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178 results on '"White III, Charles L."'

1. Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy

Author

Wang, Hui, Chang, Timothy S., Dombroski, Beth A., Cheng, Po-Liang, Patil, Vishakha, Valiente-Banuet, Leopoldo, Farrell, Kurt, Mclean, Catriona, Molina-Porcel, Laura, Rajput, Alex, De Deyn, Peter Paul, Le Bastard, Nathalie, Gearing, Marla, Kaat, Laura Donker, Van Swieten, John C., Dopper, Elise, Ghetti, Bernardino F., Newell, Kathy L., Troakes, Claire, de Yébenes, Justo G., Rábano-Gutierrez, Alberto, Meller, Tina, Oertel, Wolfgang H., Respondek, Gesine, Stamelou, Maria, Arzberger, Thomas, Roeber, Sigrun, Müller, Ulrich, Hopfner, Franziska, Pastor, Pau, Brice, Alexis, Durr, Alexandra, Le Ber, Isabelle, Beach, Thomas G., Serrano, Geidy E., Hazrati, Lili-Naz, Litvan, Irene, Rademakers, Rosa, Ross, Owen A., Galasko, Douglas, Boxer, Adam L., Miller, Bruce L., Seeley, Willian W., Van Deerlin, Vivanna M., Lee, Edward B., White, III, Charles L., Morris, Huw, de Silva, Rohan, Crary, John F., Goate, Alison M., Friedman, Jeffrey S., Leung, Yuk Yee, Coppola, Giovanni, Naj, Adam C., Wang, Li-San, Dalgard, Clifton, Dickson, Dennis W., Höglinger, Günter U., Schellenberg, Gerard D., Geschwind, Daniel H., and Lee, Wan-Ping

Published
2024
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4. Genome-wide association study and functional validation implicates JADE1 in tauopathy

Author

Farrell, Kurt, Kim, SoongHo, Han, Natalia, Iida, Megan A, Gonzalez, Elias M, Otero-Garcia, Marcos, Walker, Jamie M, Richardson, Timothy E, Renton, Alan E, Andrews, Shea J, Fulton-Howard, Brian, Humphrey, Jack, Vialle, Ricardo A, Bowles, Kathryn R, de Paiva Lopes, Katia, Whitney, Kristen, Dangoor, Diana K, Walsh, Hadley, Marcora, Edoardo, Hefti, Marco M, Casella, Alicia, Sissoko, Cheick T, Kapoor, Manav, Novikova, Gloriia, Udine, Evan, Wong, Garrett, Tang, Weijing, Bhangale, Tushar, Hunkapiller, Julie, Ayalon, Gai, Graham, Robert R, Cherry, Jonathan D, Cortes, Etty P, Borukov, Valeriy Y, McKee, Ann C, Stein, Thor D, Vonsattel, Jean-Paul, Teich, Andy F, Gearing, Marla, Glass, Jonathan, Troncoso, Juan C, Frosch, Matthew P, Hyman, Bradley T, Dickson, Dennis W, Murray, Melissa E, Attems, Johannes, Flanagan, Margaret E, Mao, Qinwen, Mesulam, M-Marsel, Weintraub, Sandra, Woltjer, Randy L, Pham, Thao, Kofler, Julia, Schneider, Julie A, Yu, Lei, Purohit, Dushyant P, Haroutunian, Vahram, Hof, Patrick R, Gandy, Sam, Sano, Mary, Beach, Thomas G, Poon, Wayne, Kawas, Claudia H, Corrada, María M, Rissman, Robert A, Metcalf, Jeff, Shuldberg, Sara, Salehi, Bahar, Nelson, Peter T, Trojanowski, John Q, Lee, Edward B, Wolk, David A, McMillan, Corey T, Keene, C Dirk, Latimer, Caitlin S, Montine, Thomas J, Kovacs, Gabor G, Lutz, Mirjam I, Fischer, Peter, Perrin, Richard J, Cairns, Nigel J, Franklin, Erin E, Cohen, Herbert T, Raj, Towfique, Cobos, Inma, Frost, Bess, Goate, Alison, White III, Charles L, and Crary, John F

Subjects
Biomedical and Clinical Sciences, Neurosciences, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Genetics, Dementia, Acquired Cognitive Impairment, Frontotemporal Dementia (FTD), Aging, Alzheimer's Disease, Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Aged, 80 and over, Animals, Cohort Studies, Drosophila, Female, Genome-Wide Association Study, Homeodomain Proteins, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Tauopathies, Tumor Suppressor Proteins, Clinical Sciences, Neurology & Neurosurgery
Abstract

Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

Published
2022

5. 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 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

Published
2023
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7. Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer’s dementia

Author

Sepulveda-Falla, Diego, Sanchez, Justin S., Almeida, Maria Camila, Boassa, Daniela, Acosta-Uribe, Juliana, Vila-Castelar, Clara, Ramirez-Gomez, Liliana, Baena, Ana, Aguillon, David, Villalba-Moreno, Nelson David, Littau, Jessica Lisa, Villegas, Andres, Beach, Thomas G., White, III, Charles L., Ellisman, Mark, Krasemann, Susanne, Glatzel, Markus, Johnson, Keith A., Sperling, Reisa A., Reiman, Eric M., Arboleda-Velasquez, Joseph F., Kosik, Kenneth S., Lopera, Francisco, and Quiroz, Yakeel T.

Published
2022
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8. Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report.

Author

Nelson, Peter T, Dickson, Dennis W, Trojanowski, John Q, Jack, Clifford R, Boyle, Patricia A, Arfanakis, Konstantinos, Rademakers, Rosa, Alafuzoff, Irina, Attems, Johannes, Brayne, Carol, Coyle-Gilchrist, Ian TS, Chui, Helena C, Fardo, David W, Flanagan, Margaret E, Halliday, Glenda, Hokkanen, Suvi RK, Hunter, Sally, Jicha, Gregory A, Katsumata, Yuriko, Kawas, Claudia H, Keene, C Dirk, Kovacs, Gabor G, Kukull, Walter A, Levey, Allan I, Makkinejad, Nazanin, Montine, Thomas J, Murayama, Shigeo, Murray, Melissa E, Nag, Sukriti, Rissman, Robert A, Seeley, William W, Sperling, Reisa A, White Iii, Charles L, Yu, Lei, and Schneider, Julie A

Subjects
Brain, Humans, Brain Diseases, Alzheimer Disease, Retrospective Studies, Aged, Aged, 80 and over, Middle Aged, Female, Male, Frontotemporal Lobar Degeneration, TDP-43 Proteinopathies, Frontotemporal Dementia, Neuroimaging, FTLD, MRI, PET, SNAP, epidemiology, and over, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the 'oldest-old' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.

Published
2019

10. Artificial intelligence-derived neurofibrillary tangle burden is associated with antemortem cognitive impairment

Author

Marx, Gabriel A., Koenigsberg, Daniel G., McKenzie, Andrew T., Kauffman, Justin, Hanson, Russell W., Whitney, Kristen, Signaevsky, Maxim, Prastawa, Marcel, Iida, Megan A., White, III, Charles L., Walker, Jamie M., Richardson, Timothy E., Koll, John, Fernandez, Gerardo, Zeineh, Jack, Cordon-Cardo, Carlos, Crary, John F., and Farrell, Kurt

Published
2022
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13. Antemortem detection of Parkinson’s disease pathology in peripheral biopsies using artificial intelligence

Author

Signaevsky, Maxim, Marami, Bahram, Prastawa, Marcel, Tabish, Nabil, Iida, Megan A., Zhang, Xiang Fu, Sawyer, Mary, Duran, Israel, Koenigsberg, Daniel G., Bryce, Clare H., Chahine, Lana M., Mollenhauer, Brit, Mosovsky, Sherri, Riley, Lindsey, Dave, Kuldip D., Eberling, Jamie, Coffey, Chris S., Adler, Charles H., Serrano, Geidy E., White, III, Charles L., Koll, John, Fernandez, Gerardo, Zeineh, Jack, Cordon-Cardo, Carlos, Beach, Thomas G., and Crary, John F.

Published
2022
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14. A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects

Author

Acosta-Uribe, Juliana, Aguillón, David, Cochran, J. Nicholas, Giraldo, Margarita, Madrigal, Lucía, Killingsworth, Bradley W., Singhal, Rijul, Labib, Sarah, Alzate, Diana, Velilla, Lina, Moreno, Sonia, García, Gloria P., Saldarriaga, Amanda, Piedrahita, Francisco, Hincapié, Liliana, López, Hugo E., Perumal, Nithesh, Morelo, Leonilde, Vallejo, Dionis, Solano, Juan Marcos, Reiman, Eric M., Surace, Ezequiel I., Itzcovich, Tatiana, Allegri, Ricardo, Sánchez-Valle, Raquel, Villegas-Lanau, Andrés, White, III, Charles L., Matallana, Diana, Myers, Richard M., Browning, Sharon R., Lopera, Francisco, and Kosik, Kenneth S.

Published
2022
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17. Predictors of cognitive impairment in primary age-related tauopathy: an autopsy study

Author

Iida, Megan A., Farrell, Kurt, Walker, Jamie M., Richardson, Timothy E., Marx, Gabriel A., Bryce, Clare H., Purohit, Dushyant, Ayalon, Gai, Beach, Thomas G., Bigio, Eileen H., Cortes, Etty P., Gearing, Marla, Haroutunian, Vahram, McMillan, Corey T., Lee, Edward B., Dickson, Dennis W., McKee, Ann C., Stein, Thor D., Trojanowski, John Q., Woltjer, Randall L., Kovacs, Gabor G., Kofler, Julia K., Kaye, Jeffrey, White, III, Charles L., and Crary, John F.

Published
2021
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18. C9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy

Author

Cali, Christopher P., Patino, Maribel, Tai, Yee Kit, Ho, Wan Yun, McLean, Catriona A., Morris, Christopher M., Seeley, William W., Miller, Bruce L., Gaig, Carles, Vonsattel, Jean Paul G., White, III, Charles L., Roeber, Sigrun, Kretzschmar, Hans, Troncoso, Juan C., Troakes, Claire, Gearing, Marla, Ghetti, Bernardino, Van Deerlin, Vivianna M., Lee, Virginia M.-Y., Trojanowski, John Q., Mok, Kin Y., Ling, Helen, Dickson, Dennis W., Schellenberg, Gerard D., Ling, Shuo-Chien, and Lee, Edward B.

Published
2019
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19. TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia

Author

van Blitterswijk, Marka, Mullen, Bianca, Nicholson, Alexandra M, Bieniek, Kevin F, Heckman, Michael G, Baker, Matthew C, DeJesus-Hernandez, Mariely, Finch, NiCole A, 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 III, Charles L, 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, Dementia, Frontotemporal Dementia (FTD), Neurodegenerative, Alzheimer's Disease Related Dementias (ADRD), Genetics, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), ALS, Human Genome, Clinical Research, Rare Diseases, Acquired Cognitive Impairment, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adult, Age of Onset, Aged, Aged, 80 and over, Alleles, C9orf72 Protein, Cohort Studies, DNA Repeat Expansion, DNA-Binding Proteins, Female, Frontotemporal Dementia, Genetic Predisposition to Disease, Genotype, Heterozygote, Humans, Male, Membrane Proteins, Middle Aged, Models, Genetic, Motor Neuron Disease, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Proteins, C9ORF72, TMEM106B, Frontotemporal dementia, Motor neuron disease, Amyotrophic lateral sclerosis, Disease modifier, Clinical Sciences, Neurology & Neurosurgery
Abstract

Variants in transmembrane protein 106 B (TMEM106B) modify the disease penetrance of frontotemporal dementia (FTD) in carriers of progranulin (GRN) mutations. We investigated whether TMEM106B is also a genetic modifier of disease in carriers of chromosome 9 open reading frame 72 (C9ORF72) expansions. We assessed the genotype of 325 C9ORF72 expansion carriers (cohort 1), 586 FTD patients lacking C9ORF72 expansions [with or without motor neuron disease (MND); cohort 2], and a total of 1,302 controls for TMEM106B variants (rs3173615 and rs1990622) using MassArray iPLEX and Taqman genotyping assays. For our primary analysis, we focused on functional variant rs3173615, and employed a recessive genotypic model. In cohort 1, patients with C9ORF72 expansions showed a significantly reduced frequency of carriers homozygous for the minor allele as compared to controls [11.9 vs. 19.1 %, odds ratio (OR) 0.57, p = 0.014; same direction as carriers of GRN mutations]. The strongest evidence was provided by FTD patients (OR 0.33, p = 0.009) followed by FTD/MND patients (OR 0.38, p = 0.017), whereas no significant difference was observed in MND patients (OR 0.85, p = 0.55). In cohort 2, the frequency of carriers homozygous for the minor allele was not significantly reduced in patients as compared to controls (OR 0.77, p = 0.079); however, a significant reduction was observed when focusing on those patients with frontotemporal lobar degeneration and TAR DNA-binding protein 43 inclusions (FTLD-TDP; OR 0.26, p < 0.001). Our study identifies TMEM106B as the first genetic factor modifying disease presentation in C9ORF72 expansion carriers. Homozygosity for the minor allele protects carriers from developing FTD, but not from developing MND; similar effects are seen in FTLD-TDP patients with yet unknown genetic causes. These new findings show that the protective effects of TMEM106B are not confined to carriers of GRN mutations and might be relevant for prognostic testing, and as a promising therapeutic target for the entire spectrum of FTLD-TDP.

Published
2014

20. Artificial intelligence in neuropathology: deep learning-based assessment of tauopathy

Author

Signaevsky, Maxim, Prastawa, Marcel, Farrell, Kurt, Tabish, Nabil, Baldwin, Elena, Han, Natalia, Iida, Megan A., Koll, John, Bryce, Clare, Purohit, Dushyant, Haroutunian, Vahram, McKee, Ann C., Stein, Thor D., White, III, Charles L., Walker, Jamie, Richardson, Timothy E., Hanson, Russell, Donovan, Michael J., Cordon-Cardo, Carlos, Zeineh, Jack, Fernandez, Gerardo, and Crary, John F.

Published
2019
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21. 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, III, Ralph B., Baker, Matt, Jenkins, Gregory D., van Blitterswijk, Marka, DeJesus-Hernandez, Mariely, van Rooij, Jeroen G. J., 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, III, 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., Seeley, William W., Mackenzie, Ian R. A., van Swieten, John C., Dickson, Dennis W., Biernacka, Joanna M., and Rademakers, Rosa

Published
2019
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22. 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, The FReJA Consortium, Dickson, Dennis W, Rademakers, Rosa, Graff-Radford, Neill R, Parisi, Joseph E, Petersen, Ronald C, Hatanpaa, Kimmo J, White III, 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
Biomedical and Clinical Sciences, Neurosciences, Neurodegenerative, Genetics, Brain Disorders, Clinical Trials and Supportive Activities, Aging, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Frontotemporal Dementia (FTD), Dementia, Clinical Research, Alzheimer's Disease Related Dementias (ADRD), Rare Diseases, Acquired Cognitive Impairment, Aetiology, 2.1 Biological and endogenous factors, Neurological, Adult, Age of Onset, DNA-Binding Proteins, Dyskinesias, Female, Frontal Lobe, Frontotemporal Lobar Degeneration, Hippocampus, Humans, Male, Mental Disorders, Middle Aged, Mutation, Prevalence, RNA-Binding Protein FUS, Sequence Analysis, DNA, tau Proteins, FTLD, FUS, FTLD-UPS, Frontotemporal, FTD, FReJA Consortium, Clinical Sciences, 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

24. 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

29. Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy

Author

Kovacs, Gabor G., Ferrer, Isidro, Grinberg, Lea T., Alafuzoff, Irina, Attems, Johannes, Budka, Herbert, Cairns, Nigel J., Crary, John F., Duyckaerts, Charles, Ghetti, Bernardino, Halliday, Glenda M., Ironside, James W., Love, Seth, Mackenzie, Ian R., Munoz, David G., Murray, Melissa E., Nelson, Peter T., Takahashi, Hitoshi, Trojanowski, John Q., Ansorge, Olaf, Arzberger, Thomas, Baborie, Atik, Beach, Thomas G., Bieniek, Kevin F., Bigio, Eileen H., Bodi, Istvan, Dugger, Brittany N., Feany, Mel, Gelpi, Ellen, Gentleman, Stephen M., Giaccone, Giorgio, Hatanpaa, Kimmo J., Heale, Richard, Hof, Patrick R., Hofer, Monika, Hortobágyi, Tibor, Jellinger, Kurt, Jicha, Gregory A., Ince, Paul, Kofler, Julia, Kövari, Enikö, Kril, Jillian J., Mann, David M., Matej, Radoslav, McKee, Ann C., McLean, Catriona, Milenkovic, Ivan, Montine, Thomas J., Murayama, Shigeo, Lee, Edward B., Rahimi, Jasmin, Rodriguez, Roberta D., Rozemüller, Annemieke, Schneider, Julie A., Schultz, Christian, Seeley, William, Seilhean, Danielle, Smith, Colin, Tagliavini, Fabrizio, Takao, Masaki, Thal, Dietmar Rudolf, Toledo, Jon B., Tolnay, Markus, Troncoso, Juan C., Vinters, Harry V., Weis, Serge, Wharton, Stephen B., White, III, Charles L., Wisniewski, Thomas, Woulfe, John M., Yamada, Masahito, and Dickson, Dennis W.

Published
2016
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32. Genome-wide association study and functional validation implicates JADE1 in tauopathy

Author

Farrell, Kurt, primary, Kim, SoongHo, additional, Han, Natalia, additional, Iida, Megan A., additional, Gonzalez, Elias M., additional, Otero-Garcia, Marcos, additional, Walker, Jamie M., additional, Richardson, Timothy E., additional, Renton, Alan E., additional, Andrews, Shea J., additional, Fulton-Howard, Brian, additional, Humphrey, Jack, additional, Vialle, Ricardo A., additional, Bowles, Kathryn R., additional, de Paiva Lopes, Katia, additional, Whitney, Kristen, additional, Dangoor, Diana K., additional, Walsh, Hadley, additional, Marcora, Edoardo, additional, Hefti, Marco M., additional, Casella, Alicia, additional, Sissoko, Cheick T., additional, Kapoor, Manav, additional, Novikova, Gloriia, additional, Udine, Evan, additional, Wong, Garrett, additional, Tang, Weijing, additional, Bhangale, Tushar, additional, Hunkapiller, Julie, additional, Ayalon, Gai, additional, Graham, Robert R., additional, Cherry, Jonathan D., additional, Cortes, Etty P., additional, Borukov, Valeriy Y., additional, McKee, Ann C., additional, Stein, Thor D., additional, Vonsattel, Jean-Paul, additional, Teich, Andy F., additional, Gearing, Marla, additional, Glass, Jonathan, additional, Troncoso, Juan C., additional, Frosch, Matthew P., additional, Hyman, Bradley T., additional, Dickson, Dennis W., additional, Murray, Melissa E., additional, Attems, Johannes, additional, Flanagan, Margaret E., additional, Mao, Qinwen, additional, Mesulam, M.-Marsel, additional, Weintraub, Sandra, additional, Woltjer, Randy L., additional, Pham, Thao, additional, Kofler, Julia, additional, Schneider, Julie A., additional, Yu, Lei, additional, Purohit, Dushyant P., additional, Haroutunian, Vahram, additional, Hof, Patrick R., additional, Gandy, Sam, additional, Sano, Mary, additional, Beach, Thomas G., additional, Poon, Wayne, additional, Kawas, Claudia H., additional, Corrada, María M., additional, Rissman, Robert A., additional, Metcalf, Jeff, additional, Shuldberg, Sara, additional, Salehi, Bahar, additional, Nelson, Peter T., additional, Trojanowski, John Q., additional, Lee, Edward B., additional, Wolk, David A., additional, McMillan, Corey T., additional, Keene, C. Dirk, additional, Latimer, Caitlin S., additional, Montine, Thomas J., additional, Kovacs, Gabor G., additional, Lutz, Mirjam I., additional, Fischer, Peter, additional, Perrin, Richard J., additional, Cairns, Nigel J., additional, Franklin, Erin E., additional, Cohen, Herbert T., additional, Raj, Towfique, additional, Cobos, Inma, additional, Frost, Bess, additional, Goate, Alison, additional, White III, Charles L., additional, and Crary, John F., additional

Published
2021
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34. 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 B. J., 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 III, Charles L., Woltjer, Randall L., Trojanowski, John Q., Lee, Virginia M. Y., Van Deerlin, Vivianna, and Chen-Plotkin, Alice S.

Published
2014
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35. Globular glial tauopathies (GGT): consensus recommendations

Author

Ahmed, Zeshan, Bigio, Eileen H., Budka, Herbert, Dickson, Dennis W., Ferrer, Isidro, Ghetti, Bernardino, Giaccone, Giorgio, Hatanpaa, Kimmo J., Holton, Janice L., Josephs, Keith A., Powers, James, Spina, Salvatore, Takahashi, Hitoshi, White, III, Charles L., Revesz, Tamas, and Kovacs, Gabor G.

Published
2013
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38. Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction

Author

Beach, Thomas G., Adler, Charles H., Lue, LihFen, Sue, Lucia I., Bachalakuri, Jyothi, Henry-Watson, Jonette, Sasse, Jeanne, Boyer, Sarah, Shirohi, Scophil, Brooks, Reed, Eschbacher, Jennifer, White, III, Charles L., Akiyama, Haru, Caviness, John, Shill, Holly A., Connor, Donald J., Sabbagh, Marwan N., Walker, Douglas G., and the Arizona Parkinson’s Disease Consortium

Published
2009
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40. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration

Author

Cairns, Nigel J., Bigio, Eileen H., Mackenzie, Ian R. A., Neumann, Manuela, Lee, Virginia M.-Y., Hatanpaa, Kimmo J., White, III, Charles L., Schneider, Julie A., Grinberg, Lea Tenenholz, Halliday, Glenda, Duyckaerts, Charles, Lowe, James S., Holm, Ida E., Tolnay, Markus, Okamoto, Koichi, Yokoo, Hideaki, Murayama, Shigeo, Woulfe, John, Munoz, David G., Dickson, Dennis W., Ince, Paul G., Trojanowski, John Q., and Mann, David M. A.

Published
2007
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43. Predictors of Life Expectancy in Autopsy-Confirmed Alzheimer's Disease.

Author

Schaffert, Jeff, LoBue, Christian, Hynan, Linda S., Hart Jr., John, Rossetti, Heidi, Carlew, Anne R., Lacritz, Laura, White III, Charles L., Cullum, C. Munro, Hart, John, and White, Charles L

Subjects
ALZHEIMER'S disease, LIFE expectancy, MINI-Mental State Examination, REGRESSION analysis, COGNITIVE ability, AUTOPSY, RETROSPECTIVE studies, RESEARCH funding
Abstract

Background: Life expectancy (LE) following Alzheimer's disease (AD) is highly variable. The literature to date is limited by smaller sample sizes and clinical diagnoses.Objective: No study to date has evaluated predictors of AD LE in a retrospective large autopsy-confirmed sample, which was the primary objective of this study.Methods: Participants (≥50 years old) clinically and neuropathologically diagnosed with AD were evaluated using National Alzheimer's Coordinating Center (N = 1,401) data. Analyses focused on 21 demographic, medical, neuropsychiatric, neurological, functional, and global cognitive predictors of LE at AD dementia diagnosis. These 21 predictors were evaluated in univariate analyses. Variables found to be significant were then entered into a forward multiple regression. LE was defined as months between AD diagnosis and death.Results: Fourteen predictors were significant in univariate analyses and entered into the regression. Seven predictors explained 27% of LE variance in 764 total participants. Mini-Mental State Examination (MMSE) score was the strongest predictor of LE, followed by sex, age, race/ethnicity, neuropsychiatric symptoms, abnormal neurological exam results, and functional impairment ratings. Post-hoc analyses revealed correlations of LE were strongest with MMSE ≤12.Conclusion: Global cognitive functioning was the strongest predictor of LE following diagnosis, and AD patients with severe impairment had the shortest LE. AD patients who are older, male, white, and have more motor symptoms, functional impairment, and neuropsychiatric symptoms were also more likely have shorter LE. While this model cannot provide individual prognoses, additional studies may focus on these variables to enhance predictions of LE in patients with AD. [ABSTRACT FROM AUTHOR]

Published
2022
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47. Deep learning reveals disease-specific signatures of white matter pathology in tauopathies.

Author

Vega, Anthony R., Chkheidze, Rati, Jarmale, Vipul, Shang, Ping, Foong, Chan, Diamond, Marc I., White III, Charles L., and Rajaram, Satwik

Subjects
WHITE matter (Nerve tissue), DEEP learning, PROGRESSIVE supranuclear palsy, GRAY matter (Nerve tissue), TAU proteins, CEREBRAL cortex, TAUOPATHIES
Abstract

Although pathology of tauopathies is characterized by abnormal tau protein aggregation in both gray and white matter regions of the brain, neuropathological investigations have generally focused on abnormalities in the cerebral cortex because the canonical aggregates that form the diagnostic criteria for these disorders predominate there. This corticocentric focus tends to deemphasize the relevance of the more complex white matter pathologies, which remain less well characterized and understood. We took a data-driven machine-learning approach to identify novel disease-specific morphologic signatures of white matter aggregates in three tauopathies: Alzheimer disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). We developed automated approaches using whole slide images of tau immunostained sections from 49 human autopsy brains (16 AD,13 CBD, 20 PSP) to identify cortex/white matter regions and individual tau aggregates, and compared tau-aggregate morphology across these diseases. Tau burden in the gray and white matter for individual subjects strongly correlated in a highly disease-specific fashion. We discovered previously unrecognized tau morphologies for AD, CBD and PSP that may be of importance in disease classification. Intriguingly, our models classified diseases equally well based on either white or gray matter tau staining. Our results suggest that tau pathology in white matter is informative, disease-specific, and linked to gray matter pathology. Machine learning has the potential to reveal latent information in histologic images that may represent previously unrecognized patterns of neuropathology, and additional studies of tau pathology in white matter could improve diagnostic accuracy. [ABSTRACT FROM AUTHOR]

Published
2021
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48. In vivo distribution of α-synuclein in multiple tissues and biofluids in Parkinson disease.

Author

Chahine, Lana M., Beach, Thomas G., Brumm, Michael C., Adler, Charles H., Coffey, Christopher S., Mosovsky, Sherri, Caspell-Garcia, Chelsea, Serrano, Geidy E., Munoz, David G., White III, Charles L., Crary, John F., Jennings, Danna, Taylor, Peggy, Foroud, Tatiana, Arnedo, Vanessa, Kopil, Catherine M., Riley, Lindsey, Dave, Kuldip D., Mollenhauer, Brit, and White, Charles L 3rd

Published
2020
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49. Multisite assessment of aging-related tau astrogliopathy (ARTAG)

Author

Kovacs, Gabor G., Xie, Sharon X., Lee, Edward B., Robinson, John L., Caswell, Carrie, Irwin, David J., Toledo, Jon B., Johnson, Victoria E., Smith, Douglas H., Alafuzoff, Irina, Attems, Johannes, Bencze, Janos, Bieniek, Kevin F., Bigio, Eileen H., Bodi, Istvan, Budka, Herbert, Dickson, Dennis W., Dugger, Brittany N., Duyckaerts, Charles, Ferrer, Isidro, Forrest, Shelley L., Gelpi, Ellen, Gentleman, Stephen M., Giaccone, Giorgio, Grinberg, Lea T., Halliday, Glenda M., Hatanpaa, Kimmo J., Hof, Patrick R., Hofer, Monika, Hortobagyi, Tibor, Ironside, James W., King, Andrew, Kofler, Julia, Kövari, Enikö, Kril, Jillian J., Love, Seth, Mackenzie, Ian R., Mao, Qinwen, Matej, Radoslav, McLean, Catriona, Muñoz, David G., Murray, Melissa E., Neltner, Janna, Nelson, Peter T., Ritchie, Diane, Rodriguez, Roberta D., Rohan, Zdenek, Rozemuller, Annemieke, Sakai, Kenji, Schultz, Christian, Seilhean, Danielle, Smith, Vanessa, Tacik, Pawel, Takahashi, Hitoshi, Takao, Masaki, Thal, Dietmar Rudolf, Weis, Serge, Wharton, Stephen B., White III, Charles L., Woulfe, John M., Yamada, Masahito, Trojanowski, John Q., Kovacs, Gabor G., Xie, Sharon X., Lee, Edward B., Robinson, John L., Caswell, Carrie, Irwin, David J., Toledo, Jon B., Johnson, Victoria E., Smith, Douglas H., Alafuzoff, Irina, Attems, Johannes, Bencze, Janos, Bieniek, Kevin F., Bigio, Eileen H., Bodi, Istvan, Budka, Herbert, Dickson, Dennis W., Dugger, Brittany N., Duyckaerts, Charles, Ferrer, Isidro, Forrest, Shelley L., Gelpi, Ellen, Gentleman, Stephen M., Giaccone, Giorgio, Grinberg, Lea T., Halliday, Glenda M., Hatanpaa, Kimmo J., Hof, Patrick R., Hofer, Monika, Hortobagyi, Tibor, Ironside, James W., King, Andrew, Kofler, Julia, Kövari, Enikö, Kril, Jillian J., Love, Seth, Mackenzie, Ian R., Mao, Qinwen, Matej, Radoslav, McLean, Catriona, Muñoz, David G., Murray, Melissa E., Neltner, Janna, Nelson, Peter T., Ritchie, Diane, Rodriguez, Roberta D., Rohan, Zdenek, Rozemuller, Annemieke, Sakai, Kenji, Schultz, Christian, Seilhean, Danielle, Smith, Vanessa, Tacik, Pawel, Takahashi, Hitoshi, Takao, Masaki, Thal, Dietmar Rudolf, Weis, Serge, Wharton, Stephen B., White III, Charles L., Woulfe, John M., Yamada, Masahito, and Trojanowski, John Q.

Abstract

Aging-related tau astrogliopathy (ARTAG) is a recently introduced terminology. To facilitate the consistent identification of ARTAG and to distinguish it from astroglial tau pathologies observed in the primary frontotemporal lobar degeneration tauopathies we evaluated how consistently neuropathologists recognize (1) different astroglial tau immunoreactivities, including those of ARTAG and those associated with primary tauopathies (Study 1); (2) ARTAG types (Study 2A); and (3) ARTAG severity (Study 2B). Microphotographs and scanned sections immunostained for phosphorylated tau (AT8) were made available for download and preview. Percentage of agreement and kappa values with 95% confidence interval (CI) were calculated for each evaluation. The overall agreement for Study 1 was >60% with a kappa value of 0.55 (95% CI 0.433–0.645). Moderate agreement (>90%, kappa 0.48, 95% CI 0.457–0.900) was reached in Study 2A for the identification of ARTAG pathology for each ARTAG subtype (kappa 0.37–0.72), whereas fair agreement (kappa 0.40, 95% CI 0.341–0.445) was reached for the evaluation of ARTAG severity. The overall assessment of ARTAG showed moderate agreement (kappa 0.60, 95% CI 0.534–0.653) among raters. Our study supports the application of the current harmonized evaluation strategy for ARTAG with a slight modification of the evaluation of its severity.

Published
2017

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