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2. 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

3. 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

7. TDP-43 pathological changes in early onset familial and sporadic Alzheimer’s disease, late onset Alzheimer’s disease and Down’s Syndrome: association with age, hippocampal sclerosis and clinical phenotype

Author

Davidson, Yvonne S., Raby, Samantha, Foulds, Penelope G., Robinson, Andrew, Thompson, Jennifer C., Sikkink, Stephen, Yusuf, Imran, Amin, Hanan, DuPlessis, Daniel, Troakes, Claire, Al-Sarraj, Safa, Sloan, Carolyn, Esiri, Margaret M., Prasher, Vee P., Allsop, David, Neary, David, Pickering-Brown, Stuart M., Snowden, Julie S., and Mann, David M. A.

Published
2011
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14. An immunohistochemical study of cases of sporadic and inherited frontotemporal lobar degeneration using 3R- and 4R-specific tau monoclonal antibodies

Author

de Silva, Rohan, Lashley, Tammaryn, Strand, Catherine, Shiarli, Anna-Maria, Shi, Jing, Tian, Jinzhou, Bailey, Kathryn L., Davies, Peter, Bigio, Eileen H., Arima, Kunimasa, Iseki, Eizo, Murayama, Shigeo, Kretzschmar, Hans, Neumann, Manuela, Lippa, Carol, Halliday, Glenda, MacKenzie, James, Ravid, Rivka, Dickson, Dennis, Wszolek, Zbigniew, Iwatsubo, Takeshi, Pickering-Brown, Stuart M., Holton, Janice, Lees, Andrew, Revesz, Tamas, and Mann, David M. A.

Published
2006
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15. Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C→T (Arg493X) mutation: an international initiative

Author

Rademakers, Rosa, Baker, Matt, Gass, Jennifer, Adamson, Jennifer, Huey, Edward D, Momeni, Parastoo, Spina, Salvatore, Coppola, Giovanni, Karydas, Anna M, Stewart, Heather, Johnson, Nancy, Hsiung, Ging-Yuek, Kelley, Brendan, Kuntz, Karen, Steinbart, Ellen, Wood, Elisabeth McCarty, Yu, Chang-En, Josephs, Keith, Sorenson, Eric, Womack, Kyle B, Weintraub, Sandra, Pickering-Brown, Stuart M, Schofield, Peter R, Brooks, William S, Van Deerlin, Vivianna M, Snowden, Julie, Clark, Christopher M, Kertesz, Andrew, Boylan, Kevin, Ghetti, Bernardino, Neary, David, Schellenberg, Gerard D, Beach, Thomas G, Mesulam, Marsel, Mann, David, Grafman, Jordan, Mackenzie, Ian R, Feldman, Howard, Bird, Thomas, Petersen, Ron, Knopman, David, Boeve, Bradley, Geschwind, Dan H, Miller, Bruce, Wszolek, Zbigniew, Lippa, Carol, Bigio, Eileen H, Dickson, Dennis, Graff-Radford, Neill, and Hutton, Mike

Published
2007
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18. Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration

Author

Chen-Plotkin, Alice S., Martinez-Lage, Maria, Sleiman, Patrick M., Hu, William, Greene, Robert, Wood, Elisabeth McCarty, Bing, Shaoxu, Grossman, Murray, Schellenberg, Gerard D., Hatanpaa, Kimmo J., Weiner, Myron F., White, Charles L., III, Brooks, William S., Halliday, Glenda M., Kril, Jillian J., Gearing, Marla, Beach, Thomas G., Graff-Radford, Neill R., Dickson, Dennis W., Rademakers, Rosa, Boeve, Bradley F., Pickering-Brown, Stuart M., Snowden, Julie, van Swieten, John C., Heutink, Peter, Seelaar, Harro, Murrell, Jill R., Ghetti, Bernardino, Spina, Salvatore, Grafman, Jordan, Kaye, Jeffrey A., Woltjer, Randall L., Mesulam, Marsel, Bigio, Eileen, Lladó, Albert, Miller, Bruce L., Alzualde, Ainhoa, Moreno, Fermin, Rohrer, Jonathan D., Mackenzie, Ian R., Feldman, Howard H., Hamilton, Ronald L., Cruts, Marc, Engelborghs, Sebastiaan, De Deyn, Peter P., Van Broeckhoven, Christine, Bird, Thomas D., Cairns, Nigel J., Goate, Allison, Frosch, Matthew P., Riederer, Peter F., Bogdanovic, Nenad, Lee, Virginia M., Trojanowski, John Q., and Van Deerlin, Vivianna M.

Published
2011
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26. Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration

Author

Gass, Jennifer, Cannon, Ashley, Mackenzie, Ian R., Boeve, Bradley, Baker, Matt, Adamson, Jennifer, Crook, Richard, Melquist, Stacey, Kuntz, Karen, Petersen, Ron, Josephs, Keith, Pickering-Brown, Stuart M., Graff-Radford, Neill, Uitti, Ryan, Dickson, Dennis, Wszolek, Zbigniew, Gonzalez, John, Beach, Thomas G., Bigio, Eileen, Johnson, Nancy, Weintraub, Sandra, Mesulam, Marsel, White, Charles L., III, Woodruff, Bryan, Caselli, Richard, Hsiung, Ging-Yuek, Feldman, Howard, Knopman, Dave, Hutton, Mike, and Rademakers, Rosa

Published
2006

27. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17

Author

Baker, Matt, Mackenzie, Ian R., Pickering-Brown, Stuart M., Gass, Jennifer, Rademakers, Rosa, Lindholm, Caroline, Snowden, Julie, Adamson, Jennifer, Sadovnick, A. Dessa, Rollinson, Sara, Cannon, Ashley, Dwosh, Emily, Neary, David, Melquist, Stacey, Richardson, Anna, Dickson, Dennis, Berger, Zdenek, Eriksen, Jason, Robinson, Todd, Zehr, Cynthia, Dickey, Chad A., Crook, Richard, McGowan, Eileen, Mann, David, Boeve, Bradley, Feldman, Howard, and Hutton, Mike

Published
2006

34. Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease

Author

Schott, Jonathan M., Crutch, Sebastian J., Carrasquillo, Minerva M., Uphill, James, Shakespeare, Tim J., Ryan, Natalie S., Yong, Keir X., Lehmann, Manja, Ertekin-Taner, Nilufer, Graff-Radford, Neill R., Boeve, Bradley F., Murray, Melissa E., Khan, Qurat ul Ain, Petersen, Ronald C., Dickson, Dennis W., Knopman, David S., Rabinovici, Gil D., Miller, Bruce L., González, Aida Suárez, Gil-Néciga, Eulogio, Snowden, Julie S., Harris, Jenny, Pickering-Brown, Stuart M., Louwersheimer, Eva, van der Flier, Wiesje M., Scheltens, Philip, Pijnenburg, Yolande A., Galasko, Douglas, Sarazin, Marie, Dubois, Bruno, Magnin, Eloi, Galimberti, Daniela, Scarpini, Elio, Cappa, Stefano F., Hodges, John R., Halliday, Glenda M., Bartley, Lauren, Carrillo, Maria C., Bras, Jose T., Hardy, John, Rossor, Martin N., Collinge, John, Fox, Nick C., Mead, Simon, Department of Neurodegenerative Disease, Alzheimer Scotland Dementia Research Centre, Department of Neuroscience, Mayo Clinic Jacksonville, Department of Neurodegenerative Diseases, MRC Prion Unit, Department of Neurology, Mayo Clinic [Rochester], Cardiovascular Research Institute (UCSF), University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Hospital Universitario Virgen del Rocío [Sevilla], Institute of Brain, Behaviour and Mental Health, University of Manchester [Manchester], Alzheimer center, VU University Medical Center [Amsterdam], Department of Epidemiology and biostatistics, School of Medicine [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), Neuro-anatomie fonctionnelle du comportement et de ses troubles, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre des Maladies Cognitives et Comportementales [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Mémoire de Ressources et de Recherche [CHRU de Besançon] (CMRR), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques [CHRU de Besançon], Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Vita-Salute San Raffaele University and Center for Translational Genomics and Bioinformatics, University of New South Wales [Sydney] (UNSW), Alzheimer's Association, Department of Molecular Neurosciences, Institute of Neurology, UCL, University of California [San Francisco] (UCSF), University of California-University of California, UC San Diego School of Medicine, Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Amsterdam Neuroscience - Neurodegeneration, Neurology, Epidemiology and Data Science, and HAL-UPMC, Gestionnaire

Subjects
Male, Epidemiology, Cell Adhesion Molecules, Neuronal, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Clinical Neurology, Selective vulnerability, Semaphorins, Polymorphism, Single Nucleotide, Cellular and Molecular Neuroscience, Apolipoproteins E, Developmental Neuroscience, Alzheimer Disease, Risk Factors, Mitochondrial Precursor Protein Import Complex Proteins, Genetics, GWAS, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Aged, Cerebral Cortex, Health Policy, Age Factors, Membrane Transport Proteins, Polynucleotide Adenylyltransferase, Proteins, Featured Article, Alzheimer's disease, Middle Aged, Psychiatry and Mental health, Posterior cortical atrophy, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Receptors, Complement 3b, Female, Geriatrics and Gerontology, Atrophy, APOE
Abstract

IntroductionThe genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain.MethodsWe genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome‐wide association study.ResultsWe confirm that variation in/near APOE/TOMM40 (P = 6 × 10−14) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10−4), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome‐wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10−10 OR = 1.9 [1.5–2.3]); rs72907046 near FAM46A (P = 1 × 10−9 OR = 3.2 [2.1–4.9]); and rs2525776 near SEMA3C (P = 1 × 10−8, OR = 3.3 [2.1–5.1]).DiscussionWe provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD.

Published
2016

38. Frontotemporal dementia and parkinsonism associated with the IVSI plus IG -> A mutation in progranulin: a clinicopathologic study

Author

Boeve, Bradley F., Baker, Matt, Dickson, Dennis W., Parisi, Joseph E., Giannini, Caterina, Josephs, Keith A., Hutton, Michael, Pickering-Brown, Stuart M., Rademakers, Rosa, Tang-Wai, David, Jack, Clifford R., Jr., Kantarci, Kejal, Shiung, Maria M., Golde, Todd, Smith, Glenn E., Geda, Yonas E., Knopman, David S., and Petersen, Ronald C.

Subjects
mental disorders, Human medicine
Abstract

We previously reported a kindred with three cases of dementia, in which the proband exhibited features typical of frontotemporal dementia and parkinsonism (FTDP). An arginine insertion at codon 352 (insR352) in the presenilin-1 (PSEN1) gene was identified in the proband, but analyses in plasma and CSF suggested a mechanism of neurodegeneration not directly related to amyloid pathophysiology. The proband was followed with yearly evaluations of functional, clinical, neuropsychologic, neuropsychiatric and radiologic status, which showed relatively linear change over the initial 4 years of assessment. Upon the proband's death at age 63, neuropathologic examination revealed frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusions (FTLD-U). We recently identified several kindreds with familial FTDP associated with mutations in the progranulin (PGRN) gene, particularly in those cases with neuronal intranuclear inclusions. Our proband was indeed found to have such inclusions, and PGRN analysis in this proband revealed the G to A mutation in the exon 1 splice donor site (IVS1+1G -> A) which is predicted to destroy the 5'-splice site of exon 1 and remove the start methionine codon and hence completely block any PGRN protein from being generated. These findings suggest that the insR352 PSEN1 is not pathogenic, and the IVS1+1G -> A mutation in PGRN causes FTDP associated with FTLD-U pathology and represents a new class of neurodegenerative disease-the 'hypoprogranulinopathies'.

Published
2006

39. Ubiquitin associated protein 1 is a risk factor for frontotemporal lobar degeneration

Author

Rollinson, Sara, Rizzu, Patrizia, Sikkink, Stephen, Baker, Matthew, Halliwell, Nicola, Snowden, Julie, Traynor, Bryan J., Ruano, Dina, Cairns, Nigel, Rohrer, Jonathan D., Mead, Simon, Collinge, John, Rossor, Martin, Akay, Ela, Guerreiro, Rita, Rademakers, Rosa, Morrison, Karen E., Pastor, Pau, Alonso, Elena, Martinez-Lage, Pablo, Graff-Radford, Neil, Neary, David, Heutink, Peter, Mann, David M.A., Van Swieten, John, and Pickering-Brown, Stuart M.

Published
2009
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40. TDP-43 pathological changes in early onset familial and sporadic Alzheimer's disease, late onset Alzheimer's disease and Down's Syndrome:association with age, hippocampal sclerosis and clinical phenotype

Author

Davidson, Yvonne S, Raby, Samantha, Foulds, Penny, Robinson, Andrew, Thompson, Jennifer C, Sikkink, Stephen, Yusuf, Imran, Amin, Hanan, Duplessis, Daniel, Troakes, Claire, Al-Sarraj, Safa, Sloan, Carolyn, Esiri, Margaret M, Prasher, Vee P, Allsop, David, Neary, David, Pickering-Brown, Stuart M, Snowden, Julie S, Mann, David M A, Davidson, Yvonne S, Raby, Samantha, Foulds, Penny, Robinson, Andrew, Thompson, Jennifer C, Sikkink, Stephen, Yusuf, Imran, Amin, Hanan, Duplessis, Daniel, Troakes, Claire, Al-Sarraj, Safa, Sloan, Carolyn, Esiri, Margaret M, Prasher, Vee P, Allsop, David, Neary, David, Pickering-Brown, Stuart M, Snowden, Julie S, and Mann, David M A

Abstract

TDP-43 immunoreactive (TDP-43-ir) pathological changes were investigated in the temporal cortex and hippocampus of 11 patients with autosomal dominant familial forms of Alzheimer’s disease (FAD), 169 patients with sporadic AD [85 with early onset disease (EOAD) (i.e before 65 years of age), and 84 with late onset after this age (LOAD)], 50 individuals with Down’s Syndrome (DS) and 5 patients with primary hippocampal sclerosis (HS). TDP-43-ir pathological changes were present, overall, in 34/180 of AD cases. They were present in 1/11 (9%) FAD, and 9/85 (10%) EOAD patients but were significantly more common (p = 0.003) in LOAD where 24/84 (29%) patients showed such changes. There were no demographic differences, other than onset age, between AD patients with or without TDP-43-ir pathological changes. Double immunolabelling indicated that these TDP-43-ir inclusions were frequently ubiquitinated, but were only rarely AT8 (tau) immunoreactive. Only 3 elderly DS individuals and 4/5 cases of primary HS showed similar changes. Overall, 21.7% of AD cases and 6% DS cases showed hippocampal sclerosis (HS). However, only 9% FAD cases and 16% EOAD cases showed HS, but 29% LOAD cases showed HS. The proportion of EOAD cases with both TDP-43 pathology and HS tended to be greater than those in LOAD, where nearly half of all the cases with TDP-43 pathology did not show HS. The presence of TDP-43-ir changes in AD and DS may therefore be a secondary phenomenon, relating more to ageing than to AD itself. Nevertheless, a challenge to such an interpretation comes from the finding in AD of a strong relationship between TDP-43 pathology and cognitive phenotype. Patients with TDP-43 pathology were significantly more likely to present with an amnestic syndrome than those without (p < 0.0001), in keeping with pathological changes in medial temporal lobe structures. HS was also associated more commonly with an amnestic presentation (p < 0.005), but this association disappeared when TDP-43-posit

Published
2011

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

Author

Van Deerlin, Vivian M, Sleiman, Patrick M. A., 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 M. A., 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 R. A., 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 B. J., 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., Lee, Virginia M-Y., Van Deerlin, Vivian M, Sleiman, Patrick M. A., 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 M. A., 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 R. A., 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 B. J., 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.

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
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42. No association of PGRN 3′UTR rs5848 in frontotemporal lobar degeneration

Author

Rollinson, Sara, primary, Rohrer, Jonathan D., additional, van der Zee, Julie, additional, Sleegers, Kristel, additional, Mead, Simon, additional, Engelborghs, Sebastiaan, additional, Collinge, John, additional, De Deyn, Peter P., additional, Mann, David M.A., additional, Van Broeckhoven, Christine, additional, and Pickering-Brown, Stuart M., additional

Published
2011
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48. Apolipoprotein E ε4 Allele Frequency and Age at Onset of Alzheimer’s Disease

Author

Davidson, Yvonne, primary, Gibbons, Linda, additional, Pritchard, Antonia, additional, Hardicre, Jayne, additional, Wren, Joanne, additional, Stopford, Cheryl, additional, Julien, Camille, additional, Thompson, Jennifer, additional, Payton, Antony, additional, Pickering-Brown, Stuart M., additional, Pendleton, Neil, additional, Horan, Michael A., additional, Burns, Alistair, additional, Purandare, Nitin, additional, Lendon, Corinne L., additional, Neary, David, additional, Snowden, Julie S., additional, and Mann, David M.A., additional

Published
2006
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50. CHMP2B mutations are not a common cause of frontotemporal lobar degeneration

Author

Cannon, Ashley, primary, Baker, Matthew, additional, Boeve, Brad, additional, Josephs, Keith, additional, Knopman, David, additional, Petersen, Ron, additional, Parisi, Joseph, additional, Dickison, Dennis, additional, Adamson, Jennifer, additional, Snowden, Julie, additional, Neary, David, additional, Mann, David, additional, Hutton, Mike, additional, and Pickering-Brown, Stuart M., additional

Published
2006
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