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1. Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia.

Author

Manzoni, Claudia, Kia, Demis, Ferrari, Raffaele, Leonenko, Ganna, Costa, Beatrice, Saba, Valentina, Jabbari, Edwin, Tan, Manuela, Albani, Diego, Alvarez, Victoria, Alvarez, Ignacio, Andreassen, Ole, Angiolillo, Antonella, Arighi, Andrea, Baker, Matt, Benussi, Luisa, Bessi, Valentina, Binetti, Giuliano, Blackburn, Daniel, Boada, Merce, Boeve, Bradley, Borrego-Ecija, Sergi, Borroni, Barbara, Bråthen, Geir, Brooks, William, Bruni, Amalia, Caroppo, Paola, Bandres-Ciga, Sara, Clarimon, Jordi, Colao, Rosanna, Cruchaga, Carlos, Danek, Adrian, de Boer, Sterre, de Rojas, Itziar, di Costanzo, Alfonso, Dickson, Dennis, Diehl-Schmid, Janine, Dobson-Stone, Carol, Dols-Icardo, Oriol, Donizetti, Aldo, Dopper, Elise, Durante, Elisabetta, Ferrari, Camilla, Forloni, Gianluigi, Frangipane, Francesca, Fratiglioni, Laura, Kramberger, Milica, Galimberti, Daniela, Gallucci, Maurizio, García-González, Pablo, Ghidoni, Roberta, Giaccone, Giorgio, Graff, Caroline, Graff-Radford, Neill, Grafman, Jordan, Halliday, Glenda, Hernandez, Dena, Hjermind, Lena, Hodges, John, Holloway, Guy, Huey, Edward, Illán-Gala, Ignacio, Josephs, Keith, Knopman, David, Kristiansen, Mark, Kwok, John, Leber, Isabelle, Leonard, Hampton, Libri, Ilenia, Lleo, Alberto, Mackenzie, Ian, Madhan, Gaganjit, Maletta, Raffaele, Marquié, Marta, Maver, Ales, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce, Morris, Christopher, Morris, Huw, Nacmias, Benedetta, Newton, Judith, Nielsen, Jørgen, Nilsson, Christer, Novelli, Valeria, Padovani, Alessandro, Pal, Suvankar, Pasquier, Florence, Pastor, Pau, Perneczky, Robert, Peterlin, Borut, Petersen, Ronald, Piguet, Olivier, Pijnenburg, Yolande, Puca, Annibale, Rademakers, Rosa, Rainero, Innocenzo, Reus, Lianne, Richardson, Anna, and Riemenschneider, Matthias

Subjects
Humans, Frontotemporal Dementia, tau Proteins, Genome-Wide Association Study, Apolipoproteins E, Male, Female, Genetic Predisposition to Disease, Aged, Polymorphism, Single Nucleotide, Genetic Loci, Middle Aged, Case-Control Studies, Myelin Proteins
Abstract

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10-12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10-12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10-8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.

Published
2024

3. Gene Expression Imputation Across Multiple Tissue Types Provides Insight Into the Genetic Architecture of Frontotemporal Dementia and Its Clinical Subtypes

Author

Reus, Lianne M, Pasaniuc, Bogdan, Posthuma, Danielle, Boltz, Toni, Consortium, International FTD-Genomics, Ferrari, Raffaele, Hernandez, Dena G, Nalls, Michael A, Rohrer, Jonathan D, Ramasamy, Adaikalavan, Kwok, John BJ, Dobson-Stone, Carol, Brooks, William S, Schofield, Peter R, Halliday, Glenda M, Hodges, John R, Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian RA, Hsiung, Ging-Yuek R, Mann, David MA, Grafman, Jordan, Morris, Christopher M, Attems, Johannes, Griffiths, Timothy D, McKeith, Ian G, Thomas, Alan J, Pietrini, Pietro, Huey, Edward D, Wassermann, Eric M, Baborie, Atik, Jaros, Evelyn, Tierney, Michael C, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B, Schlachetzki, Johannes CM, Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M, Grossman, Murray, Trojanowski, John Q, van der Zee, Julie, Van Broeckhoven, Christine, Cappa, Stefano F, Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E, Hjermind, Lena E, Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, and Gu, Wei

Subjects
Biological Sciences, Genetics, Acquired Cognitive Impairment, Frontotemporal Dementia (FTD), Aging, Dementia, Neurodegenerative, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Prevention, Alzheimer's Disease Related Dementias (ADRD), Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Neurological, Frontotemporal Dementia, Gene Expression, Humans, International FTD-Genomics Consortium, 17q21.31 inversion region, Dorsolateral prefrontal cortex, Expression quantitative trait loci, Frontotemporal dementia, SEC22B, Transcriptome-wide association study, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Biological sciences, Biomedical and clinical sciences, Psychology
Abstract

BackgroundThe etiology of frontotemporal dementia (FTD) is poorly understood. To identify genes with predicted expression levels associated with FTD, we integrated summary statistics with external reference gene expression data using a transcriptome-wide association study approach.MethodsFUSION software was used to leverage FTD summary statistics (all FTD: n = 2154 cases, n = 4308 controls; behavioral variant FTD: n = 1337 cases, n = 2754 controls; semantic dementia: n = 308 cases, n = 616 controls; progressive nonfluent aphasia: n = 269 cases, n = 538 controls; FTD with motor neuron disease: n = 200 cases, n = 400 controls) from the International FTD-Genomics Consortium with 53 expression quantitative loci tissue type panels (n = 12,205; 5 consortia). Significance was assessed using a 5% false discovery rate threshold.ResultsWe identified 73 significant gene-tissue associations for FTD, representing 44 unique genes in 34 tissue types. Most significant findings were derived from dorsolateral prefrontal cortex splicing data (n = 19 genes, 26%). The 17q21.31 inversion locus contained 23 significant associations, representing 6 unique genes. Other top hits included SEC22B (a gene involved in vesicle trafficking), TRGV5, and ZNF302. A single gene finding (RAB38) was observed for behavioral variant FTD. For other clinical subtypes, no significant associations were observed.ConclusionsWe identified novel candidate genes (e.g., SEC22B) and previously reported risk regions (e.g., 17q21.31) for FTD. Most significant associations were observed in dorsolateral prefrontal cortex splicing data despite the modest sample size of this reference panel. This suggests that our findings are specific to FTD and are likely to be biologically relevant highlights of genes at different FTD risk loci that are contributing to the disease pathology.

Published
2021

4. Prioritization of Drug Targets for Neurodegenerative Diseases by Integrating Genetic and Proteomic Data From Brain and Blood

Author

Ferrari, Raffaele, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Ramasamy, Adaikalavan, Kwok, John B.J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J., Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R.A., Hsiung, Ging-Yuek R., Mann, David M.A., Grafman, Jordan, Morris, Christopher M., Attems, Johannes, Griffiths, Timothy D., McKeith, Ian G., Thomas, Alan J., Pietrini, P., Huey, Edward D., Wassermann, Eric M., Baborie, Atik, Jaros, Evelyn, Tierney, Michael C., Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C.M., Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., van der Zee, Julie, Deschamps, William, Van Langenhove, Tim, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F., Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E., Hjermind, Lena E., Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Richardson, Anna, Gerhard, Alexander, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, van Swieten, John C., Dopper, Elise G.P., Seelaar, Harro, Pijnenburg, Yolande A.L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebert, Florence, Kapogiannis, Dimitrios, Ferrucci, Luigi, Pickering-Brown, Stuart, Singleton, Andrew B., Hardy, John, Momeni, Parastoo, Ge, Yi-Jun, Ou, Ya-Nan, Deng, Yue-Ting, Wu, Bang-Sheng, Yang, Liu, Zhang, Ya-Ru, Chen, Shi-Dong, Huang, Yu-Yuan, Dong, Qiang, Tan, Lan, and Yu, Jin-Tai

Published
2023
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7. A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers.

Author

Zhang, Ming, Ferrari, Raffaele, Tartaglia, Maria Carmela, Keith, Julia, Surace, Ezequiel I, Wolf, Uri, Sato, Christine, Grinberg, Mark, Liang, Yan, Xi, Zhengrui, Dupont, Kyle, McGoldrick, Philip, Weichert, Anna, McKeever, Paul M, Schneider, Raphael, McCorkindale, Michael D, Manzoni, Claudia, Rademakers, Rosa, Graff-Radford, Neill R, Dickson, Dennis W, Parisi, Joseph E, Boeve, Bradley F, Petersen, Ronald C, Miller, Bruce L, Seeley, William W, van Swieten, John C, van Rooij, Jeroen, Pijnenburg, Yolande, van der Zee, Julie, Van Broeckhoven, Christine, Le Ber, Isabelle, Van Deerlin, Vivianna, Suh, EunRan, Rohrer, Jonathan D, Mead, Simon, Graff, Caroline, Öijerstedt, Linn, Pickering-Brown, Stuart, Rollinson, Sara, Rossi, Giacomina, Tagliavini, Fabrizio, Brooks, William S, Dobson-Stone, Carol, Halliday, Glenda M, Hodges, John R, Piguet, Olivier, Binetti, Giuliano, Benussi, Luisa, Ghidoni, Roberta, Nacmias, Benedetta, Sorbi, Sandro, Bruni, Amalia C, Galimberti, Daniela, Scarpini, Elio, Rainero, Innocenzo, Rubino, Elisa, Clarimon, Jordi, Lleó, Alberto, Ruiz, Agustin, Hernández, Isabel, Pastor, Pau, Diez-Fairen, Monica, Borroni, Barbara, Pasquier, Florence, Deramecourt, Vincent, Lebouvier, Thibaud, Perneczky, Robert, Diehl-Schmid, Janine, Grafman, Jordan, Huey, Edward D, Mayeux, Richard, Nalls, Michael A, Hernandez, Dena, Singleton, Andrew, Momeni, Parastoo, Zeng, Zhen, Hardy, John, Robertson, Janice, Zinman, Lorne, Rogaeva, Ekaterina, and International FTD-Genomics Consortium (IFGC)

Subjects
International FTD-Genomics Consortium, Humans, Amyotrophic Lateral Sclerosis, Age of Onset, DNA Methylation, Gene Expression Regulation, CpG Islands, Genotype, Heterozygote, Polymorphism, Single Nucleotide, Aged, Middle Aged, Female, Male, Frontotemporal Dementia, C9orf72 Protein, C9orf72, genetic association, age of onset, amyotrophic lateral sclerosis, frontotemporal dementia, Polymorphism, Single Nucleotide, Neurology & Neurosurgery, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract

The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.

Published
2018

10. Poly‐GA immunohistochemistry is a reliable tool for detecting C9orf72 hexanucleotide repeat expansions.

Author

Carroll, Jordan, McCann, Heather, Halliday, Glenda M., Kwok, John B., Dobson‐Stone, Carol, and Shepherd, Claire E.

Subjects
GRANULE cells, DNA-binding proteins, FRONTOTEMPORAL lobar degeneration, CEREBELLAR cortex, GENETIC testing, MOTOR neuron diseases
Abstract

A study published in the journal Brain Pathology explores the use of poly-GA immunohistochemistry as a reliable tool for detecting C9orf72 hexanucleotide repeat expansions, which are associated with neurodegenerative diseases. The study found that poly-GA immunohistochemistry accurately identified neuronal cytoplasmic inclusions and neurites in cases with known C9orf72 repeat expansion. This method is particularly useful in research settings where genetic testing has not been performed or suitable tissue is not available post-mortem. The study highlights the potential of poly-GA immunohistochemistry as an economical and sensitive alternative to genetic testing for detecting C9orf72 repeat expansions. [Extracted from the article]

Published
2024
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12. Frontotemporal dementia and its subtypes: a genome-wide association study

Author

Ferrari, Raffaele, Hernandez, Dena G, Nalls, Michael A, Rohrer, Jonathan D, Ramasamy, Adaikalavan, Kwok, John BJ, Dobson-Stone, Carol, Brooks, William S, Schofield, Peter R, Halliday, Glenda M, Hodges, John R, Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian RA, Hsiung, Ging-Yuek R, Mann, David MA, Grafman, Jordan, Morris, Christopher M, Attems, Johannes, Griffiths, Timothy D, McKeith, Ian G, Thomas, Alan J, Pietrini, P, Huey, Edward D, Wassermann, Eric M, Baborie, Atik, Jaros, Evelyn, Tierney, Michael C, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B, Schlachetzki, Johannes CM, Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M, Grossman, Murray, Trojanowski, John Q, van der Zee, Julie, Deschamps, William, Van Langenhove, Tim, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F, Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E, Hjermind, Lena E, Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, and Rossor, Martin N

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Brain Disorders, Alzheimer's Disease Related Dementias (ADRD), Genetics, Neurodegenerative, Dementia, Acquired Cognitive Impairment, Frontotemporal Dementia (FTD), Aging, Human Genome, Clinical Research, Rare Diseases, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 2.1 Biological and endogenous factors, Aetiology, Neurological, Adult, Aged, Aged, 80 and over, Female, Frontotemporal Dementia, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundFrontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72--have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.MethodsWe did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p

Published
2014

13. TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions.

Author

Gallagher, Michael D, Suh, Eunran, Grossman, Murray, Elman, Lauren, McCluskey, Leo, Van Swieten, John C, Al-Sarraj, Safa, Neumann, Manuela, Gelpi, Ellen, Ghetti, Bernardino, Rohrer, Jonathan D, Halliday, Glenda, Van Broeckhoven, Christine, Seilhean, Danielle, Shaw, Pamela J, Frosch, Matthew P, Alafuzoff, Irina, Antonell, Anna, Bogdanovic, Nenad, Brooks, William, Cairns, Nigel J, Cooper-Knock, Johnathan, Cotman, Carl, Cras, Patrick, Cruts, Marc, De Deyn, Peter P, DeCarli, Charles, Dobson-Stone, Carol, Engelborghs, Sebastiaan, Fox, Nick, Galasko, Douglas, Gearing, Marla, Gijselinck, Ilse, Grafman, Jordan, Hartikainen, Päivi, Hatanpaa, Kimmo J, Highley, J Robin, Hodges, John, Hulette, Christine, Ince, Paul G, Jin, Lee-Way, Kirby, Janine, Kofler, Julia, Kril, Jillian, Kwok, John BJ, Levey, Allan, Lieberman, Andrew, Llado, Albert, Martin, Jean-Jacques, Masliah, Eliezer, McDermott, Christopher J, McKee, Ann, McLean, Catriona, Mead, Simon, Miller, Carol A, Miller, Josh, Munoz, David G, Murrell, Jill, Paulson, Henry, Piguet, Olivier, Rossor, Martin, Sanchez-Valle, Raquel, Sano, Mary, Schneider, Julie, Silbert, Lisa C, Spina, Salvatore, van der Zee, Julie, Van Langenhove, Tim, Warren, Jason, Wharton, Stephen B, White, Charles L, Woltjer, Randall L, Trojanowski, John Q, Lee, Virginia MY, Van Deerlin, Vivianna, and Chen-Plotkin, Alice S

Subjects
Humans, Amyotrophic Lateral Sclerosis, Genetic Predisposition to Disease, Intercellular Signaling Peptides and Proteins, Proteins, Membrane Proteins, Nerve Tissue Proteins, Cohort Studies, Age Factors, Age of Onset, DNA Repeat Expansion, Genotype, Heterozygote, Polymorphism, Single Nucleotide, Alleles, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Frontotemporal Lobar Degeneration, C9orf72 Protein, Progranulins, Rare Diseases, Aging, Neurosciences, Alzheimer's Disease Related Dementias (ADRD), Brain Disorders, Neurodegenerative, Prevention, Genetics, Dementia, Frontotemporal Dementia (FTD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Aetiology, 2.1 Biological and endogenous factors, Neurological, TMEM106B, C9orf72, Frontotemporal dementia, Frontotemporal lobar degeneration, Amyotrophic lateral sclerosis, Genetic modifier, Clinical Sciences, Neurology & Neurosurgery
Abstract

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.

Published
2014

17. Blood-Based Transcriptomic Biomarkers Are Predictive of Neurodegeneration Rather Than Alzheimer’s Disease

Author

Shvetcov, Artur, primary, Thomson, Shannon, additional, Spathos, Jessica, additional, Cho, Ann-Na, additional, Wilkins, Heather M., additional, Andrews, Shea J., additional, Delerue, Fabien, additional, Couttas, Timothy A., additional, Issar, Jasmeen Kaur, additional, Isik, Finula, additional, Kaur, Simranpreet, additional, Drummond, Eleanor, additional, Dobson-Stone, Carol, additional, Duffy, Shantel L., additional, Rogers, Natasha M., additional, Catchpoole, Daniel, additional, Gold, Wendy A., additional, Swerdlow, Russell H., additional, Brown, David A., additional, and Finney, Caitlin A., additional

Published
2023
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19. Molecular genetics of chorea-acanthocytosis

Author

Dobson-Stone, Carol N. M. and Monaco, Anthony Philip

Subjects
616.83, Neurological emergencies, Genetic aspects, Chorea, Huntington's chorea
Abstract

Chorea-acanthocytosis (ChAc) is an autosomal recessive neurological disorder whose characteristic features include hyperkinetic movements and abnormal red blood cell morphology. The disorder shares features with Huntington's disease and McLeod syndrome (MLS), and can sometimes be difficult to distinguish clinically from the latter. In 1997, ChAc was linked to a 6-cM region on chromosome 9q21-22. A novel gene, >em>CHAC, was identified in the critical region. CHAC (now renamed VPS13A) encodes a large protein called chorein, with a yeast homologue implicated in protein sorting. In this study, all 73 exons plus flanking intronic sequence in VPS13A were screened for mutations in 83 unrelated ChAc patients. We identified 88 different VPS13A mutations in 72 probands, comprising six deletions of entire exons, 22 nonsense, 36 frameshift, 19 splice-site and five missense mutations. This disorder therefore shows substantial allelic heterogeneity: however, evidence for common inheritance of the EX70_73del mutation in four French Canadian pedigrees indicates a possible founder effect in this population. Expression of VPS13A appears to be ubiquitous, as determined by tissue-specific analysis of mRNA and chorein distribution. However, chorein expression was markedly reduced or undetectable in lymphoblasts, fibroblasts and erythrocyte membranes from 14 ChAc patients. In contrast, MLS cells showed chorein expression similar to control levels, suggesting that loss of chorein expression is a diagnostic feature of ChAc. Yeast two-hybrid analysis of six different -600 amino-acid chorein fragments was used to screen a human brain cDNA library for proteins that may interact with chorein. One fragment interacted weakly with constructs derived from transcription factor NF-κB, putative protein phosphatase PP2Cη and TAB2, a protein implicated in the mitogen-activated kinase cascade. Although exogenously expressed chorein and TAB2 did not appear to colocalise, co-immunoprecipitation experiments supported an interaction between the two proteins, suggesting an avenue for future research into chorein function.

Published
2004

21. Short tandem repeat expansions in sporadic amyotrophic lateral sclerosis and frontotemporal dementia

Author

Henden, Lyndal, primary, Fearnley, Liam G., additional, Grima, Natalie, additional, McCann, Emily P., additional, Dobson-Stone, Carol, additional, Fitzpatrick, Lauren, additional, Friend, Kathryn, additional, Hobson, Lynne, additional, Chan Moi Fat, Sandrine, additional, Rowe, Dominic B., additional, D’Silva, Susan, additional, Kwok, John B., additional, Halliday, Glenda M., additional, Kiernan, Matthew C., additional, Mazumder, Srestha, additional, Timmins, Hannah C., additional, Zoing, Margaret, additional, Pamphlett, Roger, additional, Adams, Lorel, additional, Bahlo, Melanie, additional, Blair, Ian P., additional, and Williams, Kelly L., additional

Published
2023
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22. Prioritization of Drug Targets for Neurodegenerative Diseases by Integrating Genetic and Proteomic Data From Brain and Blood

Author

Ge, Yi-Jun, primary, Ou, Ya-Nan, additional, Deng, Yue-Ting, additional, Wu, Bang-Sheng, additional, Yang, Liu, additional, Zhang, Ya-Ru, additional, Chen, Shi-Dong, additional, Huang, Yu-Yuan, additional, Dong, Qiang, additional, Tan, Lan, additional, Yu, Jin-Tai, additional, Ferrari, Raffaele, additional, Hernandez, Dena G., additional, Nalls, Michael A., additional, Rohrer, Jonathan D., additional, Ramasamy, Adaikalavan, additional, Kwok, John B.J., additional, Dobson-Stone, Carol, additional, Brooks, William S., additional, Schofield, Peter R., additional, Halliday, Glenda M., additional, Hodges, John R., additional, Piguet, Olivier, additional, Bartley, Lauren, additional, Thompson, Elizabeth, additional, Haan, Eric, additional, Hernández, Isabel, additional, Ruiz, Agustín, additional, Boada, Mercè, additional, Borroni, Barbara, additional, Padovani, Alessandro, additional, Cruchaga, Carlos, additional, Cairns, Nigel J., additional, Benussi, Luisa, additional, Binetti, Giuliano, additional, Ghidoni, Roberta, additional, Forloni, Gianluigi, additional, Galimberti, Daniela, additional, Fenoglio, Chiara, additional, Serpente, Maria, additional, Scarpini, Elio, additional, Clarimón, Jordi, additional, Lleó, Alberto, additional, Blesa, Rafael, additional, Waldö, Maria Landqvist, additional, Nilsson, Karin, additional, Nilsson, Christer, additional, Mackenzie, Ian R.A., additional, Hsiung, Ging-Yuek R., additional, Mann, David M.A., additional, Grafman, Jordan, additional, Morris, Christopher M., additional, Attems, Johannes, additional, Griffiths, Timothy D., additional, McKeith, Ian G., additional, Thomas, Alan J., additional, Pietrini, P., additional, Huey, Edward D., additional, Wassermann, Eric M., additional, Baborie, Atik, additional, Jaros, Evelyn, additional, Tierney, Michael C., additional, Pastor, Pau, additional, Razquin, Cristina, additional, Ortega-Cubero, Sara, additional, Alonso, Elena, additional, Perneczky, Robert, additional, Diehl-Schmid, Janine, additional, Alexopoulos, Panagiotis, additional, Kurz, Alexander, additional, Rainero, Innocenzo, additional, Rubino, Elisa, additional, Pinessi, Lorenzo, additional, Rogaeva, Ekaterina, additional, St. George-Hyslop, Peter, additional, Rossi, Giacomina, additional, Tagliavini, Fabrizio, additional, Giaccone, Giorgio, additional, Rowe, James B., additional, Schlachetzki, Johannes C.M., additional, Uphill, James, additional, Collinge, John, additional, Mead, Simon, additional, Danek, Adrian, additional, Van Deerlin, Vivianna M., additional, Grossman, Murray, additional, Trojanowski, John Q., additional, van der Zee, Julie, additional, Deschamps, William, additional, Van Langenhove, Tim, additional, Cruts, Marc, additional, Van Broeckhoven, Christine, additional, Cappa, Stefano F., additional, Le Ber, Isabelle, additional, Hannequin, Didier, additional, Golfier, Véronique, additional, Vercelletto, Martine, additional, Brice, Alexis, additional, Nacmias, Benedetta, additional, Sorbi, Sandro, additional, Bagnoli, Silvia, additional, Piaceri, Irene, additional, Nielsen, Jørgen E., additional, Hjermind, Lena E., additional, Riemenschneider, Matthias, additional, Mayhaus, Manuel, additional, Ibach, Bernd, additional, Gasparoni, Gilles, additional, Pichler, Sabrina, additional, Gu, Wei, additional, Rossor, Martin N., additional, Fox, Nick C., additional, Warren, Jason D., additional, Spillantini, Maria Grazia, additional, Morris, Huw R., additional, Rizzu, Patrizia, additional, Heutink, Peter, additional, Snowden, Julie S., additional, Rollinson, Sara, additional, Richardson, Anna, additional, Gerhard, Alexander, additional, Bruni, Amalia C., additional, Maletta, Raffaele, additional, Frangipane, Francesca, additional, Cupidi, Chiara, additional, Bernardi, Livia, additional, Anfossi, Maria, additional, Gallo, Maura, additional, Conidi, Maria Elena, additional, Smirne, Nicoletta, additional, Rademakers, Rosa, additional, Baker, Matt, additional, Dickson, Dennis W., additional, Graff-Radford, Neill R., additional, Petersen, Ronald C., additional, Knopman, David, additional, Josephs, Keith A., additional, Boeve, Bradley F., additional, Parisi, Joseph E., additional, Seeley, William W., additional, Miller, Bruce L., additional, Karydas, Anna M., additional, Rosen, Howard, additional, van Swieten, John C., additional, Dopper, Elise G.P., additional, Seelaar, Harro, additional, Pijnenburg, Yolande A.L., additional, Scheltens, Philip, additional, Logroscino, Giancarlo, additional, Capozzo, Rosa, additional, Novelli, Valeria, additional, Puca, Annibale A., additional, Franceschi, Massimo, additional, Postiglione, Alfredo, additional, Milan, Graziella, additional, Sorrentino, Paolo, additional, Kristiansen, Mark, additional, Chiang, Huei-Hsin, additional, Graff, Caroline, additional, Pasquier, Florence, additional, Rollin, Adeline, additional, Deramecourt, Vincent, additional, Lebert, Florence, additional, Kapogiannis, Dimitrios, additional, Ferrucci, Luigi, additional, Pickering-Brown, Stuart, additional, Singleton, Andrew B., additional, Hardy, John, additional, and Momeni, Parastoo, additional

Published
2023
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37. Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing

Author

Stevanovski, Igor, primary, Chintalaphani, Sanjog R., additional, Gamaarachchi, Hasindu, additional, Ferguson, James M., additional, Pineda, Sandy S., additional, Scriba, Carolin K., additional, Tchan, Michel, additional, Fung, Victor, additional, Ng, Karl, additional, Cortese, Andrea, additional, Houlden, Henry, additional, Dobson-Stone, Carol, additional, Fitzpatrick, Lauren, additional, Halliday, Glenda, additional, Ravenscroft, Gianina, additional, Davis, Mark R., additional, Laing, Nigel G., additional, Fellner, Avi, additional, Kennerson, Marina, additional, Kumar, Kishore R., additional, and Deveson, Ira W., additional

Published
2022
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40. Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

Author

Swarup, Vivek, Hinz, Flora I., Rexach, Jessica E., Noguchi, Ken-ichi, Toyoshiba, Hiroyoshi, Oda, Akira, Hirai, Keisuke, Sarkar, Arjun, Seyfried, Nicholas T., Cheng, Chialin, Haggarty, Stephen J., Ferrari, Raffaele, Rohrer, Jonathan D., Ramasamy, Adaikalavan, Hardy, John, Hernandez, Dena G., Nalls, Michael A., Singleton, Andrew B., Kwok, John B. J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cairns, Nigel J., Cruchaga, Carlos, Binetti, Giuliano, Ghidoni, Roberta, Benussi, Luisa, Forloni, Gianluigi, Albani, Diego, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Grafman, Jordan, Morris, Christopher M., Attems, Johannes, Griffiths, Timothy D., McKeith, Ian G., Thomas, Alan J., Jaros, Evelyn, Pietrini, Pietro, Huey, Edward D., Wassermann, Eric M., Tierney, Michael C., Baborie, Atik, Pastor, Pau, Ortega-Cubero, Sara, Razquin, Cristina, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, George-Hyslop, Peter St., Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C. M., Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., Pickering-Brown, Stuart, Momeni, Parastoo, van der Zee, Julie, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F., Leber, Isabelle, Brice, Alexis, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E., Hjermind, Lena E., Riemenschneider, Matthias, Mayhaus, Manuel, Gasparoni, Gilles, Pichler, Sabrina, Ibach, Bernd, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Gerhard, Alexander, Richardson, Anna, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, Seeley, William W., van Swieten, John C., Dopper, Elise G. P., Seelaar, Harro, Pijnenburg, Yolande A. L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebouvier, Thibaud, Ferrucci, Luigi, Kapogiannis, Dimitrios, Lah, James J., Levey, Allan I., Kondou, Shinichi, Geschwind, Daniel H., Int Frontotemporal Dementia Gen, Swarup, Vivek, Hinz, Flora I., Rexach, Jessica E., Noguchi, Ken-ichi, Toyoshiba, Hiroyoshi, Oda, Akira, Hirai, Keisuke, Sarkar, Arjun, Seyfried, Nicholas T., Cheng, Chialin, Haggarty, Stephen J., Ferrari, Raffaele, Rohrer, Jonathan D., Ramasamy, Adaikalavan, Hardy, John, Hernandez, Dena G., Nalls, Michael A., Singleton, Andrew B., Kwok, John B. J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cairns, Nigel J., Cruchaga, Carlo, Binetti, Giuliano, Ghidoni, Roberta, Benussi, Luisa, Forloni, Gianluigi, Albani, Diego, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Grafman, Jordan, Morris, Christopher M., Attems, Johanne, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Jaros, Evelyn, Pietrini, Pietro, Huey, Edward D., Wassermann, Eric M., Tierney, Michael C., Baborie, Atik, Pastor, Pau, Ortega-Cubero, Sara, Razquin, Cristina, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagioti, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, George-Hyslop, Peter St., Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C. M., Uphill, Jame, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., Pickering-Brown, Stuart, Momeni, Parastoo, van der Zee, Julie, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F., Leber, Isabelle, Brice, Alexi, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E., Hjermind, Lena E., Riemenschneider, Matthia, Mayhaus, Manuel, Gasparoni, Gille, Pichler, Sabrina, Ibach, Bernd, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Gerhard, Alexander, Richardson, Anna, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, Seeley, William W., van Swieten, John C., Dopper, Elise G. P., Seelaar, Harro, Pijnenburg, Yolande A. L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebouvier, Thibaud, Ferrucci, Luigi, Kapogiannis, Dimitrio, Lah, James J., Levey, Allan I., Kondou, Shinichi, and Geschwind, Daniel H.

Subjects
Proteomics, Genetics and Molecular Biology (all), 0301 basic medicine, Messenger, Gene regulatory network, Inbred C57BL, Biochemistry, Transgenic, Mice, 0302 clinical medicine, Gene Regulatory Networks, Regulation of gene expression, Cell Death, Drug discovery, Neurodegeneration, Neurodegenerative Diseases, General Medicine, Chemistry, Frontotemporal Dementia, 030220 oncology & carcinogenesis, Frontotemporal dementia, Evolution, Systems biology, Genetic Vectors, Animals, Dementia, Disease Models, Animal, Gene Expression Regulation, Genetic Predisposition to Disease, Humans, Mice, Inbred C57BL, Mice, Transgenic, MicroRNAs, RNA, Messenger, Reproducibility of Results, Transcriptome, tau Proteins, Evolution, Molecular, Computational biology, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, microRNA, medicine, Biochemistry, Genetics and Molecular Biology (all), Animal, Molecular, medicine.disease, 030104 developmental biology, Disease Models, RNA, Human medicine
Abstract

Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.

Published
2018

41. sj-pdf-1-pmj-10.1177_02692163221116763 – Supplemental material for Evaluating a partnership model of hospice enabled dementia care: A three-phased monitoring, focus group and interview study

Author

McLaughlin, Dorry, Hasson, Felicity, Reid, Joanne, Brazil, Kevin, Rutherford, Lesley, Stone, Carol, van der Steen, Jenny T, and Ballentine, Joanne

Subjects
FOS: Clinical medicine, 111702 Aged Health Care, FOS: Health sciences, 110308 Geriatrics and Gerontology
Abstract

Supplemental material, sj-pdf-1-pmj-10.1177_02692163221116763 for Evaluating a partnership model of hospice enabled dementia care: A three-phased monitoring, focus group and interview study by Dorry McLaughlin, Felicity Hasson, Joanne Reid, Kevin Brazil, Lesley Rutherford, Carol Stone, Jenny T van der Steen and Joanne Ballentine in Palliative Medicine

Published
2022
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42. sj-pdf-2-pmj-10.1177_02692163221116763 – Supplemental material for Evaluating a partnership model of hospice enabled dementia care: A three-phased monitoring, focus group and interview study

Author

McLaughlin, Dorry, Hasson, Felicity, Reid, Joanne, Brazil, Kevin, Rutherford, Lesley, Stone, Carol, van der Steen, Jenny T, and Ballentine, Joanne

Subjects
FOS: Clinical medicine, 111702 Aged Health Care, FOS: Health sciences, 110308 Geriatrics and Gerontology
Abstract

Supplemental material, sj-pdf-2-pmj-10.1177_02692163221116763 for Evaluating a partnership model of hospice enabled dementia care: A three-phased monitoring, focus group and interview study by Dorry McLaughlin, Felicity Hasson, Joanne Reid, Kevin Brazil, Lesley Rutherford, Carol Stone, Jenny T van der Steen and Joanne Ballentine in Palliative Medicine

Published
2022
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43. Exploring Links Between Psychosis and Frontotemporal Dementia Using Multimodal Machine Learning: Dementia Praecox Revisited

Author

Koutsouleris, Nikolaos, Pantelis, Christos, Kambeitz, Joseph, Toivonen, Anna, Turtonen, Otto, Botterweck, Sonja, Kluthausen, Norman, Antoch, Gerald, Caspers, Julian, Wittsack, Hans-Jörg, Blasi, Giuseppe, Pergola, Giulio, Caforio, Grazia, Salokangas, Raimo K R, Fazio, Leonardo, Quarto, Tiziana, Gelao, Barbara, Romano, Raffaella, Andriola, Ileana, Falsetti, Andrea, Barone, Marina, Passiatore, Roberta, Sangiuliano, Marina, Surmann, Marian, Hietala, Jarmo, Bienek, Olga, Dannlowski, Udo, Solana, Ana Beatriz, Abraham, Manuela, Schirmer, Timo, Ferro, Adele, Re, Marta, Sberna, Maurizio, D'Agostino, Armando, Del Fabro, Lorenzo, Bertolino, Alessandro, Perna, Giampaolo, Nobile, Maria, Balestrieri, Matteo, Bonivento, Carolina, Cabras, Giuseppe, Fabbro, Franco, Delvecchio, Giuseppe, Maggioni, Eleonora, Squarcina, Letizia, Gritti, Davide, Brambilla, Paolo, Rossetti, Maria Gloria, Ferrari, Raffaele, Hernandez, Dena Michelle Godwin, Nalls, Michael, Rohrer, Jonathan, Ramasamy, Adaikalavan, Kwok, John, Dobson-Stone, Carol, Brooks, William, Schofield, Peter, Upthegrove, Rachel, Halliday, Glenda, Hodges, John, Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Wood, Stephen J, Cruchaga, Carlos, Cairns, Nigel, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Albani, Diego, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Lencer, Rebekka, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Landqvist Waldö, Maria, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R.A., Hsiung, Ging-Yuek, Mann, David, Borgwardt, Stefan, Grafman, Jordan, Morris, Christopher, Attems, Johannes, McKeith, Ian, Thomas, Alan, Pietrini, Pietro, Huey, Edward, Wassermann, Eric, Baborie, Atik, Jaros, Evelyn, Maj, Carlo, Tierney, Michael, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Velakoulis, Dennis, Nöthen, Markus M., Pinessi, Lorenzo, Rogaeva, Ekaterina, George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James, Schlachetzki, Johannes, Uphill, James, Collinge, John, Degenhardt, Franziska, Mead, Simon, Van Deerlin, Vivianna, Marschhauser, Anke, Regenbrecht, Frank, Thoene-Otto, Angelika, Gordulla, Jannis, Ballarini, Tommaso, Engel, Annerose, Pino, Daniele, Leuthold, Dominique, Polyakova, Maryna, Naumann, Heike, Grossman, Murray, Trojanowski, John Q, van der Zee, Julie, Van Broeckhofen, Christine, Cappa, Stefano F, Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Mueller, Karsten, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E, Hjermind, Lena E, Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Villringer, Arno, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, Rossor, Martin N, Fox, Nick C, Warren, Jason D, Spillantini, Maria Grazia, Morris, Huw R, Rizzu, Patrizia, Heutink, Peter, Danek, Adrian, Snowden, Julie S, Rollinson, Sara, Richardson, Anna, Gerhard, Alexander, Bruni, Amalia C, Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Fassbender, Klaus, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W, Graff-Radford, Neill R, Petersen, Ronald C, Knopman, David S, Josephs, Keith A, Fliessbach, Klaus, Boeve, Bradley F, Parisi, Joseph E, Seeley, William W, Miller, Bruce L, Karydas, Anna M, Rosen, Howard, van Swieten, John C, Dopper, Elise Gp, Seelaar, Harro, Pijnenburg, Yolande Al, Jahn, Holger, Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A, Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Kornhuber, Johannes, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebouvier, Thibaud, Kapogiannis, Dimitrios, Ferrucci, Luigi, Pickering-Brown, Stuart, Singleton, Andrew B, McGuire, Philip, Landwehrmeyer, Bernhard, Hardy, John, Momeni, Parastoo, Barthel, Henryk, Elisa, Semler, Jolina, Lombardi, Christine, von Arnim, Felix, Oberahauser, Kai, Schumacher, Jan, Lehmbeck, Juan-Manuel, Maler, Anderl-Straub, Sarah, Tanja, Richter-Schmidinger, Anke, Hammer-Kaspereit, Timo, Oberstein, Felix, Müller-Sarnowski, Carola, Roßmeier, Albert, Ludolph, Jan, Kassubek, Anja, Schneider, Johannes, Levin, Prudlo, Johannes, Synofzik, Matthis, Wiltfang, Jens, Riedl, Lina, Diehl-Schmid, Janine, Otto, Markus, Meisenzahl, Eva, Falkai, Peter, Dwyer, Dominic B, Schroeter, Matthias L, Consortium, the PRONIA, Haas, Shalaila, Hasan, Alkomiet, Hoff, Claudius, Khanyaree, Ifrah, Melo, Aylin, Muckenhuber-Sternbauer, Susanna, Köhler, Yanis, Urquijo-Castro, Maria-Fernanda, Öztürk, Ömer, Penzel, Nora, Rangnick, Adrian, von Saldern, Sebastian, Spangemacher, Moritz, Tupac, Ana, Weiske, Johanna, Wosgien, Antonia, Krämer, Camilla, Blume, Karsten, Paul, Riya, Hedderich, Dennis, Julkowski, Dominika, Kaiser, Nathalie, Lichtenstein, Thorsten, Milz, Ruth, Nikolaides, Alexandra, Pilgram, Tanja, Seves, Mauro, Wassen, Martina, Andreou, Christina, Dong, Sen, Egloff, Laura, Harrisberger, Fabienne, Heitz, Ulrike, Lenz, Claudia, Leanza, Letizia, Mackintosh, Amatya, Smieskova, Renata, Studerus, Erich, Walter, Anna, Widmayer, Sonja, Popovic, David, Day, Chris, Lowri Griffiths, Sian, Iqbal, Mariam, Pelton, Mirabel, Mallikarjun, Pavan, Stainton, Alexandra, Lin, Ashleigh, Lalousis, Paris, Denissoff, Alexander, Ellilä, Anu, Oeztuerk, Oemer, From, Tiina, Heinimaa, Markus, Ilonen, Tuula, Jalo, Päivi, Laurikainen, Heikki, Luutonen, Antti, Mäkela, Akseli, Paju, Janina, Pesonen, Henri, Säilä, Reetta-Liina, International FTD-Genetics Consortium (IFGC), German Frontotemporal Lobar Degeneration (FTLD) Consortium, PRONIA Consortium, and International FTD-Genetics Consortium Consortium

Subjects
Adult, Male, Medizin, genetics [Alzheimer Disease], genetics [Psychotic Disorders], Neuropsychological Tests, diagnostic imaging [Frontotemporal Dementia], diagnostic imaging [Psychotic Disorders], Machine Learning, methods [Magnetic Resonance Imaging], Brain, Female, Humans, Magnetic Resonance Imaging, Alzheimer Disease, Frontotemporal Dementia, Psychotic Disorders, Schizophrenia, pathology [Brain], genetics [Schizophrenia], ddc:610, diagnostic imaging [Brain], genetics [Frontotemporal Dementia], Settore MED/25 - Psichiatria, Psychiatry and Mental health, diagnostic imaging [Schizophrenia], diagnostic imaging [Alzheimer Disease]
Abstract

Weitere Nicht-UDE Autoren sind nicht genannt. Importance: The behavioral and cognitive symptoms of severe psychotic disorders overlap with those seen in dementia. However, shared brain alterations remain disputed, and their relevance for patients in at-risk disease stages has not been explored so far. Objective: To use machine learning to compare the expression of structural magnetic resonance imaging (MRI) patterns of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer disease (AD), and schizophrenia; estimate predictability in patients with bvFTD and schizophrenia based on sociodemographic, clinical, and biological data; and examine prognostic value, genetic underpinnings, and progression in patients with clinical high-risk (CHR) states for psychosis or recent-onset depression (ROD). Design, Setting, and Participants: This study included 1870 individuals from 5 cohorts, including (1) patients with bvFTD (n = 108), established AD (n = 44), mild cognitive impairment or early-stage AD (n = 96), schizophrenia (n = 157), or major depression (n = 102) to derive and compare diagnostic patterns and (2) patients with CHR (n = 160) or ROD (n = 161) to test patterns' prognostic relevance and progression. Healthy individuals (n = 1042) were used for age-related and cohort-related data calibration. Data were collected from January 1996 to July 2019 and analyzed between April 2020 and April 2022. Main Outcomes and Measures: Case assignments based on diagnostic patterns; sociodemographic, clinical, and biological data; 2-year functional outcomes and genetic separability of patients with CHR and ROD with high vs low pattern expression; and pattern progression from baseline to follow-up MRI scans in patients with nonrecovery vs preserved recovery. Results: Of 1870 included patients, 902 (48.2%) were female, and the mean (SD) age was 38.0 (19.3) years. The bvFTD pattern comprising prefrontal, insular, and limbic volume reductions was more expressed in patients with schizophrenia (65 of 157 [41.2%]) and major depression (22 of 102 [21.6%]) than the temporo-limbic AD patterns (28 of 157 [17.8%] and 3 of 102 [2.9%], respectively). bvFTD expression was predicted by high body mass index, psychomotor slowing, affective disinhibition, and paranoid ideation (R2= 0.11). The schizophrenia pattern was expressed in 92 of 108 patients (85.5%) with bvFTD and was linked to the C9orf72 variant, oligoclonal banding in the cerebrospinal fluid, cognitive impairment, and younger age (R2= 0.29). bvFTD and schizophrenia pattern expressions forecasted 2-year psychosocial impairments in patients with CHR and were predicted by polygenic risk scores for frontotemporal dementia, AD, and schizophrenia. Findings were not associated with AD or accelerated brain aging. Finally, 1-year bvFTD/schizophrenia pattern progression distinguished patients with nonrecovery from those with preserved recovery. Conclusions and Relevance: Neurobiological links may exist between bvFTD and psychosis focusing on prefrontal and salience system alterations. Further transdiagnostic investigations are needed to identify shared pathophysiological processes underlying the neuroanatomical interface between the 2 disease spectra.

Published
2022

45. Examining the presence and nature of delusions in Alzheimer's disease and frontotemporal dementia syndromes.

Author

Kumfor, Fiona, Liang, Cheng Tao, Hazelton, Jessica L., Leyton, Cristian E., Kaizik, Cassandra, Devenney, Emma, Connaughton, Emily, Langdon, Robyn, Mioshi, Eneida, Kwok, John B., Dobson‐Stone, Carol, Halliday, Glenda M., Piguet, Olivier, Hodges, John R., Landin‐Romero, Ramon, Dobson-Stone, Carol, and Landin-Romero, Ramon

Subjects
FRONTOTEMPORAL lobar degeneration, FRONTOTEMPORAL dementia, ALZHEIMER'S disease, PROGRESSIVE supranuclear palsy, AMYOTROPHIC lateral sclerosis, PREFRONTAL cortex
Abstract

Objectives: Abnormal beliefs and delusions have been reported in some people with dementia, however, the prevalence of delusions, and their neurocognitive basis has been underexplored. This study aimed to examine the presence, severity, content and neural correlates of delusions in a large, well-characterised cohort of dementia patients using a transdiagnostic, cross-sectional approach.Methods: Four-hundred and eighty-seven people with dementia were recruited: 102 Alzheimer's disease, 136 behavioural-variant frontotemporal dementia, 154 primary progressive aphasia, 29 motor neurone disease, 46 corticobasal syndrome, 20 progressive supranuclear palsy. All patients underwent neuropsychological assessment and brain magnetic resonance imaging, and the Neuropsychiatric Inventory was conducted with an informant, by an experienced clinician.Results: In our cohort, 48/487 patients (10.8%) had delusions. A diagnosis of behavioural-variant frontotemporal dementia (18.4%) and Alzheimer's disease (11.8%) were associated with increased risk of delusions. A positive gene mutation was observed in 11/27 people with delusions. Individuals with frequent delusions performed worse on the Addenbrooke's Cognitive Examination (p = 0.035), particularly on the orientation/attention (p = 0.022) and memory (p = 0.013) subtests. Voxel-based morphometry analyses found that increased delusional psychopathology was associated with reduced integrity of the right middle frontal gyrus, right planum temporale and left anterior temporal pole.Conclusion: Our results demonstrate that delusions are relatively common in dementia and uncover a unique cognitive and neural profile associated with the manifestation of delusions. Clinically, delusions may lead to delayed or misdiagnosis. Our results shed light on how to identify individuals at risk of neuropsychiatric features of dementia, a crucial first step to enable targeted symptom management. [ABSTRACT FROM AUTHOR]

Published
2022
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47. Interdisciplinary Collaborative Training for School-Based Health Professionals.

Author

Papa, Patricia A., Rector, Cherie, and Stone, Carol

Abstract

Interdisciplinary training and education for school-based health professionals is important, but few such programs exist. This paper describes the California State University Interprofessional Collaboration Training Project and the Catholic University of America School Nurse Practitioner Program, offering suggestions for expanding interdisciplinary training of school-based health professionals in academic institutions. (SM)

Published
1998

49. Factors That Influence Non-Motor Impairment Across the ALS-FTD Spectrum: Impact of Phenotype, Sex, Age, Onset and Disease Stage

Author

Devenney, Emma M., primary, McErlean, Kate, additional, Tse, Nga Yan, additional, Caga, Jashelle, additional, Dharmadasa, Thanuja, additional, Huynh, William, additional, Mahoney, Colin J., additional, Zoing, Margaret, additional, Mazumder, Srestha, additional, Dobson-Stone, Carol, additional, Kwok, John B., additional, Halliday, Glenda M., additional, Hodges, John R., additional, Piguet, Olivier, additional, Ahmed, Rebekah M., additional, and Kiernan, Matthew C., additional

Published
2021
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50. Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing

Author

Stevanovski, Igor, primary, Chintalaphani, Sanjog R., additional, Gamaarachchi, Hasindu, additional, Ferguson, James M., additional, Pineda, Sandy S., additional, Scriba, Carolin K., additional, Tchan, Michel, additional, Fung, Victor, additional, Ng, Karl, additional, Cortese, Andrea, additional, Houlden, Henry, additional, Dobson-Stone, Carol, additional, Fitzpatrick, Lauren, additional, Halliday, Glenda, additional, Ravenscroft, Gianina, additional, Davis, Mark R., additional, Laing, Nigel G., additional, Fellner, Avi, additional, Kennerson, Marina, additional, Kumar, Kishore R., additional, and Deveson, Ira W., additional

Published
2021
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