunen, J., Mannermaa, A., Laukkanen, J., Julkunen, V., Remes, A., Kälviäinen, R., Peltola, J., Tienari, P., Rinne, J., Ziemann, A., Esmaeeli, S., Smaoui, N., Lehtonen, A., Eaton, S., Lahdenperä, S., van Adelsberg, J., Michon, J., Kerchner, G., Bowers, N., Teng, E., Eicher, J., Mehta, V., Gormley, P., Linden, K., Whelan, C., Xu, F., Pulford, D., Färkkilä, M., Pikkarainen, S., Jussila, A., Blomster, T., Kiviniemi, M., Voutilainen, M., Georgantas, B., Heap, G., Rahimov, F., Usiskin, K., Lu, T., Oh, D., Kalpala, K., Miller, M., Mccarthy, L., Eklund, K., Palomäki, A., Isomäki, P., Pirilä, L., Kaipiainen-Seppänen, O., Huhtakangas, J., Lertratanakul, A., Hochfeld, M., Bing, N., Gordillo, J. E., Mars, N., Pelkonen, M., Kauppi, P., Kankaanranta, H., Harju, T., Close, D., Greenberg, S., Chen, H., Betts, J., Ghosh, S., Salomaa, V., Niiranen, T., Juonala, M., Metsärinne, K., Kähönen, M., Junttila, J., Laakso, M., Pihlajamäki, J., Sinisalo, J., Taskinen, M. -R., Tuomi, T., Challis, B., Peterson, A., Chu, A., Parkkinen, J., Muslin, A., Joensuu, H., Meretoja, T., Aaltonen, L., Mattson, J., Auranen, A., Karihtala, P., Kauppila, S., Auvinen, P., Elenius, K., Popovic, R., Schutzman, J., Loboda, A., Chhibber, A., Lehtonen, H., Mcdonough, S., Crohns, M., Kulkarni, D., Kaarniranta, K., Turunen, J. A., Ollila, T., Seitsonen, S., Uusitalo, H., Aaltonen, V., Uusitalo-Järvinen, H., Luodonpää, M., Hautala, N., Loomis, S., Strauss, E., Podgornaia, A., Hoffman, J., Tasanen, K., Huilaja, L., Hannula-Jouppi, K., Salmi, T., Peltonen, S., Koulu, L., Harvima, I., Wu, Y., Choy, D., Pussinen, P., Salminen, A., Salo, T., Rice, D., Nieminen, P., Palotie, U., Siponen, M., Suominen, L., Mäntylä, P., Gursoy, U., Anttonen, V., Sipilä, K., Davis, J. W., Quarless, D., Petrovski, S., Wigmore, E., Chen, C. -Y., Bronson, P., Tsai, E., Huang, Y., Maranville, J., Shaikho, E., Mohammed, E., Wadhawan, S., Kvikstad, E., Caliskan, M., Chang, D., Bhangale, T., Pendergrass, S., Holzinger, E., Chen, X., Hedman, Å., King, K. S., Wang, C., Xu, E., Auge, F., Chatelain, C., Rajpal, D., Liu, D., Xia, T. -H., Brauer, M., Kurki, M., Karjalainen, J., Havulinna, A., Jalanko, A., Palta, P., della Briotta Parolo, P., Zhou, W., Lemmelä, S., Rivas, M., Harju, J., Lehisto, A., Ganna, A., Llorens, V., Laivuori, H., Rüeger, S., Niemi, M. E., Tukiainen, T., Reeve, M. P., Heyne, H., Palin, K., Garcia-Tabuenca, J., Siirtola, H., Kiiskinen, T., Lee, J., Tsuo, K., Elliott, A., Kristiansson, K., Hyvärinen, K., Ritari, J., Koskinen, M., Pylkäs, K., Kalaoja, M., Karjalainen, M., Mantere, T., Kangasniemi, E., Heikkinen, S., Laakkonen, E., Sipeky, C., Heron, S., Karlsson, A., Jambulingam, D., Rathinakannan, V. S., Kajanne, R., Aavikko, M., Jiménez, M. G., della Briotta Parola, P., Kanai, M., Kaunisto, M., Kilpeläinen, E., Sipilä, T. P., Brein, G., Awaisa, G., Shcherban, A., Donner, K., Loukola, A., Laiho, P., Sistonen, T., Kaiharju, E., Laukkanen, M., Järvensivu, E., Lähteenmäki, S., Männikkö, L., Wong, R., Mattsson, H., Hiekkalinna, T., Paajanen, T., Pärn, K., Gracia-Tabuenca, J., Abner, E., Adams, P. M., Aguirre, A., Albert, M. S., Albin, R. L., Allen, M., Alvarez, L., Apostolova, L. G., Arnold, S. E., Asthana, S., Atwood, C. S., Ayres, G., Baldwin, C. T., Barber, R. C., Barnes, L. L., Beach, T. G., Becker, J. T., Beecham, G. W., Beekly, D., Benitez, B. A., Bennett, D., Bertelson, J., Margaret, F. E., Bird, T. D., Blacker, D., Boeve, B. F., Bowen, J. D., Boxer, A., Brewer, J., Burke, J. R., Burns, J. M., Buxbaum, J. D., Cairns, N. J., Cao, C., Carlson, C. S., Carlsson, C. M., Carney, R. M., Carrasquillo, M. M., Chasse, S., Chesselet, M. -F., Chesi, A., Chin, N. A., Chui, H. C., Craft, S., Crane, P. K., Cribbs, D. H., Crocco, E. A., Cruchaga, C., Cullum, M., Darby, E., Davis, B., De Jager, P. L., Decarli, C., Detoledo, J., Dick, M., Dickson, D. W., Dombroski, B. A., Doody, R. S., Duara, R., Ertekin-Taner, N., Evans, D. A., Fairchild, T. J., Fallon, K. B., Farlow, M. R., Farrell, J. J., Fernandez-Hernandez, V., Ferris, S., Frosch, M. P., Galasko, D. R., Gamboa, A., Gearing, M., Geschwind, D. H., Ghetti, B., Gilbert, J. R., Grabowski, T. J., Graff-Radford, N. R., Grant, S. F. A., Green, R. C., Growdon, J. H., Hakonarson, H., Hall, J., Hamilton, R. L., Harari, O., Harrell, L. E., Haut, J., Head, E., Henderson, V. W., Hernandez, M., Hohman, T., Honig, L. S., Huebinger, R. M., Huentelman, M. J., Hulette, C. M., Hyman, B. T., Hynan, L. S., Ibanez, L., Jarvik, G. P., Jayadev, S., Jin, L. -W., Johnson, K., Johnson, L., Kamboh, M. I., Karydas, A. M., Katz, M. J., Kaye, J. A., Keene, C. D., Khaleeq, A., Kim, R., Knebl, J., Kowall, N. W., Kramer, J. H., Laferla, F. M., Lah, J. J., Larson, E. B., Lee, E. B., Lerner, A., Leung, Y. Y., Leverenz, J. B., Levey, A. I., Li, M., Lieberman, A. P., Lipton, R. B., Logue, M., Lyketsos, C. G., Malamon, J., Mains, D., Marson, D. C., Martiniuk, F., Mash, D. C., Masliah, E., Massman, P., Masurkar, A., Mccormick, W. C., Mccurry, S. M., Mcdavid, A. N., Mckee, A. C., Mesulam, M., Mez, J., Miller, B. L., Miller, C. A., Miller, J. W., Montine, T. J., Monuki, E. S., Morris, J. C., Myers, A. J., Nguyen, T., O’Bryant, S., Olichney, J. M., Ory, M., Palmer, R., Parisi, J. E., Paulson, H. L., Pavlik, V., Paydarfar, D., Perez, V., Peskind, E., Petersen, R. C., Phillips-Cremins, J. E., Pierce, A., Polk, M., Poon, W. W., Potter, H., Qu, L., Quiceno, M., Quinn, J. F., Raj, A., Raskind, M., Reiman, E. M., Reisberg, B., Reisch, J. S., Ringman, J. M., Roberson, E. D., Rodriguear, M., Rogaeva, E., Rosen, H. J., Rosenberg, R. N., Royall, D. R., Sager, M. A., Sano, M., Saykin, A. J., Schneider, J. A., Schneider, L. S., Seeley, W. W., Small, S., Smith, A. G., Smith, J. P., Sonnen, J. A., Spina, S., George-Hyslop, P. S., Stern, R. A., Stevens, A. B., Strittmatter, S. M., Sultzer, D., Swerdlow, R. H., Tanzi, R. E., Tilson, J. L., Trojanowski, J. Q., Troncoso, J. C., Tsuang, D. W., Van Deerlin, V. M., van Eldik, L. J., Vassar, R., Vinters, H. V., Vonsattel, J. -P., Weintraub, S., Welsh-Bohmer, K. A., Whitehead, P. L., Wijsman, E. M., Wilhelmsen, K. C., Williams, B., Williamson, J., Wilms, H., Wingo, T. S., Wisniewski, T., Woltjer, R. L., Woon, M., Wright, C. B., C. -K., Wu, Younkin, S. G., C. -E., Yu, Yu, L., Zhang, Y., Zhu, X., Adams, H., Akinyemi, R. O., Ali, M., Armstrong, N., Aparicio, H. J., Bahadori, M., Breteler, M., Chasman, D., Chauhan, G., Comic, H., Cox, S., Cupples, A. L., Davies, G., Decarli, C. S., Duperron, M. -G., Dupuis, J., Evans, T., Fan, F., Fitzpatrick, A., Fohner, A. E., Ganguli, M., Geerlings, M., Glatt, S. J., Gonzalez, H. M., Goss, M., Grabe, H., Habes, M., Heckbert, S. R., Hofer, E., Hong, E., Hughes, T., Kautz, T. F., Knol, M., Kremen, W., Lacaze, P., Lahti, J., Grand, Q. L., Litkowski, E., Li, S., Liu, X., Loitfelder, M., Manning, A., Maillard, P., Marioni, R., Mazoyer, B., van Lent, D. M., Mei, H., Mishra, A., Nyquist, P., O’Connell, J., Paus, T., Pausova, Z., Raikkonen-Talvitie, K., Riaz, M., Rich, S., Rotter, J., Romero, J., Roshchupkin, G., Saba, Y., Sargurupremraj, M., Schmidt, H., Schmidt, R., Shulman, J. M., Smith, J., Sekhar, H., Rajula, R., Shin, J., Simino, J., Sliz, E., Teumer, A., Thomas, A., Tin, A., Tucker-Drob, E., Vojinovic, D., Wang, Y., Weinstein, G., Williams, D., Wittfeld, K., Yanek, L., Yang, Y., Farrer, L. A., Psaty, B. M., Ghanbari, M., Raj, T., Sachdev, P., Mather, K., Jessen, F., Ikram, M. A., de Mendonça, A., Hort, J., Tsolaki, M., Pericak-Vance, M. A., Amouyel, P., Williams, J., Frikke-Schmidt, R., Clarimon, J., Deleuze, J. -F., Rossi, G., Seshadri, S., Andreassen, O. A., Ingelsson, M., Hiltunen, M., Sleegers, K., Schellenberg, G. D., van Duijn, C. M., Sims, R., van der Flier, W. M., Ruiz, A., Ramirez, A., Lambert J., -C, Jan, Laczo, Vaclav, Matoska, Maria, Serpente, Francesca, Assogna, Fabrizio, Piras, Federica, Piras, Valentina, Ciullo, Jacob, Shofany, Carlo, Ferrarese, Simona, Andreoni, Gessica, Sala, Chiara Paola Zoia, Maria Del Zompo, Benussi, Alberto, Patrizia, Bastiani, Mari, Takalo, Teemu, Natunen, Tiina, Laatikainen, Jaakko, Tuomilehto, Riitta, Antikainen, Timo, Strandberg, Jaana, Lindström, Markku, Peltonen, Richard, Abraham, Ammar, Al-Chalabi, Nicholas, J Bass, Carol, Brayne, Kristelle, S Brown, John, Collinge, David, Craig, Pangiotis, Deloukas, Nick, Fox, Amy, Gerrish, Michael, Gill, Rhian, Gwilliam, Denise, Harold, Paul, Hollingworth, Jarret, A Johnston, Lesley, Jones, Brian, Lawlor, Gill, Livingston, Simon, Lovestone, Michelle, Lupton, Aoibhinn, Lynch, David, Mann, Bernadette, Mcguinness, Andrew, Mcquillin, Michael, C O'Donovan, Michael, J Owen, Peter, Passmore, John, F Powell, Petra, Proitsi, Martin, Rossor, Christopher, E Shaw, A David Smith, Hugh, Gurling, Stephen, Todd, Catherine, Mummery, Nathalie, Ryan, Giordano, Lacidogna, Adarmes-Gómez, Ad, Ana, Mauleón, Ana, Pancho, Anna, Gailhajenet, Asunción, Lafuente, Macias-García, D, Elvira, Martín, Esther, Pelejà, Carrillo, F, Isabel Sastre Merlín, Garrote-Espina, L, Liliana, Vargas, Carrion-Claro, M, Marín, M, Labrador, Ma, Mar, Buendia, María Dolores Alonso, Marina, Guitart, Mariona, Moreno, Marta, Ibarria, Periñán, Mt, Nuria, Aguilera, Gómez-Garre, P, Pilar, Cañabate, Escuela, R, Pineda-Sánchez, R, Vigo-Ortega, R, Jesús, S, Silvia, Preckler, Silvia, Rodrigo-Herrero, Susana, Diego, Alessandro, Vacca, Fausto, Roveta, Nicola, Salvadori, Elena, Chipi, Henning, Boecker, Christoph, Laske, Robert, Perneczky, Costas, Anastasiou, Daniel, Janowitz, Rainer, Malik, Anna, Anastasiou, Kayenat, Parveen, Carmen, Lage, Sara, López-García, Anna, Antonell, Kalina Yonkova Mihova, Diyana, Belezhanska, Heike, Weber, Silvia, Kochen, Patricia, Solis, Nancy, Medel, Julieta, Lisso, Zulma, Sevillano, Daniel, G Politis, Valeria, Cores, Carolina, Cuesta, Cecilia, Ortiz, Juan Ignacio Bacha, Mario, Rios, Aldo, Saenz, Mariana Sanchez Abalos, Eduardo, Kohler, Dana Lis Palacio, Ignacio, Etchepareborda, Matias, Kohler, Gisela, Novack, Federico Ariel Prestia, Pablo, Galeano, Eduardo, M Castaño, Sandra, Germani, Carlos Reyes Toso, Matias, Rojo, Carlos, Ingino, Carlos, Mangone, David, C Rubinsztein, Stefan, Teipel, Nathalie, Fievet, Vincent, Deramerourt, Charlotte, Forsell, Håkan, Thonberg, Maria, Bjerke, Ellen De Roeck, María Teresa Martínez-Larrad, Natividad, Olivar, Amanda, Cano, Juan, Macias, Olalla, Maroñas, Raúl, Nuñez-Llaves, Clàudia, Olivé, Ester, Pelejá, Astrid, D Adarmes-Gómez, Guillermo, Amer-Ferrer, Martirio, Antequera, Juan Andrés Burguera, Fátima, Carrillo, Mario, Carrión-Claro, María José Casajeros, Marian Martinez de Pancorbo, Rocío, Escuela, Lorena, Garrote-Espina, Pilar, Gómez-Garre, Saray, Hevilla, Silvia, Jesús, Miguel Angel Labrador Espinosa, Agustina, Legaz, Daniel, Macias-García, Salvadora, Manzanares, Marta, Marín, Juan, Marín-Muñoz, Tamara, Marín, Begoña, Martínez, Victoriana, Martínez, Pablo Martínez-Lage Álvarez, Maite Mendioroz Iriarte, María Teresa Periñán-Tocino, Rocío, Pineda-Sánchez, Diego Real de Asúa, Silvia, Rodrigo, Isabel, Sastre, Maria Pilar Vicente, Rosario, Vigo-Ortega, Liliana, Vivancos, Jacques, Epelbaum, Didier, Hannequin, Dominique, Campion, Vincent, Deramecourt, Christophe, Tzourio, Alexis, Brice, Bruno, Dubois, Amy, Williams, Charlene, Thomas, Chloe, Davies, William, Nash, Kimberley, Dowzell, Atahualpa Castillo Morales, Mateus, Bernardo-Harrington, James, Turton, Jenny, Lord, Kristelle, Brown, Emma, Vardy, Elizabeth, Fisher, Jason, D Warren, Natalie, S Ryan, Rita, Guerreiro, James, Uphill, Nick, Bass, Reinhard, Heun, Heike, Kölsch, Britta, Schürmann, André, Lacour, Christine, Herold, Janet, A Johnston, John, Powell, Yogen, Patel, Angela, Hodges, Tim, Becker, Donald, Warden, Gordon, Wilcock, Robert, Clarke, Panagiotis, Deloukas, Yoav, Ben-Shlomo, Nigel, M Hooper, Stuart, Pickering-Brown, Rebecca, Sussams, Nick, Warner, Anthony, Bayer, Isabella, Heuser, Dmitriy, Drichel, Norman, Klopp, Manuel, Mayhaus, Matthias, Riemenschneider, Sabrina, Pinchler, Thomas, Feulner, Wei, Gu, Hendrik van den Bussche, Michael, Hüll, Lutz, Frölich, H-Erich, Wichmann, Karl-Heinz, Jöckel, Michael, O'Donovan, Michael, Owen, Shahram, Bahrami, Ingunn, Bosnes, Per, Selnes, Sverre, Bergh, Aarno, Palotie, Mark, Daly, Howard, Jacob, Athena, Matakidou, Heiko, Runz, Sally, John, Robert, Plenge, Mark, Mccarthy, Julie, Hunkapiller, Meg, Ehm, Dawn, Waterworth, Caroline, Fox, Anders, Malarstig, Kathy, Klinger, Kathy, Call, Tim, Behrens, Patrick, Loerch, Tomi, Mäkelä, Jaakko, Kaprio, Petri, Virolainen, Kari, Pulkki, Terhi, Kilpi, Markus, Perola, Jukka, Partanen, Anne, Pitkäranta, Riitta, Kaarteenaho, Seppo, Vainio, Miia, Turpeinen, Raisa, Serpi, Tarja, Laitinen, Johanna, Mäkelä, Veli-Matti, Kosma, Urho, Kujala, Outi, Tuovila, Minna, Hendolin, Raimo, Pakkanen, Jeff, Waring, Bridget, Riley-Gillis, Jimmy, Liu, Shameek, Biswas, Dorothee, Diogo, Catherine, Marshall, Xinli, Hu, Matthias, Gossel, Robert, Graham, Beryl, Cummings, Samuli, Ripatti, Johanna, Schleutker, Mikko, Arvas, Olli, Carpén, Reetta, Hinttala, Johannes, Kettunen, Arto, Mannermaa, Jari, Laukkanen, Valtteri, Julkunen, Anne, Remes, Reetta, Kälviäinen, Jukka, Peltola, Pentti, Tienari, Juha, Rinne, Adam, Ziemann, Jeffrey, Waring, Sahar, Esmaeeli, Nizar, Smaoui, Anne, Lehtonen, Susan, Eaton, Sanni, Lahdenperä, Janet van Adelsberg, John, Michon, Geoff, Kerchner, Natalie, Bowers, Edmond, Teng, John, Eicher, Vinay, Mehta, Padhraig, Gormley, Kari, Linden, Christopher, Whelan, Fanli, Xu, David, Pulford, Martti, Färkkilä, Sampsa, Pikkarainen, Airi, Jussila, Timo, Blomster, Mikko, Kiviniemi, Markku, Voutilainen, Bob, Georgantas, Graham, Heap, Fedik, Rahimov, Keith, Usiskin, Tim, Lu, Danny, Oh, Kirsi, Kalpala, Melissa, Miller, Linda, Mccarthy, Kari, Eklund, Antti, Palomäki, Pia, Isomäki, Laura, Pirilä, Oili, Kaipiainen-Seppänen, Johanna, Huhtakangas, Apinya, Lertratanakul, Marla, Hochfeld, Nan, Bing, Jorge Esparza Gordillo, Nina, Mars, Margit, Pelkonen, Paula, Kauppi, Hannu, Kankaanranta, Terttu, Harju, David, Close, Steven, Greenberg, Hubert, Chen, Betts, Jo, Soumitra, Ghosh, Veikko, Salomaa, Teemu, Niiranen, Markus, Juonala, Kaj, Metsärinne, Mika, Kähönen, Juhani, Junttila, Markku, Laakso, Jussi, Pihlajamäki, Juha, Sinisalo, Marja-Riitta, Taskinen, Tiinamaija, Tuomi, Ben, Challis, Andrew, Peterson, Audrey, Chu, Jaakko, Parkkinen, Anthony, Muslin, Heikki, Joensuu, Tuomo, Meretoja, Lauri, Aaltonen, Johanna, Mattson, Annika, Auranen, Peeter, Karihtala, Saila, Kauppila, Päivi, Auvinen, Klaus, Elenius, Relja, Popovic, Jennifer, Schutzman, Andrey, Loboda, Aparna, Chhibber, Heli, Lehtonen, Stefan, Mcdonough, Marika, Crohns, Diptee, Kulkarni, Kai, Kaarniranta, Joni, A Turunen, Terhi, Ollila, Sanna, Seitsonen, Hannu, Uusitalo, Vesa, Aaltonen, Hannele, Uusitalo-Järvinen, Marja, Luodonpää, Nina, Hautala, Stephanie, Loomis, Erich, Strauss, Hao, Chen, Anna, Podgornaia, Joshua, Hoffman, Kaisa, Tasanen, Laura, Huilaja, Katariina, Hannula-Jouppi, Teea, Salmi, Sirkku, Peltonen, Leena, Koulu, Ilkka, Harvima, Ying, Wu, David, Choy, Pirkko, Pussinen, Aino, Salminen, Tuula, Salo, David, Rice, Pekka, Nieminen, Ulla, Palotie, Maria, Siponen, Liisa, Suominen, Päivi, Mäntylä, Ulvi, Gursoy, Vuokko, Anttonen, Kirsi, Sipilä, Justin Wade Davis, Danjuma, Quarless, Slavé, Petrovski, Eleonor, Wigmore, Chia-Yen, Chen, Paola, Bronson, Ellen, Tsai, Yunfeng, Huang, Joseph, Maranville, Elmutaz, Shaikho, Elhaj, Mohammed, Samir, Wadhawan, Erika, Kvikstad, Minal, Caliskan, Diana, Chang, Tushar, Bhangale, Sarah, Pendergrass, Emily, Holzinger, Xing, Chen, Åsa, Hedman, Karen, S King, Clarence, Wang, Ethan, Xu, Franck, Auge, Clement, Chatelain, Deepak, Rajpal, Dongyu, Liu, Katherine, Call, Tai-He, Xia, Matt, Brauer, Mitja, Kurki, Juha, Karjalainen, Aki, Havulinna, Anu, Jalanko, Priit, Palta, Pietro Della Briotta Parolo, Wei, Zhou, Susanna, Lemmelä, Manuel, Rivas, Jarmo, Harju, Arto, Lehisto, Andrea, Ganna, Vincent, Llorens, Hannele, Laivuori, Sina, Rüeger, Mari, E Niemi, Taru, Tukiainen, Mary Pat Reeve, Henrike, Heyne, Kimmo, Palin, Javier, Garcia-Tabuenca, Harri, Siirtola, Tuomo, Kiiskinen, Jiwoo, Lee, Kristin, Tsuo, Amanda, Elliott, Kati, Kristiansson, Kati, Hyvärinen, Jarmo, Ritari, Miika, Koskinen, Katri, Pylkäs, Marita, Kalaoja, Minna, Karjalainen, Tuomo, Mantere, Eeva, Kangasniemi, Sami, Heikkinen, Eija, Laakkonen, Csilla, Sipeky, Samuel, Heron, Antti, Karlsson, Dhanaprakash, Jambulingam, Venkat Subramaniam Rathinakannan, Risto, Kajanne, Mervi, Aavikko, Manuel González Jiménez, Pietro Della Briotta Parola, Arto, Lehistö, Masahiro, Kanai, Mari, Kaunisto, Elina, Kilpeläinen, Timo, P Sipilä, Georg, Brein, Ghazal, Awaisa, Anastasia, Shcherban, Kati, Donner, Anu, Loukola, Päivi, Laiho, Tuuli, Sistonen, Essi, Kaiharju, Markku, Laukkanen, Elina, Järvensivu, Sini, Lähteenmäki, Lotta, Männikkö, Regis, Wong, Hannele, Mattsson, Tero, Hiekkalinna, Teemu, Paajanen, Kalle, Pärn, Javier, Gracia-Tabuenca, Erin, Abner, Perrie, M Adams, Alyssa, Aguirre, Marilyn, S Albert, Roger, L Albin, Mariet, Allen, Lisa, Alvarez, Liana, G Apostolova, Steven, E Arnold, Sanjay, Asthana, Craig, S Atwood, Gayle, Ayres, Clinton, T Baldwin, Robert, C Barber, Lisa, L Barnes, Sandra, Barral, Thomas, G Beach, James, T Becker, Gary, W Beecham, Duane, Beekly, Jennifer, E Below, Penelope, Benchek, Bruno, A Benitez, David, Bennett, John, Bertelson, Flanagan, E Margaret, Thomas, D Bird, Deborah, Blacker, Bradley, F Boeve, James, D Bowen, Adam, Boxer, James, Brewer, James, R Burke, Jeffrey, M Burns, Will, S Bush, Joseph, D Buxbaum, Nigel, J Cairns, Chuanhai, Cao, Christopher, S Carlson, Cynthia, M Carlsson, Regina, M Carney, Minerva, M Carrasquillo, Scott, Chasse, Marie-Francoise, Chesselet, Alessandra, Chesi, Nathaniel, A Chin, Helena, C Chui, Jaeyoon, Chung, Suzanne, Craft, Paul, K Crane, David, H Cribbs, Elizabeth, A Crocco, Carlos, Cruchaga, Michael, L Cuccaro, Munro, Cullum, Eveleen, Darby, Barbara, Davis, Philip, L De Jager, Charles, Decarli, John, Detoledo, Malcolm, Dick, Dennis, W Dickson, Beth, A Dombroski, Rachelle, S Doody, Ranjan, Duara, Nilüfer, Ertekin-Taner, Denis, A Evans, Thomas, J Fairchild, Kenneth, B Fallon, Martin, R Farlow, John, J Farrell, Victoria, Fernandez-Hernandez, Steven, Ferris, Matthew, P Frosch, Brian, Fulton-Howard, Douglas, R Galasko, Adriana, Gamboa, Marla, Gearing, Daniel, H Geschwind, Bernardino, Ghetti, John, R Gilbert, Thomas, J Grabowski, Neill, R Graff-Radford, Struan F, A Grant, Robert, C Green, John, H Growdon, Jonathan, L Haines, Hakon, Hakonarson, James, Hall, Ronald, L Hamilton, Oscar, Harari, Lindy, E Harrell, Jacob, Haut, Elizabeth, Head, Victor, W Henderson, Michelle, Hernandez, Timothy, Hohman, Lawrence, S Honig, Ryan, M Huebinger, Matthew, J Huentelman, Christine, M Hulette, Bradley, T Hyman, Linda, S Hynan, Laura, Ibanez, Gail, P Jarvik, Suman, Jayadev, Lee-Way, Jin, Kim, Johnson, Leigh, Johnson, M Ilyas Kamboh, Anna, M Karydas, Mindy, J Katz, Jeffrey, A Kaye, C Dirk Keene, Aisha, Khaleeq, Ronald, Kim, Janice, Knebl, Neil, W Kowall, Joel, H Kramer, Pavel, P Kuksa, Frank, M LaFerla, James, J Lah, Eric, B Larson, Chien-Yueh, Lee, Edward, B Lee, Alan, Lerner, Yuk Yee Leung, James, B Leverenz, Allan, I Levey, Mingyao, Li, Andrew, P Lieberman, Richard, B Lipton, Mark, Logue, Constantine, G Lyketsos, John, Malamon, Douglas, Mains, Daniel, C Marson, Frank, Martiniuk, Deborah, C Mash, Eliezer, Masliah, Paul, Massman, Arjun, Masurkar, Wayne, C McCormick, Susan, M McCurry, Andrew, N McDavid, Ann, C McKee, Marsel, Mesulam, Jesse, Mez, Bruce, L Miller, Carol, A Miller, Joshua, W Miller, Thomas, J Montine, Edwin, S Monuki, John, C Morris, Amanda, J Myers, Trung, Nguyen, Sid, O'Bryant, John, M Olichney, Marcia, Ory, Raymond, Palmer, Joseph, E Parisi, Henry, L Paulson, Valory, Pavlik, David, Paydarfar, Victoria, Perez, Elaine, Peskind, Ronald, C Petersen, Jennifer, E Phillips-Cremins, Aimee, Pierce, Marsha, Polk, Wayne, W Poon, Huntington, Potter, Liming, Qu, Mary, Quiceno, Joseph, F Quinn, Ashok, Raj, Murray, Raskind, Eric, M Reiman, Barry, Reisberg, Joan, S Reisch, John, M Ringman, Erik, D Roberson, Monica, Rodriguear, Ekaterina, Rogaeva, Howard, J Rosen, Roger, N Rosenberg, Donald, R Royall, Mark, A Sager, Mary, Sano, Andrew, J Saykin, Julie, A Schneider, Lon, S Schneider, William, W Seeley, Susan, H Slifer, Scott, Small, Amanda, G Smith, Janet, P Smith, Yeunjoo, E Song, Joshua, A Sonnen, Salvatore, Spina, Peter St George-Hyslop, Robert, A Stern, Alan, B Stevens, Stephen, M Strittmatter, David, Sultzer, Russell, H Swerdlow, Rudolph, E Tanzi, Jeffrey, L Tilson, John, Q Trojanowski, Juan, C Troncoso, Debby, W Tsuang, Otto, Valladares, Vivianna, M Van Deerlin, Linda, J van Eldik, Robert, Vassar, Harry, V Vinters, Jean-Paul, Vonsattel, Sandra, Weintraub, Kathleen, A Welsh-Bohmer, Patrice, L Whitehead, Ellen, M Wijsman, Kirk, C Wilhelmsen, Benjamin, Williams, Jennifer, Williamson, Henrik, Wilms, Thomas, S Wingo, Thomas, Wisniewski, Randall, L Woltjer, Martin, Woon, Clinton, B Wright, Chuang-Kuo, Wu, Steven, G Younkin, Chang-En, Yu, Lei, Yu, Yuanchao, Zhang, Zhao, Yi, Xiongwei, Zhu, Hieab, Adams, Rufus, O Akinyemi, Muhammad, Ali, Nicola, Armstrong, Hugo, J Aparicio, Maryam, Bahadori, Monique, Breteler, Daniel, Chasman, Ganesh, Chauhan, Hata, Comic, Simon, Cox, Adrienne, L Cupples, Gail, Davies, Charles, S DeCarli, Marie-Gabrielle, Duperron, Josée, Dupuis, Tavia, Evans, Frank, Fan, Annette, Fitzpatrick, Alison, E Fohner, Mary, Ganguli, Mirjam, Geerlings, Stephen, J Glatt, Hector, M Gonzalez, Monica, Goss, Hans, Grabe, Mohamad, Habes, Susan, R Heckbert, Edith, Hofer, Elliot, Hong, Timothy, Hughes, Tiffany, F Kautz, Maria, Knol, William, Kremen, Paul, Lacaze, Jari, Lahti, Quentin Le Grand, Elizabeth, Litkowski, Shuo, Li, Dan, Liu, Xuan, Liu, Marisa, Loitfelder, Alisa, Manning, Pauline, Maillard, Riccardo, Marioni, Bernard, Mazoyer, Debora Melo van Lent, Hao, Mei, Aniket, Mishra, Paul, Nyquist, Jeffrey, O'Connell, Yash, Patel, Tomas, Paus, Zdenka, Pausova, Katri, Raikkonen-Talvitie, Moeen, Riaz, Stephen, Rich, Jerome, Rotter, Jose, Romero, Gena, Roshchupkin, Yasaman, Saba, Murali, Sargurupremraj, Helena, Schmidt, Reinhold, Schmidt, Joshua, M Shulman, Jennifer, Smith, Hema, Sekhar, Reddy, Rajula, Jean, Shin, Jeannette, Simino, Eeva, Sliz, Alexander, Teumer, Alvin, Thomas, Adrienne, Tin, Elliot, Tucker-Drob, Dina, Vojinovic, Yanbing, Wang, Galit, Weinstein, Dylan, Williams, Katharina, Wittfeld, Lisa, Yanek, Yunju, Yang, Bellenguez, C, Küçükali, F, Jansen, I, Kleineidam, L, Moreno-Grau, S, Amin, N, Naj, A, Campos-Martin, R, Grenier-Boley, B, Andrade, V, Holmans, P, Boland, A, Damotte, V, van der Lee, S, Costa, M, Kuulasmaa, T, Yang, Q, de Rojas, I, Bis, J, Yaqub, A, Prokic, I, Chapuis, J, Ahmad, S, Giedraitis, V, Aarsland, D, Garcia-Gonzalez, P, Abdelnour, C, Alarcón-Martín, E, Alcolea, D, Alegret, M, Alvarez, I, Álvarez, V, Armstrong, N, Tsolaki, A, Antúnez, C, Appollonio, I, Arcaro, M, Archetti, S, Pastor, A, Arosio, B, Athanasiu, L, Bailly, H, Banaj, N, Baquero, M, Barral, S, Beiser, A, Below, J, Benchek, P, Benussi, L, Berr, C, Besse, C, Bessi, V, Binetti, G, Bizarro, A, Blesa, R, Boada, M, Boerwinkle, E, Borroni, B, Boschi, S, Bossù, P, Bråthen, G, Bressler, J, Bresner, C, Brodaty, H, Brookes, K, Brusco, L, Buiza-Rueda, D, Bûrger, K, Burholt, V, Bush, W, Calero, M, Cantwell, L, Chene, G, Chung, J, Cuccaro, M, Carracedo, Á, Cecchetti, R, Cervera-Carles, L, Charbonnier, C, Chen, H, Chillotti, C, Ciccone, S, Claassen, J, Clark, C, Conti, E, Corma-Gómez, A, Costantini, E, Custodero, C, Daian, D, Dalmasso, M, Daniele, A, Dardiotis, E, Dartigues, J, de Deyn, P, de Paiva Lopes, K, de Witte, L, Debette, S, Deckert, J, Del Ser, T, Denning, N, Destefano, A, Dichgans, M, Diehl-Schmid, J, Diez-Fairen, M, Rossi, P, Djurovic, S, Duron, E, Düzel, E, Dufouil, C, Eiriksdottir, G, Engelborghs, S, Escott-Price, V, Espinosa, A, Ewers, M, Faber, K, Fabrizio, T, Nielsen, S, Fardo, D, Farotti, L, Fenoglio, C, Fernández-Fuertes, M, Ferrari, R, Ferreira, C, Ferri, E, Fin, B, Fischer, P, Fladby, T, Fließbach, K, Fongang, B, Fornage, M, Fortea, J, Foroud, T, Fostinelli, S, Fox, N, Franco-Macías, E, Bullido, M, Frank-García, A, Froelich, L, Fulton-Howard, B, Galimberti, D, García-Alberca, J, García-González, P, Garcia-Madrona, S, Garcia-Ribas, G, Ghidoni, R, Giegling, I, Giorgio, G, Goate, A, Goldhardt, O, Gomez-Fonseca, D, González-Pérez, A, Graff, C, Grande, G, Green, E, Grimmer, T, Grünblatt, E, Grunin, M, Gudnason, V, Guetta-Baranes, T, Haapasalo, A, Hadjigeorgiou, G, Haines, J, Hamilton-Nelson, K, Hampel, H, Hanon, O, Hardy, J, Hartmann, A, Hausner, L, Harwood, J, Heilmann-Heimbach, S, Helisalmi, S, Heneka, M, Hernández, I, Herrmann, M, Hoffmann, P, Holmes, C, Holstege, H, Vilas, R, Hulsman, M, Humphrey, J, Biessels, G, Jian, X, Johansson, C, Jun, G, Kastumata, Y, Kauwe, J, Kehoe, P, Kilander, L, Ståhlbom, A, Kivipelto, M, Koivisto, A, Kornhuber, J, Kosmidis, M, Kukull, W, Kuksa, P, Kunkle, B, Kuzma, A, Lage, C, Laukka, E, Launer, L, Lauria, A, Lee, C, Lehtisalo, J, Lerch, O, Lleó, A, Longstreth, W, Lopez, O, de Munain, A, Love, S, Löwemark, M, Luckcuck, L, Lunetta, K, Ma, Y, Macías, J, Macleod, C, Maier, W, Mangialasche, F, Spallazzi, M, Marquié, M, Marshall, R, Martin, E, Montes, A, Rodríguez, C, Masullo, C, Mayeux, R, Mead, S, Mecocci, P, Medina, M, Meggy, A, Mehrabian, S, Mendoza, S, Menéndez-González, M, Mir, P, Moebus, S, Mol, M, Molina-Porcel, L, Montrreal, L, Morelli, L, Moreno, F, Morgan, K, Mosley, T, Nöthen, M, Muchnik, C, Mukherjee, S, Nacmias, B, Ngandu, T, Nicolas, G, Nordestgaard, B, Olaso, R, Orellana, A, Orsini, M, Ortega, G, Padovani, A, Paolo, C, Papenberg, G, Parnetti, L, Pasquier, F, Pastor, P, Peloso, G, Pérez-Cordón, A, Pérez-Tur, J, Pericard, P, Peters, O, Pijnenburg, Y, Pineda, J, Piñol-Ripoll, G, Pisanu, C, Polak, T, Popp, J, Posthuma, D, Priller, J, Puerta, R, Quenez, O, Quintela, I, Thomassen, J, Rábano, A, Rainero, I, Rajabli, F, Ramakers, I, Real, L, Reinders, M, Reitz, C, Reyes-Dumeyer, D, Ridge, P, Riedel-Heller, S, Riederer, P, Roberto, N, Rodriguez-Rodriguez, E, Rongve, A, Allende, I, Rosende-Roca, M, Royo, J, Rubino, E, Rujescu, D, Sáez, M, Sakka, P, Saltvedt, I, Sanabria, Á, Sánchez-Arjona, M, Sanchez-Garcia, F, Juan, P, Sánchez-Valle, R, Sando, S, Sarnowski, C, Satizabal, C, Scamosci, M, Scarmeas, N, Scarpini, E, Scheltens, P, Scherbaum, N, Scherer, M, Schmid, M, Schneider, A, Schott, J, Selbæk, G, Seripa, D, Serrano, M, Sha, J, Shadrin, A, Skrobot, O, Slifer, S, Snijders, G, Soininen, H, Solfrizzi, V, Solomon, A, Song, Y, Sorbi, S, Sotolongo-Grau, O, Spalletta, G, Spottke, A, Squassina, A, Stordal, E, Tartan, J, Tárraga, L, Tesí, N, Thalamuthu, A, Thomas, T, Tosto, G, Traykov, L, Tremolizzo, L, Tybjærg-Hansen, A, Uitterlinden, A, Ullgren, A, Ulstein, I, Valero, S, Valladares, O, Broeckhoven, C, Vance, J, Vardarajan, B, van der Lugt, A, Dongen, J, van Rooij, J, van Swieten, J, Vandenberghe, R, Verhey, F, Vidal, J, Vogelgsang, J, Vyhnalek, M, Wagner, M, Wallon, D, Wang, L, Wang, R, Weinhold, L, Wiltfang, J, Windle, G, Woods, B, Yannakoulia, M, Zare, H, Zhao, Y, Zhang, X, Zhu, C, Zulaica, M, Andreoni, S, Ferrarese, C, Sala, G, Zoia, C, Farrer, L, Psaty, B, Ghanbari, M, Raj, T, Sachdev, P, Mather, K, Jessen, F, Ikram, M, de Mendonça, A, Hort, J, Tsolaki, M, Pericak-Vance, M, Amouyel, P, Williams, J, Frikke-Schmidt, R, Clarimon, J, Deleuze, J, Rossi, G, Seshadri, S, Andreassen, O, Ingelsson, M, Hiltunen, M, Sleegers, K, Schellenberg, G, van Duijn, C, Sims, R, van der Flier, W, Ruiz, A, Ramirez, A, Lambert, J, VU University medical center, Amsterdam Neuroscience - Neurodegeneration, Neurology, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, APH - Personalized Medicine, APH - Methodology, Bellenguez, Céline [0000-0002-1240-7874], Küçükali, Fahri [0000-0002-3835-9639], Amin, Najaf [0000-0002-8944-1771], Holmans, Peter A [0000-0003-0870-9412], van der Lee, Sven J [0000-0003-1606-8643], Costa, Marcos R [0000-0002-4928-2163], Kuulasmaa, Teemu [0000-0002-1795-7314], Yang, Qiong [0000-0002-3658-1375], de Rojas, Itziar [0000-0002-2148-381X], Bis, Joshua C [0000-0002-3409-1110], Yaqub, Amber [0000-0002-3579-8054], Prokic, Ivana [0000-0002-0370-1473], Chapuis, Julien [0000-0002-5802-2857], Ahmad, Shahzad [0000-0002-8658-3790], Giedraitis, Vilmantas [0000-0003-3423-2021], Garcia-Gonzalez, Pablo [0000-0003-0125-5403], Alcolea, Daniel [0000-0002-3819-3245], Alvarez, Ignacio [0000-0002-8537-3935], Tsolaki, Anthoula [0000-0002-5563-7776], Baquero, Miquel [0000-0002-6861-1831], Pastor, Ana Belén [0000-0001-9637-4688], Berr, Claudine [0000-0001-5254-7655], Bessi, Valentina [0000-0002-6176-3584], Boada, Mercè [0000-0003-2617-3009], Bossù, Paola [0000-0002-1432-0078], Bråthen, Geir [0000-0003-3224-7983], Bressler, Jan [0000-0001-6578-4772], Bresner, Catherine [0000-0003-2673-9762], Brodaty, Henry [0000-0001-9487-6617], Brookes, Keeley J [0000-0003-2427-2513], Burholt, Vanessa [0000-0002-6789-127X], Bush, William S [0000-0002-9729-6519], Calero, Miguel [0000-0001-5366-3324], Chung, Jaeyoon [0000-0002-6431-9454], Cervera-Carles, Laura [0000-0003-2286-200X], Costantini, Emanuele [0000-0002-1096-8221], Dalmasso, Maria Carolina [0000-0002-4901-9955], de Paiva Lopes, Katia [0000-0002-0240-0126], de Witte, Lot D [0000-0002-7235-9958], Debette, Stéphanie [0000-0001-8675-7968], Del Ser, Teodoro [0000-0001-9806-7083], Dichgans, Martin [0000-0002-0654-387X], Diehl-Schmid, Janine [0000-0002-7745-1382], Diez-Fairen, Mónica [0000-0003-1882-0309], Djurovic, Srdjan [0000-0002-8140-8061], Dufouil, Carole [0000-0003-2442-4476], Escott-Price, Valentina [0000-0003-1784-5483], Ewers, Michael [0000-0001-5231-1714], Fabrizio, Tagliavini [0000-0003-1039-7315], Fladby, Tormod [0000-0002-9984-9797], Fornage, Myriam [0000-0003-0677-8158], Fox, Nick C [0000-0002-6660-657X], Bullido, María J [0000-0002-6477-1117], Froelich, Lutz [0000-0003-1494-0813], Galimberti, Daniela [0000-0002-9284-5953], García-Alberca, Jose Maria [0000-0003-2951-6644], Goate, Alison M [0000-0002-0576-2472], González-Pérez, Antonio [0000-0001-9771-5982], Green, Emma [0000-0002-8687-5590], Grünblatt, Edna [0000-0001-8505-7265], Gudnason, Vilmundur [0000-0001-5696-0084], Haapasalo, Annakaisa [0000-0003-0959-2957], Harwood, Janet [0000-0002-3225-0069], Heilmann-Heimbach, Stefanie [0000-0003-1057-465X], Herrmann, Martin J [0000-0001-9970-2122], Holstege, Henne [0000-0002-7688-3087], Biessels, Geert Jan [0000-0001-6862-2496], Jian, Xueqiu [0000-0002-0313-6494], Johansson, Charlotte [0000-0002-5351-1950], Jun, Gyungah R [0000-0002-3230-8697], Kastumata, Yuriko [0000-0002-0188-8094], Kehoe, Patrick G [0000-0002-7542-1139], Kornhuber, Johannes [0000-0002-8096-3987], Kosmidis, Mary H [0000-0001-8790-1220], Lage, Carmen [0000-0003-1703-121X], Launer, Lenore [0000-0002-3238-7612], Lee, Chien-Yueh [0000-0002-4304-974X], Lleó, Alberto [0000-0002-2568-5478], Lopez, Oscar [0000-0002-8546-8256], de Munain, Adolfo Lopez [0000-0002-9509-4032], Lunetta, Kathryn L [0000-0002-9268-810X], Ma, Yiyi [0000-0002-3609-8877], MacLeod, Catherine A [0000-0002-9314-7380], Marquié, Marta [0000-0002-0660-0950], Montes, Angel Martín [0000-0002-1694-786X], Mead, Simon [0000-0002-4326-1468], Medina, Miguel [0000-0002-7016-5340], Menéndez-González, Manuel [0000-0002-5218-0774], Mol, Merel [0000-0003-2533-2530], Morgan, Kevin [0000-0002-8217-2396], Nöthen, Markus M [0000-0002-8770-2464], Muchnik, Carolina [0000-0002-1542-3706], Nacmias, Benedetta [0000-0001-9338-9040], Nicolas, Gael [0000-0001-9391-7800], Nordestgaard, Børge G [0000-0002-1954-7220], Pasquier, Florence [0000-0001-9880-9788], Pastor, Pau [0000-0002-7493-8777], Peloso, Gina [0000-0002-5355-8636], Pérez-Cordón, Alba [0000-0002-6028-0791], Pérez-Tur, Jordi [0000-0002-9111-1712], Pericard, Pierre [0000-0001-8167-6448], Pineda, Juan A [0000-0002-3751-0296], Pisanu, Claudia [0000-0002-9151-4319], Posthuma, Danielle [0000-0001-7582-2365], Puerta, Raquel [0000-0002-1191-5893], Quenez, Olivier [0000-0002-8273-8505], Thomassen, Jesper Qvist [0000-0003-3484-9531], Real, Luis M [0000-0003-4932-7429], Reinders, Marcel JT [0000-0002-1148-1562], Reitz, Christiane [0000-0001-8757-7889], Riedel-Heller, Steffi [0000-0003-4321-6090], Rodriguez-Rodriguez, Eloy [0000-0001-7742-677X], Rongve, Arvid [0000-0002-0476-4134], Sáez, María Eugenia [0000-0001-9299-2534], Saltvedt, Ingvild [0000-0002-7897-9808], Juan, Pascual Sánchez [0000-0002-6081-8037], Sarnowski, Chloé [0000-0002-6090-7099], Satizabal, Claudia L [0000-0002-1115-4430], Schott, Jonathan M [0000-0003-2059-024X], Selbæk, Geir [0000-0001-6511-8219], Shadrin, Alexey A [0000-0002-7467-250X], Soininen, Hilkka [0000-0002-2785-9937], Solfrizzi, Vincenzo [0000-0002-8524-0315], Song, Yeunjoo [0000-0002-7452-3731], Sotolongo-Grau, Oscar [0000-0002-9679-0670], Spalletta, Gianfranco [0000-0002-7432-4249], Squassina, Alessio [0000-0001-7415-7607], Stordal, Eystein [0000-0002-2443-7923], Tosto, Giuseppe [0000-0001-7075-8245], Uitterlinden, Andre [0000-0002-7276-3387], Valladares, Otto [0000-0001-8055-2187], Broeckhoven, Christine Van [0000-0003-0183-7665], Vidal, Jean-Sébastien [0000-0001-6770-0720], Vogelgsang, Jonathan [0000-0001-9326-8193], Wagner, Michael [0000-0003-2589-6440], Wallon, David [0000-0002-2634-7198], Wiltfang, Jens [0000-0003-1492-5330], Woods, Bob [0000-0002-6781-651X], Yannakoulia, Mary [0000-0003-2171-7337], Zare, Habil [0000-0001-5902-6238], Zhang, Xiaoling [0000-0001-8237-1857], Farrer, Lindsay A [0000-0001-5533-4225], Psaty, Bruce M [0000-0002-7278-2190], Ghanbari, Mohsen [0000-0002-9476-7143], Raj, Towfique [0000-0002-9355-5704], Sachdev, Perminder [0000-0002-9595-3220], Mather, Karen [0000-0003-4143-8941], Ikram, M Arfan [0000-0003-0372-8585], Tsolaki, Magda [0000-0002-2072-8010], Pericak-Vance, Margaret A [0000-0001-7283-8804], Amouyel, Philippe [0000-0001-9088-234X], Williams, Julie [0000-0002-4069-0259], Frikke-Schmidt, Ruth [0000-0003-4084-5027], Seshadri, Sudha [0000-0001-6135-2622], Andreassen, Ole A [0000-0002-4461-3568], Sleegers, Kristel [0000-0002-0283-2332], van Duijn, Cornelia M [0000-0002-2374-9204], Sims, Rebecca [0000-0002-3885-1199], van der Flier, Wiesje M [0000-0001-8766-6224], Ramirez, Alfredo [0000-0003-4991-763X], Lambert, Jean-Charles [0000-0003-0829-7817], Apollo - University of Cambridge Repository, Complex Trait Genetics, Clinical sciences, Neuroprotection & Neuromodulation, Pathologic Biochemistry and Physiology, Clinical Biology, Epidemiology, Internal Medicine, Psychiatrie & Neuropsychologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Med Staf Spec Psychiatrie (9), UAM. Departamento de Biología Molecular, University of Helsinki, Department of Neurosciences, HUS Internal Medicine and Rehabilitation, Timo Strandberg / Principal Investigator, Department of Medicine, Clinicum, HUS Neurocenter, Neurologian yksikkö, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale (France), European Commission, LabEx DISTALZ, Pérez-Tur, Jordi, University Children’s Hospital Basel (Suiza), INSERM (Francia), Lille Métropole Communauté Urbaine, Government of France (Francia), EADB, GR@ACE, DEGESCO, EADI, GERAD, Demgene, FinnGen, ADGC, CHARGE, Holmans, Peter A. [0000-0003-0870-9412], van der Lee, Sven J. [0000-0003-1606-8643], Costa, Marcos R. [0000-0002-4928-2163], Bis, Joshua C. [0000-0002-3409-1110], Brookes, Keeley J. [0000-0003-2427-2513], Bush, William S. [0000-0002-9729-6519], de Witte, Lot D. [0000-0002-7235-9958], del Ser, Teodoro [0000-0001-9806-7083], Fox, Nick C. [0000-0002-6660-657X], Bullido, María J. [0000-0002-6477-1117], Goate, Alison M. [0000-0002-0576-2472], Herrmann, Martin J. [0000-0001-9970-2122], Jun, Gyungah R. [0000-0002-3230-8697], Kehoe, Patrick G. [0000-0002-7542-1139], Kosmidis, Mary H. [0000-0001-8790-1220], Lunetta, Kathryn L. [0000-0002-9268-810X], MacLeod, Catherine A. [0000-0002-9314-7380], Nöthen, Markus M. [0000-0002-8770-2464], Nordestgaard, Børge G. [0000-0002-1954-7220], Pineda, Juan A. [0000-0002-3751-0296], Real, Luis M. [0000-0003-4932-7429], Reinders, Marcel J. T. [0000-0002-1148-1562], Satizabal, Claudia L. [0000-0002-1115-4430], Schott, Jonathan M. [0000-0003-2059-024X], Shadrin, Alexey A. [0000-0002-7467-250X], Farrer, Lindsay A. [0000-0001-5533-4225], Psaty, Bruce M. [0000-0002-7278-2190], Ikram, M. Arfan [0000-0003-0372-8585], Pericak-Vance, Margaret A. [0000-0001-7283-8804], Andreassen, Ole A. [0000-0002-4461-3568], van Duijn, Cornelia M. [0000-0002-2374-9204], van der Flier, Wiesje M. [0000-0001-8766-6224], and Molecular Neuroscience and Ageing Research (MOLAR)
- Subjects
tau Proteins/genetics ,Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1] ,Neurologi ,MED/03 - GENETICA MEDICA ,45/43 ,Medizin ,Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] ,genetics [Alzheimer Disease] ,Genome-Wide Association Study ,Humans ,tau Proteins ,Alzheimer Disease ,Cognitive Dysfunction ,VARIANTS ,pathology [Alzheimer Disease] ,Tau Proteins ,Settore BIO/13 - Biologia Applicata ,Cognitive Dysfunction/psychology ,692/699/375/365/1283 ,IMPUTATION ,article ,1184 Genetics, developmental biology, physiology ,Biología y Biomedicina / Biología ,AMYLOID-BETA ,Settore MED/26 - NEUROLOGIA ,Neurology ,psychology [Cognitive Dysfunction] ,Medical Genetics ,Human ,Neuroscience(all) ,631/208/205/2138 ,All institutes and research themes of the Radboud University Medical Center ,SDG 3 - Good Health and Well-being ,ddc:570 ,Genetics ,Genetic Predisposition to Disease ,GENOME-WIDE ASSOCIATION ,METAANALYSIS ,Medicinsk genetik ,MED/26 - NEUROLOGIA ,Alzheimer Disease/genetics ,neurology ,tau Protein ,NECROSIS-FACTOR-ALPHA ,RISK LOCI ,genetics [tau Proteins] ,PREDICTION MODELS ,Human medicine ,GENERATION ,RESPONSES - Abstract
25 páginas, 6 figuras, 2 tablas, Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele., This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine and French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Full consortium acknowledgements and funding are in the Supplementary Not
- Published
- 2022
28. Case of a Man with Hemichorea and Behavioral Changes: 'A Red Herring'
- Author
-
Galit, Kleiner, Stephen A, Ryan, Juan, Bilbao, Julia, Keith, Ekaterina, Rogaeva, Sandra E, Black, Anthony E, Lang, and Mario, Masellis
- Subjects
Neurology ,Clinico‐pathological Case ,Neurology (clinical) - Abstract
BACKGROUND: Progressive supranuclear palsy (PSP)–pallido‐nigro‐luysian atrophy (PNLA) is a neuropathological entity thought to be a variant of classic PSP. Clinical features and pathologic hallmarks are the same in both conditions; however, age and order of symptom onset, disease duration and prognosis, and distribution and density of pathology differentiate the 2 entities. OBJECTIVES: This study presents a PSP‐PNLA case confirmed pathologically with a clinical presentation of hemichorea/ballism, spasticity, progressive hemiparesis, and a frontal behavioral syndrome with relative cognitive sparing early in the disease course. METHODS: We describe the clinical progression in this unique case supplemented with video and imaging findings in the form of magnetic resonance imaging and brain single photon emission computed tomography. Final diagnosis is via pathological analysis at autopsy. RESULTS: We present an elderly gentleman who manifested a clinical syndrome consisting of subacute onset of chorea that at presentation was distinctly unilateral and a frontal behavioral syndrome in the setting of mild thrombocytopenia and elevated anticardiolipin antibodies. Positive antiphospholipid antibodies resulted in an initial antemortem diagnosis of primary antiphospholipid syndrome as a cause of his chorea. Longitudinal follow‐up over 5 years demonstrated a progression of clinical features with hemi‐motor impersistence/chorea, disinhibition and impulsivity, and eventually corticospinal distribution weakness on the initially affected side. He required nursing home care and falls necessitated wheelchair use. Postmortem neuropathological study revealed a diagnosis of frontotemporal lobar degeneration‐tau, PSP‐PNLA. CONCLUSIONS: This case broadens the phenotype of PSP‐PNLA and to our knowledge is the only case presenting with unilateral chorea.
- Published
- 2022
29. Characteristics of the Ontario Neurodegenerative Disease Research Initiative cohort
- Author
-
Kelly M, Sunderland, Derek, Beaton, Stephen R, Arnott, Peter, Kleinstiver, Donna, Kwan, Jane M, Lawrence-Dewar, Joel, Ramirez, Brian, Tan, Robert, Bartha, Sandra E, Black, Michael, Borrie, Donald, Brien, Leanne K, Casaubon, Brian C, Coe, Benjamin, Cornish, Allison A, Dilliott, Dar, Dowlatshahi, Elizabeth, Finger, Corinne, Fischer, Andrew, Frank, Julia, Fraser, Morris, Freedman, Barry, Greenberg, David A, Grimes, Ayman, Hassan, Wendy, Hatch, Robert A, Hegele, Christopher, Hudson, Mandar, Jog, Sanjeev, Kumar, Anthony, Lang, Brian, Levine, Wendy, Lou, Jennifer, Mandzia, Connie, Marras, William, McIlroy, Manuel, Montero-Odasso, David G, Munoz, Douglas P, Munoz, Joseph B, Orange, David S, Park, Stephen H, Pasternak, Frederico, Pieruccini-Faria, Tarek K, Rajji, Angela C, Roberts, John F, Robinson, Ekaterina, Rogaeva, Demetrios J, Sahlas, Gustavo, Saposnik, Christopher J M, Scott, Dallas, Seitz, Christen, Shoesmith, Thomas D L, Steeves, Michael J, Strong, Stephen C, Strother, Richard H, Swartz, Sean, Symons, David F, Tang-Wai, Maria Carmela, Tartaglia, Angela K, Troyer, John, Turnbull, Lorne, Zinman, Paula M, McLaughlin, Mario, Masellis, Malcolm A, Binns, and Guangyong, Zou
- Subjects
Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Abstract
Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap.This multi-site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes.We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation.Data will be shared with the global scientific community. Within-disease and disease-agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.
- Published
- 2022
30. Marked Differences in C9orf72 Methylation Status and Isoform Expression between C9/ALS Human Embryonic and Induced Pluripotent Stem Cells
- Author
-
Yaara Cohen-Hadad, Gheona Altarescu, Talia Eldar-Geva, Ephrat Levi-Lahad, Ming Zhang, Ekaterina Rogaeva, Marc Gotkine, Osnat Bartok, Reut Ashwal-Fluss, Sebastian Kadener, Silvina Epsztejn-Litman, and Rachel Eiges
- Subjects
C9/ALS ,unstable repeat expansions ,DNA methylation ,CpG islands ,pluripotent stem cells ,disease modelling ,neurodegeneration ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
We established two human embryonic stem cell (hESC) lines with a GGGGCC expansion in the C9orf72 gene (C9), and compared them with haploidentical and unrelated C9 induced pluripotent stem cells (iPSCs). We found a marked difference in C9 methylation between the cells. hESCs and parental fibroblasts are entirely unmethylated while the iPSCs are hypermethylated. In addition, we show that the expansion alters promoter usage and interferes with the proper splicing of intron 1, eventually leading to the accumulation of repeat-containing mRNA following neural differentiation. These changes are attenuated in C9 iPSCs, presumably owing to hypermethylation. Altogether, this study highlights the importance of neural differentiation in the pathogenesis of disease and points to the potential role of hypermethylation as a neuroprotective mechanism against pathogenic mRNAs, envisaging a milder phenotype in C9 iPSCs.
- Published
- 2016
- Full Text
- View/download PDF
31. Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson’s Disease
- Author
-
Athina Simitsi, Grazia Annesi, Hirotaka Matsuo, Leonor Correia Guedes, Mario Ezquerra, Kenya Nishioka, Ashwin Ashok Kumar Sreelatha, Simona Petrucci, Dimitri Krainc, Angela Deutschländer, Ekaterina Rogaeva, Lasse Pihlstrøm, Manu Sharma, Thomas Gasser, Mathias Toft, Jan O. Aasly, Cloé Domenighetti, Monica Diez-Fairen, Milena Radivojkov-Blagojevic, Sandeep Grover, Andrew B. Singleton, Bart P.C. van de Warrenburg, Yun Joong Kim, Andrea Quattrone, Sun Ju Chung, Gianni Pezzoli, Pierre-Emmanuel Sugier, Sulev Kõks, Lena F. Burbulla, Jonathan Carr, Walter Pirker, Efthimos Dardiotis, Karin Wirdefeldt, George D. Mellick, Jean-Christophe Corvol, Dheeraj Reddy Bobbili, Anthony E. Lang, Eugénie Mutez, Georges M. Hadjigeorgiou, Anna Zecchinelli, Laura Brighina, Connor Edsall, Océane Mohamed, Berta Portugal, Andreas Puschmann, Nancy L. Pedersen, Alexander Zimprich, Patrick May, Matthew J. Farrer, Leonidas Stefanis, Yusuke Kawamura, Eduardo Tolosa, Claudia Schulte, Alexis Brice, Caroline Ran, Manuela Tan, Pille Taba, Peter Lichtner, Alexis Elbaz, Dena G. Hernandez, Monica Gagliardi, Andrea Carmine Belin, Joaquim J. Ferreira, Suzanne Lesage, Pierre Kolber, Kathrin Brockmann, Marie-Christine Chartier-Harlin, Carl E Clarke, Karen E. Morrison, Nobutaka Hattori, Stefano Duga, Letizia Straniero, Rejko Krüger, Carlo Ferrarese, Pau Pastor, Soraya Bardien, Clara Hellberg, Bastiaan R. Bloem, Enza Maria Valente, Domenighetti, C, Sugier, P, Sreelatha, A, Schulte, C, Grover, S, Mohamed, O, Portugal, B, May, P, Bobbili, D, Radivojkov-Blagojevic, M, Lichtner, P, Singleton, A, Hernandez, D, Edsall, C, Mellick, G, Zimprich, A, Pirker, W, Rogaeva, E, Lang, A, Koks, S, Taba, P, Lesage, S, Brice, A, Corvol, J, Chartier-Harlin, M, Mutez, E, Brockmann, K, Deutschlander, A, Hadjigeorgiou, G, Dardiotis, E, Stefanis, L, Simitsi, A, Valente, E, Petrucci, S, Duga, S, Straniero, L, Zecchinelli, A, Pezzoli, G, Brighina, L, Ferrarese, C, Annesi, G, Quattrone, A, Gagliardi, M, Matsuo, H, Kawamura, Y, Hattori, N, Nishioka, K, Chung, S, Kim, Y, Kolber, P, Van De Warrenburg, B, Bloem, B, Aasly, J, Toft, M, Pihlstrom, L, Guedes, L, Ferreira, J, Bardien, S, Carr, J, Tolosa, E, Ezquerra, M, Pastor, P, Diez-Fairen, M, Wirdefeldt, K, Pedersen, N, Ran, C, Belin, A, Puschmann, A, Hellberg, C, Clarke, C, Morrison, K, Tan, M, Krainc, D, Burbulla, L, Farrer, M, Kruger, R, Gasser, T, Sharma, M, and Elbaz, A
- Subjects
Inverse Association ,Parkinson's disease ,parkinson’s disease ,Alcohol Drinking ,coffee ,Alcohol ,Disease ,epidemiology [Alcohol Drinking] ,Coffee ,Article ,Cellular and Molecular Neuroscience ,symbols.namesake ,chemistry.chemical_compound ,genetics [Parkinson Disease] ,Risk Factors ,epidemiology [Smoking] ,Humans ,Medicine ,ddc:610 ,Coffee drinking ,Aged ,alcohol ,business.industry ,Smoking ,Confounding ,Parkinson Disease ,Odds ratio ,Mendelian Randomization Analysis ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,medicine.disease ,mendelian randomisation ,chemistry ,genetics [Alcohol Drinking] ,Parkinson’s disease ,smoking ,aged ,alcohol drinking ,genome-wide association study ,humans ,mendelian randomization analysis ,risk factors ,parkinson disease ,Mendelian inheritance ,symbols ,etiology [Parkinson Disease] ,Neurology (clinical) ,business ,Genome-Wide Association Study ,Demography - Abstract
Contains fulltext : 248871.pdf (Publisher’s version ) (Open Access) BACKGROUND: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. OBJECTIVE: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. METHODS: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). RESULTS: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. CONCLUSION: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.
- Published
- 2022
32. Axial Impairment Following Deep Brain Stimulation in Parkinson’s Disease: A Surgicogenomic Approach
- Author
-
Rajasumi Rajalingam, Ziv Gan-Or, Erfan Ghani Kakhki, Melanie Cohn, Mahdi Ghani, Maryam Naghibzadeh, Ekaterina Rogaeva, Yu-Yan Poon, Taline Naranian, Renato P. Munhoz, Jürgen Germann, Eric Yu, Marta Statucka, Suneil K. Kalia, Maryam Abdollahi, Anthony E. Lang, Alexandre Boutet, Mojgan Hodaie, Gavin J B Elias, Alfonso Fasano, Christine Sato, Naomi P. Visanji, Danielle Moreno, and Andres M. Lozano
- Subjects
Oncology ,medicine.medical_specialty ,Linkage disequilibrium ,Levodopa ,Deep brain stimulation ,Parkinson's disease ,Deep Brain Stimulation ,medicine.medical_treatment ,Disease ,Cellular and Molecular Neuroscience ,Internal medicine ,Humans ,Medicine ,Trypsin ,Genotyping ,Allele frequency ,Retrospective Studies ,business.industry ,Parkinson Disease ,medicine.disease ,Subthalamic nucleus ,Treatment Outcome ,Neurology (clinical) ,business ,medicine.drug - Abstract
Background: Postoperative outcome following deep brain stimulation (DBS) of the subthalamic nucleus is variable, particularly with respect to axial motor improvement. We hypothesized a genetic underpinning to the response to surgical intervention, termed “surgicogenomics”. Objective: We aimed to identify genetic variants associated with clinical heterogeneity in DBS outcome of Parkinson’s disease (PD) patients that could then be applied clinically to target selection leading to improved surgical outcome. Methods: Retrospective clinical data was extracted from 150 patient’s charts. Each individual was genotyped using the genome-wide NeuroX array tailored to study neurologic diseases. Genetic data were clustered based on surgical outcome assessed by comparing pre- and post-operative scores of levodopa equivalent daily dose and axial impairment at one and five years post-surgery. Allele frequencies were compared between patients with excellent vs. moderate/poor outcomes grouped using a priori defined cut-offs. We analyzed common variants, burden of rare coding variants, and PD polygenic risk score. Results: NeuroX identified 2,917 polymorphic markers at 113 genes mapped to known PD loci. The gene-burden analyses of 202 rare nonsynonymous variants suggested a nominal association of axial impairment with 14 genes (most consistent with CRHR1, IP6K2, and PRSS3). The strongest association with surgical outcome was detected between a reduction in levodopa equivalent daily dose and common variations tagging two linkage disequilibrium blocks with SH3GL2. Conclusion: Once validated in independent populations, our findings may be implemented to improve patient selection for DBS in PD.
- Published
- 2022
33. The Rossy Progressive Supranuclear Palsy Centre: creation and initial experience
- Author
-
Blas Couto, Susan Fox, Maria Carmela Tartaglia, Ekaterina Rogaeva, Jeffrey Antwi, Puja Bhakta, Gabor G. Kovacs, and Anthony E. Lang
- Subjects
Neurology ,Neurology (clinical) ,General Medicine - Abstract
Objective: To describe the development and initial experience of a clinical research program in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) in Canada: The Rossy PSP Centre, to share the data acquisition tools adopted, and to report preliminary results. Methods: Extensive demographic and longitudinal clinical information is collected every 6 months using standardized forms. Biofluids are collected for biobanking and genetic analysis, and many patients are enrolled in neuroimaging research protocols. Brain donation is an important component of the program, and standardized processing protocols have been established, including very short death to autopsy times in patients undergoing medical assistance in dying. Results: Between Oct 2019 and Dec 2021, 132 patients were screened, 91 fulfilling criteria for PSP and 19 for CBS; age 71 years; 41% female; duration 5 years, age-of-onset 66 years. The most common symptoms at onset were postural instability and falls (45%), cognitive-behavioral changes (22%), and Parkinsonism (9%). The predominant clinical phenotype was Richardson syndrome (82%). Levodopa and amantadine resulted in partial and short-lasting benefit. Conclusions: The Rossy PSP Centre has been established to advance clinical and basic research in PSP and related tauopathies. The extent of the clinical data collected permits deep phenotyping of patients and allows for future clinical and basic research. Preliminary results showed expected distribution of phenotypes, demographics, and response to symptomatic treatments in our cohort. Longitudinal data will provide insight into the early diagnosis and management of PSP. Future steps include enrollment of patients in earlier stages, development of biomarkers, and fast-tracking well-characterized patients into clinical trials.
- Published
- 2023
34. Genome-wide structural variant analysis identifies risk loci for non-Alzheimer's dementias
- Author
-
Karri Kaivola, Ruth Chia, Jinhui Ding, Memoona Rasheed, Masashi Fujita, Vilas Menon, Ronald L. Walton, Ryan L. Collins, Kimberley Billingsley, Harrison Brand, Michael Talkowski, Xuefang Zhao, Ramita Dewan, Ali Stark, Anindita Ray, Sultana Solaiman, Pilar Alvarez Jerez, Laksh Malik, Ted M. Dawson, Liana S. Rosenthal, Marilyn S. Albert, Olga Pletnikova, Juan C. Troncoso, Mario Masellis, Julia Keith, Sandra E. Black, Luigi Ferrucci, Susan M. Resnick, Toshiko Tanaka, Eric Topol, Ali Torkamani, Pentti Tienari, Tatiana M. Foroud, Bernardino Ghetti, John E. Landers, Mina Ryten, Huw R. Morris, John A. Hardy, Letizia Mazzini, Sandra D'Alfonso, Cristina Moglia, Andrea Calvo, Geidy E. Serrano, Thomas G. Beach, Tanis Ferman, Neill R. Graff-Radford, Bradley F. Boeve, Zbigniew K. Wszolek, Dennis W. Dickson, Adriano Chiò, David A. Bennett, Philip L. De Jager, Owen A. Ross, Clifton L. Dalgard, J. Raphael Gibbs, Bryan J. Traynor, Sonja W. Scholz, Anthony R. Soltis, Coralie Viollet, Gauthaman Sukumar, Camille Alba, Nathaniel Lott, Elisa McGrath Martinez, Meila Tuck, Jatinder Singh, Dagmar Bacikova, Xijun Zhang, Daniel N. Hupalo, Adelani Adeleye, Matthew D. Wilkerson, Harvey B. Pollard, Ziv Gan-Or, Ekaterina Rogaeva, Alexis Brice, Suzanne Lesage, Georgia Xiromerisiou, Antonio Canosa, Adriano Chio, Giancarlo Logroscino, Gabriele Mora, Reijko Krüger, Patrick May, Daniel Alcolea, Jordi Clarimon, Juan Fortea, Isabel Gonzalez-Aramburu, Jon Infante, Carmen Lage, Alberto Lleó, Pau Pastor, Pascual Sanchez-Juan, Francesca Brett, Dag Aarsland, Safa Al-Sarraj, Johannes Attems, Steve Gentleman, Angela K. Hodges, Seth Love, Ian G. McKeith, Christopher M. Morris, Laura Palmer, Stuart Pickering-Brown, Alan J. Thomas, Claire Troakes, Matthew J. Barrett, Lynn M. Bekris, Kelley Faber, Margaret E. Flanagan, Alison Goate, David S. Goldstein, Horacio Kaufmann, Walter A. Kukull, James B. Leverenz, Grisel Lopez, Qinwen Mao, Eliezer Masliah, Edwin Monuki, Kathy L. Newell, Jose-Alberto Palma, Matthew Perkins, Alan E. Renton, Clemens R. Scherzer, Vikram G. Shakkottai, Ellen Sidransky, Nahid Tayebi, Randy Woltjer, Robert H. Baloh, Robert Bowser, James Broach, William Camu, John Cooper-Knock, Carsten Drepper, Vivian E. Drory, Travis L. Dunckley, Eva Feldman, Pietro Fratta, Glenn Gerhard, Summer B. Gibson, Jonathan D. Glass, Matthew B. Harms, Terry D. Heiman-Patterson, Lilja Jansson, Janine Kirby, Justin Kwan, Hannu Laaksovirta, Francesco Landi, Isabelle Le Ber, Serge Lumbroso, Daniel J.L. MacGowan, Nicholas J. Maragakis, Kevin Mouzat, Liisa Myllykangas, Richard W. Orrell, Lyle W. Ostrow, Roger Pamphlett, Erik Pioro, Stefan M. Pulst, John M. Ravits, Wim Robberecht, Jeffrey D. Rothstein, Michael Sendtner, Pamela J. Shaw, Katie C. Sidle, Zachary Simmons, Thor Stein, David J. Stone, Pentti J. Tienari, Miko Valori, Philip Van Damme, Vivianna M. Van Deerlin, Ludo Van Den Bosch, Lorne Zinman, Fonds National de la Recherche - FnR [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], and Luxembourg Institute of Health - LIH [research center]
- Subjects
amyotrophic lateral sclerosis ,Neurologie [D14] [Sciences de la santé humaine] ,genome-wide association study ,Neurology [D14] [Human health sciences] ,case-control study ,Non-Alzheimer dementia ,resource ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,frontotemporal dementia ,structural variant ,Genetics ,non–Alzheimer's dementia ,Genetics & genetic processes [F10] [Life sciences] ,Lewy body dementia ,Structural variants ,Génétique & processus génétiques [F10] [Sciences du vivant] - Abstract
We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer’s dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.
- Published
- 2023
35. Soluble Epoxide Hydrolase Derived Linoleic Acid Oxylipins, Small Vessel Disease Markers, and Neurodegeneration in Stroke
- Author
-
Di Yu, Nuanyi Liang, Julia Zebarth, Qing Shen, Miracle Ozzoude, Maged Goubran, Jennifer S. Rabin, Joel Ramirez, Christopher J. M. Scott, Fuqiang Gao, Robert Bartha, Sean Symons, Seyyed Mohammad Hassan Haddad, Courtney Berezuk, Brian Tan, Donna Kwan, Robert A. Hegele, Allison A. Dilliott, Nuwan D. Nanayakkara, Malcolm A. Binns, Derek Beaton, Stephen R. Arnott, Jane M. Lawrence‐Dewar, Ayman Hassan, Dar Dowlatshahi, Jennifer Mandzia, Demetrios Sahlas, Leanne Casaubon, Gustavo Saposnik, Yurika Otoki, Krista L. Lanctôt, Mario Masellis, Sandra E. Black, Richard H. Swartz, Ameer Y. Taha, Walter Swardfager, Natalie Rashkovan, Agessandro Abrahao, Lorne Zinman, Alisia Bonnick, Christopher Scott, Melissa Holmes, Sabrina Adamo, Morris Freedman, Mojdeh Zamyadi, Stephen Arnott, Malcolm Binns, Pradeep Raamana, Stephen Strother, Kelly Sunderland, Athena Theyers, Abiramy Uthirakumaran, Brian Levine, Angela Troyer, Michael Strong, Peter Kleinstiver, Michael Borrie, Elizabeth Finger, Christen Shoesmith, Frederico Faria, Manuel Montero‐Odasso, Yanina Sarquis‐Adamson, Alanna Black, Allison Ann Dilliott, Rob Hegele, John Robinson, Sali Farhan, Rob Bartha, Hassan Haddad, Nuwan Nanayakkara, Guangyong Zou, Stephen Pasternak, JB Orange, Angela Roberts, Mandar Jog, Dallas Seitz, Don Brien, Ying Chen, Brian Coe, Doug Munoz, Paula McLaughlin, Alicia Peltsch, Susan Bronskill, Wendy Lou, Sanjeev Kumar, Bruce Pollock, Tarek Rajji, David Tang‐Wai, Carmela Tartaglia, Brenda Varriano, Marvin Chum, John Turnbull, Jane Lawrence‐Dewar, Julia Fraser, Bill McIlroy, Ben Cornish, Karen Van Ooteghem, Chris Hudson, Elena Leontieva, Wendy Hatch, Faryan Tayyari, Sherif Defrawy, Edward Margolin, Efrem Mandelcorn, Barry Greenberg, Anthony Lang, Connie Marras, Andrew Frank, David Grimes, Dennis Bulman, John Woulfe, Mahdi Ghani, Tom Steeves, David Munoz, Corinne Fischer, Ekaterina Rogaeva, Sujeevini Sujanthan, David Breen, and Roger A. Dixon
- Subjects
Epoxide Hydrolases ,small vessel disease ,white matter hyperintensity ,Neurosciences ,Water ,lacunar stroke ,soluble epoxide hydrolase ,Cardiorespiratory Medicine and Haematology ,oxylipin ,Magnetic Resonance Imaging ,Brain Disorders ,Linoleic Acid ,Stroke ,Cerebral Small Vessel Diseases ,Humans ,Biomedical Imaging ,Oxylipins ,Atrophy ,Cardiology and Cardiovascular Medicine ,ONDRI Investigators [Link] - Abstract
Background Cerebral small vessel disease is associated with higher ratios of soluble‐epoxide hydrolase derived linoleic acid diols (12,13‐dihydroxyoctadecenoic acid [DiHOME] and 9,10‐DiHOME) to their parent epoxides (12(13)‐epoxyoctadecenoic acid [EpOME] and 9(10)‐EpOME); however, the relationship has not yet been examined in stroke. Methods and Results Participants with mild to moderate small vessel stroke or large vessel stroke were selected based on clinical and imaging criteria. Metabolites were quantified by ultra‐high‐performance liquid chromatography–mass spectrometry. Volumes of stroke, lacunes, white matter hyperintensities, magnetic resonance imaging visible perivascular spaces, and free water diffusion were quantified from structural and diffusion magnetic resonance imaging (3 Tesla). Adjusted linear regression models were used for analysis. Compared with participants with large vessel stroke (n=30), participants with small vessel stroke (n=50) had a higher 12,13‐DiHOME/12(13)‐EpOME ratio (β=0.251, P =0.023). The 12,13‐DiHOME/12(13)‐EpOME ratio was associated with more lacunes (β=0.266, P =0.028) but not with large vessel stroke volumes. Ratios of 12,13‐DiHOME/12(13)‐EpOME and 9,10‐DiHOME/9(10)‐EpOME were associated with greater volumes of white matter hyperintensities (β=0.364, P P P =0.011; β=0.314, P =0.006). In small vessel stroke, the 12,13‐DiHOME/12(13)‐EpOME ratio was associated with higher white matter free water diffusion (β=0.439, P =0.016), which was specific to the temporal lobe in exploratory regional analyses. The 9,10‐DiHOME/9(10)‐EpOME ratio was associated with temporal lobe atrophy (β=−0.277, P =0.031). Conclusions Linoleic acid markers of cytochrome P450/soluble‐epoxide hydrolase activity were associated with small versus large vessel stroke, with small vessel disease markers consistent with blood brain barrier and neurovascular‐glial disruption, and temporal lobe atrophy. The findings may indicate a novel modifiable risk factor for small vessel disease and related neurodegeneration.
- Published
- 2022
36. Identification of a sex-specific genetic signature in dementia with Lewy bodies: a meta-analysis of genome-wide association studies
- Author
-
Elizabeth Gibbons, Arvid Rongve, Itziar de Rojas, Alexey Shadrin, Kaitlyn Westra, Allison Baumgartner, Levi Rosendall, Zachary Madaj, Dena G. Hernandez, Owen A. Ross, Valentina Escott-Price, Claire Shepherd, Laura Parkkinen, Sonja W. Scholz, Juan C. Troncoso, Olga Pletnikova, Ted Dawson, Liana Rosenthal, Olaf Ansorge, Jordi Clarimon, Alberto Lleo, Estrella Morenas-Rodriguez, Lorraine Clark, Lawrence S Honig, Karen Marder, Afina Lemstra, Ekaterina Rogaeva, Peter St. George-Hyslop, Elisabet Londos, Henrik Zetterberg, Kevin Morgan, Claire Troakes, Safa Al-Sarraj, Tammaryn Lashley, Janice Holton, Yaroslau Compta, Vivianna Van Deerlin, Geidy E Serrano, Thomas G Beach, Suzanne Lesage, Douglas Galasko, Eliezer Masliah, Isabel Santana, Pau Pastor, Monica Diez-Fairen, Miquel Aguilar, Marta Marquie, Pablo Garcia-Gonzalez, Claudia Olive, Raquel Puerta, Amanda Cano, Oscar Sotolongo-Grau, Sergi Valero, Vanesa Veronica Pytel, Maitee Rosende-Roca, Montserrat Alegret, Lluis Tarraga, Merce Boada, Angel Carracedo, Emilio Franco-Macias, Jordi Perez-Tur, Jose Luis Royo, Jose Maria Garcia-Alberca, Luis Miguel Real, Maria Eugenia Saez, Maria Jesus Bullido, Miguel Calero, Miguel Medina, Pablo Mir, Pascual Sanchez-Juan, Victoria Alvarez, Kayenat Parveen, Kumar Parijat Tripathi, Stefanie Heilmann-Heimbach, Alfredo Ramirez, Pentti J. Tienari, Olivier Bousiges, Frederic Blanc, Chiara Fenoglio, Alessandro Padovani, Barbara Borroni, Andrea Pilotto, Flavio Nobili, Ingvild Saltvedt, Tormod Fladby, Geir Selbaek, Ingunn Bosnes, Geir Brathen, Annette Hartmann, Afina W. Lemstra, Dan Rujescu, Brit Mollenhauer, Byron Creese, Marie-Christine Chartier-Harlin, Lavinia Athanasiu, Srdjan Djurovic, Leonidas Chouliaras, John T. OBrien, Liisa Myllykangas, Minna Oinas, Tamas Revesz, Andrew Lees, Brad F Boeve, Ronald C. Petersen, Tanis J Ferman, Neill Graff-Radford, Nigel J. Cairns, John C. Morris, Glenda M. Halliday, John Hardy, Dennis W. Dickson, Andrew Singleton, David J. Stone, Ole A. Andreassen, Agustin Ruiz, Dag Aarsland, Rita Guerreiro, and Jose Bras
- Abstract
BackgroundGenome-wide Association Studies (GWAS) have reshaped our understanding of the genetic bases of complex diseases in general and neurodegenerative diseases in particular. Despite being a common disorder, dementia with Lewy bodies (DLB), which, together with Parkinson’s disease dementia (PDD), comprise the umbrella term Lewy body dementias (LBD), is far from being well-characterized genetically. This is primarily due to a lack of familial cases and difficulty recruiting large, deeply characterized cohorts, given the high rate of misdiagnosis. By performing the largest GWAS in DLB, we aimed to identify novel risk loci to gain a better understanding of this disease’s pathobiology.MethodsHere, we conducted the largest meta-analysis of genome-wide association studies performed in LBD, using a total of 5,119 cases and 20,988 controls, from five independent datasets, aggregating all previously published DLB genome-wide association results to date, as well as two previously undescribed cohorts. Additionally, we performed a sex stratified GWAS using the discovery datasets. We updated the heritability estimates for DLB and, to fine map these estimates, we used local heritability analysis. We calculated genetic correlation estimates between DLB and a range of other diseases and traits to identify potential pleiotropy. We also performed gene-set analysis to identify genes with excess burden of rare variability and pathway analysis. Lastly, we used the UK Biobank data to perform a PheWas using individuals at the extremes of genetic risk for DLB.FindingsBetween November 2018 and September 2022 we analyzed 8.6 million single nucleotide polymorphisms in 3293 DLB cases, 1826 LBD cases and 20,988 controls, as well as phenotypes from the UK Biobank dataset. Despite more than doubling the sample size from the previous GWAS in DLB, we did not identify significant loci in addition to those previously reported atGBA, SNCA, STX1B, andAPOE. However, the sex-stratified analysis revealed that theGBAandSNCAsignals are mainly driven by males, suggesting a sex-specific genetic architecture of disease. Using only clinical and neuropathologically diagnosed cases, we highlight four loci surpassing the significance threshold. Using the largest cohort of DLB we update our heritability estimates to 13% and fine map these results highlighting regions of the genome with high heritability but no genome-wide significant result so far.InterpretationThese data provide the most comprehensive analysis of genetic variability in DLB to date. The fact that no novel risk loci have been identified after doubling the cohort size indicates the potentially significant role of rare variants in the genetic architecture of DLB and stresses the urgent need for larger, well-characterized cohorts of this disease for genetic studies. The sex-stratified analysis shows that males and females have different signatures of genetic risk for DLB. These results have widespread implications for clinical practice and clinical trials’ design in DLB.
- Published
- 2022
37. Generation of five induced pluripotent stem cells lines from four members of the same family carrying a C9orf72 repeat expansion and one wild-type member
- Author
-
Chiara Lattuada, Serena Santangelo, Silvia Peverelli, Philip McGoldrick, Ekaterina Rogaeva, Lorne Zinman, Georg Haase, Vincent Géli, Vincenzo Silani, Janice Robertson, Antonia Ratti, and Patrizia Bossolasco
- Subjects
Cell Biology ,General Medicine ,Developmental Biology - Abstract
The most common genetic cause of Amyotrophic Lateral Sclerosis (ALS) is the expansion of a G4C2 hexanucleotide repeat in the C9orf72 gene. The size of the repeat expansion is highly variable and a cut-off of 30 repeats has been suggested as the lower pathological limit. Repeat size variability has been observed intergenerationally and intraindividually in tissues from different organs and within the same tissue, suggesting instability of the pathological repeat expansion. In order to study this genomic instability, we established iPSCs from five members of the same family of which four carried a C9orf72 repeat expansion and one was wild-type.
- Published
- 2022
38. Amyloid-β toxicity modulates tau phosphorylation through the PAX6 signalling pathway
- Author
-
Dana S.M. Wong, Siwen Li, Christopher Bohm, Yahyah Aman, Yalun Zhang, Ming Yue, Yizhen Jia, Evandro Fei Fang, Paul E. Fraser, Binbin Wang, Ekaterina Rogaeva, Dong-Yan Jin, Qiuju Yuan, You-Qiang Song, Kin Chiu, Peter St George-Hyslop, CT Ng, Yi Zhang, Wing-Hin Chau, Zhi-Gang Zhang, and Jennifer K. Griffin
- Subjects
endocrine system ,PAX6 Transcription Factor ,Tau protein ,Hyperphosphorylation ,Mice, Transgenic ,tau Proteins ,Biology ,Mice ,Alzheimer Disease ,Cyclin-dependent kinase ,mental disorders ,Animals ,Humans ,E2F1 ,Phosphorylation ,Transcription factor ,Cells, Cultured ,Amyloid beta-Peptides ,Brain ,Cell cycle ,Peptide Fragments ,Cell biology ,Mice, Inbred C57BL ,HEK293 Cells ,biology.protein ,Neurology (clinical) ,PAX6 ,Signal transduction ,Signal Transduction - Abstract
The molecular link between amyloid-β plaques and neurofibrillary tangles, the two pathological hallmarks of Alzheimer’s disease, is still unclear. Increasing evidence suggests that amyloid-β peptide activates multiple regulators of cell cycle pathways, including transcription factors CDKs and E2F1, leading to hyperphosphorylation of tau protein. However, the exact pathways downstream of amyloid-β-induced cell cycle imbalance are unknown. Here, we show that PAX6, a transcription factor essential for eye and brain development which is quiescent in adults, is increased in the brains of patients with Alzheimer’s disease and in APP transgenic mice, and plays a key role between amyloid-β and tau hyperphosphorylation. Downregulation of PAX6 protects against amyloid-β peptide-induced neuronal death, suggesting that PAX6 is a key executor of the amyloid-β toxicity pathway. Mechanistically, amyloid-β upregulates E2F1, followed by the induction of PAX6 and c-Myb, while Pax6 is a direct target for both E2F1 and its downstream target c-Myb. Furthermore, PAX6 directly regulates transcription of GSK-3β, a kinase involved in tau hyperphosphorylation and neurofibrillary tangles formation, and its phosphorylation of tau at Ser356, Ser396 and Ser404. In conclusion, we show that signalling pathways that include CDK/pRB/E2F1 modulate neuronal death signals by activating downstream transcription factors c-Myb and PAX6, leading to GSK-3β activation and tau pathology, providing novel potential targets for pharmaceutical intervention.
- Published
- 2021
39. Time-course global proteome analyses reveal an inverse correlation between Aβ burden and immunoglobulin M levels in the APPNL-F mouse model of Alzheimer disease.
- Author
-
Hansen Wang, Declan Williams, Jennifer Griffin, Takashi Saito, Takaomi C Saido, Paul E Fraser, Ekaterina Rogaeva, and Gerold Schmitt-Ulms
- Subjects
Medicine ,Science - Abstract
Alzheimer disease (AD) stands out amongst highly prevalent diseases because there is no effective treatment nor can the disease be reliably diagnosed at an early stage. A hallmark of AD is the accumulation of aggregation-prone amyloid β peptides (Aβ), the main constituent of amyloid plaques. To identify Aβ-dependent changes to the global proteome we used the recently introduced APPNL-F mouse model of AD, which faithfully recapitulates the Aβ pathology of the disease, and a workflow that interrogated the brain proteome of these mice by quantitative mass spectrometry at three different ages. The elevated Aβ burden in these mice was observed to cause almost no changes to steady-state protein levels of the most abundant >2,500 brain proteins, including 12 proteins encoded by well-confirmed AD risk loci. The notable exception was a striking reduction in immunoglobulin heavy mu chain (IGHM) protein levels in homozygote APPNL-F/NL-F mice, relative to APPNL-F/wt littermates. Follow-up experiments revealed that IGHM levels generally increase with age in this model. Although discovered with brain samples, the relative IGHM depletion in APPNL-F/NL-F mice was validated to manifest systemically in the blood, and did not extend to other blood proteins, including immunoglobulin G. Results presented are consistent with a cause-effect relationship between the excessive accumulation of Aβ and the selective depletion of IGHM levels, which may be of relevance for understanding the etiology of the disease and ongoing efforts to devise blood-based AD diagnostics.
- Published
- 2017
- Full Text
- View/download PDF
40. Reply: Is Pathology Always the Diagnostic Gold Standard in Neurodegeneration?
- Author
-
Stephen A. Ryan, Mario Masellis, Juan Bilbao, Julia Keith, Ekaterina Rogaeva, Sandra E. Black, Anthony E. Lang, and Galit Kleiner
- Subjects
Neurology ,Neurology (clinical) - Published
- 2022
41. Progressive Supranuclear Palsy Syndrome Associated With a Novel Tauopathy: Case Study
- Author
-
Shelley L. Forrest, Maria Carmela Tartaglia, Ain Kim, Paula Alcaide-Leon, Ekaterina Rogaeva, Anthony Lang, and Gabor G. Kovacs
- Subjects
Neurology (clinical) - Abstract
Background and ObjectivesTo report a novel tauopathy in a patient with protracted course progressive supranuclear palsy (PC-PSP).MethodsThis was a clinical follow-up, gene analysis, neuropathologic study.ResultsA 73-year-old man presented with diplopia, slowness, shuffling gait, and falls. Neurologic examination revealed slowed saccades, restricted up-gaze, and mild parkinsonism. Three years after onset, he developed personality changes. Slowly progressive parkinsonism was associated with memory and executive deficits. MRI showed subtle bilateral hippocampal and midbrain tegmentum atrophy and hyperintensity in the brainstem tegmentum and white matter of the medial temporal lobe. The duration of illness was 11 years. There were no pathogenic mutations in 80 genes known to be involved in neurodegeneration, includingMAPT(H1/H1 haplotype) andAPOE(ε3/ε3 genotype). Neuropathology revealed PSP type pathology together with the pathology described in the novel limbic-predominant neuronal inclusion body 4-repeat tauopathy (LNT) correlating well with the signal alterations seen in MRI.DiscussionOur observation broadens the spectrum of tau pathology associated with PC-PSP and suggests that memory deficit and hippocampal atrophy may be suggestive of non-Alzheimer disease pathology, including LNT. Understanding the diverse range of tau morphologies may help explain phenotypic heterogeneity seen in PSP.
- Published
- 2022
42. Combined epigenetic/genetic study identified an ALS age of onset modifier
- Author
-
Lorne Zinman, Bryan J. Traynor, Zhengrui Xi, Mahdi Montazer Haghighi, Ruth Chia, Ekaterina Rogaeva, Danielle Moreno, Christine Sato, Ming Zhang, and Sara Saez-Atienzar
- Subjects
Oncology ,Epigenomics ,Male ,medicine.medical_specialty ,Heterozygote ,Age of onset ,Locus (genetics) ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,Pathology and Forensic Medicine ,Epigenesis, Genetic ,Cohort Studies ,Cellular and Molecular Neuroscience ,C9orf72 ,Internal medicine ,medicine ,Humans ,Amyotrophic lateral sclerosis ,Modifier ,RC346-429 ,Genetic Association Studies ,Genetic association ,Cathepsin S ,Aged ,DNA methylation ,C9orf72 Protein ,Research ,Amyotrophic Lateral Sclerosis ,dNaM ,Middle Aged ,medicine.disease ,CpG-SNPs ,Female ,Neurology (clinical) ,Neurology. Diseases of the nervous system ,ALS - Abstract
Age at onset of amyotrophic lateral sclerosis (ALS) is highly variable (eg, 27–74 years in carriers of the G4C2-expansion in C9orf72). It might be influenced by environmental and genetic factors via the modulation of DNA methylation (DNAm) at CpG-sites. Hence, we combined an epigenetic and genetic approach to test the hypothesis that some common single nucleotide polymorphisms (SNPs) at CpG-sites (CpG-SNPs) could modify ALS age of onset. Our genome-wide DNAm analysis suggested three CpG-SNPs whose DNAm levels are significantly associated with age of onset in 249 ALS patients (q C9orf72-carriers (n = 333; P = 0.025), suggesting that each A-allele delays onset by 1.6 years. Analysis of Genotype-Tissue Expression data revealed that the protective A-allele is linked with the reduced expression of CTSS in cerebellum (P = 0.00018), which is a critical brain region in the distributed neural circuits subserving motor control. CTSS encodes cathepsin S protein playing a key role in antigen presentation. In conclusion, we identified a 16 Kb locus tagged by rs4970944 as a modifier of ALS age of onset. Our findings support the role of antigen presenting processes in modulating age of onset of ALS and suggest potential drug targets (eg, CTSS). Future replication studies are encouraged to validate the link between the locus tagged by rs4970944 and age of onset in independent ALS cohorts, including different ethnic groups.
- Published
- 2021
43. Drug Repositioning for Alzheimer's Disease Based on Systematic 'omics' Data Mining.
- Author
-
Ming Zhang, Gerold Schmitt-Ulms, Christine Sato, Zhengrui Xi, Yalun Zhang, Ye Zhou, Peter St George-Hyslop, and Ekaterina Rogaeva
- Subjects
Medicine ,Science - Abstract
Traditional drug development for Alzheimer's disease (AD) is costly, time consuming and burdened by a very low success rate. An alternative strategy is drug repositioning, redirecting existing drugs for another disease. The large amount of biological data accumulated to date warrants a comprehensive investigation to better understand AD pathogenesis and facilitate the process of anti-AD drug repositioning. Hence, we generated a list of anti-AD protein targets by analyzing the most recent publically available 'omics' data, including genomics, epigenomics, proteomics and metabolomics data. The information related to AD pathogenesis was obtained from the OMIM and PubMed databases. Drug-target data was extracted from the DrugBank and Therapeutic Target Database. We generated a list of 524 AD-related proteins, 18 of which are targets for 75 existing drugs-novel candidates for repurposing as anti-AD treatments. We developed a ranking algorithm to prioritize the anti-AD targets, which revealed CD33 and MIF as the strongest candidates with seven existing drugs. We also found 7 drugs inhibiting a known anti-AD target (acetylcholinesterase) that may be repurposed for treating the cognitive symptoms of AD. The CAD protein and 8 proteins implicated by two 'omics' approaches (ABCA7, APOE, BIN1, PICALM, CELF1, INPP5D, SPON1, and SOD3) might also be promising targets for anti-AD drug development. Our systematic 'omics' mining suggested drugs with novel anti-AD indications, including drugs modulating the immune system or reducing neuroinflammation that are particularly promising for AD intervention. Furthermore, the list of 524 AD-related proteins could be useful not only as potential anti-AD targets but also considered for AD biomarker development.
- Published
- 2016
- Full Text
- View/download PDF
44. Parkinson's Disease,<scp>NOTCH3</scp>Genetic Variants, and White Matter Hyperintensities
- Author
-
David P. Breen, Connie Marras, Mario Masellis, Malcolm A. Binns, Robert A. Hegele, Ekaterina Rogaeva, Christopher J.M. Scott, David Grimes, Joel Ramirez, Derek Beaton, Allison A Dilliott, Melissa F. Holmes, Sean P. Symons, Donna Kwan, Paula M. McLaughlin, Stephen C. Strother, Anne Joutel, Miracle Ozzoude, Sandra E. Black, Mandar Jog, Richard H. Swartz, Emily C Evans, and Anthony E. Lang
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Parkinson's disease ,Population ,Disease ,behavioral disciplines and activities ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,mental disorders ,medicine ,Humans ,CADASIL ,education ,Receptor, Notch3 ,Ontario ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,Genetic variants ,Bayes Theorem ,Neurodegenerative Diseases ,Parkinson Disease ,Magnetic resonance imaging ,medicine.disease ,Magnetic Resonance Imaging ,White Matter ,Hyperintensity ,030104 developmental biology ,Neurology ,Cohort ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
BACKGROUND White matter hyperintensities (WMH) on magnetic resonance imaging may influence clinical presentation in patients with Parkinson's disease (PD), although their significance and pathophysiological origins remain unresolved. Studies examining WMH have identified pathogenic variants in NOTCH3 as an underlying cause of inherited forms of cerebral small vessel disease. METHODS We examined NOTCH3 variants, WMH volumes, and clinical correlates in 139 PD patients in the Ontario Neurodegenerative Disease Research Initiative cohort. RESULTS We identified 13 PD patients (~9%) with rare (
- Published
- 2020
45. Social cognition impairment in genetic frontotemporal dementia within the GENFI cohort
- Author
-
Rachelle Shafei, Benjamin Bender, Jackie M. Poos, Maria Carmela Tartaglia, Janne M. Papma, Lieke H.H. Meeter, Isabel Santana, Christen Shoesmith, Mikel Tainta, Simon Mead, Albert Lladó, Alazne Gabilondo, Emanuela Rotondo, Alexander Gerhard, Simon Ducharme, Myriam Barandiaran, Mario Masellis, Caroline V. Greaves, Jaume Olives, Rita Guerreiro, Andrea Arighi, Diana Duro NPsych, Sara Mitchell, Roberto Gasparotti, Mathieu Vandenbulcke, Tobias Langheinrich, Thomas E. Cope, Martina Bocchetta, Robart Bartha, Daid Tang-Wai, Jessica L. Panman, Maria Rosário Almeida, Christopher C Butler, Rose Bruffaerts, Núria Bargalló, Pietro Tiraboschi, Beatriz Santiago, Elisabeth Wlasich, Philip Vandamme, Giorgio Giaccone, Sergi Borrego-Écija, Sonja Schönecker, Robert Laforce, Paola Caroppo, Katrina M. Moore, Ione O.C. Woollacott, Maria de Arriba, Veronica Redaelli, Rick van Minkelen, Jorge Villanua, Sónia Afonso, Matthis Synofzik, Nick C. Fox, Jennifer M. Nicholas, David L. Thomas, James B. Rowe, Carlo Wilke, Miren Zulaica, Pedro Rosa-Neto, Jonathan D. Rohrer, Elizabeth Finger, Carolyn Timberlake, C. Ferreira, David M. Cash, Timothy Rittman, Alessandro Padovani, Barbara Borroni, Ricardo Taipa, John C. van Swieten, Sandra V. Loosli, Begoña Indakoetxea, Daniela Galimberti, Sandra E. Black, Ana Gorostidi, Vesna Jelic, Catharina Prix, Ron Keren, Y.A.L. Pijnenburg, Michele Veldsman, Rosa Rademakers, Adrian Danek, Zigor Diaz, Miguel Tábuas-Pereira, Johannes Levin, Raquel Sánchez-Valle, Jose Bras, Rhian S Convery, Silvana Archetti, Markus Otto, Miguel Castelo-Branco, Rik Vandenberghe, Anna Antonell, Fabrizio Tagliavini, Sarah Anderl-Straub, Giuseppe Di Fede, Martin N. Rossor, Carolina Maruta MPsych, Enrico Premi, Giorgio G. Fumagalli, Sara Prioni, Cristina Muscio, Maria João Leitão, Lucy L. Russell, Håkan Thonberg, Ana Verdelho, Gabriel Miltenberger, Ekaterina Rogaeva, Giacomina Rossi, Linn Öijerstedt, Christin Andersson, Caroline Graff, Serge Gauthier, Maura Cosseddu MPsych, Carolin Heller, Stefano Gazzina, Jason D. Warren, Chiara Fenoglio, Tobias Hoegen, Elio Scarpini, Morris Freedman, Fermin Moreno, Mircea Balasa, Lize C. Jiskoot, Alexandre de Mendonça, Paul Thompson, Elisa Semler, Hans-Otto Karnarth, Amsterdam Neuroscience - Neurodegeneration, Neurology, Clinical Genetics, and Repositório da Universidade de Lisboa
- Subjects
Social Cognition ,C9orf72 ,Emotion processing ,Facial emotion recognition ,Faux pas ,Frontotemporal dementia ,MAPT ,Progranulin ,Theory of mind ,1702 Cognitive Sciences ,Medizin ,Social Sciences ,Audiology ,DISEASE ,Behavioural Neurology ,genetics [Progranulins] ,0302 clinical medicine ,Progranulins ,Psychology ,genetics [Frontotemporal Dementia] ,Faux pa ,Psychology, Experimental ,NEUROANATOMY ,05 social sciences ,Genetic FTD Initiative, GENFI ,Experimental Psychology ,MIND ,Magnetic Resonance Imaging ,ORBITOFRONTAL CORTEX ,Neuropsychology and Physiological Psychology ,Frontal lobe ,Frontotemporal Dementia ,Life Sciences & Biomedicine ,Behavioral Sciences ,medicine.medical_specialty ,Cognitive Neuroscience ,FRONTAL VARIANT ,Experimental and Cognitive Psychology ,050105 experimental psychology ,Lateralization of brain function ,Temporal lobe ,03 medical and health sciences ,AGE ,Social cognition ,mental disorders ,medicine ,Humans ,0501 psychology and cognitive sciences ,ddc:610 ,genetics [C9orf72 Protein] ,DECLINE ,Science & Technology ,EMOTION RECOGNITION ,C9orf72 Protein ,Neurosciences ,PERFORMANCE ,medicine.disease ,Facial emotion recognitions ,1701 Psychology ,Mutation ,Orbitofrontal cortex ,Neurosciences & Neurology ,GENDER ,1109 Neurosciences ,Insula ,030217 neurology & neurosurgery - Abstract
© 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)., A key symptom of frontotemporal dementia (FTD) is difficulty interacting socially with others. Social cognition problems in FTD include impaired emotion processing and theory of mind difficulties, and whilst these have been studied extensively in sporadic FTD, few studies have investigated them in familial FTD. Facial Emotion Recognition (FER) and Faux Pas (FP) recognition tests were used to study social cognition within the Genetic Frontotemporal Dementia Initiative (GENFI), a large familial FTD cohort of C9orf72, GRN, and MAPT mutation carriers. 627 participants undertook at least one of the tasks, and were separated into mutation-negative healthy controls, presymptomatic mutation carriers (split into early and late groups) and symptomatic mutation carriers. Groups were compared using a linear regression model with bootstrapping, adjusting for age, sex, education, and for the FP recognition test, language. Neural correlates of social cognition deficits were explored using a voxel-based morphometry (VBM) study. All three of the symptomatic genetic groups were impaired on both tasks with no significant difference between them. However, prior to onset, only the late presymptomatic C9orf72 mutation carriers on the FER test were impaired compared to the control group, with a subanalysis showing differences particularly in fear and sadness. The VBM analysis revealed that impaired social cognition was mainly associated with a left hemisphere predominant network of regions involving particularly the striatum, orbitofrontal cortex and insula, and to a lesser extent the inferomedial temporal lobe and other areas of the frontal lobe. In conclusion, theory of mind and emotion processing abilities are impaired in familial FTD, with early changes occurring prior to symptom onset in C9orf72 presymptomatic mutation carriers. Future work should investigate how performance changes over time, in order to gain a clearer insight into social cognitive impairment over the course of the disease.
- Published
- 2020
46. CAPTURE ALS: the comprehensive analysis platform to understand, remedy and eliminate ALS
- Author
-
Vincent Picher-Martel, Claire Magnussen, Mathieu Blais, Tania Bubela, Samir Das, Annie Dionne, Alan C. Evans, Angela Genge, Russell Greiner, Yasser Iturria-Medina, Wendy Johnston, Kelvin Jones, Hannah Kaneb, Jason Karamchandani, Sara Moradipoor, Janice Robertson, Ekaterina Rogaeva, David M. Taylor, Christine Vande Velde, Yana Yunusova, Lorne Zinman, Sanjay Kalra, and Nicolas Dupré
- Subjects
Neurology ,Neurology (clinical) - Abstract
The absence of disease modifying treatments for amyotrophic lateral sclerosis (ALS) is in large part a consequence of its complexity and heterogeneity. Deep clinical and biological phenotyping of people living with ALS would assist in the development of effective treatments and target specific biomarkers to monitor disease progression and inform on treatment efficacy. The objective of this paper is to present the Comprehensive Analysis Platform To Understand Remedy and Eliminate ALS (CAPTURE ALS), an open and translational platform for the scientific community currently in development. CAPTURE ALS is a Canadian-based platform designed to include participants' voices in its development and through execution. Standardized methods will be used to longitudinally characterize ALS patients and healthy controls through deep clinical phenotyping, neuroimaging, neurocognitive and speech assessments, genotyping and multisource biospecimen collection. This effort plugs into complementary Canadian and international initiatives to share common resources. Here, we describe in detail the infrastructure, operating procedures, and long-term vision of CAPTURE ALS to facilitate and accelerate translational ALS research in Canada and beyond.
- Published
- 2022
47. Epigenetic clock acceleration is linked to age-at-onset of idiopathic and LRRK2 Parkinson’s disease
- Author
-
Xuelin Tang, Paulina Gonzalez-Latapi, Connie Marras, Naomi P. Visanji, Wanli Yang, Christine Sato, Anthony E. Lang, Ekaterina Rogaeva, and Ming Zhang
- Abstract
Parkinson’s disease is a clinically and genetically heterogeneous movement disorder with highly variable age-at-onset. DNA methylation (DNAm) age is an epigenetic clock that could reflect biological aging. Studies of DNAm-age acceleration (difference between DNAm-age and chronological age) are pertinent to neurodegenerative diseases (e.g., Parkinson’s disease), for which aging is the strongest risk-factor. We assessed DNAm-age in idiopathic Parkinson’s disease (n=96) and a longitudinal LRRK2 cohort at four time-points over a 3-year period (n=220), including manifesting (n=91) and non-manifesting (n=129) G2019S-carriers. A highly variable age-at-onset was observed in both the idiopathic cohort (26-77 years) and manifesting G2019S-carriers (39-79 years). Increased DNAm-age acceleration was significantly associated with younger onset in idiopathic and LRRK2-related Parkinson’s disease, suggesting that every 5-year increase in DNAm-age acceleration is linked to about 6-year earlier onset. At an individual level, DNAm-age acceleration remained steady over a 3-year period for most G2019S-carriers, indicating that it might serve as a stable biomarker of biological aging. Future studies should evaluate the stability of DNAm-age acceleration over longer time-periods, especially for phenoconverters from non-manifesting to manifesting subjects. In conclusion, DNAm-age acceleration is linked to disease onset, and could be used in disease-modifying clinical trials of prodromal Parkinson’s disease.
- Published
- 2022
48. A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers
- Author
-
Yolande A.L. Pijnenburg, Alessandro Padovani, Lieke H.H. Meeter, Rita Guerreiro, Mathieu Vandenbulcke, Rose Bruffaerts, Sonja Schönecker, Sofia Bergström, Florence Pasquier, Mikel Tainta, Beatriz Santiago, Roberto Gasparotti, Maria Rosário Almeida, Núria Bargalló, Abbe Ullgren, Martina Bocchetta, James B. Rowe, Pietro Tiraboschi, Robart Bartha, Rachelle Shafei, Benjamin Bender, Anna Månberg, Enrico Premi, Sergi Borrego-Écija, Sandro Sorbi, Christopher C Butler, Rick van Minkelen, Alberto Benussi, Marta Cañada, Carlo Wilke, Christin Andersson, Caroline Graff, Isabel Santana, Elisa Semler, Valentina Bessi, Miren Zulaica, Benedetta Nacmias, Tobias Langheinrich, Christen Shoesmith, Philip Van Damme, Camilla Ferrari, Martin Rosser, Pedro Rosa-Neto, Alexandre de Mendonça, Jennifer M. Nicholas, Catharina Prix, Sebastien Ourselin, Michele Veldsman, Jessica L. Panman, Håkan Thonberg, Jennie Olofsson, Paul M. Thompson, Ana Gorostidi, Andrea Arighi, Raquel Sánchez-Valle, Anna Antonell, Vesna Jelic, Ana Verdelho, Sara Mitchell, Janne M. Papma, Alina Díez, Giuliano Binetti, Rhian S Convery, Silvana Archetti, Ekaterina Rogaeva, Michela Pievani, C. Ferreira, Hans-Otto Karnath, Veronica Redaelli, Giuseppe Di Fede, Giovanni B. Frisoni, Carolina Maruta, Giacomina Rossi, Jaume Olives, Simon Ducharme, Roberta Ghidoni, Alexander Gerhard, Ron Keren, Johannes Levin, Sandra V. Loosli, Jose Bras, Isabelle Le Ber, Emily Todd, Robert Laforce, Sónia Afonso, Matthis Synofzik, Alazne Gabilondo, Elizabeth Finger, Thomas E. Cope, Paola Caroppo, Jorge Villanua, Diana Duro, Georgia Peakman, Giorgio G. Fumagalli, Serge Gauthier, Mario Masellis, Markus Otto, Caroline V. Greaves, Carolyn Timberlake, Harro Seelaar, Ione O.C. Woollacott, Sara Prioni, Jason D. Warren, Cristina Polito, Miguel Tábuas-Pereira, David F. Tang-Wai, Carmela Tartaglia, Linn Öijerstedt, Luisa Benussi, Barbara Borroni, Ricardo Taipa, Albert Lladó, Mircea Balasa, Rosa Rademakers, Lize C. Jiskoot, Miguel Castelo-Branco, Julia Remnestål, Fabrizio Tagliavini, Giorgio Giaccone, Maria João Leitão, Henrik Zetterberg, Valentina Cantoni, Daniela Galimberti, Sarah Anderl-Straub, Simon Mead, Myriam Barandiaran, Adrian Danek, Timothy Rittman, Chiara Fenoglio, Katrina M. Moore, David M. Cash, Rik Vandenberghe, Peter Nilsson, Elisabeth Wlasich, John C. van Swieten, Morris Freedman, Sandra E. Black, Carolin Heller, Stefano Gazzina, Gabriel Miltenberger, Fermin Moreno, Nick C. Fox, David L. Thomas, Jonathan D. Rohrer, Begoña Indakoetxea, Tobias Hoegen, Gemma Lombardi, Elio Scarpini, Bergström, Sofia [0000-0003-2910-4754], Apollo - University of Cambridge Repository, Neurology, Amsterdam Neuroscience - Neurodegeneration, Genetic Frontotemporal Dementia Initiative (GENFI), Jiskoot, Lize (Beitragende*r), Rowe, James B. (Beitragende*r), de Mendonça, Alexandre (Beitragende*r), Tagliavini, Fabrizio (Beitragende*r), Santana, Isabel (Beitragende*r), Le Ber, Isabelle (Beitragende*r), Levin, Johannes (Beitragende*r), Danek, Adrian (Beitragende*r), Otto, Markus (Beitragende*r), Frisoni, Giovanni (Beitragende*r), Ghidoni, Roberta (Beitragende*r), Sorbi, Sandro (Beitragende*r), Pasquier, Florence (Beitragende*r), Jelic, Vesna (Beitragende*r), Andersson, Christin (Beitragende*r), Afonso, Sónia (Beitragende*r), Almeida, Maria Rosario (Beitragende*r), Anderl-Straub, Sarah (Beitragende*r), Antonell, Anna (Beitragende*r), Archetti, Silvana (Beitragende*r), Arighi, Andrea (Beitragende*r), Balasa, Mircea (Beitragende*r), Barandiaran, Myriam (Beitragende*r), Bargalló, Nuria (Beitragende*r), Bartha, Robart (Beitragende*r), Bender, Benjamin (Beitragende*r), Benussi, Alberto (Beitragende*r), Benussi, Luisa (Beitragende*r), Bessi, Valentina (Beitragende*r), Binetti, Giuliano (Beitragende*r), Black, Sandra (Beitragende*r), Bocchetta, Martina (Beitragende*r), Borrego-Ecija, Sergi (Beitragende*r), Bras, Jose (Beitragende*r), Bruffaerts, Rose (Beitragende*r), Cañada, Marta (Beitragende*r), Cantoni, Valentina (Beitragende*r), Caroppo, Paola (Beitragende*r), Cash, David (Beitragende*r), Castelo-Branco, Miguel (Beitragende*r), Convery, Rhian (Beitragende*r), Cope, Thomas (Beitragende*r), Di Fede, Giuseppe (Beitragende*r), Díez, Alina (Beitragende*r), Duro, Diana (Beitragende*r), Fenoglio, Chiara (Beitragende*r), Ferrari, Camilla (Beitragende*r), Ferreira, Catarina B. (Beitragende*r), Fox, Nick (Beitragende*r), Freedman, Morris (Beitragende*r), Fumagalli, Giorgio (Beitragende*r), Gabilondo, Alazne (Beitragende*r), Gasparotti, Roberto (Beitragende*r), Gauthier, Serge (Beitragende*r), Gazzina, Stefano (Beitragende*r), Giaccone, Giorgio (Beitragende*r), Gorostidi, Ana (Beitragende*r), Greaves, Caroline (Beitragende*r), Guerreiro, Rita (Beitragende*r), Heller, Carolin (Beitragende*r), Hoegen, Tobias (Beitragende*r), Indakoetxea, Begoña (Beitragende*r), Karnath, Hans-Otto (Beitragende*r), Keren, Ron (Beitragende*r), Langheinrich, Tobias (Beitragende*r), Leitão, Maria João (Beitragende*r), Lladó, Albert (Beitragende*r), Lombardi, Gemma (Beitragende*r), Loosli, Sandra (Beitragende*r), Maruta, Carolina (Beitragende*r), Mead, Simon (Beitragende*r), Meeter, Lieke (Beitragende*r), Miltenberger, Gabriel (Beitragende*r), van Minkelen, Rick (Beitragende*r), Mitchell, Sara (Beitragende*r), Moore, Katrina (Beitragende*r), Nacmias, Benedetta (Beitragende*r), Nicholas, Jennifer (Beitragende*r), Olives, Jaume (Beitragende*r), Ourselin, Sebastien (Beitragende*r), Padovani, Alessandro (Beitragende*r), Panman, Jessica (Beitragende*r), Papma, Janne M. (Beitragende*r), Peakman, Georgia (Beitragende*r), Pievani, Michela (Beitragende*r), Pijnenburg, Yolande (Beitragende*r), Polito, Cristina (Beitragende*r), Premi, Enrico (Beitragende*r), Prioni, Sara (Beitragende*r), Prix, Catharina (Beitragende*r), Rademakers, Rosa (Beitragende*r), Redaelli, Veronica (Beitragende*r), Rittman, Tim (Beitragende*r), Rogaeva, Ekaterina (Beitragende*r), Rosa-Neto, Pedro (Beitragende*r), Rossi, Giacomina (Beitragende*r), Rosser, Martin (Beitragende*r), Santiago, Beatriz (Beitragende*r), Scarpini, Elio (Beitragende*r), Schönecker, Sonja (Beitragende*r), Semler, Elisa (Beitragende*r), Shafei, Rachelle (Beitragende*r), Shoesmith, Christen (Beitragende*r), Tábuas-Pereira, Miguel (Beitragende*r), Tainta, Mikel (Beitragende*r), Taipa, Ricardo (Beitragende*r), Tang-Wai, David (Beitragende*r), Thomas, David L. (Beitragende*r), Thompson, Paul (Beitragende*r), Thonberg, Håkan (Beitragende*r), Timberlake, Carolyn (Beitragende*r), Tiraboschi, Pietro (Beitragende*r), Todd, Emily (Beitragende*r), Van Damme, Philip (Beitragende*r), Vandenbulcke, Mathieu (Beitragende*r), Veldsman, Michele (Beitragende*r), Verdelho, Ana (Beitragende*r), Villanua, Jorge (Beitragende*r), Warren, Jason (Beitragende*r), Wilke, Carlo (Beitragende*r), Woollacott, Ione (Beitragende*r), Wlasich, Elisabeth (Beitragende*r), Zetterberg, Henrik (Beitragende*r), and Zulaica, Miren (Beitragende*r)
- Subjects
medicine.medical_specialty ,Neurology ,NEFM ,Medizin ,genetics [Mutation] ,LASSO ,Biology ,Aquaporin 4 (AQP4) ,Neurosecretory protein VGF (VGF) ,DISEASE ,genetics [Progranulins] ,Cellular and Molecular Neuroscience ,Progranulins ,CEREBROSPINAL-FLUID ,C9orf72 ,ddc:570 ,medicine ,CRITERIA ,Humans ,Neuronal pentraxin 2 (NPTX2) ,RC346-429 ,genetics [Frontotemporal Dementia] ,Molecular Biology ,Pathological ,Genetics ,Science & Technology ,Neurosciences ,RC952-954.6 ,Brain ,Neurofilament medium polypeptide (NEFM) ,medicine.disease ,Molecular medicine ,Cerebrospinal fluid ,Aquaporin 4 ,Geriatrics ,Suspension bead array ,Frontotemporal Dementia ,Mutation ,Mutation (genetic algorithm) ,Neurosciences & Neurology ,Neurology. Diseases of the nervous system ,Neurology (clinical) ,Life Sciences & Biomedicine ,Random forest ,Biomarkers ,Research Article ,Frontotemporal dementia - Abstract
Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Supplementary Information: Additional file 1 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study; Additional file 2 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study; both files are available online at https://doi.org/10.1186/s13024-021-00499-4 Copyright © The Author(s) 2021. Background: A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. Methods: A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. Results: When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). Conclusion: In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD. This study has received support from the Swedish FTD initiative funded by the Schörling Family Foundation. This work was also funded by KTH Center for Applied Precision Medicine (KCAP) funded by the Erling-Persson Family Foundation, grants from Vetenskapsrådet Dnr 529-2014-7504, VR 2015-02926 and 2018-02754, Swedish Alzheimer Foundation, Swedish Brain Foundation, Åhlén foundation, Demensfonden, Stohnes foundation, Gamla Tjänarinnor and Stockholm County Council ALF. Furthermore, support was received by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project, the JPND GENFI-PROX grant (2019-02248), the Dioraphte Foundation [grant numbers 09-02-00]; the Association for Frontotemporal Dementias Research Grant 2009; The Netherlands Organization for Scientific Research (NWO) (grant HCMI 056-13-018); ZonMw Memorabel (Deltaplan Dementie), (project numbers 733 050 103 and 733 050 813); JPND PreFrontAls consortium (project number 733051042). JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510. M.S. was supported by the JPND grant “GENFI-prox” (by DLR/BMBF to M. S, joint with JDR., J.vS., M.O., B.B. and C.G.). Open Access funding provided by Royal Institute of Technology.
- Published
- 2021
49. Contribution of rare variant associations to neurodegenerative disease presentation
- Author
-
Ekaterina Rogaeva, Leanne K. Casaubon, David F. Tang-Wai, Corinne E. Fischer, Michael Borrie, Morris Freedman, Christen Shoesmith, Donna Kwan, Elizabeth Finger, Brian Tan, Maria Carmela Tartaglia, Gustavo Saposnik, Sanjeev Kumar, Malcolm A. Binns, Dallas Seitz, Sandra E. Black, Mandar Jog, Richard H. Swartz, Sali M K Farhan, John Turnbull, Andrew Frank, Abdalla Abdelhady, Bruce G. Pollock, Kelly M Sunderland, Robert A. Hegele, David Grimes, Agessandro Abrahao, Stephen H. Pasternak, Thomas Steeves, Demetrios J. Sahlas, Dar Dowlatshahi, Christine Sato, Ayman Hassan, Anthony E. Lang, Lorne Zinman, Ondri Investigators, Mario Masellis, Adam D. McIntyre, Allison A Dilliott, Tarek K. Rajji, and Jennifer Mandzia
- Subjects
Nonsynonymous substitution ,Genetics ,Neurodegenerative diseases ,Neurodegeneration ,Disease ,QH426-470 ,Targeted resequencing ,Biology ,medicine.disease ,Article ,Disease Presentation ,medicine ,Medicine ,Amyotrophic lateral sclerosis ,Molecular Biology ,Genetics (clinical) ,Loss function ,Genetic association study ,Genetic association ,Frontotemporal dementia - Abstract
Genetic factors contribute to neurodegenerative diseases, with high heritability estimates across diagnoses; however, a large portion of the genetic influence remains poorly understood. Many previous studies have attempted to fill the gaps by performing linkage analyses and association studies in individual disease cohorts, but have failed to consider the clinical and pathological overlap observed across neurodegenerative diseases and the potential for genetic overlap between the phenotypes. Here, we leveraged rare variant association analyses (RVAAs) to elucidate the genetic overlap among multiple neurodegenerative diagnoses, including Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), mild cognitive impairment, and Parkinson’s disease (PD), as well as cerebrovascular disease, using the data generated with a custom-designed neurodegenerative disease gene panel in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). As expected, only ~3% of ONDRI participants harboured a monogenic variant likely driving their disease presentation. Yet, when genes were binned based on previous disease associations, we observed an enrichment of putative loss of function variants in PD genes across all ONDRI cohorts. Further, individual gene-based RVAA identified significant enrichment of rare, nonsynonymous variants in PARK2 in the FTD cohort, and in NOTCH3 in the PD cohort. The results indicate that there may be greater heterogeneity in the genetic factors contributing to neurodegeneration than previously appreciated. Although the mechanisms by which these genes contribute to disease presentation must be further explored, we hypothesize they may be a result of rare variants of moderate phenotypic effect contributing to overlapping pathology and clinical features observed across neurodegenerative diagnoses.
- Published
- 2021
50. SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration
- Author
-
Barbier, Mathieu, Camuzat, Agnès, Hachimi, Khalid El, Guegan, Justine, Rinaldi, Daisy, Lattante, Serena, Houot, Marion, Sánchez-Valle, Raquel, Sabatelli, Mario, Antonell, Anna, Molina-Porcel, Laura, Clot, Fabienne, Couratier, Philippe, van der Ende, Emma, van der Zee, Julie, Manzoni, Claudia, Camu, William, Cazeneuve, Cécile, Sellal, François, Didic, Mira, Golfier, Véronique, Pasquier, Florence, Duyckaerts, Charles, Rossi, Giacomina, Bruni, Amalia C, Alvarez, Victoria, Gómez-Tortosa, Estrella, de Mendonça, Alexandre, Graff, Caroline, Masellis, Mario, Nacmias, Benedetta, Oumoussa, Badreddine Mohand, Jornea, Ludmila, Forlani, Sylvie, Van Deerlin, Viviana, Rohrer, Jonathan D, Gelpi, Ellen, Rademakers, Rosa, Van Swieten, John, Le Guern, Eric, Van Broeckhoven, Christine, Ferrari, Raffaele, Génin, Emmanuelle, Brice, Alexis, Ber, Le, Isabelle Alexis Brice, Sophie, Auriacombe, Serge, Belliard, Anne, Bertrand, Anne, Bissery, Fre ́ de, ́ ric Blanc, Marie-Paule, Boncoeur, Ste, ́ phanie Bombois, Claire Boutoleau-Bretonnie` re, Agne`, s Camuzat, Mathieu, Ceccaldi, Marie, Chupin, Philippe, Couratier, Olivier, Colliot, Vincent, Deramecourt, Mira, Didic, Bruno, Dubois, Charles, Duyckaerts, Fre ́ de, ́ rique Etcharry-Bouyx, Aure, ́ lie Guignebert-Funkiewiez, Maı ̈te, ́ Formaglio, ́ ronique Golfier, Ve, Marie-Odile, Habert, Didier, Hannequin, Lucette, Lacomblez, Julien, Lagarde, ́ raldine Lautrette, Ge, Isabelle Le Ber, Benjamin Le Toullec, Richard, Levy, Marie-Anne, Mackowiak, Bernard-Franc ̧ois Michel, Florence, Pasquier, Thibaud, Lebouvier, Carole Roue, ́ -Jagot, Christel Thauvin- Robinet, Catherine, Thomas-Anterion, Je ́ re, ́ mie Pariente, Franc ̧ois Salachas, Sabrina, Sayah, Franc ̧ois Sellal, Assi-Herve, ́ Oya, Daisy, Rinaldi, Adeline, Rollin-Sillaire, Martine, Vercelletto, David, Wallon, Armelle, Rametti-Lacroux, Raffaele, Ferrari, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Adaikalavan, Ramasamy, Kwok, John B. J., Carol Dobson- Stone, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Olivier, Piguet, Lauren, Bartley, Elizabeth, Thompson, Isabel Herna, ́ ndez, Agustı ́n Ruiz, Merce`, Boada, Barbara, Borroni, Alessandro, Padovani, Carlos, Cruchaga, Cairns, Nigel J., Luisa, Benussi, Giuliano, Binetti, Roberta, Ghidoni, Gianluigi, Forloni, Diego, Albani, Daniela, Galimberti, Chiara, Fenoglio, Maria, Serpente, Elio, Scarpini, ́ n, Jordi Clarimo, Alberto Lleo, ́, Rafael, Blesa, Maria Landqvist Waldo, ̈, Karin, Nilsson, Christer, Nilsson, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Jordan, Grafman, Morris, Christopher M., Johannes, Attems, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Pietro, Pietrini, Edward, Uey, Wassermann, Eric M., Atik, Baborie, Evelyn, Jaros, Tierney, Michael C., Pau, Pastor, Cristina, Razquin, Sara, Ortega-Cubero, Elena, Alonso, Robert, Perneczky, Janine, Diehl-Schmid, Panagiotis, Alexopoulos, Alexander, Kurz, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Ekaterina, Rogaeva, Peter St George-Hyslop, Giacomina, Rossi, Fabrizio, Tagliavini, Giorgio, Giaccone, Rowe, James B., Schlachetzki, Johannes C. M., James, Uphill, John, Collinge, Simon, Mead, Adrian, Danek, Van Deerlin, Vivianna M., Murray, Grossman, Trojanowski, John Q., Julie van der Zee, Christine Van Broeckhoven, Cappa, Stefano F., Isabelle, Leber, Alexis, Brice, Benedetta, Nacmias, Sandro, Sorbi, Silvia, Bagnoli, Irene, Piaceri, Nielsen, Jørgen E., Hjermind, Lena E., Matthias, Riemenschneider, Manuel, Mayhaus, Bernd, Ibach, Gilles, Gasparoni, Sabrina, Pichler, Wei, Gu, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Maria Grazia Spillantini, Morris, Huw R., Patrizia, Rizzu, Peter, Heutink, Snowden, Julie S., Sara, Rollinson, Anna, Richardson, Alexander, Gerhard, Bruni, Amalia C., Raffaele, Maletta, Francesca, Frangipane, Chiara, Cupidi, Livia, Bernardi, Maria, Anfossi, Maura, Gallo, Maria Elena Conidi, Nicoletta, Smirne, Rosa, Rademakers, Matt, Baker, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., David, Knopman, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Howard, Rosen, van Swieten, John C., Dopper, Elise G. P., Harro, Seelaar, Pijnenburg, Yolande A. L., Philip, Scheltens, Giancarlo, Logroscino, Rosa, Capozzo, Valeria, Novelli, Puca, Annibale A., Massimo, Franceschi, Alfredo, Postiglione, Graziella, Milan, Paolo, Sorrentino, Mark, Kristiansen, Huei-Hsin, Chiang, Caroline, Graff, Adeline, Rollin, Dimitrios, Kapogiannis, Luigi, Ferrucci, Stuart, Pickering-Brown, Singleton, Andrew B., John, Hardy, Parastoo, Momeni., Neurology, Amsterdam Neuroscience - Neurodegeneration, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Dupuytren [CHU Limoges], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Center for Molecular Neurology (VIB-UAntwerp), University of Antwerp (UA), University College of London [London] (UCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Yves le Foll, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Hospital Central de Asturias, Institute of Health Research of Principado de Asturias (ISPA), Fundación Jiménez Díaz, Fundacion Jimenez Diaz [Madrid] (FJD), Faculdade de Medicina [Lisboa], Universidade de Lisboa = University of Lisbon (ULISBOA), Karolinska University Hospital [Stockholm], Sunnybrook Research Institute [Toronto] (SRI), Sunnybrook Health Sciences Centre, Università degli Studi di Firenze = University of Florence (UniFI), Fondazione Don Carlo Gnocchi, Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), The French clinical and genetic Research network on FTLD/FTLD-ALS and PREVDEMALS, The International Frontotemporal Dementia Genomics Consortium, The European Early Onset Dementia (EU -EOD) Consortium, Brainbank Neuro-CEB Neuropathology Network, and Neurological Tissue Bank of the Biobank Hospital Clinic-IDIBAPS
- Subjects
Adult ,Male ,TDP-43 ,C9orf72 ,SLITRK2 ,amyotrophic lateral sclerosis ,frontotemporal dementia ,Nerve Tissue Proteins ,Settore MED/03 - GENETICA MEDICA ,Polymorphism, Single Nucleotide ,Cohort Studies ,Genes, X-Linked ,80 and over ,Medicine ,Dementia ,Humans ,Allele ,Age of Onset ,Polymorphism ,Aged ,Aged, 80 and over ,biology ,C9orf72 Protein ,business.industry ,Membrane Proteins ,MESH: Frontotemporal Lobar Degeneration / epidemiology ,Frontotemporal Lobar ,Degeneration / genetics ,Genes, X-Linked / genetics ,Genome-Wide Association Study / methods ,Frontotemporal lobar degeneration ,Single Nucleotide ,Middle Aged ,X-Linked ,medicine.disease ,Amyotrophic lateral sclerosis ,Minor allele frequency ,Genes ,Immunology ,Synaptophysin ,biology.protein ,Female ,MESH: Adult ,C9orf72 Protein / genetics ,Frontotemporal Lobar Degeneration / diagnosis ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Human medicine ,Neurology (clinical) ,MESH: Humans ,Membrane Proteins / genetics ,Nerve Tissue Proteins / genetics ,Polymorphism, Single Nucleotide / genetics ,Age of onset ,Frontotemporal Lobar Degeneration ,business ,Frontotemporal dementia ,Genome-Wide Association Study - Abstract
The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.
- Published
- 2021
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.