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2. Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS

Author

Chatterjee, Madhurima, Özdemir, Selcuk, Fritz, Christian, Möbius, Wiebke, Kleineidam, Luca, Mandelkow, Eckhard, Biernat, Jacek, Doğdu, Cem, Peters, Oliver, Cosma, Nicoleta Carmen, Wang, Xiao, Schneider, Luisa-Sophia, Priller, Josef, Spruth, Eike, Kühn, Andrea A., Krause, Patricia, Klockgether, Thomas, Vogt, Ina R., Kimmich, Okka, Spottke, Annika, Hoffmann, Daniel C., Fliessbach, Klaus, Miklitz, Carolin, McCormick, Cornelia, Weydt, Patrick, Falkenburger, Björn, Brandt, Moritz, Guenther, René, Dinter, Elisabeth, Wiltfang, Jens, Hansen, Niels, Bähr, Mathias, Zerr, Inga, Flöel, Agnes, Nestor, Peter J., Düzel, Emrah, Glanz, Wenzel, Incesoy, Enise, Bürger, Katharina, Janowitz, Daniel, Perneczky, Robert, Rauchmann, Boris S., Hopfner, Franziska, Wagemann, Olivia, Levin, Johannes, Teipel, Stefan, Kilimann, Ingo, Goerss, Doreen, Prudlo, Johannes, Gasser, Thomas, Brockmann, Kathrin, Mengel, David, Zimmermann, Milan, Synofzik, Matthis, Wilke, Carlo, Selma-González, Judit, Turon-Sans, Janina, Santos-Santos, Miguel Angel, Alcolea, Daniel, Rubio-Guerra, Sara, Fortea, Juan, Carbayo, Álvaro, Lleó, Alberto, Rojas-García, Ricardo, Illán-Gala, Ignacio, Wagner, Michael, Frommann, Ingo, Roeske, Sandra, Bertram, Lucas, Heneka, Michael T., Brosseron, Frederic, Ramirez, Alfredo, Schmid, Matthias, Beschorner, Rudi, Halle, Annett, Herms, Jochen, Neumann, Manuela, Barthélemy, Nicolas R., Bateman, Randall J., Rizzu, Patrizia, Heutink, Peter, Dols-Icardo, Oriol, Höglinger, Günter, Hermann, Andreas, and Schneider, Anja

Published
2024
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3. LATE-NC staging in routine neuropathologic diagnosis: an update

Author

Nelson, Peter T, Lee, Edward B, Cykowski, Matthew D, Alafuzoff, Irina, Arfanakis, Konstantinos, Attems, Johannes, Brayne, Carol, Corrada, Maria M, Dugger, Brittany N, Flanagan, Margaret E, Ghetti, Bernardino, Grinberg, Lea T, Grossman, Murray, Grothe, Michel J, Halliday, Glenda M, Hasegawa, Masato, Hokkanen, Suvi RK, Hunter, Sally, Jellinger, Kurt, Kawas, Claudia H, Keene, C Dirk, Kouri, Naomi, Kovacs, Gabor G, Leverenz, James B, Latimer, Caitlin S, Mackenzie, Ian R, Mao, Qinwen, McAleese, Kirsty E, Merrick, Richard, Montine, Thomas J, Murray, Melissa E, Myllykangas, Liisa, Nag, Sukriti, Neltner, Janna H, Newell, Kathy L, Rissman, Robert A, Saito, Yuko, Sajjadi, S Ahmad, Schwetye, Katherine E, Teich, Andrew F, Thal, Dietmar R, Tomé, Sandra O, Troncoso, Juan C, Wang, Shih-Hsiu J, White, Charles L, Wisniewski, Thomas, Yang, Hyun-Sik, Schneider, Julie A, Dickson, Dennis W, and Neumann, Manuela

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Neurosciences, Genetics, Acquired Cognitive Impairment, Neurodegenerative, Brain Disorders, Dementia, Rare Diseases, Neurological, Humans, Alzheimer Disease, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, DNA-Binding Proteins, Processes, NCI, TDP-43, FTD, Stages, Hippocampal sclerosis, Neuroanatomy, Aging, Neurology & Neurosurgery
Abstract

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

Published
2023

4. Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy.

Author

Hopfner, Franziska, Tietz, Anja, Ruf, Viktoria, Ross, Owen, Koga, Shunsuke, Dickson, Dennis, Aguzzi, Adriano, Attems, Johannes, Beach, Thomas, Beller, Allison, Cheshire, William, van Deerlin, Vivianna, Deuschl, Günther, Duyckaerts, Charles, Ellinghaus, David, Evsyukov, Valentin, Flanagan, Margaret, Franke, Andre, Frosch, Matthew, Gearing, Marla, Gelpi, Ellen, van Gerpen, Jay, Ghetti, Bernardino, Glass, Jonathan, Halliday, Glenda, Helbig, Ingo, Höllerhage, Matthias, Huitinga, Inge, Irwin, David, Keene, Dirk, Kovacs, Gabor, Lee, Edward, Levin, Johannes, Martí, Maria, Mackenzie, Ian, McKeith, Ian, Mclean, Catriona, Mollenhauer, Brit, Neumann, Manuela, Newell, Kathy, Pantelyat, Alex, Pendziwiat, Manuela, Peters, Annette, Molina Porcel, Laura, Rabano, Alberto, Matěj, Radoslav, Rajput, Alex, Rajput, Ali, Reimann, Regina, Scott, William, Selvackadunco, Sashika, Simuni, Tanya, Stadelmann, Christine, Svenningsson, Per, Thomas, Alan, Trenkwalder, Claudia, Troakes, Claire, Trojanowski, John, Uitti, Ryan, White, Charles, Wszolek, Zbigniew, Xie, Tao, Ximelis, Teresa, Yebenes, Justo, Müller, Ulrich, Schellenberg, Gerard, Herms, Jochen, Kuhlenbäumer, Gregor, Höglinger, Günter, Grinberg, Lea, Seeley, William, and Desplats, Paula

Subjects
ZIC1, ZIC4, autopsy-confirmed, genome-wide association study, multiple system atrophy, Autoantibodies, Autopsy, Genome-Wide Association Study, Humans, Multiple System Atrophy, Nerve Tissue Proteins, Olivopontocerebellar Atrophies, Striatonigral Degeneration, Transcription Factors, alpha-Synuclein
Abstract

BACKGROUND: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. OBJECTIVE: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. METHODS: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). RESULTS: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). INTERPRETATION: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Published
2022

5. A multi-omics dataset for the analysis of frontotemporal dementia genetic subtypes

Author

Menden, Kevin, Francescatto, Margherita, Nyima, Tenzin, Blauwendraat, Cornelis, Dhingra, Ashutosh, Castillo-Lizardo, Melissa, Fernandes, Noémia, Kaurani, Lalit, Kronenberg-Versteeg, Deborah, Atasu, Burcu, Sadikoglou, Eldem, Borroni, Barbara, Rodriguez-Nieto, Salvador, Simon-Sanchez, Javier, Fischer, Andre, Craig, David Wesley, Neumann, Manuela, Bonn, Stefan, Rizzu, Patrizia, and Heutink, Peter

Published
2023
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7. Reply to: Re-evaluating evidence for adaptive mutation rate variation

Author

Monroe, J. Grey, Murray, Kevin D., Xian, Wenfei, Srikant, Thanvi, Carbonell-Bejerano, Pablo, Becker, Claude, Lensink, Mariele, Exposito-Alonso, Moises, Klein, Marie, Hildebrandt, Julia, Neumann, Manuela, Kliebenstein, Daniel, Weng, Mao-Lun, Imbert, Eric, Ågren, Jon, Rutter, Matthew T., Fenster, Charles B., and Weigel, Detlef

Published
2023
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9. MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study

Author

Warner, Thomas T, Jaunmuktane, Zane, Boeve, Bradley F, Duara, Ranjan, Graff-Radford, Neill R, Josephs, Keith A, Knopman, David S, Koga, Shunsuke, Murray, Melissa E, Lyons, Kelly E, Pahwa, Rajesh, Petersen, Ronald C, Whitwell, Jennifer L, Grinberg, Lea T, Miller, Bruce, Schlereth, Athena, Spina, Salvatore, Grossman, Murray, Irwin, David J, Suh, EunRan, Trojanowski, John Q, Van Deerlin, Vivianna M, Wolk, David A, Connors, Theresa R, Dooley, Patrick M, Oakley, Derek H, Aldecoa, Iban, Balasa, Mircea, Gelpi, Ellen, Borrego-Écija, Sergi, Gascon-Bayarri, Jordi, Sánchez-Valle, Raquel, Sanz-Cartagena, Pilar, Piñol-Ripoll, Gerard, Bigio, Eileen H, Flanagan, Margaret E, Rogalski, Emily J, Weintraub, Sandra, Schneider, Julie A, Peng, Lihua, Zhu, Xiongwei, Chang, Koping, Troncoso, Juan C, Prokop, Stefan, Newell, Kathy L, Jones, Matthew, Richardson, Anna, Roncaroli, Federico, Snowden, Julie, Allinson, Kieren, Singh, Poonam, Serrano, Geidy E, Flowers, Xena E, Goldman, James E, Heaps, Allison C, Leskinen, Sandra P, Black, Sandra E, Masellis, Mario, King, Andrew, Al-Sarraj, Safa, Troakes, Claire, Hodges, John R, Kril, Jillian J, Kwok, John B, Piguet, Olivier, Roeber, Sigrun, Attems, Johannes, Thomas, Alan J, Evers, Bret M., Bieniek, Kevin F, Sieben, Anne A, Cras, Patrick P, De Vil, Bart B, Bird, Thomas, Castellani, Rudolph J, Chaffee, Ann, Franklin, Erin, Haroutunian, Vahram, Jacobsen, Max, Keene, Dirk, Latimer, Caitlin S, Metcalf, Jeff, Perrin, Richard J, Purohit, Dushyant P, Rissman, Robert A, Schantz, Aimee, Walker, Jamie, De Deyn, Peter P, Duyckaerts, Charles, Le Ber, Isabelle, Seilhean, Danielle, Turbant-Leclere, Sabrina, Ervin, John F, Nennesmo, Inger, Riehl, James, Nacmias, Benedetta, Finger, Elizabeth C, Blauwendraat, Cornelis, Nalls, Mike A, Singleton, Andrew B, Vitale, Dan, Cunha, Cristina, Wszolek, Zbigniew K, Valentino, Rebecca R, Scotton, William J, Roemer, Shanu F, Lashley, Tammaryn, Heckman, Michael G, Shoai, Maryam, Martinez-Carrasco, Alejandro, Tamvaka, Nicole, Walton, Ronald L, Baker, Matthew C, Macpherson, Hannah L, Real, Raquel, Soto-Beasley, Alexandra I, Mok, Kin, Revesz, Tamas, Christopher, Elizabeth A, DeTure, Michael, Seeley, William W, Lee, Edward B, Frosch, Matthew P, Molina-Porcel, Laura, Gefen, Tamar, Redding-Ochoa, Javier, Ghetti, Bernardino, Robinson, Andrew C, Kobylecki, Christopher, Rowe, James B, Beach, Thomas G, Teich, Andrew F, Keith, Julia L, Bodi, Istvan, Halliday, Glenda M, Gearing, Marla, Arzberger, Thomas, Morris, Christopher M, White, Charles L, 3rd, Mechawar, Naguib, Boluda, Susana, MacKenzie, Ian R, McLean, Catriona, Cykowski, Matthew D, Wang, Shih-Hsiu J, Graff, Caroline, Nagra, Rashed M, Kovacs, Gabor G, Giaccone, Giorgio, Neumann, Manuela, Ang, Lee-Cyn, Carvalho, Agostinho, Morris, Huw R, Rademakers, Rosa, Hardy, John A, Dickson, Dennis W, Rohrer, Jonathan D, and Ross, Owen A

Published
2024
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10. Mutation bias reflects natural selection in Arabidopsis thaliana

Author

Monroe, J Grey, Srikant, Thanvi, Carbonell-Bejerano, Pablo, Becker, Claude, Lensink, Mariele, Exposito-Alonso, Moises, Klein, Marie, Hildebrandt, Julia, Neumann, Manuela, Kliebenstein, Daniel, Weng, Mao-Lun, Imbert, Eric, Ågren, Jon, Rutter, Matthew T, Fenster, Charles B, and Weigel, Detlef

Subjects
Human Genome, Genetics, Generic health relevance, Arabidopsis, Epigenome, Epigenomics, Evolution, Molecular, Gene Frequency, Genes, Essential, Genes, Plant, Genome, Plant, Models, Genetic, Mutagenesis, Mutation, Mutation Rate, Polymorphism, Genetic, Selection, Genetic, General Science & Technology
Abstract

Since the first half of the twentieth century, evolutionary theory has been dominated by the idea that mutations occur randomly with respect to their consequences1. Here we test this assumption with large surveys of de novo mutations in the plant Arabidopsis thaliana. In contrast to expectations, we find that mutations occur less often in functionally constrained regions of the genome-mutation frequency is reduced by half inside gene bodies and by two-thirds in essential genes. With independent genomic mutation datasets, including from the largest Arabidopsis mutation accumulation experiment conducted to date, we demonstrate that epigenomic and physical features explain over 90% of variance in the genome-wide pattern of mutation bias surrounding genes. Observed mutation frequencies around genes in turn accurately predict patterns of genetic polymorphisms in natural Arabidopsis accessions (r = 0.96). That mutation bias is the primary force behind patterns of sequence evolution around genes in natural accessions is supported by analyses of allele frequencies. Finally, we find that genes subject to stronger purifying selection have a lower mutation rate. We conclude that epigenome-associated mutation bias2 reduces the occurrence of deleterious mutations in Arabidopsis, challenging the prevailing paradigm that mutation is a directionless force in evolution.

Published
2022

12. Neuropathological consensus criteria for the evaluation of Lewy pathology in post-mortem brains: a multi-centre study

Author

Attems, Johannes, Toledo, Jon B, Walker, Lauren, Gelpi, Ellen, Gentleman, Steve, Halliday, Glenda, Hortobagyi, Tibor, Jellinger, Kurt, Kovacs, Gabor G, Lee, Edward B, Love, Seth, McAleese, Kirsty E, Nelson, Peter T, Neumann, Manuela, Parkkinen, Laura, Polvikoski, Tuomo, Sikorska, Beata, Smith, Colin, Grinberg, Lea Tenenholz, Thal, Dietmar R, Trojanowski, John Q, and McKeith, Ian G

Subjects
Biomedical and Clinical Sciences, Neurosciences, Brain Disorders, Neurological, Autopsy, Brain, Brain Mapping, Consensus, Humans, Lewy Bodies, Lewy Body Disease, Observer Variation, Reproducibility of Results, Aging, Dementia, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Alzheimer's Disease, Parkinson's Disease, 2.1 Biological and endogenous factors, Aetiology, Aged, Aged, 80 and over, Alzheimer Disease, Cluster Analysis, Female, Male, Parkinson Disease, alpha-Synuclein, Lewy body disease, Diagnostic neuropathology, Clinical Sciences, Neurology & Neurosurgery
Abstract

Currently, the neuropathological diagnosis of Lewy body disease (LBD) may be stated according to several staging systems, which include the Braak Lewy body stages (Braak), the consensus criteria by McKeith and colleagues (McKeith), the modified McKeith system by Leverenz and colleagues (Leverenz), and the Unified Staging System by Beach and colleagues (Beach). All of these systems use semi-quantitative scoring (4- or 5-tier scales) of Lewy pathology (LP; i.e., Lewy bodies and Lewy neurites) in defined cortical and subcortical areas. While these systems are widely used, some suffer from low inter-rater reliability and/or an inability to unequivocally classify all cases with LP. To address these limitations, we devised a new system, the LP consensus criteria (LPC), which is based on the McKeith system, but applies a dichotomous approach for the scoring of LP (i.e., "absent" vs. "present") and includes amygdala-predominant and olfactory-only stages. α-Synuclein-stained slides from brainstem, limbic system, neocortex, and olfactory bulb from a total of 34 cases with LP provided by the Newcastle Brain Tissue Resource (NBTR) and the University of Pennsylvania brain bank (UPBB) were scanned and assessed by 16 raters, who provided diagnostic categories for each case according to Braak, McKeith, Leverenz, Beach, and LPC systems. In addition, using LP scores available from neuropathological reports of LP cases from UPBB (n = 202) and NBTR (n = 134), JT (UPBB) and JA (NBTR) assigned categories according to all staging systems to these cases. McKeith, Leverenz, and LPC systems reached good (Krippendorff's α ≈ 0.6), while both Braak and Beach systems had lower (Krippendorff's α ≈ 0.4) inter-rater reliability, respectively. Using the LPC system, all cases could be unequivocally classified by the majority of raters, which was also seen for 97.1% when the Beach system was used. However, a considerable proportion of cases could not be classified when using Leverenz (11.8%), McKeith (26.5%), or Braak (29.4%) systems. The category of neocortical LP according to the LPC system was associated with a 5.9 OR (p

Published
2021

13. Immunotherapy targeting the C-terminal domain of TDP-43 decreases neuropathology and confers neuroprotection in mouse models of ALS/FTD

Author

Afroz, Tariq, Chevalier, Elodie, Audrain, Mickael, Dumayne, Christopher, Ziehm, Tamar, Moser, Roger, Egesipe, Anne-Laure, Mottier, Lorène, Ratnam, Monisha, Neumann, Manuela, Havas, Daniel, Ollier, Romain, Piorkowska, Kasia, Chauhan, Mayank, Silva, Alberto B., Thapa, Samjhana, Stöhr, Jan, Bavdek, Andrej, Eligert, Valerie, Adolfsson, Oskar, Nelson, Peter T., Porta, Sílvia, Lee, Virginia M.-Y., Pfeifer, Andrea, Kosco-Vilbois, Marie, and Seredenina, Tamara

Published
2023
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14. Germline findings in patients with advanced malignancies screened with paired blood–tumour testing for personalised treatment approaches

Author

Roggia, Cristiana, Armeanu-Ebinger, Sorin, Gschwind, Axel, Seibel-Kelemen, Olga, Hertler, Sonja, Faust, Ulrike, Liebmann, Alexandra, Haack, Tobias B., Neumann, Manuela, Bonzheim, Irina, Forschner, Andrea, Kopp, Hans-Georg, Herster, Franziska, Hartkopf, Andreas, Bitzer, Michael, Malek, Nisar P., Brecht, Ines B., Ruhm, Kristina, Möller, Yvonne, Löwenheim, Hubert, Ossowski, Stephan, Rieß, Olaf H., and Schroeder, Christopher

Published
2023
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15. LATE to the PART-y

Author

Josephs, Keith A, Mackenzie, Ian, Frosch, Matthew P, Bigio, Eileen H, Neumann, Manuela, Arai, Tetsuaki, Dugger, Brittany N, Ghetti, Bernardino, Grossman, Murray, Hasegawa, Masato, Herrup, Karl, Holton, Janice, Jellinger, Kurt, Lashley, Tammaryn, McAleese, Kirsty E, Parisi, Joseph E, Revesz, Tamas, Saito, Yuko, Vonsattel, Jean Paul, Whitwell, Jennifer L, Wisniewski, Thomas, and Hu, William

Subjects
Biomedical and Clinical Sciences, Health Sciences, Psychology, Consensus, DNA-Binding Proteins, Humans, Limbic Encephalitis, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences
Published
2019

16. Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD

Author

Pottier, Cyril, Ren, Yingxue, Perkerson, Ralph B, Baker, Matt, Jenkins, Gregory D, van Blitterswijk, Marka, DeJesus-Hernandez, Mariely, van Rooij, Jeroen GJ, Murray, Melissa E, Christopher, Elizabeth, McDonnell, Shannon K, Fogarty, Zachary, Batzler, Anthony, Tian, Shulan, Vicente, Cristina T, Matchett, Billie, Karydas, Anna M, Hsiung, Ging-Yuek Robin, Seelaar, Harro, Mol, Merel O, Finger, Elizabeth C, Graff, Caroline, Öijerstedt, Linn, Neumann, Manuela, Heutink, Peter, Synofzik, Matthis, Wilke, Carlo, Prudlo, Johannes, Rizzu, Patrizia, Simon-Sanchez, Javier, Edbauer, Dieter, Roeber, Sigrun, Diehl-Schmid, Janine, Evers, Bret M, King, Andrew, Mesulam, M Marsel, Weintraub, Sandra, Geula, Changiz, Bieniek, Kevin F, Petrucelli, Leonard, Ahern, Geoffrey L, Reiman, Eric M, Woodruff, Bryan K, Caselli, Richard J, Huey, Edward D, Farlow, Martin R, Grafman, Jordan, Mead, Simon, Grinberg, Lea T, Spina, Salvatore, Grossman, Murray, Irwin, David J, Lee, Edward B, Suh, EunRan, Snowden, Julie, Mann, David, Ertekin-Taner, Nilufer, Uitti, Ryan J, Wszolek, Zbigniew K, Josephs, Keith A, Parisi, Joseph E, Knopman, David S, Petersen, Ronald C, Hodges, John R, Piguet, Olivier, Geier, Ethan G, Yokoyama, Jennifer S, Rissman, Robert A, Rogaeva, Ekaterina, Keith, Julia, Zinman, Lorne, Tartaglia, Maria Carmela, Cairns, Nigel J, Cruchaga, Carlos, Ghetti, Bernardino, Kofler, Julia, Lopez, Oscar L, Beach, Thomas G, Arzberger, Thomas, Herms, Jochen, Honig, Lawrence S, Vonsattel, Jean Paul, Halliday, Glenda M, Kwok, John B, White, Charles L, Gearing, Marla, Glass, Jonathan, Rollinson, Sara, Pickering-Brown, Stuart, Rohrer, Jonathan D, Trojanowski, John Q, Van Deerlin, Vivianna, Bigio, Eileen H, Troakes, Claire, Al-Sarraj, Safa, Asmann, Yan, Miller, Bruce L, Graff-Radford, Neill R, Boeve, Bradley F, and Seeley, William W

Subjects
Biomedical and Clinical Sciences, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Research, Brain Disorders, Rare Diseases, Human Genome, Alzheimer's Disease Related Dementias (ADRD), Dementia, Prevention, Genetics, Frontotemporal Dementia (FTD), Neurodegenerative, Acquired Cognitive Impairment, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Aged, DNA Repeat Expansion, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Female, Frontal Lobe, Frontotemporal Lobar Degeneration, Genetic Predisposition to Disease, Genome-Wide Association Study, HLA-DQ Antigens, Humans, Intracellular Signaling Peptides and Proteins, Loss of Function Mutation, Male, Middle Aged, Nerve Tissue Proteins, Potassium Channels, Progranulins, Protein Serine-Threonine Kinases, Proteins, RNA, Messenger, Risk Factors, Sequence Analysis, RNA, Societies, Scientific, TDP-43 Proteinopathies, White People, Whole-genome sequencing FTLD-TDP, TBK1, DPP6, UNC13A, HLA, Immunity, Clinical Sciences, Neurology & Neurosurgery
Abstract

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e - 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e - 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e - 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.

Published
2019

22. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study

Author

Pottier, Cyril, Zhou, Xiaolai, Perkerson, Ralph B, Baker, Matt, Jenkins, Gregory D, Serie, Daniel J, Ghidoni, Roberta, Benussi, Luisa, Binetti, Giuliano, de Munain, Adolfo López, Zulaica, Miren, Moreno, Fermin, Le Ber, Isabelle, Pasquier, Florence, Hannequin, Didier, Sánchez-Valle, Raquel, Antonell, Anna, Lladó, Albert, Parsons, Tammee M, Finch, NiCole A, Finger, Elizabeth C, Lippa, Carol F, Huey, Edward D, Neumann, Manuela, Heutink, Peter, Synofzik, Matthis, Wilke, Carlo, Rissman, Robert A, Slawek, Jaroslaw, Sitek, Emilia, Johannsen, Peter, Nielsen, Jørgen E, Ren, Yingxue, van Blitterswijk, Marka, DeJesus-Hernandez, Mariely, Christopher, Elizabeth, Murray, Melissa E, Bieniek, Kevin F, Evers, Bret M, Ferrari, Camilla, Rollinson, Sara, Richardson, Anna, Scarpini, Elio, Fumagalli, Giorgio G, Padovani, Alessandro, Hardy, John, Momeni, Parastoo, Ferrari, Raffaele, Frangipane, Francesca, Maletta, Raffaele, Anfossi, Maria, Gallo, Maura, Petrucelli, Leonard, Suh, EunRan, Lopez, Oscar L, Wong, Tsz H, van Rooij, Jeroen GJ, Seelaar, Harro, Mead, Simon, Caselli, Richard J, Reiman, Eric M, Sabbagh, Marwan Noel, Kjolby, Mads, Nykjaer, Anders, Karydas, Anna M, Boxer, Adam L, Grinberg, Lea T, Grafman, Jordan, Spina, Salvatore, Oblak, Adrian, Mesulam, M-Marsel, Weintraub, Sandra, Geula, Changiz, Hodges, John R, Piguet, Olivier, Brooks, William S, Irwin, David J, Trojanowski, John Q, Lee, Edward B, Josephs, Keith A, Parisi, Joseph E, Ertekin-Taner, Nilüfer, Knopman, David S, Nacmias, Benedetta, Piaceri, Irene, Bagnoli, Silvia, Sorbi, Sandro, Gearing, Marla, Glass, Jonathan, Beach, Thomas G, Black, Sandra E, Masellis, Mario, Rogaeva, Ekaterina, Vonsattel, Jean-Paul, Honig, Lawrence S, Kofler, Julia, Bruni, Amalia C, Snowden, Julie, Mann, David, and Pickering-Brown, Stuart

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Frontotemporal Dementia (FTD), Neurodegenerative, Dementia, Genetics, Aging, Prevention, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Human Genome, Alzheimer's Disease Related Dementias (ADRD), Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Aetiology, Neurological, Age of Onset, Aged, Case-Control Studies, Cerebellum, Female, Frontotemporal Lobar Degeneration, Genetic Predisposition to Disease, Genome-Wide Association Study, Glial Cell Line-Derived Neurotrophic Factor Receptors, Humans, Male, Middle Aged, Mutation, Progranulins, RNA, Messenger, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundLoss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers.MethodsThe study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p

Published
2018

23. MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study

Author

Valentino, Rebecca R, primary, Scotton, William J, additional, Roemer, Shanu F, additional, Lashley, Tammaryn, additional, Heckman, Michael G, additional, Shoai, Maryam, additional, Martinez-Carrasco, Alejandro, additional, Tamvaka, Nicole, additional, Walton, Ronald L, additional, Baker, Matthew C, additional, Macpherson, Hannah L, additional, Real, Raquel, additional, Soto-Beasley, Alexandra I, additional, Mok, Kin, additional, Revesz, Tamas, additional, Christopher, Elizabeth A, additional, DeTure, Michael, additional, Seeley, William W, additional, Lee, Edward B, additional, Frosch, Matthew P, additional, Molina-Porcel, Laura, additional, Gefen, Tamar, additional, Redding-Ochoa, Javier, additional, Ghetti, Bernardino, additional, Robinson, Andrew C, additional, Kobylecki, Christopher, additional, Rowe, James B, additional, Beach, Thomas G, additional, Teich, Andrew F, additional, Keith, Julia L, additional, Bodi, Istvan, additional, Halliday, Glenda M, additional, Gearing, Marla, additional, Arzberger, Thomas, additional, Morris, Christopher M, additional, White, Charles L, additional, Mechawar, Naguib, additional, Boluda, Susana, additional, MacKenzie, Ian R, additional, McLean, Catriona, additional, Cykowski, Matthew D, additional, Wang, Shih-Hsiu J, additional, Graff, Caroline, additional, Nagra, Rashed M, additional, Kovacs, Gabor G, additional, Giaccone, Giorgio, additional, Neumann, Manuela, additional, Ang, Lee-Cyn, additional, Carvalho, Agostinho, additional, Morris, Huw R, additional, Rademakers, Rosa, additional, Hardy, John A, additional, Dickson, Dennis W, additional, Rohrer, Jonathan D, additional, Ross, Owen A, additional, Warner, Thomas T, additional, Jaunmuktane, Zane, additional, Boeve, Bradley F, additional, Duara, Ranjan, additional, Graff-Radford, Neill R, additional, Josephs, Keith A, additional, Knopman, David S, additional, Koga, Shunsuke, additional, Murray, Melissa E, additional, Lyons, Kelly E, additional, Pahwa, Rajesh, additional, Petersen, Ronald C, additional, Whitwell, Jennifer L, additional, Grinberg, Lea T, additional, Miller, Bruce, additional, Schlereth, Athena, additional, Spina, Salvatore, additional, Grossman, Murray, additional, Irwin, David J, additional, Suh, EunRan, additional, Trojanowski, John Q, additional, Van Deerlin, Vivianna M, additional, Wolk, David A, additional, Connors, Theresa R, additional, Dooley, Patrick M, additional, Oakley, Derek H, additional, Aldecoa, Iban, additional, Balasa, Mircea, additional, Gelpi, Ellen, additional, Borrego-Écija, Sergi, additional, Gascon-Bayarri, Jordi, additional, Sánchez-Valle, Raquel, additional, Sanz-Cartagena, Pilar, additional, Piñol-Ripoll, Gerard, additional, Bigio, Eileen H, additional, Flanagan, Margaret E, additional, Rogalski, Emily J, additional, Weintraub, Sandra, additional, Schneider, Julie A, additional, Peng, Lihua, additional, Zhu, Xiongwei, additional, Chang, Koping, additional, Troncoso, Juan C, additional, Prokop, Stefan, additional, Newell, Kathy L, additional, Jones, Matthew, additional, Richardson, Anna, additional, Roncaroli, Federico, additional, Snowden, Julie, additional, Allinson, Kieren, additional, Singh, Poonam, additional, Serrano, Geidy E, additional, Flowers, Xena E, additional, Goldman, James E, additional, Heaps, Allison C, additional, Leskinen, Sandra P, additional, Black, Sandra E, additional, Masellis, Mario, additional, King, Andrew, additional, Al-Sarraj, Safa, additional, Troakes, Claire, additional, Hodges, John R, additional, Kril, Jillian J, additional, Kwok, John B, additional, Piguet, Olivier, additional, Roeber, Sigrun, additional, Attems, Johannes, additional, Thomas, Alan J, additional, Evers, Bret M., additional, Bieniek, Kevin F, additional, Sieben, Anne A, additional, Cras, Patrick P, additional, De Vil, Bart B, additional, Bird, Thomas, additional, Castellani, Rudolph J, additional, Chaffee, Ann, additional, Franklin, Erin, additional, Haroutunian, Vahram, additional, Jacobsen, Max, additional, Keene, Dirk, additional, Latimer, Caitlin S, additional, Metcalf, Jeff, additional, Perrin, Richard J, additional, Purohit, Dushyant P, additional, Rissman, Robert A, additional, Schantz, Aimee, additional, Walker, Jamie, additional, De Deyn, Peter P, additional, Duyckaerts, Charles, additional, Le Ber, Isabelle, additional, Seilhean, Danielle, additional, Turbant-Leclere, Sabrina, additional, Ervin, John F, additional, Nennesmo, Inger, additional, Riehl, James, additional, Nacmias, Benedetta, additional, Finger, Elizabeth C, additional, Blauwendraat, Cornelis, additional, Nalls, Mike A, additional, Singleton, Andrew B, additional, Vitale, Dan, additional, Cunha, Cristina, additional, and Wszolek, Zbigniew K, additional

Published
2024
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28. Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers

Author

van Blitterswijk, Marka, Mullen, Bianca, Heckman, Michael G, Baker, Matthew C, DeJesus-Hernandez, Mariely, Brown, Patricia H, Murray, Melissa E, Hsiung, Ging-Yuek R, Stewart, Heather, Karydas, Anna M, Finger, Elizabeth, Kertesz, Andrew, Bigio, Eileen H, Weintraub, Sandra, Mesulam, Marsel, Hatanpaa, Kimmo J, White, Charles L, Neumann, Manuela, Strong, Michael J, Beach, Thomas G, Wszolek, Zbigniew K, Lippa, Carol, Caselli, Richard, Petrucelli, Leonard, Josephs, Keith A, Parisi, Joseph E, Knopman, David S, Petersen, Ronald C, Mackenzie, Ian R, Seeley, William W, Grinberg, Lea T, Miller, Bruce L, Boylan, Kevin B, Graff-Radford, Neill R, Boeve, Bradley F, Dickson, Dennis W, and Rademakers, Rosa

Subjects
Biomedical and Clinical Sciences, Neurosciences, Genetics, ALS, Neurodegenerative, Acquired Cognitive Impairment, Clinical Research, Dementia, Frontotemporal Dementia (FTD), Rare Diseases, Aging, Brain Disorders, Neurological, Adult, Ataxins, C9orf72 Protein, Cohort Studies, DNA Repeat Expansion, Frontotemporal Dementia, Genetic Association Studies, Heterozygote, Humans, Male, Membrane Proteins, Middle Aged, Motor Neuron Disease, Nerve Tissue Proteins, Proteins, Survival of Motor Neuron 1 Protein, Survival of Motor Neuron 2 Protein, C9ORF72, Ataxin-2, ATXN2, Motor neuron disease, Amyotrophic lateral sclerosis, Frontotemporal dementia, Disease modifier, Clinical Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are an important cause of both motor neuron disease (MND) and frontotemporal dementia (FTD). Currently, little is known about factors that could account for the phenotypic heterogeneity detected in C9ORF72 expansion carriers. In this study, we investigated 4 genes that could represent genetic modifiers: ataxin-2 (ATXN2), non-imprinted in Prader-Willi/Angelman syndrome 1 (NIPA1), survival motor neuron 1 (SMN1), and survival motor neuron 2 (SMN2). Assessment of these genes, in a unique cohort of 331 C9ORF72 expansion carriers and 376 control subjects, revealed that intermediate repeat lengths in ATXN2 possibly act as disease modifier in C9ORF72 expansion carriers; no evidence was provided for a potential role of NIPA1, SMN1, or SMN2. The effects of intermediate ATXN2 repeats were most profound in probands with MND or FTD/MND (2.1% vs. 0% in control subjects, p = 0.013), whereas the frequency in probands with FTD was identical to control subjects. Though intermediate ATXN2 repeats were already known to be associated with MND risk, previous reports did not focus on individuals with clear pathogenic mutations, such as repeat expansions in C9ORF72. Based on our present findings, we postulate that intermediate ATXN2 repeat lengths may render C9ORF72 expansion carriers more susceptible to the development of MND; further studies are needed, however, to validate our findings.

Published
2014

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

Author

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

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

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

Published
2014

30. Mutations in protein N-arginine methyltransferases are not the cause of FTLD-FUS

Author

Ravenscroft, Thomas A, Baker, Matt C, Rutherford, Nicola J, Neumann, Manuela, Mackenzie, Ian R, Josephs, Keith A, Boeve, Bradley F, Petersen, Ronald, Halliday, Glenda M, Kril, Jillian, van Swieten, John C, Seeley, William W, Dickson, Dennis W, and Rademakers, Rosa

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Research, Acquired Cognitive Impairment, Neurodegenerative, Brain Disorders, Frontotemporal Dementia (FTD), Genetics, Clinical Trials and Supportive Activities, Dementia, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, 3' Untranslated Regions, 5' Untranslated Regions, DNA, Frontotemporal Lobar Degeneration, Humans, Membrane Proteins, Mutation, Protein-Arginine N-Methyltransferases, RNA, Messenger, Real-Time Polymerase Chain Reaction, Repressor Proteins, Sequence Analysis, Protein, Frontotemporal lobar degeneration, FUS, FET proteins, PRMT1, PRMT3, PRMT8, Protein N-arginine methyltransferase, Clinical Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

The nuclear protein fused in sarcoma (FUS) is found in cytoplasmic inclusions in a subset of patients with the neurodegenerative disorder frontotemporal lobar degeneration (FTLD-FUS). FUS contains a methylated arginine-glycine-glycine domain that is required for transport into the nucleus. Recent findings have shown that this domain is hypomethylated in patients with FTLD-FUS. To determine whether the cause of hypomethylation is the result of mutations in protein N-arginine methyltransferases (PRMTs), we selected 3 candidate genes (PRMT1, PRMT3, and PRMT8) and performed complete sequencing analysis and real-time polymerase chain reaction mRNA expression analysis in 20 FTLD-FUS cases. No mutations or statistically significant changes in expression were observed in our patient samples, suggesting that defects in PRMTs are not the cause of FTLD-FUS.

Published
2013

32. Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype

Author

Rutherford, Nicola J, Heckman, Michael G, DeJesus-Hernandez, Mariely, Baker, Matt C, Soto-Ortolaza, Alexandra I, Rayaprolu, Sruti, Stewart, Heather, Finger, Elizabeth, Volkening, Kathryn, Seeley, William W, Hatanpaa, Kimmo J, Lomen-Hoerth, Catherine, Kertesz, Andrew, Bigio, Eileen H, Lippa, Carol, Knopman, David S, Kretzschmar, Hans A, Neumann, Manuela, Caselli, Richard J, White, Charles L, Mackenzie, Ian R, Petersen, Ronald C, Strong, Michael J, Miller, Bruce L, Boeve, Bradley F, Uitti, Ryan J, Boylan, Kevin B, Wszolek, Zbigniew K, Graff-Radford, Neill R, Dickson, Dennis W, Ross, Owen A, and Rademakers, Rosa

Subjects
Biomedical and Clinical Sciences, Neurosciences, Acquired Cognitive Impairment, ALS, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Rare Diseases, Brain Disorders, Genetics, Dementia, Frontotemporal Dementia (FTD), Alzheimer's Disease Related Dementias (ADRD), Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, C9orf72 Protein, DNA Repeat Expansion, Female, Frontotemporal Dementia, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Proteins, Amyotrophic lateral sclerosis, Frontotemporal dementia, C9ORF72, Repeat-expansion disease, Association study, Clinical Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Expansions of the noncoding GGGGCC hexanucleotide repeat in the Chromosome 9 open reading frame 72 (C9ORF72) gene cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In this study we aimed to determine whether the length of the normal-unexpanded-allele of the GGGGCC repeat in C9ORF72 plays a role in the presentation of disease or affects age at onset in C9ORF72 mutation carriers. We also studied whether the GGGGCC repeat length confers risk or affects age at onset in FTD and ALS patients without C9ORF72 repeat expansions. C9ORF72 genotyping was performed in 580 FTD, 995 ALS, and 160 FTD-ALS patients, and 1444 controls, leading to the identification of 211 patients with pathogenic C9ORF72 repeat expansions. No meaningful association between the repeat length of the normal alleles of the GGGGCC repeat in C9ORF72 and disease phenotype or age at onset was observed in C9ORF72 mutation carriers or nonmutation carriers.

Published
2012

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

Author

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

Subjects
FReJA Consortium, Hippocampus, Frontal Lobe, Humans, Dyskinesias, RNA-Binding Protein FUS, tau Proteins, DNA-Binding Proteins, Prevalence, Sequence Analysis, DNA, Mental Disorders, Age of Onset, Mutation, Adult, Middle Aged, Female, Male, Frontotemporal Lobar Degeneration, Sequence Analysis, DNA, Clinical Sciences, Neurosciences, Neurology & Neurosurgery
Abstract

Through an international consortium, we have collected 37 tau- and TAR DNA-binding protein 43 (TDP-43)-negative frontotemporal lobar degeneration (FTLD) cases, and present here the first comprehensive analysis of these cases in terms of neuropathology, genetics, demographics and clinical data. 92% (34/37) had fused in sarcoma (FUS) protein pathology, indicating that FTLD-FUS is an important FTLD subtype. This FTLD-FUS collection specifically focussed on aFTLD-U cases, one of three recently defined subtypes of FTLD-FUS. The aFTLD-U subtype of FTLD-FUS is characterised clinically by behavioural variant frontotemporal dementia (bvFTD) and has a particularly young age of onset with a mean of 41 years. Further, this subtype had a high prevalence of psychotic symptoms (36% of cases) and low prevalence of motor symptoms (3% of cases). We did not find FUS mutations in any aFTLD-U case. To date, the only subtype of cases reported to have ubiquitin-positive but tau-, TDP-43- and FUS-negative pathology, termed FTLD-UPS, is the result of charged multivesicular body protein 2B gene (CHMP2B) mutation. We identified three FTLD-UPS cases, which are negative for CHMP2B mutation, suggesting that the full complement of FTLD pathologies is yet to be elucidated.

Published
2010

34. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions

Author

Van Deerlin, Vivianna M, Sleiman, Patrick MA, Martinez-Lage, Maria, Chen-Plotkin, Alice, Wang, Li-San, Graff-Radford, Neill R, Dickson, Dennis W, Rademakers, Rosa, Boeve, Bradley F, Grossman, Murray, Arnold, Steven E, Mann, David MA, Pickering-Brown, Stuart M, Seelaar, Harro, Heutink, Peter, van Swieten, John C, Murrell, Jill R, Ghetti, Bernardino, Spina, Salvatore, Grafman, Jordan, Hodges, John, Spillantini, Maria Grazia, Gilman, Sid, Lieberman, Andrew P, Kaye, Jeffrey A, Woltjer, Randall L, Bigio, Eileen H, Mesulam, Marsel, al-Sarraj, Safa, Troakes, Claire, Rosenberg, Roger N, White, Charles L, Ferrer, Isidro, Lladó, Albert, Neumann, Manuela, Kretzschmar, Hans A, Hulette, Christine Marie, Welsh-Bohmer, Kathleen A, Miller, Bruce L, Alzualde, Ainhoa, de Munain, Adolfo Lopez, McKee, Ann C, Gearing, Marla, Levey, Allan I, Lah, James J, Hardy, John, Rohrer, Jonathan D, Lashley, Tammaryn, Mackenzie, Ian RA, Feldman, Howard H, Hamilton, Ronald L, Dekosky, Steven T, van der Zee, Julie, Kumar-Singh, Samir, Van Broeckhoven, Christine, Mayeux, Richard, Vonsattel, Jean Paul G, Troncoso, Juan C, Kril, Jillian J, Kwok, John BJ, Halliday, Glenda M, Bird, Thomas D, Ince, Paul G, Shaw, Pamela J, Cairns, Nigel J, Morris, John C, McLean, Catriona Ann, DeCarli, Charles, Ellis, William G, Freeman, Stefanie H, Frosch, Matthew P, Growdon, John H, Perl, Daniel P, Sano, Mary, Bennett, David A, Schneider, Julie A, Beach, Thomas G, Reiman, Eric M, Woodruff, Bryan K, Cummings, Jeffrey, Vinters, Harry V, Miller, Carol A, Chui, Helena C, Alafuzoff, Irina, Hartikainen, Päivi, Seilhean, Danielle, Galasko, Douglas, Masliah, Eliezer, Cotman, Carl W, Tuñón, M Teresa, Martínez, M Cristina Caballero, Munoz, David G, Carroll, Steven L, Marson, Daniel, Riederer, Peter F, Bogdanovic, Nenad, Schellenberg, Gerard D, Hakonarson, Hakon, Trojanowski, John Q, and Lee, Virginia M-Y

Subjects
Biological Sciences, Genetics, Frontotemporal Dementia (FTD), Neurodegenerative, Dementia, Rare Diseases, Brain Disorders, Neurosciences, Acquired Cognitive Impairment, Aetiology, 2.1 Biological and endogenous factors, Case-Control Studies, Chromosomes, Human, Pair 7, DNA-Binding Proteins, Frontotemporal Lobar Degeneration, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Inclusion Bodies, Intercellular Signaling Peptides and Proteins, Linkage Disequilibrium, Membrane Proteins, Polymorphism, Single Nucleotide, Progranulins, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.

Published
2010

36. AAV-mediated expression of a new conformational anti-aggregated α-synuclein antibody prolongs survival in a genetic model of α-synucleinopathies

Author

Düchs, Matthias, primary, Blazevic, Dragica, additional, Rechtsteiner, Philipp, additional, Kenny, Cynthia, additional, Lamla, Thorsten, additional, Low, Sarah, additional, Savistchenko, Jimmy, additional, Neumann, Manuela, additional, Melki, Ronald, additional, Schönberger, Tanja, additional, Stierstorfer, Birgit, additional, Wyatt, David, additional, Igney, Frederik, additional, and Ciossek, Thomas, additional

Published
2023
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37. TDP-43 in the Ubiquitin Pathology of Frontotemporal Dementia With VCP Gene Mutations

Author

Neumann, Manuela, Mackenzie, Ian R, Cairns, Nigel J, Boyer, Philip J, Markesbery, William R, Smith, Charles D, Taylor, J Paul, Kretzschmar, Hans A, Kimonis, Virginia E, and Forman, Mark S

Subjects
Dementia, Genetics, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Rare Diseases, Brain Disorders, Acquired Cognitive Impairment, Aging, Frontotemporal Dementia (FTD), Neurosciences, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adenosine Triphosphatases, Aged, Cell Cycle Proteins, Cerebral Cortex, DNA-Binding Proteins, Female, Humans, Inclusion Bodies, Male, Middle Aged, Mutation, Myositis, Inclusion Body, Neurons, Osteitis Deformans, Ubiquitin, Valosin Containing Protein, frontotemporal dementia, neurodegeneration, TDP-43, ubiquitin, valosin-containing protein, Clinical Sciences, Neurology & Neurosurgery
Abstract

Frontotemporal dementia with inclusion body myopathy and Paget disease of bone is a rare, autosomal-dominant disorder caused by mutations in the gene valosin-containing protein (VCP). The CNS pathology is characterized by a novel pattern of ubiquitin pathology distinct from sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) without VCP mutations. TAR DNA binding protein 43 (TDP-43) was recently identified as a major disease protein in the ubiquitin-positive inclusions of sporadic and familial FTLD-U. To determine whether the ubiquitin pathology associated with mutations in VCP is characterized by the accumulation of TDP-43, we analyzed TDP-43 in the CNS pathology of five patients with VCP gene mutations. Accumulations of TDP-43 colocalized with ubiquitin pathology in inclusion body myopathy and Paget disease of bone, including both intranuclear inclusions and dystrophic neurites. Similar to FTLD-U, phosphorylated TDP-43 was detected only in insoluble brain extracts from affected brain regions. Identification of TDP-43, but not VCP, within ubiquitin-positive inclusions supports the hypothesis that VCP gene mutations lead to a dominant negative loss or alteration of VCP function culminating in impaired degradation of TDP-43. TDP-43 is a common pathologic substrate linking a variety of distinct patterns of FTLD-U pathology caused by different genetic alterations.

Published
2007

38. Update on quality assurance in neuropathology: Summary of the round robin trials on TERT promoter mutation, H3-3A mutation, 1p/19q codeletion, and KIAA1549::BRAF fusion testing in Germany in 2020 and 2021

Author

Pohl, Sandra, primary, Dimitrova, Lora, additional, Grassow-Narlik, Maja, additional, Jöhrens, Korinna, additional, Acker, Till, additional, Dohmen, Hildegard, additional, Herms, Jochen, additional, Dorostkar, Mario, additional, Hartmann, Christian, additional, Hasselblatt, Martin, additional, Neumann, Manuela, additional, Reifenberger, Guido, additional, Felsberg, Jörg, additional, Schüller, Ulrich, additional, Zoubaa, Saida, additional, Lorenz, Julia, additional, Rothhammer-Hampl, Tanja, additional, Mauch-Mücke, Katrin, additional, and Riemenschneider, Markus J., additional

Published
2023
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39. Creating the Pick’s disease International Consortium: Association study ofMAPTH2 haplotype with risk of Pick’s disease

Author

Valentino, Rebecca R, primary, Scotton, William J, additional, Roemer, Shanu F, additional, Lashley, Tammaryn, additional, Heckman, Michael G, additional, Shoai, Maryam, additional, Martinez-Carrasco, Alejandro, additional, Tamvaka, Nicole, additional, Walton, Ronald L, additional, Baker, Matthew C, additional, Macpherson, Hannah L, additional, Real, Raquel, additional, Soto-Beasley, Alexandra I, additional, Mok, Kin, additional, Revesz, Tamas, additional, Warner, Thomas T, additional, Jaunmuktane, Zane, additional, Boeve, Bradley F, additional, Christopher, Elizabeth A, additional, DeTure, Michael, additional, Duara, Ranjan, additional, Graff-Radford, Neill R, additional, Josephs, Keith A, additional, Knopman, David S, additional, Koga, Shunsuke, additional, Murray, Melissa E, additional, Lyons, Kelly E, additional, Pahwa, Rajesh, additional, Parisi, Joseph E, additional, Petersen, Ronald C, additional, Whitwell, Jennifer, additional, Grinberg, Lea T, additional, Miller, Bruce, additional, Schlereth, Athena, additional, Seeley, William W, additional, Spina, Salvatore, additional, Grossman, Murray, additional, Irwin, David J, additional, Lee, Edward B, additional, Suh, EunRan, additional, Trojanowski, John Q, additional, Van Deerlin, Vivianna M, additional, Wolk, David A, additional, Connors, Theresa R, additional, Dooley, Patrick M, additional, Frosch, Matthew P, additional, Oakley, Derek H, additional, Aldecoa, Iban, additional, Balasa, Mircea, additional, Gelpi, Ellen, additional, Borrego-Écija, Sergi, additional, de Eugenio Huélamo, Rosa Maria, additional, Gascon-Bayarri, Jordi, additional, Sánchez-Valle, Raquel, additional, Sanz-Cartagena, Pilar, additional, Piñol-Ripoll, Gerard, additional, Molina-Porcel, Laura, additional, Bigio, Eileen H, additional, Flanagan, Margaret E, additional, Gefen, Tamar, additional, Rogalski, Emily J, additional, Weintraub, Sandra, additional, Redding-Ochoa, Javier, additional, Chang, Koping, additional, Troncoso, Juan C, additional, Prokop, Stefan, additional, Newell, Kathy L, additional, Ghetti, Bernardino, additional, Jones, Matthew, additional, Richardson, Anna, additional, Robinson, Andrew C, additional, Roncaroli, Federico, additional, Snowden, Julie, additional, Allinson, Kieren, additional, Green, Oliver, additional, Rowe, James B, additional, Singh, Poonam, additional, Beach, Thomas G, additional, Serrano, Geidy E, additional, Flowers, Xena E, additional, Goldman, James E, additional, Heaps, Allison C, additional, Leskinen, Sandra P, additional, Teich, Andrew F, additional, Black, Sandra E, additional, Keith, Julia L, additional, Masellis, Mario, additional, Bodi, Istvan, additional, King, Andrew, additional, Sarraj, Safa-Al, additional, Troakes, Claire, additional, Halliday, Glenda M, additional, Hodges, John R, additional, Kril, Jillian J, additional, Kwok, John B, additional, Piguet, Olivier, additional, Gearing, Marla, additional, Arzberger, Thomas, additional, Roeber, Sigrun, additional, Attems, Johannes, additional, Morris, Christopher M, additional, Thomas, Alan J, additional, Evers, Bret M., additional, White, Charles L, additional, Mechawar, Naguib, additional, Sieben, Anne A, additional, Cras, Patrick P, additional, De Vil, Bart B, additional, De Deyn, Peter Paul P.P., additional, Duyckaerts, Charles, additional, Ber, Isabelle Le, additional, Seihean, Danielle, additional, Turbant-Leclere, Sabrina, additional, MacKenzie, Ian R, additional, McLean, Catriona, additional, Cykowski, Matthew D, additional, Ervin, John F, additional, Wang, Shih-Hsiu J, additional, Graff, Caroline, additional, Nennesmo, Inger, additional, Nagra, Rashed M, additional, Riehl, James, additional, Kovacs, Gabor G, additional, Giaccone, Giorgio, additional, Nacmias, Benedetta, additional, Neumann, Manuela, additional, Ang, Lee-Cyn, additional, Finger, Elizabeth C, additional, Blauwendraat, Cornelis, additional, Nalls, Mike A, additional, Singleton, Andrew B, additional, Vitale, Dan, additional, Cunha, Cristina, additional, Carvalho, Agostinho, additional, Wszolek, Zbigniew K, additional, Morris, Huw R, additional, Rademakers, Rosa, additional, Hardy, John A, additional, Dickson, Dennis W, additional, Rohrer, Jonathan D, additional, and Ross, Owen A, additional

Published
2023
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40. C9ORF72 knockdown triggers FTD-like symptoms and cell pathology in mice

Author

Lopez-Herdoiza, Maria-Belen, primary, Bauché, Stephanie, additional, Wilmet, Baptiste, additional, Le Duigou, Caroline, additional, Roussel, Delphine, additional, Frah, Magali, additional, Béal, Jonas, additional, Devely, Gabin, additional, Boluda, Susana, additional, Frick, Petra, additional, Bouteiller, Delphine, additional, Dussaud, Sébastien, additional, Guillabert, Pierre, additional, Dalle, Carine, additional, Dumont, Magali, additional, Camuzat, Agnes, additional, Saracino, Dario, additional, Barbier, Mathieu, additional, Bruneteau, Gaelle, additional, Ravassard, Phillippe, additional, Neumann, Manuela, additional, Nicole, Sophie, additional, Le Ber, Isabelle, additional, Brice, Alexis, additional, and Latouche, Morwena, additional

Published
2023
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41. LATE-NC staging in routine neuropathologic diagnosis: an update

Author

National Institutes of Health (US), California Department of Public Health, California Department of Finance, Academy of Finland, Edmond J. Safra Philanthropic Foundation, Rossy Foundation, Nomis Foundation, Alzheimer Forschung Initiative, Medical Research Council (UK), Addenbrooke's Charitable Trust, Life and Health Foundation, Paul G. Allen Family Foundation, Alzheimer's Research UK, Alzheimer Society, National Institute for Health Research (UK), Cambridge Biomedical Research Centre, Research Foundation - Flanders, KU Leuven, BrightFocus Foundation, Instituto de Salud Carlos III, European Commission, Nelson, Peter T., Lee, Edward B., Cykowski, Matthew D., Alafuzoff, Irina, Arfanakis, Konstantinos, Attems, Johannes, Brayne, Carol, Corrada, Maria M., Dugger, Brittany N., Flanagan, Margaret E., Ghetti, Bernardino, Grinberg, Lea T., Grossman, Murray, Grothe, Michel J., Halliday, Glenda M., Hasegawa, Masato, Hokkanen, Suvi R. K., Hunter, Sally, Jellinger, Kurt, Kawas, Claudia H., Keene, C. Dirk, Kouri, Naomi, Kovacs, Gabor G., Leverenz, James B., Latimer, Caitlin S., Mackenzie, Ian R., Mao, Qinwen, McAleese, Kirsty E., Merrick, Richard, Montine, Thomas J., Murray, Melissa E., Myllykangas, Liisa, Nag, Sukriti, Neltner, Janna H., Newell, Kathy L., Rissman, Robert A., Saito, Yuko, Sajjadi, S. Ahmad, Schwetye, Katherine E., Teich, Andrew F., Thal, Dietmar R., Tomé, Sandra O., Troncoso, Juan C., Wang, Shih-Hsiu J., White III, Charles L., Wisniewski, Thomas, Yang, Hyun-Sik, Schneider, Julie A., Dickson, Dennis W., Neumann, Manuela, National Institutes of Health (US), California Department of Public Health, California Department of Finance, Academy of Finland, Edmond J. Safra Philanthropic Foundation, Rossy Foundation, Nomis Foundation, Alzheimer Forschung Initiative, Medical Research Council (UK), Addenbrooke's Charitable Trust, Life and Health Foundation, Paul G. Allen Family Foundation, Alzheimer's Research UK, Alzheimer Society, National Institute for Health Research (UK), Cambridge Biomedical Research Centre, Research Foundation - Flanders, KU Leuven, BrightFocus Foundation, Instituto de Salud Carlos III, European Commission, Nelson, Peter T., Lee, Edward B., Cykowski, Matthew D., Alafuzoff, Irina, Arfanakis, Konstantinos, Attems, Johannes, Brayne, Carol, Corrada, Maria M., Dugger, Brittany N., Flanagan, Margaret E., Ghetti, Bernardino, Grinberg, Lea T., Grossman, Murray, Grothe, Michel J., Halliday, Glenda M., Hasegawa, Masato, Hokkanen, Suvi R. K., Hunter, Sally, Jellinger, Kurt, Kawas, Claudia H., Keene, C. Dirk, Kouri, Naomi, Kovacs, Gabor G., Leverenz, James B., Latimer, Caitlin S., Mackenzie, Ian R., Mao, Qinwen, McAleese, Kirsty E., Merrick, Richard, Montine, Thomas J., Murray, Melissa E., Myllykangas, Liisa, Nag, Sukriti, Neltner, Janna H., Newell, Kathy L., Rissman, Robert A., Saito, Yuko, Sajjadi, S. Ahmad, Schwetye, Katherine E., Teich, Andrew F., Thal, Dietmar R., Tomé, Sandra O., Troncoso, Juan C., Wang, Shih-Hsiu J., White III, Charles L., Wisniewski, Thomas, Yang, Hyun-Sik, Schneider, Julie A., Dickson, Dennis W., and Neumann, Manuela

Abstract

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer’s disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

Published
2023

42. Reply to: Re-evaluating evidence for adaptive mutation rate variation

Author

University of California, Davis, Monroe, J. Grey, Murray, Kevin D., Xian, Wenfei, Srikant, Thanvi, Carbonell-Bejerano, Pablo, Becker, Claude, Lensink, Mariele, Exposito-Alonso, Moises, Klein, Marie, Hildebrandt, Julia, Neumann, Manuela, Kliebenstein, Daniel, Weng, Mao-Lun, Imbert, Eric, Ågren, Jon, Rutter, Matthew T., Fenster, Charles B., Weigel, Detlef, University of California, Davis, Monroe, J. Grey, Murray, Kevin D., Xian, Wenfei, Srikant, Thanvi, Carbonell-Bejerano, Pablo, Becker, Claude, Lensink, Mariele, Exposito-Alonso, Moises, Klein, Marie, Hildebrandt, Julia, Neumann, Manuela, Kliebenstein, Daniel, Weng, Mao-Lun, Imbert, Eric, Ågren, Jon, Rutter, Matthew T., Fenster, Charles B., and Weigel, Detlef

Abstract

Wang and colleagues1 argue that our report2 of lower mutation rates in gene bodies, essential genes and regions marked by H3K4me1 must result from DNA sequencing errors. We appreciate the issues raised by them and by other colleagues3. Although we overlooked some sources of errors, these are insufficient to invalidate our conclusions, which are confirmed by more stringent reanalyses of our original data, new analyses restricted to high-confidence germline mutations4, and direct demonstration of plant DNA repair proteins being recruited to gene bodies, essential genes and H3K4me1, where they reduce local mutation rates5,6.

Published
2023

43. GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response.

Author

Wilke, Carlo, Pellerin, David, Mengel, David, Traschütz, Andreas, Danzi, Matt C, Dicaire, Marie-Josée, Neumann, Manuela, Lerche, Holger, Bender, Benjamin, Houlden, Henry, group, RFC1 study, Züchner, Stephan, Schöls, Ludger, Brais, Bernard, and Synofzik, Matthis

Subjects
SPINOCEREBELLAR ataxia, PROGRESSIVE supranuclear palsy, NATURAL history, ATAXIA, PHENOTYPES
Abstract

Ataxia due to an autosomal dominant intronic GAA repeat expansion in FGF14 [GAA- FGF14 ataxia, spinocerebellar ataxia 27B (SCA27B)] has recently been identified as one of the most common genetic late-onset ataxias. We here aimed to characterize its phenotypic profile, natural history progression, and 4-aminopyridine (4-AP) treatment response. We conducted a multi-modal cohort study of 50 GAA- FGF14 patients, comprising in-depth phenotyping, cross-sectional and longitudinal progression data (up to 7 years), MRI findings, serum neurofilament light (sNfL) levels, neuropathology, and 4-AP treatment response data, including a series of n -of-1 treatment studies. GAA- FGF14 ataxia consistently presented as late-onset [60.0 years (53.5–68.5), median (interquartile range)] pancerebellar syndrome, partly combined with afferent sensory deficits (55%) and dysautonomia (28%). Dysautonomia increased with duration while cognitive impairment remained infrequent, even in advanced stages. Cross-sectional and longitudinal assessments consistently indicated mild progression of ataxia [0.29 Scale for the Assessment and Rating of Ataxia (SARA) points/year], not exceeding a moderate disease severity even in advanced stages (maximum SARA score: 18 points). Functional impairment increased relatively slowly (unilateral mobility aids after 8 years in 50% of patients). Corresponding to slow progression and low extra-cerebellar involvement, sNfL was not increased relative to controls. Concurrent second diseases (including progressive supranuclear palsy neuropathology) represented major individual aggravators of disease severity, constituting important caveats for planning future GAA- FGF14 trials. A treatment response to 4-AP with relevance for everyday living was reported by 86% of treated patients. A series of three prospective n -of-1 treatment experiences with on/off design showed marked reduction in daily symptomatic time and symptom severity on 4-AP. Our study characterizes the phenotypic profile, natural history progression, and 4-AP treatment response of GAA- FGF14 ataxia. It paves the way towards large-scale natural history studies and 4-AP treatment trials in this newly discovered, possibly most frequent, and treatable late-onset ataxia. [ABSTRACT FROM AUTHOR]

Published
2023
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44. Clinical outcome of biomarker-guided therapies in adult patients with tumors of the nervous system

Author

Renovanz, Mirjam, primary, Kurz, Sylvia C, additional, Rieger, Johannes, additional, Walter, Bianca, additional, Becker, Hannes, additional, Hille, Hanni, additional, Bombach, Paula, additional, Rieger, David, additional, Grosse, Lucia, additional, Häusser, Lara, additional, Skardelly, Marco, additional, Merk, Daniel J, additional, Paulsen, Frank, additional, Hoffmann, Elgin, additional, Gani, Cihan, additional, Neumann, Manuela, additional, Beschorner, Rudi, additional, Rieß, Olaf, additional, Roggia, Cristiana, additional, Schroeder, Christopher, additional, Ossowski, Stephan, additional, Armeanu-Ebinger, Sorin, additional, Gschwind, Axel, additional, Biskup, Saskia, additional, Schulze, Martin, additional, Fend, Falko, additional, Singer, Stephan, additional, Zender, Lars, additional, Lengerke, Claudia, additional, Brucker, Sara Yvonne, additional, Engler, Tobias, additional, Forschner, Andrea, additional, Stenzl, Arnulf, additional, Kohlbacher, Oliver, additional, Nahnsen, Sven, additional, Gabernet, Gisela, additional, Fillinger, Sven, additional, Bender, Benjamin, additional, Ernemann, Ulrike, additional, Öner, Öznur, additional, Beha, Janina, additional, Malek, Holly Sundberg, additional, Möller, Yvonne, additional, Ruhm, Kristina, additional, Tatagiba, Marcos, additional, Schittenhelm, Jens, additional, Bitzer, Michael, additional, Malek, Nisar, additional, Zips, Daniel, additional, and Tabatabai, Ghazaleh, additional

Published
2023
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47. LATE-NC staging in routine neuropathologic diagnosis: an update

Author

Nelson, Peter T., primary, Lee, Edward B., additional, Cykowski, Matthew D., additional, Alafuzoff, Irina, additional, Arfanakis, Konstantinos, additional, Attems, Johannes, additional, Brayne, Carol, additional, Corrada, Maria M., additional, Dugger, Brittany N., additional, Flanagan, Margaret E., additional, Ghetti, Bernardino, additional, Grinberg, Lea T., additional, Grossman, Murray, additional, Grothe, Michel J., additional, Halliday, Glenda M., additional, Hasegawa, Masato, additional, Hokkanen, Suvi R. K., additional, Hunter, Sally, additional, Jellinger, Kurt, additional, Kawas, Claudia H., additional, Keene, C. Dirk, additional, Kouri, Naomi, additional, Kovacs, Gabor G., additional, Leverenz, James B., additional, Latimer, Caitlin S., additional, Mackenzie, Ian R., additional, Mao, Qinwen, additional, McAleese, Kirsty E., additional, Merrick, Richard, additional, Montine, Thomas J., additional, Murray, Melissa E., additional, Myllykangas, Liisa, additional, Nag, Sukriti, additional, Neltner, Janna H., additional, Newell, Kathy L., additional, Rissman, Robert A., additional, Saito, Yuko, additional, Sajjadi, S. Ahmad, additional, Schwetye, Katherine E., additional, Teich, Andrew F., additional, Thal, Dietmar R., additional, Tomé, Sandra O., additional, Troncoso, Juan C., additional, Wang, Shih-Hsiu J., additional, White, Charles L., additional, Wisniewski, Thomas, additional, Yang, Hyun-Sik, additional, Schneider, Julie A., additional, Dickson, Dennis W., additional, and Neumann, Manuela, additional

Published
2022
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48. AAV-mediated Expression of a Novel Conformational Anti-Aggregated α-Synuclein Antibody Prolongs Survival in a Genetic Model of α-Synucleinopathies

Author

Düchs, Matthias, primary, Blazevic, Dragica, additional, Rechtsteiner, Philipp, additional, Kenny, Cynthia, additional, Lamla, Thorsten, additional, Low, Sarah, additional, Savistchenko, Jimmy, additional, Neumann, Manuela, additional, Melki, Ronald, additional, Schönberger, Tanja, additional, Stierstorfer, Birgit, additional, Wyatt, David, additional, Igney, Frederik, additional, and Ciossek, Thomas, additional

Published
2022
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