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1. Protein network analysis reveals selectively vulnerable regions and biological processes in FTD

Author

Bonham, Luke W, Steele, Natasha ZR, Karch, Celeste M, Manzoni, Claudia, Geier, Ethan G, Wen, Natalie, Ofori-Kuragu, Aaron, Momeni, Parastoo, Hardy, John, Miller, Zachary A, Hess, Christopher P, Lewis, Patrick, Miller, Bruce L, Seeley, William W, Baranzini, Sergio E, Desikan, Rahul S, Ferrari, Raffaele, Yokoyama, Jennifer S, Ferrari, R, Hernandez, DG, Nalls, MA, Rohrer, JD, Ramasamy, A, Kwok, JBJ, Dobson-Stone, C, Schofield, PR, Halliday, GM, Hodges, JR, Piguet, O, Bartley, L, Thompson, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, NJ, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Waldö, M Landqvist, Nilsson, K, Nilsson, C, Mackenzie, IRA, Hsiung, G-YR, Mann, D, Grafman, J, Morris, CM, Attems, J, Griffiths, TD, McKeith, IG, Thomas, AJ, Pietrini, P, Huey, ED, Wassermann, EM, Baborie, A, Jaros, E, Tierney, MC, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, JB, Schlachetzki, JCM, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, VM, Grossman, M, Trojanowski, JQ, van der Zee, J, Van Broeckhoven, C, Cappa, SF, Leber, I, Hannequin, D, and Golfier, V

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease Related Dementias (ADRD), Frontotemporal Dementia (FTD), Acquired Cognitive Impairment, Dementia, Biotechnology, Neurodegenerative, Rare Diseases, Neurosciences, Brain Disorders, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Neurological, International FTD-Genomics Consortium, Clinical sciences
Abstract

ObjectiveThe neuroanatomical profile of behavioral variant frontotemporal dementia (bvFTD) suggests a common biological etiology of disease despite disparate pathologic causes; we investigated the genetic underpinnings of this selective regional vulnerability to identify new risk factors for bvFTD.MethodsWe used recently developed analytical techniques designed to address the limitations of genome-wide association studies to generate a protein interaction network of 63 bvFTD risk genes. We characterized this network using gene expression data from healthy and diseased human brain tissue, evaluating regional network expression patterns across the lifespan as well as the cell types and biological processes most affected in bvFTD.ResultsWe found that bvFTD network genes show enriched expression across the human lifespan in vulnerable neuronal populations, are implicated in cell signaling, cell cycle, immune function, and development, and are differentially expressed in pathologically confirmed frontotemporal lobar degeneration cases. Five of the genes highlighted by our differential expression analyses, BAIAP2, ERBB3, POU2F2, SMARCA2, and CDC37, appear to be novel bvFTD risk loci.ConclusionsOur findings suggest that the cumulative burden of common genetic variation in an interacting protein network expressed in specific brain regions across the lifespan may influence susceptibility to bvFTD.

Published
2018

2. A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers

Author

Zhang M1, 2 3, Ferrari R4, Tartaglia MC3, 5 6, Keith J7, Surace EI8, Wolf U9, Sato C3, Grinberg M3, Liang Y3, Xi Z3, Dupont K3, McGoldrick P3, Weichert A3, McKeever PM3, Schneider R3, 6 7, McCorkindale MD4, Manzoni C10, Rademakers R11, Graff-Radford NR12, Dickson DW11, Parisi JE13, Boeve BF14, Petersen RC14, Miller BL15, Seeley WW16, van Swieten JC17, van Rooij J17, Pijnenburg Y18, van der Zee J19, Van Broeckhoven C19, Le Ber I21, Van Deerlin V23, Suh E23, Rohrer JD24, Mead S25, Graff C26, Öijerstedt L26, Pickering-Brown S28, Rollinson S28, Rossi G29, Tagliavini F30, Brooks WS31, Dobson-Stone C32, Halliday GM32, Hodges JR32, Piguet O34, Binetti G36, Benussi L37, Ghidoni R37, Nacmias B38, Sorbi S38, Bruni AC40, Galimberti D41, Scarpini E41, Rainero I42, Rubino E42, Clarimon J43, Lleó A43, Ruiz A45, Hernández I45, Pastor P46, Diez-Fairen M46, Borroni B48, Pasquier F49, Deramecourt V49, Lebouvier T49, Perneczky R50, 51 52, Diehl-Schmid J50, Grafman J53, Huey ED55, Mayeux R55, Nalls MA57, Hernandez D57, Singleton A57, Momeni P58, Zeng Z59, Hardy J4, Robertson J3, Zinman L6, 7, Rogaeva E3, 6, International FTD-Genomics Consortium (IFGC), Ferrari R, Hernandez DG, Nalls MA, Rohrer JD, Ramasamy A, Kwok JBJ, Dobson-Stone C, Brooks WS, Schofield PR, Halliday GM, Hodges JR, Piguet O, Bartley L, Thompson E, Hernández I, Ruiz A, Boada M, Borroni B, Padovani A, Cruchaga C, Cairns NJ, Benussi L, Binetti G, Ghidoni R, Forloni G, Albani D, Galimberti D, Fenoglio C, Serpente M, Scarpini E, Clarimón J, Lleó A, Blesa R, Wald Ouml ML, Nilsson K, Nilsson C, Mackenzie IRA, Hsiung GR, Mann DMA, Grafman J, Morris CM, Attems J, Griffiths TD, McKeith IG, Thomas AJ, Pietrini P, Huey ED, Wassermann EM, Baborie A, Jaros E, Tierney MC, Pastor P, Razquin C, Ortega-Cubero S, Alonso E, Perneczky R, Diehl-Schmid J, Alexopoulos P, Kurz A, Rainero I, Rubino E, Pinessi L, Rogaeva E, St George-Hyslop P, Rossi G, Tagliavini F, Giaccone G, Rowe JB, Schlachetzki JCM, Uphill J, Collinge J, Mead S, Danek A, Van Deerlin VM, Grossman M, Trojanowski JQ, van der Zee J, Van Broeckhoven C, Cappa SF, Leber I, Hannequin D, Golfier V, Vercelletto M, Brice A, Nacmias B, Sorbi S, Bagnoli S, Piaceri I, Nielsen JE, Hjermind LE, Riemenschneider M, Mayhaus M, Ibach B, Gasparoni G, Pichler S, Gu W, Rossor MN, Fox NC, Warren JD, Grazia Spillantini M, Morris HR, Rizzu P, Heutink P, Snowden JS, Rollinson S, Richardson A, Gerhard A, Bruni AC, Maletta R, Frangipane F, Cupidi C, Bernardi L, Anfossi M, Gallo M, Elena Conidi M, Smirne N, Rademakers R, Baker M, Dickson DW, Graff-Radford NR, Petersen RC, Knopman D, Josephs KA, Boeve BF, Parisi JE, Seeley WW, Miller BL, Karydas AM, Rosen H, van Swieten JC, Dopper EGP, Seelaar H, Pijnenburg YAL, Scheltens P, Logroscino G, Capozzo R, Novelli V, Puca AA, Franceschi M, Postiglione A, Milan G, Sorrentino P, Kristiansen M, Chiang HH, Graff C, Pasquier F, Rollin A, Deramecourt V, Lebouvier T, Kapogiannis D, Ferrucci L, Pickering-Brown S, Singleton AB, Hardy J, Momeni P, Human genetics, Amsterdam Neuroscience - Neurodegeneration, Neurology, Divisions, Zhang, M1, 2, 3, Ferrari, R4, Tartaglia, Mc3, 5, 6, Keith, J7, Surace, Ei8, Wolf, U9, Sato, C3, Grinberg, M3, Liang, Y3, Xi, Z3, Dupont, K3, Mcgoldrick, P3, Weichert, A3, Mckeever, Pm3, Schneider, R3, 6, 7, Mccorkindale, Md4, Manzoni, C10, Rademakers, R11, Graff-Radford, Nr12, Dickson, Dw11, Parisi, Je13, Boeve, Bf14, Petersen, Rc14, Miller, Bl15, Seeley, Ww16, van Swieten, Jc17, van Rooij, J17, Pijnenburg, Y18, van der Zee, J19, Van Broeckhoven, C19, Le Ber, I21, Van Deerlin, V23, Suh, E23, Rohrer, Jd24, Mead, S25, Graff, C26, Öijerstedt, L26, Pickering-Brown, S28, Rollinson, S28, Rossi, G29, Tagliavini, F30, Brooks, Ws31, Dobson-Stone, C32, Halliday, Gm32, Hodges, Jr32, Piguet, O34, Binetti, G36, Benussi, L37, Ghidoni, R37, Nacmias, B38, Sorbi, S38, Bruni, Ac40, Galimberti, D41, Scarpini, E41, Rainero, I42, Rubino, E42, Clarimon, J43, Lleó, A43, Ruiz, A45, Hernández, I45, Pastor, P46, Diez-Fairen, M46, Borroni, B48, Pasquier, F49, Deramecourt, V49, Lebouvier, T49, Perneczky, R50, 51, 52, Diehl-Schmid, J50, Grafman, J53, Huey, Ed55, Mayeux, R55, Nalls, Ma57, Hernandez, D57, Singleton, A57, Momeni, P58, Zeng, Z59, Hardy, J4, Robertson, J3, Zinman, L6, Rogaeva, E3, International FTD-Genomics Consortium, (IFGC), Ferrari, R, Hernandez, Dg, Nalls, Ma, Rohrer, Jd, Ramasamy, A, Kwok, Jbj, Dobson-Stone, C, Brooks, W, Schofield, Pr, Halliday, Gm, Hodges, Jr, Piguet, O, Bartley, L, Thompson, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, Nj, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Wald Ouml, Ml, Nilsson, K, Nilsson, C, Mackenzie, Ira, Hsiung, Gr, Mann, Dma, Grafman, J, Morris, Cm, Attems, J, Griffiths, Td, Mckeith, Ig, Thomas, Aj, Pietrini, P, Huey, Ed, Wassermann, Em, Baborie, A, Jaros, E, Tierney, Mc, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, Jb, Schlachetzki, Jcm, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, Vm, Grossman, M, Trojanowski, Jq, van der Zee, J, Van Broeckhoven, C, Cappa, Sf, Leber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, Je, Hjermind, Le, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, Mn, Fox, Nc, Warren, Jd, Grazia Spillantini, M, Morris, Hr, Rizzu, P, Heutink, P, Snowden, J, Rollinson, S, Richardson, A, Gerhard, A, Bruni, Ac, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Elena Conidi, M, Smirne, N, Rademakers, R, Baker, M, Dickson, Dw, Graff-Radford, Nr, Petersen, Rc, Knopman, D, Josephs, Ka, Boeve, Bf, Parisi, Je, Seeley, Ww, Miller, Bl, Karydas, Am, Rosen, H, van Swieten, Jc, Dopper, Egp, Seelaar, H, Pijnenburg, Yal, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, Aa, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, Hh, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebouvier, T, Kapogiannis, D, Ferrucci, L, Pickering-Brown, S, Singleton, Ab, Hardy, J, Momeni, P, and Int FTD-Genomics Consortium IFGC

Subjects
Male, Heterozygote, amyotrophic lateral sclerosis, Genotype, genetic association, Age of onset, Polymorphism, Single Nucleotide, frontotemporal dementia, age of onset, C9orf72, Humans, amyotrophic lateral sclerosi, Aged, C9orf72 Protein, Original Articles, DNA Methylation, Middle Aged, Amyotrophic lateral sclerosis, Gene Expression Regulation, Genetic association, CpG Islands, Female, Human medicine, Neurology (clinical), Frontotemporal dementia
Abstract

Discovery of disease age-of-onset modifiers is important for clinical trials and drug design. Zhang et al. perform a genome-wide analysis of epigenetic functional polymorphisms and identify an association between the C6orf10/LOC101929163 locus and age of FTD/ALS onset. The risk allele may be associated with a pro-inflammatory state in the brain., 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

7. Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

Author

Swarup, V, Hinz, FI, Rexach, JE, Noguchi, KI, Toyoshiba, H, Oda, A, Hirai, K, Sarkar, A, Seyfried, NT, Cheng, C, Haggarty, SJ, Ferrari, R, Rohrer, JD, Ramasamy, A, Hardy, J, Hernandez, DG, Nalls, MA, Singleton, AB, Kwok, JBJ, Dobson-Stone, C, Brooks, WS, Schofield, PR, Halliday, GM, Hodges, JR, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cairns, NJ, Cruchaga, C, Binetti, G, Ghidoni, R, Benussi, L, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Waldö, ML, Nilsson, K, Nilsson, C, Mackenzie, IRA, Hsiung, GYR, Mann, DMA, Grafman, J, Morris, CM, Attems, J, Griffiths, TD, McKeith, IG, Thomas, AJ, Jaros, E, Pietrini, P, Huey, ED, Wassermann, EM, Tierney, MC, Baborie, A, Pastor, P, Ortega-Cubero, S, Razquin, C, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, George-Hyslop, PS, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, JB, Schlachetzki, JCM, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, VM, Grossman, M, Trojanowski, JQ, Pickering-Brown, S, Momeni, P, van der Zee, J, Cruts, M, Van Broeckhoven, C, Cappa, SF, Leber, I, Brice, A, Hannequin, D, Golfier, V, Swarup, V, Hinz, FI, Rexach, JE, Noguchi, KI, Toyoshiba, H, Oda, A, Hirai, K, Sarkar, A, Seyfried, NT, Cheng, C, Haggarty, SJ, Ferrari, R, Rohrer, JD, Ramasamy, A, Hardy, J, Hernandez, DG, Nalls, MA, Singleton, AB, Kwok, JBJ, Dobson-Stone, C, Brooks, WS, Schofield, PR, Halliday, GM, Hodges, JR, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cairns, NJ, Cruchaga, C, Binetti, G, Ghidoni, R, Benussi, L, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Waldö, ML, Nilsson, K, Nilsson, C, Mackenzie, IRA, Hsiung, GYR, Mann, DMA, Grafman, J, Morris, CM, Attems, J, Griffiths, TD, McKeith, IG, Thomas, AJ, Jaros, E, Pietrini, P, Huey, ED, Wassermann, EM, Tierney, MC, Baborie, A, Pastor, P, Ortega-Cubero, S, Razquin, C, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, George-Hyslop, PS, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, JB, Schlachetzki, JCM, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, VM, Grossman, M, Trojanowski, JQ, Pickering-Brown, S, Momeni, P, van der Zee, J, Cruts, M, Van Broeckhoven, C, Cappa, SF, Leber, I, Brice, A, Hannequin, D, and Golfier, V

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
2019

8. CXCR4 involvement in neurodegenerative diseases

Author

Bonham, LW, Karch, CM, Fan, CC, Tan, C, Geier, EG, Wang, Y, Wen, N, Broce, IJ, Li, Y, Barkovich, MJ, Ferrari, R, Hardy, J, Momeni, P, Höglinger, G, Müller, U, Hess, CP, Sugrue, LP, Dillon, WP, Schellenberg, GD, Miller, BL, Andreassen, OA, Dale, AM, Barkovich, AJ, Yokoyama, JS, Desikan, RS, Hernandez, DG, Nalls, MA, Rohrer, JD, Ramasamy, A, Kwok, JBJ, Dobson-Stone, C, Schofield, PR, Halliday, GM, Hodges, JR, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, NJ, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Waldö, ML, Nilsson, K, Nilsson, C, MacKenzie, IRA, Hsiung, GYR, Mann, DMA, Grafman, J, Morris, CM, Attems, J, Griffiths, TD, McKeith, IG, Thomas, AJ, Pietrini, P, Huey, ED, Wassermann, EM, Baborie, A, Jaros, E, Tierney, MC, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, George-Hyslop, PS, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, JB, Schlachetzki, JCM, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, VM, Rowe, James [0000-0001-7216-8679], and Apollo - University of Cambridge Repository

Subjects
Receptors, CXCR4, Risk Factors, Animals, Brain, Gene Expression, Humans, Gene Regulatory Networks, Genetic Predisposition to Disease, Mice, Transgenic, Neurodegenerative Diseases, Microglia, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Abstract

© 2017 The Author(s). Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson's disease (PD) and Alzheimer's disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12, TLR2, RALB, and CCR5. Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT, we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a 'network' of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases.

Published
2018
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9. Protein network analysis reveals selectively vulnerable regions and biological processes in FTD

Author

Bonham, Lw1, Steele, Nzr1, Karch, Cm1, Manzoni, C1, Geier, Eg1, Wen, N1, Ofori-Kuragu, A1, Momeni, P1, Hardy, J1, Miller, Za1, Hess, Cp1, Lewis, P1, Miller, Bl1, Seeley, Ww1, Baranzini, Se1, Desikan, Rs1, Ferrari, R1, Yokoyama, Js1, ( Ferrari R, International FTD-Genomics Consortium, Hernandez, Dg, Nalls, Ma, Rohrer, Jd, Ramasamy, A, Kwok, Jbj, Dobson-Stone, C, Schofield, Pr, Halliday, Gm, Hodges, Jr, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, Nj, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Landqvist Waldö, M, Nilsson, C, Mackenzie, Ira, Hsiung, Gyr, Mann, Dma, Grafman, J, Morris, Cm, Attems, J, Griffiths, Td, Mckeith, Ig, Thomas, Aj, Pietrini, P, Huey, Ed, Wassermann, Em, Baborie, A, Jaros, E, Tierney, Mc, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, Jb, Schlachetzki, Jcm, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin VM, Grossman, M, Trojanowski, Jq, van der Zee, J, Cruts, M, Van Broeckhoven, C, Cappa, Sf, Leber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, Je, Hjermind, Le, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, Mn, Fox, Nc, Warren, Jd, Spillantini, Mg, Morris, Hr, Rizzu, P, Heutink, P, Snowden, Js, Rollinson, S, Richardson, A, Gerhard, A, Bruni, Ac, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Conidi, Me, Smirne, N, Rademakers, R, Baker, M, Dickson, Dw, Graff-Radford, Nr, Petersen, Rc, Knopman, D, Josephs, Ka, Boeve, Bf, Parisi, Je, Seeley, Ww, Miller, Bl, Karydas, Am, Rosen, H, van Swieten JC, Dopper, Eg, Seelaar, H, Pijnenburg, Yal, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, Aa, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, Hh, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebouvier, T, Kapogiannis, D, Ferrucci, L, Pickering-Brown, S, Singleton, Ab, Hardy, J, and Momeni, P.

Subjects
0301 basic medicine, Cell type, Disease, Frontotemporal lobar degeneration, Biology, medicine.disease, Article, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Interaction network, Genetic variation, medicine, Neurology (clinical), Gene, Neuroscience, 030217 neurology & neurosurgery, Genetics (clinical), Frontotemporal dementia, Genetic association
Abstract

ObjectiveThe neuroanatomical profile of behavioral variant frontotemporal dementia (bvFTD) suggests a common biological etiology of disease despite disparate pathologic causes; we investigated the genetic underpinnings of this selective regional vulnerability to identify new risk factors for bvFTD.MethodsWe used recently developed analytical techniques designed to address the limitations of genome-wide association studies to generate a protein interaction network of 63 bvFTD risk genes. We characterized this network using gene expression data from healthy and diseased human brain tissue, evaluating regional network expression patterns across the lifespan as well as the cell types and biological processes most affected in bvFTD.ResultsWe found that bvFTD network genes show enriched expression across the human lifespan in vulnerable neuronal populations, are implicated in cell signaling, cell cycle, immune function, and development, and are differentially expressed in pathologically confirmed frontotemporal lobar degeneration cases. Five of the genes highlighted by our differential expression analyses, BAIAP2, ERBB3, POU2F2, SMARCA2, and CDC37, appear to be novel bvFTD risk loci.ConclusionsOur findings suggest that the cumulative burden of common genetic variation in an interacting protein network expressed in specific brain regions across the lifespan may influence susceptibility to bvFTD.

Published
2018

10. Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer’s and Parkinson’s diseases

Author

Ferrari R, Wang Y, Vandrovcova J, Guelfi S, Witeolar A, Karch CM, Schork AJ, Fan CC, Brewer JB, International FTD-Genomics Consortium (IFGC), International Parkinson's Disease Genomics Consortium (IPDGC), International Genomics of Alzheimer's Project (IGAP), Momeni P, Schellenberg GD, Dillon WP, Sugrue LP, Hess CP, Yokoyama JS, Bonham LW, Rabinovici GD, Miller BL, Andreassen OA, Dale AM, Hardy J, Desikan RS, Collaborators: Ferrari R, Hernandez DG, Nalls MA, Rohrer JD, Ramasamy A, Kwok JBJ, Dobson-Stone C, Schofield PR, Halliday GM, Hodges JR, Piguet O, Bartley L, Thompson E, Haan E, Hernández I, Ruiz A, Boada M, Borroni B, Padovani A, Cruchaga C, Cairns NJ, Benussi L, Binetti G, Ghidoni R, Forloni G, Albani D, Galimberti D, Fenoglio C, Serpente M, Scarpini E, Clarimón J, Lleó A, Blesa R, Landqvist Waldö M, Nilsson C, Mackenzie IRA, Hsiung GYR, Mann DMA, Grafman J, Morris CM, Attems J, Griffiths TD, McKeith IG, Thomas AJ, Pietrini P, Huey ED, Wassermann EM, Baborie A, Jaros E, Tierney MC, Pastor P, Razquin C, Ortega-Cubero S, Alonso E, Perneczky R, Diehl-Schmid J, Alexopoulos P, Kurz A, Rainero I, Rubino E, Pinessi L, Rogaeva E, St George-Hyslop P, Rossi G, Tagliavini F, Giaccone G, Rowe JB, Schlachetzki JCM, Uphill J, Collinge J, Mead S, Danek A, Van Deerlin VM, Grossman M, Trojanowski JQ, van der Zee J, Cruts M, Van Broeckhoven C, Cappa SF, Leber I, Hannequin D, Golfier V, Vercelletto M, Brice A, Nacmias B, Sorbi S, Bagnoli S, Piaceri I, Nielsen JE, Hjermind LE, Riemenschneider M, Mayhaus M, Ibach B, Gasparoni G, Pichler S, Gu W, Rossor MN, Fox NC, Warren JD, Spillantini MG, Morris HR, Rizzu P, Heutink P, Snowden JS, Rollinson S, Richardson A, Gerhard A, Bruni AC, Maletta R, Frangipane F, Cupidi C, Bernardi L, Anfossi M, Gallo M, Conidi ME, Smirne N, Rademakers R, Baker M, Dickson DW, Graff-Radford NR, Petersen RC, Knopman D, Josephs KA, Boeve BF, Parisi JE, Seeley WW, Karydas AM, Rosen H, van Swieten JC, Dopper EG, Seelaar H, Pijnenburg YAL, Scheltens P, Logroscino G, Capozzo R, Novelli V, Puca AA, Franceschi M, Postiglione A, Milan G, Sorrentino P, Kristiansen M, Chiang HH, Graff C, Pasquier F, Rollin A, Deramecourt V, Lebouvier T, Kapogiannis D, Ferrucci L, Pickering-Brown S, Singleton AB, Momeni P., Neurology, VU University medical center, Human genetics, Amsterdam Neuroscience - Neurodegeneration, CCA - Imaging and biomarkers, Divisions, Van Broeckhoven, Christine, Rademakers, Rosa, International FTD-Genomics Consortium (IFGC), International Parkinson's Disease Genomics Consortium (IPDGC), International Genomics of Alzheimer's Project (IGAP), Ferrari, R, Wang, Y, Vandrovcova, J, Guelfi, S, Witeolar, A, Karch, Cm, Schork, Aj, Fan, Cc, Brewer, Jb, International FTD-Genomics Consortium, (IFGC), International Parkinson's Disease Genomics Consortium, (IPDGC), International Genomics of Alzheimer's Project, (IGAP), Momeni, P, Schellenberg, Gd, Dillon, Wp, Sugrue, Lp, Hess, Cp, Yokoyama, J, Bonham, Lw, Rabinovici, Gd, Miller, Bl, Andreassen, Oa, Dale, Am, Hardy, J, Desikan, R, Collaborators: Ferrari, R, Hernandez, Dg, Nalls, Ma, Rohrer, Jd, Ramasamy, A, Kwok, Jbj, Dobson-Stone, C, Schofield, Pr, Halliday, Gm, Hodges, Jr, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, Nj, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Landqvist Waldö, M, Nilsson, C, Mackenzie, Ira, Hsiung, Gyr, Mann, Dma, Grafman, J, Morris, Cm, Attems, J, Griffiths, Td, Mckeith, Ig, Thomas, Aj, Pietrini, P, Huey, Ed, Wassermann, Em, Baborie, A, Jaros, E, Tierney, Mc, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, Jb, Schlachetzki, Jcm, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, Vm, Grossman, M, Trojanowski, Jq, van der Zee, J, Cruts, M, Van Broeckhoven, C, Cappa, Sf, Leber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, Je, Hjermind, Le, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, Mn, Fox, Nc, Warren, Jd, Spillantini, Mg, Morris, Hr, Rizzu, P, Heutink, P, Snowden, J, Rollinson, S, Richardson, A, Gerhard, A, Bruni, Ac, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Conidi, Me, Smirne, N, Rademakers, R, Baker, M, Dickson, Dw, Graff-Radford, Nr, Petersen, Rc, Knopman, D, Josephs, Ka, Boeve, Bf, Parisi, Je, Seeley, Ww, Karydas, Am, Rosen, H, van Swieten, Jc, Dopper, Eg, Seelaar, H, Pijnenburg, Yal, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, Aa, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, Hh, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebouvier, T, Kapogiannis, D, Ferrucci, L, Pickering-Brown, S, Singleton, Ab, and Momeni, P.

Subjects
0301 basic medicine, Genotype, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, mental disorders, Genetic Pleiotropy, Genetic predisposition, Medicine, Humans, Genetic Predisposition to Disease, Allele, Polymorphism, Biology, Alleles, Genetic association, Genetics, business.industry, Frontotemporal Dementia, Genome-Wide Association Study, Parkinson Disease, Surgery, Neurology (clinical), Psychiatry and Mental Health, Single Nucleotide, medicine.disease, Genetic architecture, nervous system diseases, 030104 developmental biology, Human medicine, business, Neuroscience, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

Background Clinical, pathological and genetic overlap between sporadic frontotemporal dementia (FTD), Alzheimer9s disease (AD) and Parkinson9s disease (PD) has been suggested; however, the relationship between these disorders is still not well understood. Here we evaluated genetic overlap between FTD, AD and PD to assess shared pathobiology and identify novel genetic variants associated with increased risk for FTD. Methods Summary statistics were obtained from the International FTD Genomics Consortium, International PD Genetics Consortium and International Genomics of AD Project (n>75 000 cases and controls). We used conjunction false discovery rate (FDR) to evaluate genetic pleiotropy and conditional FDR to identify novel FTD-associated SNPs. Relevant variants were further evaluated for expression quantitative loci. Results We observed SNPs within the HLA , MAPT and APOE regions jointly contributing to increased risk for FTD and AD or PD. By conditioning on polymorphisms associated with PD and AD, we found 11 loci associated with increased risk for FTD. Meta-analysis across two independent FTD cohorts revealed a genome-wide signal within the APOE region (rs6857, 3′-UTR= PVRL2 , p=2.21×10 –12 ), and a suggestive signal for rs1358071 within the MAPT region (intronic= CRHR1 , p=4.91×10 −7 ) with the effect allele tagging the H1 haplotype. Pleiotropic SNPs at the HLA and MAPT loci associated with expression changes in cis -genes supporting involvement of intracellular vesicular trafficking, immune response and endo/lysosomal processes. Conclusions Our findings demonstrate genetic pleiotropy in these neurodegenerative diseases and indicate that sporadic FTD is a polygenic disorder where multiple pleiotropic loci with small effects contribute to increased disease risk.

Published
2016

11. Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies

Author

Broce, I, Karch, CM, Wen, N, Fan, CC, Wang, Y, Hong Tan, C, Kouri, N, Ross, OA, Höglinger, GU, Muller, U, Hardy, J, Momeni, P, Hess, CP, Dillon, WP, Miller, ZA, Bonham, LW, Rabinovici, GD, Rosen, HJ, Schellenberg, GD, Franke, A, Karlsen, TH, Veldink, JH, Ferrari, R, Yokoyama, JS, Miller, BL, Andreassen, OA, Dale, AM, Desikan, RS, Sugrue, LP, Hernandez, DG, Nalls, MA, Rohrer, JD, Ramasamy, A, Kwok, JBJ, Dobson-Stone, C, Brooks, WS, Schofield, PR, Halliday, GM, Hodges, JR, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, NJ, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Landqvist Waldö, M, Nilsson, K, Nilsson, C, Mackenzie, IRA, Hsiung, GYR, Mann, DMA, Grafman, J, Morris, CM, Attems, J, Griffiths, TD, G McKeith, I, Thomas, AJ, Pietrini, P, Huey, ED, Wassermann, EM, Baborie, A, Jaros, E, Tierney, MC, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, JB, Schlachetzki, JCM, Uphill, J, Broce, I, Karch, CM, Wen, N, Fan, CC, Wang, Y, Hong Tan, C, Kouri, N, Ross, OA, Höglinger, GU, Muller, U, Hardy, J, Momeni, P, Hess, CP, Dillon, WP, Miller, ZA, Bonham, LW, Rabinovici, GD, Rosen, HJ, Schellenberg, GD, Franke, A, Karlsen, TH, Veldink, JH, Ferrari, R, Yokoyama, JS, Miller, BL, Andreassen, OA, Dale, AM, Desikan, RS, Sugrue, LP, Hernandez, DG, Nalls, MA, Rohrer, JD, Ramasamy, A, Kwok, JBJ, Dobson-Stone, C, Brooks, WS, Schofield, PR, Halliday, GM, Hodges, JR, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, NJ, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Landqvist Waldö, M, Nilsson, K, Nilsson, C, Mackenzie, IRA, Hsiung, GYR, Mann, DMA, Grafman, J, Morris, CM, Attems, J, Griffiths, TD, G McKeith, I, Thomas, AJ, Pietrini, P, Huey, ED, Wassermann, EM, Baborie, A, Jaros, E, Tierney, MC, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, JB, Schlachetzki, JCM, and Uphill, J

Abstract

Background: Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. Methods and findings: Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders—namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)—and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (pi

Published
2018

12. Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies

Author

Broce, Iris, Karch, Celeste M., Wen, Natalie, Fan, Chun C., Wang, Yunpeng, Hong Tan, Chin, Kouri, Naomi, Ross, Owen A., Höglinger, Günter U., Muller, Ulrich, Hardy, John, Momeni, Parastoo, Hess, Christopher P., Dillon, William P., Miller, Zachary A., Bonham, Luke W., Rabinovici, Gil D., Rosen, Howard J., Schellenberg, Gerard D., Franke, Andre, Karlsen, Tom H., Veldink, Jan H., Ferrari, Raffaele, Yokoyama, Jennifer S., Miller, Bruce L., Andreassen, Ole A., Dale, Anders M., Desikan, Rahul S., Sugrue, Leo P., Ferrari R, Hernandez DG, Nalls MA, Rohrer JD, Ramasamy A, Kwok JBJ, Dobson-Stone C, Brooks WS, Schofield PR, Halliday GM, Hodges JR, Piguet O, Bartley L, Thompson E, Haan E, Hernández I, Ruiz A, Boada M, Borroni B, Padovani A, Cruchaga C, Cairns NJ, Benussi L, Binetti G, Ghidoni R, Forloni G, Galimberti D, Fenoglio C, Serpente M, Scarpini E, Clarimón J, Lleó A, Blesa R, Waldö ML, Nilsson K, Nilsson C, Mackenzie IRA, Hsuing GYR, Mann DMA, Grafman J, Morris CM, Attems J, Griffiths TD, McKeith IG, Thomas AJ, Pietrini P, Huey ED, Wasserman EM, Baborie A, Jaros E, Tierney MC, Pastor P, Razquin C, Ortega-Cubero S, Alonso E, Perneczky E, Diehl-Schmid J, Alexopoulos P, Kurz A, Rainero I, Rubino E, Pinessi L, Rogaeva E, St George-Hyslop P, Rossi G, Tagliavini F, Giaccone G, Rowe JB, Schlachetzki JCM, Uphill J, Collinge J, Mead S, Danek A, Van Deerlin VM, Grossmann M, Trojanowski JQ, van der Zee J, Deschamps W, Van Langenhove T, Cruts M, Van Broeckhoven C, Cappa SF, Le Ber I, Hannequin D, Golfier V, Vercelletto M, Brice A, Nacmias B, Sorbi S, Bagnoli S, Piaceri I, Nielsen JE, Hjermind LE, Riemenschneider M, Mayhaus M, Ibach B, Gasparoni G, Pichler S, Gu W, Rossor MN, Fox NC, Warren JD, Spillantini MG, Morris HR, Rizzu P, Heutnik P, Snowden J, Rollinson S, Richardson A, Gerhard A, Bruni AC, Maletta R, Frangipane F, Cupidi C, Bernardi L, Anfossi M, Gallo M, Conidi ME, Smirne N, Rademakers R, Baker M, Dickson DW, Graff-Radford NR, Peterson RC, Knopman D, Josephs KA, Boeve BF, Parisi JE, Seeley WW, Miller BL, Karydas AM, Rosen H, van Swieten JC, Dopper EGP, Seelaar H, Pijnenburg YAL, Scheltens P, Logroscino G, Capozzo R, Novelli V, Puca AA, Franceschi M, Postiglione A, Milan G, Sorrentino P, Kristiansen M, Chiang HH, Graff C, Pasquier F, Rollin A, Deramecourt V, Lebert F, Kapogiannis D, Ferucci L, Pickering-Brown S, Singleton AB, Hardy J, Momeni P., Broce, Iris [0000-0003-4932-1430], Karch, Celeste M [0000-0002-6854-5547], Wang, Yunpeng [0000-0001-9831-1090], Tan, Chin Hong [0000-0002-0980-9936], Kouri, Naomi [0000-0002-6841-9882], Hess, Christopher P [0000-0002-5132-5302], Miller, Zachary A [0000-0002-5991-3053], Bonham, Luke W [0000-0002-2533-1266], Veldink, Jan H [0000-0001-5572-9657], Dale, Anders M [0000-0002-6126-2966], Desikan, Rahul S [0000-0002-4151-6017], Sugrue, Leo P [0000-0001-7315-4519], Apollo - University of Cambridge Repository, Neurology, Human genetics, Amsterdam Neuroscience - Neurodegeneration, Divisions, Rademakers, Rosa, Int FTD-Genomics Consortium, Broce, Iri, Karch, Celeste M., Wen, Natalie, Fan, Chun C., Wang, Yunpeng, Hong Tan, Chin, Kouri, Naomi, Ross, Owen A., Höglinger, Günter U., Muller, Ulrich, Hardy, John, Momeni, Parastoo, Hess, Christopher P., Dillon, William P., Miller, Zachary A., Bonham, Luke W., Rabinovici, Gil D., Rosen, Howard J., Schellenberg, Gerard D., Franke, Andre, Karlsen, Tom H., Veldink, Jan H., Ferrari, Raffaele, Yokoyama, Jennifer S., Miller, Bruce L., Andreassen, Ole A., Dale, Anders M., Desikan, Rahul S., Sugrue, Leo P., Ferrari, R, Hernandez, Dg, Nalls, Ma, Rohrer, Jd, Ramasamy, A, Kwok, Jbj, Dobson-Stone, C, Brooks, W, Schofield, Pr, Halliday, Gm, Hodges, Jr, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, Nj, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Waldö, Ml, Nilsson, K, Nilsson, C, Mackenzie, Ira, Hsuing, Gyr, Mann, Dma, Grafman, J, Morris, Cm, Attems, J, Griffiths, Td, Mckeith, Ig, Thomas, Aj, Pietrini, P, Huey, Ed, Wasserman, Em, Baborie, A, Jaros, E, Tierney, Mc, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, E, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, Jb, Schlachetzki, Jcm, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, Vm, Grossmann, M, Trojanowski, Jq, van der Zee, J, Deschamps, W, Van Langenhove, T, Cruts, M, Van Broeckhoven, C, Cappa, Sf, Le Ber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, Je, Hjermind, Le, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, Mn, Fox, Nc, Warren, Jd, Spillantini, Mg, Morris, Hr, Rizzu, P, Heutnik, P, Snowden, J, Rollinson, S, Richardson, A, Gerhard, A, Bruni, Ac, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Conidi, Me, Smirne, N, Rademakers, R, Baker, M, Dickson, Dw, Graff-Radford, Nr, Peterson, Rc, Knopman, D, Josephs, Ka, Boeve, Bf, Parisi, Je, Seeley, Ww, Miller, Bl, Karydas, Am, Rosen, H, van Swieten, Jc, Dopper, Egp, Seelaar, H, Pijnenburg, Yal, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, Aa, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, Hh, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebert, F, Kapogiannis, D, Ferucci, L, Pickering-Brown, S, Singleton, Ab, Hardy, J, and Momeni, P.

Subjects
0301 basic medicine, Linkage disequilibrium, Gene Expression, Genome-wide association study, Neurodegenerative, Medical and Health Sciences, Motor Neuron Diseases, 0302 clinical medicine, Medicine and Health Sciences, 2.1 Biological and endogenous factors, Corticobasal degeneration, genetics [Genetic Predisposition to Disease], genetics [Frontotemporal Dementia], Genetics, Medicine (all), Neurodegenerative Diseases, Single Nucleotide, Genomics, General Medicine, Middle Aged, Colitis, LRRK2, 3. Good health, Neurology, Manchester Institute for Collaborative Research on Ageing, Frontotemporal Dementia, Neurological, Medicine, Research Article, Frontotemporal dementia, ResearchInstitutes_Networks_Beacons/MICRA, Immunology, Rheumatoid Arthritis, Single-nucleotide polymorphism, Gastroenterology and Hepatology, Human leukocyte antigen, Biology, Autoimmune Disease, Polymorphism, Single Nucleotide, Autoimmune Diseases, 03 medical and health sciences, Rare Diseases, Rheumatology, Clinical Research, General & Internal Medicine, FTD GWA, Mental Health and Psychiatry, mental disorders, Acquired Cognitive Impairment, Genome-Wide Association Studies, medicine, Ulcerative Colitis, Humans, Inflammatory and Immune System, Genetic Predisposition to Disease, ddc:610, Polymorphism, Aged, Genetic association, Genome-Wide Association Study, International FTD-Genomics Consortium, Prevention, Arthritis, Human Genome, Inflammatory Bowel Disease, Amyotrophic Lateral Sclerosis, Neurosciences, Correction, Biology and Life Sciences, Computational Biology, nutritional and metabolic diseases, Human Genetics, Genome Analysis, medicine.disease, Brain Disorders, nervous system diseases, 030104 developmental biology, Genetic Loci, Genetics of Disease, Dementia, Clinical Immunology, Human medicine, Clinical Medicine, Digestive Diseases, 030217 neurology & neurosurgery
Abstract

Background Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. Methods and findings Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders—namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)—and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD–immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal. Conclusions We show immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD., Rahul Desikan and colleagues use summary data from genome-wide association studies to investigate genetic overlap between frontotemporal dementia and a several immune-mediated diseases, and identify microglia and inflammation-associated genes that may play a role in FTD pathogenesis., Author summary Why was this study done? Frontotemporal dementia (FTD) is the leading cause of dementia in individuals less than 65 years old. Currently, there is no approved treatment of FTD and no diagnostic tests for predicting disease onset or measuring progression. Increasing evidence suggests that inflammation and immune system dysfunction play an important role in the pathogenesis of FTD. What did the researchers do and find? We used summary data from genome-wide association studies to investigate genetic overlap, or “pleiotropy,” between FTD and a variety of immune-mediated diseases. Through this approach, we found extensive FTD–immune genetic overlap within the HLA region on Chromosome 6, an area rich in genes related to microglial function, as well as in 3 genes not previously identified as contributing to the pathophysiology of FTD. Pointing to the functional relevance of these genetic results, we found that these candidate FTD–immune genes are differentially expressed in postmortem brains from patients with FTD compared to controls, and in microglia/macrophages compared with other central nervous system cells. Using bioinformatics tools, we explored protein and genetic interactions among our candidate FTD–immune genes. These results suggest that rather than a few individual loci, large portions of the HLA region may be associated with increased FTD risk. What do these findings mean? Immune dysfunction may play a role in the pathophysiology of a subset of FTD cases. For a subset of patients in whom immune dysfunction in general—and microglial activation in particular—is central to disease pathophysiology, anti-inflammatory treatment is an important area for further investigation.

Published
2018

13. Artificial grammar learning in vascular and progressive non-fluent aphasias

Author

Cope, TE, Wilson, B, Robson, H, Drinkall, R, Dean, L, Grube, M, Jones, PS, Patterson, K, Griffiths, TD, Rowe, JB, Petkov, CI, Cope, Thomas [0000-0002-4751-1786], Jones, Simon [0000-0001-9695-0702], Patterson, Karalyn [0000-0003-1927-7424], Rowe, James [0000-0001-7216-8679], and Apollo - University of Cambridge Repository

Subjects
education, grammar, frontotemporal dementia, implicit learning, stroke, aphasia
Abstract

Patients with non-fluent aphasias display impairments of expressive and receptive grammar. This has been attributed to deficits in processing configurational and hierarchical sequencing relationships. This hypothesis had not been formally tested. It was also controversial whether impairments are specific to language, or reflect domain general deficits in processing structured auditory sequences. Here we used an artificial grammar learning paradigm to compare the abilities of controls to participants with agrammatic aphasia of two different aetiologies: stroke and frontotemporal dementia. Ten patients with non-fluent variant primary progressive aphasia (nfvPPA), 12 with non-fluent aphasia due to stroke, and 11 controls implicitly learned a novel mixed-complexity artificial grammar designed to assess processing of increasingly complex sequencing relationships. We compared response profiles for otherwise identical sequences of speech tokens (nonsense words) and tone sweeps. In all three groups the ability to detect grammatical violations varied with sequence complexity, with performance improving over time and being better for adjacent than non-adjacent relationships. Patients performed less well than controls overall, and this was related more strongly to aphasia severity than to aetiology. All groups improved with practice and performed well at a control task of detecting oddball nonwords. Crucially, group differences did not interact with sequence complexity, demonstrating that aphasic patients were not disproportionately impaired on complex structures. Hierarchical cluster analysis revealed that response patterns were very similar across all three groups, but very different between the nonsense word and tone tasks, despite identical artificial grammar structures. Overall, we demonstrate that agrammatic aphasics of two different aetiologies are not disproportionately impaired on complex sequencing relationships, and that the learning of phonological and non-linguistic sequences occurs independently. The similarity of profiles of discriminatory abilities and rule learning across groups suggests that insights from previous studies of implicit sequence learning in vascular aphasia are likely to prove applicable in nfvPPA. [Abstract copyright: Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.]

Published
2017

14. Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS

Author

Taskesen, E, Mishra, A, van der Sluis, S, Ferrari, R, Veldink, Jh, van Es MA4, Smit, Ab5, Posthuma, D1, 2, Hernandez DG, Pijnenburg Y., Nalls, Ma, Rohrer, Jd, Ramasamy, A, Kwok, Jbj, Dobson-Stone, C, Schofield, Pr, Halliday, Gm, Hodges, Jr, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, Nj, Benussi, L, Binetti, G, Ghidoni, Roberta, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Waldö, Ml, Nilsson, K, Nilsson, C, Mackenzie, Ira, Hsiung, Gr, Mann, Dma, Grafman, J, Morris, Cm, Attems, J, Griffiths, Td, Mckeith, Ig, Thomas, Aj, Pietrini, P, Huey, Ed, Wassermann, Em, Baborie, A, Jaros, E, Tierney, Mc, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, George-Hyslop, Ps, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, Jb, Schlachetzki, Jcm, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin VM, Grossman, M, Trojanowski, Jq, van der Zee, J, Van Broeckhoven, C, Cappa, Sf, Leber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, Je, Hjermind, Le, Riemenschneider, GUNNAR MARKUS, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, Mn, Fox, Nc, Warren, Jd, Spillantini, Mg, Morris, Hr, Rizzu, P, Heutink, P, Snowden, Js, Rollinson, S, Richardson, A, Gerhard, A, Bruni, Ac, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, Lara, Anfossi, M, Gallo, M, Conidi, Me, Smirne, N, Rademakers, R, Baker, M, Dickson, Dw, Graff-Radford, Nr, Petersen, Rc, Knopman, D, Josephs, Ka, Boeve, Bf, Parisi, Je, Seeley, Ww, Miller, Bl, Karydas, Am, Rosen, H, van Swieten JC, Dopper, Egp, Seelaar, H, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, Aa, Franceschi, M, Postiglione, Antonio, Milan, Gian Luca, Sorrentino, Paolo Luigi, Kristiansen, M, Chiang, Hh, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebouvier, T, Kapogiannis, D, Ferrucci, L, Pickering-Brown, S, Singleton, Ab, Hardy, J, Momeni, P., Rademakers, Rosa, International FTD-Genomics Consortium, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience - Neurodegeneration, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Human genetics, APH - Quality of Care, Midwifery Science, Divisions, Neurology, Amsterdam Reproduction & Development (AR&D), Mishra, A [0000-0002-8141-1543], van der Sluis, S [0000-0001-9958-7216], van Es, MA [0000-0002-7709-5883], Posthuma, D [0000-0001-7582-2365], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Candidate gene, Science, Genome-wide association study, Biology, Neurodegenerative, Article, 03 medical and health sciences, 0302 clinical medicine, Rare Diseases, SDG 3 - Good Health and Well-being, mental disorders, medicine, Journal Article, Acquired Cognitive Impairment, Genetics, 2.1 Biological and endogenous factors, Amyotrophic lateral sclerosis, Aetiology, General, Alzheimer's Disease Related Dementias (ADRD), Genetic association, Multidisciplinary, Genetic heterogeneity, International FTD-Genomics Consortium, Neurodegeneration, Human Genome, Neurosciences, nutritional and metabolic diseases, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), medicine.disease, nervous system diseases, Brain Disorders, Frontotemporal Dementia (FTD), 030104 developmental biology, DNA methylation, Neurological, Medicine, Dementia, Human medicine, ALS, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting the frontal and temporal lobes. Genome-wide association studies (GWAS) on FTD identified only a few risk loci. One of the possible explanations is that FTD is clinically, pathologically, and genetically heterogeneous. An important open question is to what extent epigenetic factors contribute to FTD and whether these factors vary between FTD clinical subgroup. We compared the DNA-methylation levels of FTD cases (n = 128), and of FTD cases with Amyotrophic Lateral Sclerosis (FTD-ALS; n = 7) to those of unaffected controls (n = 193), which resulted in 14 and 224 candidate genes, respectively. Cluster analysis revealed significant class separation of FTD-ALS from controls. We could further specify genes with increased susceptibility for abnormal gene-transcript behavior by jointly analyzing DNA-methylation levels with the presence of mutations in a GWAS FTD-cohort. For FTD-ALS, this resulted in 9 potential candidate genes, whereas for FTD we detected 1 candidate gene (ELP2). Independent validation-sets confirmed the genes DLG1, METTL7A, KIAA1147, IGHMBP2, PCNX, UBTD2, WDR35, and ELP2/SLC39A6 among others. We could furthermore demonstrate that genes harboring mutations and/or displaying differential DNA-methylation, are involved in common pathways, and may therefore be critical for neurodegeneration in both FTD and FTD-ALS.

Published
2017

15. Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases

Author

Ferrari, R, Wang, Y, Vandrovcova, J, Guelfi, S, Witeolar, A, Karch, CM, Schork, AJ, Fan, CC, Brewer, JB, Momeni, P, Schellenberg, GD, Dillon, WP, Sugrue, LP, Hess, CP, Yokoyama, JS, Bonham, LW, Rabinovici, GD, Miller, BL, Andreassen, OA, Dale, AM, Hardy, J, Desikan, RS, Hernandez, DG, Nalls, MA, Rohrer, JD, Ramasamy, A, Kwok, JBJ, Dobson-Stone, C, Schofield, PR, Halliday, GM, Hodges, JR, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, NJ, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Landqvist Waldö, M, Nilsson, K, Nilsson, C, Mackenzie, IRA, Hsiung, GYR, Mann, DMA, Grafman, J, Morris, CM, Attems, J, Griffiths, TD, McKeith, IG, Thomas, AJ, Pietrini, P, Huey, ED, Wassermann, EM, Baborie, A, Jaros, E, Tierney, MC, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, JB, Schlachetzki, JCM, and Uphill, J

Subjects
mental disorders, nervous system diseases
Abstract

© Published by the BMJ Publishing Group Limited. Background Clinical, pathological and genetic overlap between sporadic frontotemporal dementia (FTD), Alzheimer's disease (AD) and Parkinson's disease (PD) has been suggested; however, the relationship between these disorders is still not well understood. Here we evaluated genetic overlap between FTD, AD and PD to assess shared pathobiology and identify novel genetic variants associated with increased risk for FTD. Methods Summary statistics were obtained from the International FTD Genomics Consortium, International PD Genetics Consortium and International Genomics of AD Project (n>75000 cases and controls). We used conjunction false discovery rate (FDR) to evaluate genetic pleiotropy and conditional FDR to identify novel FTD-associated SNPs. Relevant variants were further evaluated for expression quantitative loci. Results We observed SNPs within the HLA, MAPT and APOE regions jointly contributing to increased risk for FTD and AD or PD. By conditioning on polymorphisms associated with PD and AD, we found 11 loci associated with increased risk for FTD. Meta-analysis across two independent FTD cohorts revealed a genome-wide signal within the APOE region (rs6857, 3′-UTR=PVRL2, p=2.21×10 -12), and a suggestive signal for rs1358071 within the MAPT region (intronic=CRHR1, p=4.91×10 -7) with the effect allele tagging the H1 haplotype. Pleiotropic SNPs at the HLA and MAPT loci associated with expression changes in cis-genes supporting involvement of intracellular vesicular trafficking, immune response and endo/lysosomal processes. Conclusions Our findings demonstrate genetic pleiotropy in these neurodegenerative diseases and indicate that sporadic FTD is a polygenic disorder where multiple pleiotropic loci with small effects contribute to increased disease risk.

Published
2017

16. Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia

Author

Yokoyama, Jennifer S., Karch, Celeste M., Fan, Chun C., Bonham, Luke W., Naomi, Kouri, Ross, Owen A., Rosa, Rademakers, Jungsu, Kim, Yunpeng, Wang, Höglinger, Günter U., Ulrich, Muller, Raffaele, Ferrari, John, Hardy, International FTD-Genomics Consortium (IFGC Ferrari, R, Hernandez, Dg, Nalls, Ma, Rohrer, Jd, Ramasamy, A, Kwok, Jbj, Dobson-Stone, C, Schofield, Pr, Halliday, Gm, Hodges, Jr, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, Nj, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Landqvist Waldö, M, Nilsson, C, Mackenzie, Ira, Hsiung, Gyr, Mann, Dma, Grafman, J, Morris, Cm, Attems, J, Griffiths, Td, Mckeith, Ig, Thomas, Aj, Pietrini, P, Huey, Ed, Wassermann, Em, Baborie, A, Jaros, E, Tierney, Mc, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, Jb, Schlachetzki, Jcm, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin VM, Grossman, M, Trojanowski, Jq, van der Zee, J, Cruts, M, Van Broeckhoven, C, Cappa, Sf, Leber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, Je, Hjermind, Le, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, Mn, Fox, Nc, Warren, Jd, Spillantini, Mg, Morris, Hr, Rizzu, P, Heutink, P, Snowden, Js, Rollinson, S, Richardson, A, Gerhard, A, Bruni, Ac, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Conidi, Me, Smirne, N, Rademakers, R, Baker, M, Dickson, Dw, Graff-Radford, Nr, Petersen, Rc, Knopman, D, Josephs, Ka, Boeve, Bf, Parisi, Je, Seeley, Ww, Miller, Bl, Karydas, Am, Rosen, H, van Swieten JC, Dopper, Eg, Seelaar, H, Pijnenburg, Yal, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, Aa, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, Hh, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebouvier, T, Kapogiannis, D, Ferrucci, L, Pickering-Brown, S, Singleton, Ab, Hardy, J, Momeni, P. )., Parastoo, Momeni, Sugrue, Leo P., Hess, Christopher P., James Barkovich, A., Boxer, Adam L., Seele, William W., Rabinovici, Gil D., Rosen, Howard J., Miller, Bruce L., Schmansky, Nicholas J., Bruce, Fischl, Hyman, Bradley T., Dickson, Dennis W., Schellenberg, Gerard D., Andreassen, Ole A., Dale, Anders M., Desikan, and Rahul S., and Int FTD-Genomics Consortium

Subjects
pathology [Tauopathies], 0301 basic medicine, Pathology, Aging, genetics [Basal Ganglia Diseases], Genome-wide association study, Neurodegenerative, diagnosis [Supranuclear Palsy, Progressive], diagnosis [Frontotemporal Dementia], pathology [Inclusion Bodies], 0302 clinical medicine, Neurology (clinical), Cellular and Molecular Neuroscience, Risk Factors, pathology [Neurons], Corticobasal degeneration, Supranuclear Palsy, 2.1 Biological and endogenous factors, Aetiology, genetics [Frontotemporal Dementia], Alzheimer's Disease Related Dementias (ADRD), Genetics, Inclusion Bodies, Neurons, genetics [Supranuclear Palsy, Progressive], Frontotemporal Dementia (FTD), Tauopathies, Frontotemporal Dementia, Neurological, Supranuclear Palsy, Progressive, Frontotemporal dementia, medicine.medical_specialty, pathology [Supranuclear Palsy, Progressive], Clinical Sciences, MAPT protein, human, Locus (genetics), Single-nucleotide polymorphism, tau Proteins, Biology, Article, Pathology and Forensic Medicine, Progressive supranuclear palsy, 03 medical and health sciences, Rare Diseases, Progressive, Basal Ganglia Diseases, mental disorders, medicine, Acquired Cognitive Impairment, Humans, ddc:610, Genetic association, Neurology & Neurosurgery, International FTD-Genomics Consortium, Prevention, Haplotype, Human Genome, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), medicine.disease, metabolism [tau Proteins], digestive system diseases, Brain Disorders, 030104 developmental biology, pathology [Frontotemporal Dementia], Dementia, Human medicine, pathology [Basal Ganglia Diseases], 030217 neurology & neurosurgery
Abstract

Corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and a subset of frontotemporal dementia (FTD) are neurodegenerative disorders characterized by tau inclusions in neurons and glia (tauopathies). Although clinical, pathological and genetic evidence suggests overlapping pathobiology between CBD, PSP, and FTD, the relationship between these disorders is still not well understood. Using summary statistics (odds ratios and p values) from large genome-wide association studies (total n=14,286 cases and controls) and recently established genetic methods, we investigated the genetic overlap between CBD and PSP and CBD and FTD. We found up to 800-fold enrichment of genetic risk in CBD across different levels of significance for PSP or FTD. In addition to NSF (tagging the MAPT H1 haplotype), we observed that SNPs in or near MOBP, CXCR4, EGFR, and GLDC showed significant genetic overlap between CBD and PSP, whereas only SNPs tagging the MAPT haplotype overlapped between CBD and FTD. The risk alleles of the shared SNPs were associated with expression changes in cis-genes. Evaluating transcriptome levels across adult human brains, we found a unique neuroanatomic gene expression signature for each of the five overlapping gene loci (omnibus ANOVA p&nbsp

Published
2017

18. Working memory for time intervals in auditory rhythmic sequences

Author

Teki, S and Griffiths, TD

Subjects
auditory perception, Psychology, Original Research Article, time perception, General Psychology, working memory, interval timing, rhythm perception
Abstract

The brain can hold information about multiple objects in working memory. It is not known, however, whether intervals of time can be stored in memory as distinct items. Here, we developed a novel paradigm to examine temporal memory where listeners were required to reproduce the duration of a single probed interval from a sequence of intervals. We demonstrate that memory performance significantly varies as a function of temporal structure (better memory in regular vs. irregular sequences), interval size (better memory for sub- vs. supra-second intervals), and memory load (poor memory for higher load). In contrast memory performance is invariant to attentional cueing. Our data represent the first systematic investigation of temporal memory in sequences that goes beyond previous work based on single intervals. The results support the emerging hypothesis that time intervals are allocated a working memory resource that varies with the amount of other temporal information in a sequence.

Published
2014

19. Frontotemporal dementia and its subtypes: A genome-wide association study

Author

Ferrari, R, Hernandez, DG, Nalls, MA, Rohrer, JD, Ramasamy, A, Kwok, JBJ, Dobson-Stone, C, Brooks William S., BS, Schofield, PR, Halliday, GM, Hodges, JR, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, NJ, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Waldö, ML, Nilsson, K, Nilsson, C, Mackenzie, IRA, Hsiung, GYR, Mann, DMA, Grafman, J, Morris, CM, Attems, J, Griffiths, TD, McKeith, IG, Thomas, AJ, Pietrini, P, Huey, ED, Wassermann, EM, Baborie, A, Jaros, E, Tierney, MC, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, JB, Schlachetzki, JCM, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, VM, Grossman, M, Trojanowski, JQ, Van der Zee, J, Deschamps, W, Van Langenhove, T, Cruts, M, Van Broeckhoven, C, Cappa, SF, Le Ber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, JE, Hjermind, LE, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, MN, Ferrari, R, Hernandez, DG, Nalls, MA, Rohrer, JD, Ramasamy, A, Kwok, JBJ, Dobson-Stone, C, Brooks William S., BS, Schofield, PR, Halliday, GM, Hodges, JR, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, NJ, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Waldö, ML, Nilsson, K, Nilsson, C, Mackenzie, IRA, Hsiung, GYR, Mann, DMA, Grafman, J, Morris, CM, Attems, J, Griffiths, TD, McKeith, IG, Thomas, AJ, Pietrini, P, Huey, ED, Wassermann, EM, Baborie, A, Jaros, E, Tierney, MC, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, JB, Schlachetzki, JCM, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, VM, Grossman, M, Trojanowski, JQ, Van der Zee, J, Deschamps, W, Van Langenhove, T, Cruts, M, Van Broeckhoven, C, Cappa, SF, Le Ber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, JE, Hjermind, LE, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, and Rossor, MN

Abstract

Background: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 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<5 × 10-8) single-nucleotide polymorphisms. Findings: We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10-8). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10-8; odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51 × 10-9; 0·809 [0·76-0·86]) and rs1980493 (p value=1·57 × 10-8, 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10-7; 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci migh

Published
2014

21. Single-subject oscillatory γ responses in tinnitus.

Author

Sedley W, Teki S, Kumar S, Barnes GR, Bamiou DE, Griffiths TD, Sedley, William, Teki, Sundeep, Kumar, Sukhbinder, Barnes, Gareth Robert, Bamiou, Doris-Eva, and Griffiths, Timothy David

Abstract

This study used magnetoencephalography to record oscillatory activity in a group of 17 patients with chronic tinnitus. Two methods, residual inhibition and residual excitation, were used to bring about transient changes in spontaneous tinnitus intensity in order to measure dynamic tinnitus correlates in individual patients. In residual inhibition, a positive correlation was seen between tinnitus intensity and both delta/theta (6/14 patients) and gamma band (8/14 patients) oscillations in auditory cortex, suggesting an increased thalamocortical input and cortical gamma response, respectively, associated with higher tinnitus states. Conversely, 4/4 patients exhibiting residual excitation demonstrated an inverse correlation between perceived tinnitus intensity and auditory cortex gamma oscillations (with no delta/theta changes) that cannot be explained by existing models. Significant oscillatory power changes were also identified in a variety of cortical regions, most commonly midline lobar regions in the default mode network, cerebellum, insula and anterior temporal lobe. These were highly variable across patients in terms of areas and frequency bands involved, and in direction of power change. We suggest a model based on a local circuit function of cortical gamma-band oscillations as a process of mutual inhibition that might suppress abnormal cortical activity in tinnitus. The work implicates auditory cortex gamma-band oscillations as a fundamental intrinsic mechanism for attenuating phantom auditory perception. [ABSTRACT FROM AUTHOR]

Published
2012
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22. Course and outcome of acute limbic encephalitis with negative voltage-gated potassium channel antibodies.

Author

Samarasekera SR, Vincent A, Welch JL, Jackson M, Nichols P, Griffiths TD, Samarasekera, S R, Vincent, A, Welch, J L, Jackson, M, Nichols, P, and Griffiths, T D

Abstract

Background: Limbic encephalitis is a potentially treatable immunological condition. The presence of voltage-gated potassium channel antibodies (VGKC-Ab) in the cerebrospinal fluid (CSF) and serum of patients with the condition is a marker of the disease associated with a non-paraneoplastic form and good response to treatment. Recent work has highlighted absent serum VGKC-Ab and distinct immunology in patients with the paraneoplastic form of limbic encephalitis.Methods: The cases of four patients with the typical clinical presentation, neuropsychological features and brain imaging of acute limbic encephalitis, in the absence of any evidence for associated cancer during a follow-up of at least 18 months are described here.Results: All patients had negative testing for VGKC-Ab measured during their acute presentation. All patients made some recovery, although they were left with marked cognitive deficits and persistent seizures.Conclusion: These cases demonstrate that the absence of VGKC-Ab in limbic encephalitis does not necessarily imply a paraneoplastic form. Further work is required to establish the immunological basis for the disorder in these patients, and the optimal treatment regimen. [ABSTRACT FROM AUTHOR]

Published
2007

24. Review. Disorders of human complex sound processing.

Author

Griffiths, TD, Rees, A, and Green, GGR

Abstract

Considers reports of patients with disordered complex sound processing. Definition of complex sound processing; Contribution of end-organ dysfunction; Complex sound disorders occurring in the ascending auditory pathway; Complex sound disorders due to cerebral lesions.

Published
1999
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25. A neural substrate for musical hallucinosis.

Author

Griffiths, TD, Jackson, MC, Spillane, JA, Friston, KJ, and Frackowiak, RSJ

Abstract

Presents information on a study which used Positron Emission Tomography to define areas of brain activation during musical hallucinosis in a single subject with deafness but no psychiatric or central neurologic condition. Nature of musical hallucinations; Method used in the study; Discussion.

Published
1997
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29. Modification by Cysteamine of Ultrasound Lethality to Chinese Hamster V-79 Cells

Author

Griffiths Td, Fu Yk, Christopher S. Lange, Morton W. Miller, and Gary E. Kaufman

Subjects
Radiation, Plating efficiency, Lysis, biology, business.industry, Stereochemistry, Radical, Sonication, Ultrasound, Biophysics, biology.organism_classification, Chinese hamster, chemistry.chemical_compound, chemistry, Cell culture, Radiology, Nuclear Medicine and imaging, Cysteamine, business
Abstract

Exposure of Chinese hamster V-79 cells to 1.1-MHz continuous wave (CW) ultrasound at intensities of 10, 20, and $30\ {\rm W}/{\rm cm}^{2}$ resulted in cell lysis and the loss of reproductive integrity (i.e., a decrease in plating efficiency) in the remaining intact cells. Sonication in the presence of 8 mM cysteamine, a free-radical scavenger, did not alter the amount of cell lysis, but did result in a smaller decrease in plating efficiency at 20 and $30\ {\rm W}/{\rm cm}^{2}$ . Hence, while free radicals do not appear responsible for ultrasonically induced cell lysis, free radicals do appear to be at least partially responsible for loss of reproductive integrity in the remaining intact cells.

Published
1979

31. Rhythm deficits in 'tone deafness'.

Author

Foxton JM, Nandy RK, and Griffiths TD

Abstract

It is commonly observed that 'tone deaf' individuals are unable to hear the beat of a tune, yet deficits on simple timing tests have not been found. In this study, we investigated rhythm processing in nine individuals with congenital amusia ('tone deafness') and nine controls. Participants were presented with pairs of 5-note sequences, and were required to detect the presence of a lengthened interval. In different conditions the sound sequences were presented isochronously or in an integer-ratio rhythm, and these were either monotonic or varied randomly in pitch. It was found that the 'tone deaf' participants exhibited inferior rhythm analysis for the sequences that varied in pitch compared to those that did not, whereas the controls obtained equivalent thresholds for these two conditions. These results suggest that the rhythm deficits in congenital amusia result from the pitch-variations in music. [ABSTRACT FROM AUTHOR]

Published
2006
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32. Frontotemporal dementia and its subtypes: A genome-wide association study

Author

Yolande A.L. Pijnenburg, Wei Gu, Harro Seelaar, Robert Perneczky, Alfredo Postiglione, Ronald C. Petersen, Timothy D. Griffiths, Pau Pastor, Marc Cruts, Elise G.P. Dopper, Sabrina Pichler, Chiara Fenoglio, Patrizia Rizzu, Adeline Rollin, Maria Serpente, Peter Heutink, Sandro Sorbi, Lauren Bartley, Maria Landqvist Waldö, Luigi Ferrucci, William S. Brooks, Luisa Benussi, William W. Seeley, Maria Anfossi, Atik Baborie, Innocenzo Rainero, Rosa Capozzo, Alessandro Padovani, Stefano F. Cappa, Glenda M. Halliday, Jørgen E. Nielsen, Sara Ortega-Cubero, Vivianna M. Van Deerlin, Ekaterina Rogaeva, Mike A. Nalls, Giacomina Rossi, Alberto Lleó, Edward D. Huey, Jordi Clarimón, Simon Mead, Janine Diehl-Schmid, John Q. Trojanowski, Adaikalavan Ramasamy, Matthias Riemenschneider, John Hardy, Annibale Alessandro Puca, Cristina Razquin, Mercè Boada, Martine Vercelletto, Isabelle Le Ber, Graziella Milan, Johannes Attems, Francesca Frangipane, Jason D. Warren, Lena E. Hjermind, John R. Hodges, Gianluigi Forloni, Dennis W. Dickson, Daniela Galimberti, Elisa Rubino, Karin Nilsson, Raffaele Maletta, Christine Van Broeckhoven, Valeria Novelli, Anna Richardson, Anna Karydas, David S. Knopman, Nick C. Fox, Stuart Pickering-Brown, Carlos Cruchaga, Isabel Hernández, Livia Bernardi, Philip Scheltens, Martin N. Rossor, Julie S. Snowden, Massimo Franceschi, Rosa Rademakers, Bruce L. Miller, Alan J. Thomas, Florence Lebert, Matthew C. Baker, Jonathan D. Rohrer, Keith A. Josephs, Tim Van Langenhove, Fabrizio Tagliavini, Carol Dobson-Stone, Elizabeth Thompson, Silvia Bagnoli, Barbara Borroni, Sara Rollinson, Irene Piaceri, David M. A. Mann, Bernd Ibach, Ian G. McKeith, Agustín Ruiz, Huw R. Morris, Giancarlo Logroscino, Maura Gallo, Elena Alonso, Alexis Brice, Adrian Danek, Paolo Sorrentino, Nicoletta Smirne, Raffaele Ferrari, Panagiotis Alexopoulos, Johannes C. M. Schlachetzki, Alexander Gerhard, Manuel Mayhaus, Alexander Kurz, Amalia C. Bruni, Michael Tierney, Didier Hannequin, William Deschamps, Florence Pasquier, Joseph E. Parisi, Rafael Blesa, Elio Scarpini, Ian R. A. Mackenzie, Peter R. Schofield, Giuliano Binetti, Evelyn Jaros, Julie van der Zee, John Collinge, Maria Elena Conidi, Howard J. Rosen, Caroline Graff, Christer Nilsson, Huei-Hsin Chiang, Nigel J. Cairns, Jordan Grafman, Eric M. Wassermann, Parastoo Momeni, Maria Grazia Spillantini, Ging-Yuek Robin Hsiung, Andrew B. Singleton, Chiara Cupidi, James Uphill, Dimitrios Kapogiannis, Bradley F. Boeve, Christopher Morris, Vincent Deramecourt, Giorgio Giaccone, James B. Rowe, Murray Grossman, Benedetta Nacmias, Roberta Ghidoni, Véronique Golfier, Dena G. Hernandez, Lorenzo Pinessi, Neill R. Graff-Radford, John C. van Swieten, Pietro Pietrini, Gilles Gasparoni, Peter St George-Hyslop, Mark Kristiansen, Eric Haan, Olivier Piguet, John B.J. Kwok, Human genetics, Neurology, NCA - neurodegeneration, Surgery, Clinical Genetics, Erasmus MC other, Ferrari, R, Hernandez, Dg, Nalls, Ma, Rohrer, Jd, Ramasamy, A, Kwok, Jb, Dobson Stone, C, Brooks, W, Schofield, Pr, Halliday, Gm, Hodges, Jr, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hern?ndez, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, Nj, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarim?n, J, Lle?, A, Blesa, R, Wald?, Ml, Nilsson, K, Nilsson, C, Mackenzie, Ir, Hsiung, Gy, Mann, Dm, Grafman, J, Morris, Cm, Attems, J, Griffiths, Td, Mckeith, Ig, Thomas, Aj, Pietrini, P, Huey, Ed, Wassermann, Em, Baborie, A, Jaros, E, Tierney, Mc, Pastor, P, Razquin, C, Ortega Cubero, S, Alonso, E, Perneczky, R, Diehl Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, Jb, Schlachetzki, Jc, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, Vm, Grossman, M, Trojanowski, Jq, van der Zee, J, Deschamps, W, Van Langenhove, T, Cruts, M, Van Broeckhoven, C, Cappa, Sf, Le Ber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, Je, Hjermind, Le, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, Mn, Fox, Nc, Warren, Jd, Spillantini, Mg, Morris, Hr, Rizzu, P, Heutink, P, Snowden, J, Rollinson, S, Richardson, A, Gerhard, A, Bruni, Ac, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Conidi, Me, Smirne, N, Rademakers, R, Baker, M, Dickson, Dw, Graff Radford, Nr, Petersen, Rc, Knopman, D, Josephs, Ka, Boeve, Bf, Parisi, Je, Seeley, Ww, Miller, Bl, Karydas, Am, Rosen, H, van Swieten, Jc, Dopper, Eg, Seelaar, H, Pijnenburg, Ya, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, Aa, Franceschi, M, Postiglione, Alfredo, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, Hh, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebert, F, Kapogiannis, D, Ferrucci, L, Pickering Brown, S, Singleton, Ab, Hardy, J, and Momeni, P.

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Genotype, Semantic dementia, Genome-wide association study, Locus (genetics), classification [Frontotemporal Dementia], methods [Genome-Wide Association Study], diagnosis [Frontotemporal Dementia], C9orf72, mental disorders, medicine, Dementia, Humans, ddc:610, genetics [Frontotemporal Dementia], Aged, Genetics, Aged, 80 and over, Genetic heterogeneity, Middle Aged, medicine.disease, Frontotemporal Dementia, Female, Human medicine, Neurology (clinical), Alzheimer's disease, Psychology, Frontotemporal dementia, Genome-Wide Association Study
Abstract

Summary Background Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes— MAPT , GRN , and C9orf72 —have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 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 −8 ) single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p −8 ). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10 −8 ; odds ratio=1·204 [95% CI 1·11–1·30]), rs9268856 (p=5·51 × 10 −9 ; 0·809 [0·76–0·86]) and rs1980493 (p value=1·57 × 10 −8 , 0·775 [0·69–0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38 / CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10 −7 ; 0·814 [0·71–0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis . Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center.

Published
2014

34. Spatial selective auditory attention is preserved in older age but is degraded by peripheral hearing loss.

Author

Caso A, Griffiths TD, and Holmes E

Subjects
Humans, Aged, Middle Aged, Adult, Male, Female, Aged, 80 and over, Adolescent, Young Adult, Hearing Loss physiopathology, Auditory Perception physiology, Speech Perception physiology, Hearing physiology, Attention physiology, Aging physiology
Abstract

Interest in how ageing affects attention is long-standing, although interactions between sensory and attentional processing in older age are not fully understood. Here, we examined interactions between peripheral hearing and selective attention in a spatialised cocktail party listening paradigm, in which three talkers spoke different sentences simultaneously and participants were asked to report the sentence spoken by a talker at a particular location. By comparing a sample of older (N = 61; age = 55-80 years) and younger (N = 58; age = 18-35 years) adults, we show that, as a group, older adults benefit as much as younger adults from preparatory spatial attention. Although, for older adults, this benefit significantly reduces with greater age-related hearing loss. These results demonstrate that older adults with excellent hearing retain the ability to direct spatial selective attention, but this ability deteriorates, in a graded manner, with age-related hearing loss. Thus, reductions in spatial selective attention likely contribute to difficulties communicating in social settings for older adults with age-related hearing loss. Overall, these findings demonstrate a relationship between mild perceptual decline and attention in older age., (© 2024. The Author(s).)

Published
2024
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36. The contribution of short-term memory for sound features to speech-in-noise perception and cognition.

Author

Lad M, Taylor JP, and Griffiths TD

Subjects
Humans, Female, Male, Middle Aged, Adult, Aged, Young Adult, Pitch Perception, Bayes Theorem, Aged, 80 and over, Audiometry, Pure-Tone, Hearing, Auditory Threshold, Dichotic Listening Tests, Speech Perception, Noise adverse effects, Memory, Short-Term, Cognition, Perceptual Masking, Acoustic Stimulation
Abstract

Speech-in-noise (SIN) perception is a fundamental ability that declines with aging, as does general cognition. We assess whether auditory cognitive ability, in particular short-term memory for sound features, contributes to both. We examined how auditory memory for fundamental sound features, the carrier frequency and amplitude modulation rate of modulated white noise, contributes to SIN perception. We assessed SIN in 153 healthy participants with varying degrees of hearing loss using measures that require single-digit perception (the Digits-in-Noise, DIN) and sentence perception (Speech-in-Babble, SIB). Independent variables were auditory memory and a range of other factors including the Pure Tone Audiogram (PTA), a measure of dichotic pitch-in-noise perception (Huggins pitch), and demographic variables including age and sex. Multiple linear regression models were compared using Bayesian Model Comparison. The best predictor model for DIN included PTA and Huggins pitch (r 2 = 0.32, p < 0.001), whereas the model for SIB included the addition of auditory memory for sound features (r 2 = 0.24, p < 0.001). Further analysis demonstrated that auditory memory also explained a significant portion of the variance (28 %) in scores for a screening cognitive test for dementia. Auditory memory for non-speech sounds may therefore provide an important predictor of both SIN and cognitive ability., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Published
2024
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37. Brain Charts for the Rhesus Macaque Lifespan.

Author

Alldritt S, Ramirez JSB, de Wael RV, Bethlehem R, Seidlitz J, Wang Z, Nenning K, Esper NB, Smallwood J, Franco AR, Byeon K, Alexander-Bloch A, Amaral DG, Amiez C, Balezeau F, Baxter MG, Becker G, Bennett J, Berkner O, Blezer ELA, Brambrink AM, Brochier T, Butler B, Campos LJ, Canet-Soulas E, Chalet L, Chen A, Cléry J, Constantinidis C, Cook DJ, Dehaene S, Dorfschmidt L, Drzewiecki CM, Erdman JW, Everling S, Falchier A, Fleysher L, Fox A, Freiwald W, Froesel M, Froudist-Walsh S, Fudge J, Funck T, Gacoin M, Gale DJ, Gallivan J, Garin CM, Griffiths TD, Guedj C, Hadj-Bouziane F, Hamed SB, Harel N, Hartig R, Hiba B, Howell BR, Jarraya B, Jung B, Kalin N, Karpf J, Kastner S, Klink C, Kovacs-Balint ZA, Kroenke C, Kuchan MJ, Kwok SC, Lala KN, Leopold DA, Li G, Lindenfors P, Linn G, Mars RB, Masiello K, Menon RS, Messinger A, Meunier M, Mok K, Morrison JH, Nacef J, Nagy J, Neudecker V, Neuringer M, Noonan MP, Ortiz-Rios M, Perez-Zoghbi JF, Petkov CI, Pinsk M, Poirier C, Procyk E, Rajimehr R, Reader SM, Rudko DA, Rushworth MFS, Russ BE, Sallet J, Sanchez MM, Schmid MC, Schwiedrzik CM, Scott JA, Sein J, Sharma KK, Shmuel A, Styner M, Sullivan EL, Thiele A, Todorov OS, Tsao D, Tusche A, Vlasova R, Wang Z, Wang L, Wang J, Weiss AR, Wilson CRE, Yacoub E, Zarco W, Zhou Y, Zhu J, Margulies D, Fair D, Schroeder C, Milham M, and Xu T

Abstract

Recent efforts to chart human brain growth across the lifespan using large-scale MRI data have provided reference standards for human brain development. However, similar models for nonhuman primate (NHP) growth are lacking. The rhesus macaque, a widely used NHP in translational neuroscience due to its similarities in brain anatomy, phylogenetics, cognitive, and social behaviors to humans, serves as an ideal NHP model. This study aimed to create normative growth charts for brain structure across the macaque lifespan, enhancing our understanding of neurodevelopment and aging, and facilitating cross-species translational research. Leveraging data from the PRIMatE Data Exchange (PRIME-DE) and other sources, we aggregated 1,522 MRI scans from 1,024 rhesus macaques. We mapped non-linear developmental trajectories for global and regional brain structural changes in volume, cortical thickness, and surface area over the lifespan. Our findings provided normative charts with centile scores for macaque brain structures and revealed key developmental milestones from prenatal stages to aging, highlighting both species-specific and comparable brain maturation patterns between macaques and humans. The charts offer a valuable resource for future NHP studies, particularly those with small sample sizes. Furthermore, the interactive open resource (https://interspeciesmap.childmind.org) supports cross-species comparisons to advance translational neuroscience research.

Published
2024
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38. Subjective hearing loss is not associated with an increased risk of Alzheimer's disease dementia.

Author

Lad M, Taylor JP, and Griffiths TD

Abstract

Hearing loss is a risk-factor for dementia but the reasons for this are unclear. Subjective hearing loss is related to increased future dementia risk, however, this metric has not been previously examined with cognitive, neuroimaging and biochemical measures that are relevant to Alzheimer's disease. We assessed Cognitively Normal and Mild Cognitively Impaired participants from the Alzheimer's Disease Neuroimaging Initiative with subjective hearing loss to examine if they had faster decline in episodic memory scores, hippocampal volume and greater pTau positivity. The likelihood of a dementia diagnosis in hearing impaired participants over a 5-year period was also assessed. There were no statistically significant differences between the hearing subgroups over a 5-year period nor were there in conversions to a dementia diagnosis. Objective hearing loss metrics may provide a more reliable link between hearing loss and dementia risk., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Published
2024
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39. Sensory Loss and Risk of Dementia.

Author

Lad M, Sedley W, and Griffiths TD

Subjects
Humans, Smell, Risk Factors, Alzheimer Disease, Parkinson Disease, Hearing Loss complications
Abstract

Sensory loss in olfaction, vision, and hearing is a risk factor for dementia, but the reasons for this are unclear. This review presents the neurobiological evidence linking each sensory modality to specific dementias and explores the potential mechanisms underlying this. Olfactory deficits can be linked to direct neuropathologic changes in the olfactory system due to Alzheimer disease and Parkinson disease, and may be a marker of disease severity. Visual deficits potentially increase dementia risk in a vulnerable individual by reducing resilience to dementia. Hearing deficits may indicate a susceptibility to Alzheimer disease through a variety of mechanisms. More generally, sensory impairment could be related to factors associated with resilience against dementia. Further research is needed to tease out the specific and synergistic effects of sensory impairment. Studying sensory loss in relation to neurodegenerative biomarkers is necessary to clarify the mechanisms involved. This could produce new monitoring and management strategies for people at risk of dementia., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Published
2024
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40. What is the role of the hippocampus and parahippocampal gyrus in the persistence of tinnitus?

Author

Berger JI, Billig AJ, Sedley W, Kumar S, Griffiths TD, and Gander PE

Subjects
Animals, Humans, Hippocampus diagnostic imaging, Parahippocampal Gyrus diagnostic imaging, Limbic System, Tinnitus diagnostic imaging, Auditory Cortex
Abstract

The hippocampus and parahippocampal gyrus have been implicated as part of a tinnitus network by a number of studies. These structures are usually considered in the context of a "limbic system," a concept typically invoked to explain the emotional response to tinnitus. Despite this common framing, it is not apparent from current literature that this is necessarily the main functional role of these structures in persistent tinnitus. Here, we highlight a different role that encompasses their most commonly implicated functional position within the brain-that is, as a memory system. We consider tinnitus as an auditory object that is held in memory, which may be made persistent by associated activity from the hippocampus and parahippocampal gyrus. Evidence from animal and human studies implicating these structures in tinnitus is reviewed and used as an anchor for this hypothesis. We highlight the potential for the hippocampus/parahippocampal gyrus to facilitate maintenance of the memory of the tinnitus percept via communication with auditory cortex, rather than (or in addition to) mediating emotional responses to this percept., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Published
2024
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42. Spectral Grouping of Electrically Encoded Sound Predicts Speech-in-Noise Performance in Cochlear Implantees.

Author

Choi I, Gander PE, Berger JI, Woo J, Choy MH, Hong J, Colby S, McMurray B, and Griffiths TD

Subjects
Speech, Noise, Speech Perception, Cochlear Implants, Cochlear Implantation
Abstract

Objectives: Cochlear implant (CI) users exhibit large variability in understanding speech in noise. Past work in CI users found that spectral and temporal resolution correlates with speech-in-noise ability, but a large portion of variance remains unexplained. Recent work on normal-hearing listeners showed that the ability to group temporally and spectrally coherent tones in a complex auditory scene predicts speech-in-noise ability independently of the audiogram, highlighting a central mechanism for auditory scene analysis that contributes to speech-in-noise. The current study examined whether the auditory grouping ability also contributes to speech-in-noise understanding in CI users., Design: Forty-seven post-lingually deafened CI users were tested with psychophysical measures of spectral and temporal resolution, a stochastic figure-ground task that depends on the detection of a figure by grouping multiple fixed frequency elements against a random background, and a sentence-in-noise measure. Multiple linear regression was used to predict sentence-in-noise performance from the other tasks., Results: No co-linearity was found between any predictor variables. All three predictors (spectral and temporal resolution plus the figure-ground task) exhibited significant contribution in the multiple linear regression model, indicating that the auditory grouping ability in a complex auditory scene explains a further proportion of variance in CI users' speech-in-noise performance that was not explained by spectral and temporal resolution., Conclusion: Measures of cross-frequency grouping reflect an auditory cognitive mechanism that determines speech-in-noise understanding independently of cochlear function. Such measures are easily implemented clinically as predictors of CI success and suggest potential strategies for rehabilitation based on training with non-speech stimuli., (© 2023. The Author(s).)

Published
2023
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43. Immediate neural impact and incomplete compensation after semantic hub disconnection.

Author

Kocsis Z, Jenison RL, Taylor PN, Calmus RM, McMurray B, Rhone AE, Sarrett ME, Deifelt Streese C, Kikuchi Y, Gander PE, Berger JI, Kovach CK, Choi I, Greenlee JD, Kawasaki H, Cope TE, Griffiths TD, Howard MA 3rd, and Petkov CI

Subjects
Humans, Brain Mapping methods, Magnetic Resonance Imaging, Temporal Lobe surgery, Temporal Lobe physiology, Semantics, Diaschisis
Abstract

The human brain extracts meaning using an extensive neural system for semantic knowledge. Whether broadly distributed systems depend on or can compensate after losing a highly interconnected hub is controversial. We report intracranial recordings from two patients during a speech prediction task, obtained minutes before and after neurosurgical treatment requiring disconnection of the left anterior temporal lobe (ATL), a candidate semantic knowledge hub. Informed by modern diaschisis and predictive coding frameworks, we tested hypotheses ranging from solely neural network disruption to complete compensation by the indirectly affected language-related and speech-processing sites. Immediately after ATL disconnection, we observed neurophysiological alterations in the recorded frontal and auditory sites, providing direct evidence for the importance of the ATL as a semantic hub. We also obtained evidence for rapid, albeit incomplete, attempts at neural network compensation, with neural impact largely in the forms stipulated by the predictive coding framework, in specificity, and the modern diaschisis framework, more generally. The overall results validate these frameworks and reveal an immediate impact and capability of the human brain to adjust after losing a brain hub., (© 2023. Springer Nature Limited.)

Published
2023
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44. Neurovascular coupling and cerebrovascular hemodynamics are modified by exercise training status at different stages of maturation during youth.

Author

Talbot JS, Perkins DR, Dawkins TG, Douglas AJM, Griffiths TD, Richards CT, Owen K, Lord RN, Pugh CJA, Oliver JL, Lloyd RS, Ainslie PN, McManus AM, and Stembridge M

Subjects
Male, Female, Humans, Adolescent, Child, Hemodynamics, Exercise, Middle Cerebral Artery diagnostic imaging, Ultrasonography, Doppler, Transcranial, Cerebrovascular Circulation, Neurovascular Coupling
Abstract

Neurovascular coupling (NVC) is mediated via nitric oxide signaling, which is independently influenced by sex hormones and exercise training. Whether exercise training differentially modifies NVC pre- versus postpuberty, where levels of circulating sex hormones will differ greatly within and between sexes, remains to be determined. Therefore, we investigated the influence of exercise training status on resting intracranial hemodynamics and NVC at different stages of maturation. Posterior and middle cerebral artery velocities (PCA v and MCA v ) and pulsatility index (PCA PI and MCA PI ) were assessed via transcranial Doppler ultrasound at rest and during visual NVC stimuli. N = 121 exercise-trained (males, n = 32; females, n = 32) and untrained (males, n = 28; females, n = 29) participants were characterized as pre (males, n = 33; females, n = 29)- or post (males, n = 27; females, n = 32)-peak height velocity (PHV). Exercise-trained youth demonstrated higher resting MCA v ( P = 0.010). Maturity and training status did not affect the ΔPCA v and ΔMCA v during NVC. However, pre-PHV untrained males (19.4 ± 13.5 vs. 6.8 ± 6.0%; P ≤ 0.001) and females (19.3 ± 10.8 vs. 6.4 ± 7.1%; P ≤ 0.001) had a higher ΔPCA PI during NVC than post-PHV untrained counterparts, whereas the ΔPCA PI was similar in pre- and post-PHV trained youth. Pre-PHV untrained males (19.4 ± 13.5 vs. 7.9 ± 6.0%; P ≤ 0.001) and females (19.3 ± 10.8 vs. 11.1 ± 7.3%; P = 0.016) also had a larger ΔPCA PI than their pre-PHV trained counterparts during NVC, but the ΔPCA PI was similar in trained and untrained post-PHV youth. Collectively, our data indicate that exercise training elevates regional cerebral blood velocities during youth, but training-mediated adaptations in NVC are only attainable during early stages of adolescence. Therefore, childhood provides a unique opportunity for exercise-mediated adaptations in NVC. NEW & NOTEWORTHY We report that the change in cerebral blood velocity during a neurovascular coupling task (NVC) is similar in pre- and postpubertal youth, regardless of exercise-training status. However, prepubertal untrained youth demonstrated a greater increase in cerebral blood pulsatility during the NVC task when compared with their trained counterparts. Our findings highlight that childhood represents a unique opportunity for exercise-mediated adaptations in cerebrovascular hemodynamics during NVC, which may confer long-term benefits in cerebrovascular function.

Published
2023
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45. Neural Correlates of Individual Differences in Speech-in-Noise Performance in a Large Cohort of Cochlear Implant Users.

Author

Berger JI, Gander PE, Kim S, Schwalje AT, Woo J, Na YM, Holmes A, Hong JM, Dunn CC, Hansen MR, Gantz BJ, McMurray B, Griffiths TD, and Choi I

Subjects
Humans, Speech, Individuality, Noise, Cochlear Implants, Cochlear Implantation, Speech Perception physiology
Abstract

Objectives: Understanding speech-in-noise (SiN) is a complex task that recruits multiple cortical subsystems. Individuals vary in their ability to understand SiN. This cannot be explained by simple peripheral hearing profiles, but recent work by our group ( Kim et al. 2021 , Neuroimage ) highlighted central neural factors underlying the variance in SiN ability in normal hearing (NH) subjects. The present study examined neural predictors of SiN ability in a large cohort of cochlear-implant (CI) users., Design: We recorded electroencephalography in 114 postlingually deafened CI users while they completed the California consonant test: a word-in-noise task. In many subjects, data were also collected on two other commonly used clinical measures of speech perception: a word-in-quiet task (consonant-nucleus-consonant) word and a sentence-in-noise task (AzBio sentences). Neural activity was assessed at a vertex electrode (Cz), which could help maximize eventual generalizability to clinical situations. The N1-P2 complex of event-related potentials (ERPs) at this location were included in multiple linear regression analyses, along with several other demographic and hearing factors as predictors of SiN performance., Results: In general, there was a good agreement between the scores on the three speech perception tasks. ERP amplitudes did not predict AzBio performance, which was predicted by the duration of device use, low-frequency hearing thresholds, and age. However, ERP amplitudes were strong predictors for performance for both word recognition tasks: the California consonant test (which was conducted simultaneously with electroencephalography recording) and the consonant-nucleus-consonant (conducted offline). These correlations held even after accounting for known predictors of performance including residual low-frequency hearing thresholds. In CI-users, better performance was predicted by an increased cortical response to the target word, in contrast to previous reports in normal-hearing subjects in whom speech perception ability was accounted for by the ability to suppress noise., Conclusions: These data indicate a neurophysiological correlate of SiN performance, thereby revealing a richer profile of an individual's hearing performance than shown by psychoacoustic measures alone. These results also highlight important differences between sentence and word recognition measures of performance and suggest that individual differences in these measures may be underwritten by different mechanisms. Finally, the contrast with prior reports of NH listeners in the same task suggests CI-users performance may be explained by a different weighting of neural processes than NH listeners., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 The Authors. Ear & Hearing is published on behalf of the American Auditory Society, by Wolters Kluwer Health, Inc.)

Published
2023
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46. Distribution of multiunit pitch responses recorded intracranially from human auditory cortex.

Author

Berger JI, Gander PE, Kikuchi Y, Petkov CI, Kumar S, Kovach C, Oya H, Kawasaki H, Howard MA, and Griffiths TD

Subjects
Animals, Humans, Pitch Perception physiology, Acoustic Stimulation, Brain Mapping, Evoked Potentials, Auditory physiology, Auditory Perception, Auditory Cortex physiology
Abstract

The perception of pitch is a fundamental percept, which is mediated by the auditory system, requiring the abstraction of stimulus properties related to the spectro-temporal structure of sound. Despite its importance, there is still debate as to the precise areas responsible for its encoding, which may be due to species differences or differences in the recording measures and choices of stimuli used in previous studies. Moreover, it was unknown whether the human brain contains pitch neurons and how distributed such neurons might be. Here, we present the first study to measure multiunit neural activity in response to pitch stimuli in the auditory cortex of intracranially implanted humans. The stimulus sets were regular-interval noise with a pitch strength that is related to the temporal regularity and a pitch value determined by the repetition rate and harmonic complexes. Specifically, we demonstrate reliable responses to these different pitch-inducing paradigms that are distributed throughout Heschl's gyrus, rather than being localized to a particular region, and this finding was evident regardless of the stimulus presented. These data provide a bridge across animal and human studies and aid our understanding of the processing of a critical percept associated with acoustic stimuli., (© The Author(s) 2023. Published by Oxford University Press.)

Published
2023
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47. Temporal lobe perceptual predictions for speech are instantiated in motor cortex and reconciled by inferior frontal cortex.

Author

Cope TE, Sohoglu E, Peterson KA, Jones PS, Rua C, Passamonti L, Sedley W, Post B, Coebergh J, Butler CR, Garrard P, Abdel-Aziz K, Husain M, Griffiths TD, Patterson K, Davis MH, and Rowe JB

Subjects
Humans, Brain Mapping, Frontal Lobe physiology, Brain, Temporal Lobe, Magnetic Resonance Imaging methods, Speech physiology, Motor Cortex
Abstract

Humans use predictions to improve speech perception, especially in noisy environments. Here we use 7-T functional MRI (fMRI) to decode brain representations of written phonological predictions and degraded speech signals in healthy humans and people with selective frontal neurodegeneration (non-fluent variant primary progressive aphasia [nfvPPA]). Multivariate analyses of item-specific patterns of neural activation indicate dissimilar representations of verified and violated predictions in left inferior frontal gyrus, suggestive of processing by distinct neural populations. In contrast, precentral gyrus represents a combination of phonological information and weighted prediction error. In the presence of intact temporal cortex, frontal neurodegeneration results in inflexible predictions. This manifests neurally as a failure to suppress incorrect predictions in anterior superior temporal gyrus and reduced stability of phonological representations in precentral gyrus. We propose a tripartite speech perception network in which inferior frontal gyrus supports prediction reconciliation in echoic memory, and precentral gyrus invokes a motor model to instantiate and refine perceptual predictions for speech., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2023
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48. Hallucinations in Hearing Impairment: How Informed Are Clinicians?

Author

Marschall TM, van Dijk P, Kluk K, Koops S, Linszen MMJ, Griffiths TD, Toh WL, Malicka AN, Kovačić D, Mulert C, Sommer IEC, and Ćurčić-Blake B

Subjects
Humans, Hallucinations, Emotions, Anxiety, Hearing Loss, Disabled Persons
Abstract

Background and Hypothesis: Patients with hearing impairment (HI) may experience hearing sounds without external sources, ranging from random meaningless noises (tinnitus) to music and other auditory hallucinations (AHs) with meaningful qualities. To ensure appropriate assessment and management, clinicians need to be aware of these phenomena. However, sensory impairment studies have shown that such clinical awareness is low., Study Design: An online survey was conducted investigating awareness of AHs among clinicians and their opinions about these hallucinations., Study Results: In total, 125 clinicians (68.8% audiologists; 18.4% Ear-Nose-Throat [ENT] specialists) across 10 countries participated in the survey. The majority (96.8%) was at least slightly aware of AHs in HI. About 69.6% of participants reported encountering patients with AHs less than once every 6 months in their clinic. Awareness was significantly associated with clinicians' belief that patients feel anxious about their hallucinations (β = .018, t(118) = 2.47, P < .01), their belief that clinicians should be more aware of these hallucinations (β =.018, t(118) = 2.60, P < .01), and with confidence of clinicians in their skills to assess them (β = .017, t(118) = 2.63, P < .01). Clinicians felt underequipped to treat AHs (Median = 31; U = 1838; PFDRadj < .01)., Conclusions: Awareness of AHs among the surveyed clinicians was high. Yet, the low frequency of encounters with hallucinating patients and their belief in music as the most commonly perceived sound suggest unreported cases. Clinicians in this study expressed a lack of confidence regarding the assessment and treatment of AHs and welcome more information., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Published
2023
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49. Predicting speech-in-noise ability in normal and impaired hearing based on auditory cognitive measures.

Author

Griffiths TD

Abstract

Problems with speech-in-noise (SiN) perception are extremely common in hearing loss. Clinical tests have generally been based on measurement of SiN. My group has developed an approach to SiN based on the auditory cognitive mechanisms that subserve this, that might be relevant to speakers of any language. I describe how well these predict SiN, the brain systems for them, and tests of auditory cognition based on them that might be used to characterise SiN deficits in the clinic., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Griffiths.)

Published
2023
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50. The hearing hippocampus.

Author

Billig AJ, Lad M, Sedley W, and Griffiths TD

Subjects
Auditory Perception physiology, Cognition, Hearing, Humans, Learning physiology, Auditory Cortex, Hippocampus physiology
Abstract

The hippocampus has a well-established role in spatial and episodic memory but a broader function has been proposed including aspects of perception and relational processing. Neural bases of sound analysis have been described in the pathway to auditory cortex, but wider networks supporting auditory cognition are still being established. We review what is known about the role of the hippocampus in processing auditory information, and how the hippocampus itself is shaped by sound. In examining imaging, recording, and lesion studies in species from rodents to humans, we uncover a hierarchy of hippocampal responses to sound including during passive exposure, active listening, and the learning of associations between sounds and other stimuli. We describe how the hippocampus' connectivity and computational architecture allow it to track and manipulate auditory information - whether in the form of speech, music, or environmental, emotional, or phantom sounds. Functional and structural correlates of auditory experience are also identified. The extent of auditory-hippocampal interactions is consistent with the view that the hippocampus makes broad contributions to perception and cognition, beyond spatial and episodic memory. More deeply understanding these interactions may unlock applications including entraining hippocampal rhythms to support cognition, and intervening in links between hearing loss and dementia., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2022
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