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2. Author Correction: Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein

Author

Mao, Xiaobo, Gu, Hao, Kim, Donghoon, Kimura, Yasuyoshi, Wang, Ning, Xu, Enquan, Kumbhar, Ramhari, Ming, Xiaotian, Wang, Haibo, Chen, Chan, Zhang, Shengnan, Jia, Chunyu, Liu, Yuqing, Bian, Hetao, Karuppagounder, Senthilkumar S., Akkentli, Fatih, Chen, Qi, Jia, Longgang, Hwang, Heehong, Lee, Su Hyun, Ke, Xiyu, Chang, Michael, Li, Amanda, Yang, Jun, Rastegar, Cyrus, Sriparna, Manjari, Ge, Preston, Brahmachari, Saurav, Kim, Sangjune, Zhang, Shu, Shimoda, Yasushi, Saar, Martina, Liu, Haiqing, Kweon, Sin Ho, Ying, Mingyao, Workman, Creg J., Vignali, Dario A. A., Muller, Ulrike C., Liu, Cong, Ko, Han Seok, Dawson, Valina L., and Dawson, Ted M.

Published
2024
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4. Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein

Author

Mao, Xiaobo, Gu, Hao, Kim, Donghoon, Kimura, Yasuyoshi, Wang, Ning, Xu, Enquan, Kumbhar, Ramhari, Ming, Xiaotian, Wang, Haibo, Chen, Chan, Zhang, Shengnan, Jia, Chunyu, Liu, Yuqing, Bian, Hetao, Karuppagounder, Senthilkumar S., Akkentli, Fatih, Chen, Qi, Jia, Longgang, Hwang, Heehong, Lee, Su Hyun, Ke, Xiyu, Chang, Michael, Li, Amanda, Yang, Jun, Rastegar, Cyrus, Sriparna, Manjari, Ge, Preston, Brahmachari, Saurav, Kim, Sangjune, Zhang, Shu, Shimoda, Yasushi, Saar, Martina, Liu, Haiqing, Kweon, Sin Ho, Ying, Mingyao, Workman, Creg J., Vignali, Dario A. A., Muller, Ulrike C., Liu, Cong, Ko, Han Seok, Dawson, Valina L., and Dawson, Ted M.

Published
2024
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5. Differential methylation analysis in neuropathologically confirmed dementia with Lewy bodies

Author

Reho, Paolo, Saez-Atienzar, Sara, Ruffo, Paola, Solaiman, Sultana, Shah, Zalak, Chia, Ruth, Kaivola, Karri, Traynor, Bryan J., Tilley, Bension S., Gentleman, Steve M., Hodges, Angela K., Aarsland, Dag, Monuki, Edwin S., Newell, Kathy L., Woltjer, Randy, Albert, Marilyn S., Dawson, Ted M., Rosenthal, Liana S., Troncoso, Juan C., Pletnikova, Olga, Serrano, Geidy E., Beach, Thomas G., Easwaran, Hariharan P., and Scholz, Sonja W.

Published
2024
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6. Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias

Author

Kaivola, Karri, Chia, Ruth, Ding, Jinhui, Rasheed, Memoona, Fujita, Masashi, Menon, Vilas, Walton, Ronald L, Collins, Ryan L, Billingsley, Kimberley, Brand, Harrison, Talkowski, Michael, Zhao, Xuefang, Dewan, Ramita, Stark, Ali, Ray, Anindita, Solaiman, Jerez, Pilar Alvarez, Malik, Laksh, Dawson, Ted M, Rosenthal, Liana S, Albert, Marilyn S, Pletnikova, Olga, Troncoso, Juan C, Masellis, Mario, Keith, Julia, Black, Sandra E, Ferrucci, Luigi, Resnick, Susan M, Tanaka, Toshiko, Soltis, Anthony R, Viollet, Coralie, Sukumar, Gauthaman, Alba, Camille, Lott, Nathaniel, Martinez, Elisa McGrath, Tuck, Meila, Singh, Jatinder, Bacikova, Dagmar, Zhang, Xijun, Hupalo, Daniel N, Adeleye, Adelani, Wilkerson, Matthew D, Pollard, Harvey B, Dalgard, Clifton L, Gan-Or, Ziv, Rogaeva, Ekaterina, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Calvo, Andrea, Canosa, Antonio, Chio, Adriano, Logroscino, Giancarlo, Mora, Gabriele, Krüger, Reijko, May, Patrick, Alcolea, Daniel, Clarimon, Jordi, Fortea, Juan, Gonzalez-Aramburu, Isabel, Infante, Jon, Lage, Carmen, Lleó, Alberto, Pastor, Pau, Sanchez-Juan, Pascual, Brett, Francesca, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Gentleman, Steve, Hardy, John A, Hodges, Angela K, Love, Seth, McKeith, Ian G, Morris, Christopher M, Morris, Huw R, Palmer, Laura, Pickering-Brown, Stuart, Ryten, Mina, Thomas, Alan J, Troakes, Claire, Barrett, Matthew J, Beach, Thomas G, Bekris, Lynn M, Bennett, David A, Boeve, Bradley F, Dickson, Dennis W, Faber, Kelley, Ferman, Tanis, Flanagan, Margaret E, Foroud, Tatiana M, Ghetti, Bernardino, and Gibbs, J Raphael

Subjects
Biological Sciences, Genetics, Brain Disorders, Dementia, ALS, Rare Diseases, Neurodegenerative, Neurosciences, Human Genome, Frontotemporal Dementia (FTD), Alzheimer's Disease, Alzheimer's Disease Related Dementias (ADRD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Aging, Aetiology, 2.1 Biological and endogenous factors, Neurological, American Genome Center, International LBD Genomics Consortium, International ALS/FTD Consortium, PROSPECT Consortium, Lewy body dementia, amyotrophic lateral sclerosis, case-control study, frontotemporal dementia, genome-wide association study, non–Alzheimer's dementia, resource, structural variant
Abstract

We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer's dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.

Published
2023

7. Apoptotic cell death in disease—Current understanding of the NCCD 2023

Author

Vitale, Ilio, Pietrocola, Federico, Guilbaud, Emma, Aaronson, Stuart A, Abrams, John M, Adam, Dieter, Agostini, Massimiliano, Agostinis, Patrizia, Alnemri, Emad S, Altucci, Lucia, Amelio, Ivano, Andrews, David W, Aqeilan, Rami I, Arama, Eli, Baehrecke, Eric H, Balachandran, Siddharth, Bano, Daniele, Barlev, Nickolai A, Bartek, Jiri, Bazan, Nicolas G, Becker, Christoph, Bernassola, Francesca, Bertrand, Mathieu JM, Bianchi, Marco E, Blagosklonny, Mikhail V, Blander, J Magarian, Blandino, Giovanni, Blomgren, Klas, Borner, Christoph, Bortner, Carl D, Bove, Pierluigi, Boya, Patricia, Brenner, Catherine, Broz, Petr, Brunner, Thomas, Damgaard, Rune Busk, Calin, George A, Campanella, Michelangelo, Candi, Eleonora, Carbone, Michele, Carmona-Gutierrez, Didac, Cecconi, Francesco, Chan, Francis K-M, Chen, Guo-Qiang, Chen, Quan, Chen, Youhai H, Cheng, Emily H, Chipuk, Jerry E, Cidlowski, John A, Ciechanover, Aaron, Ciliberto, Gennaro, Conrad, Marcus, Cubillos-Ruiz, Juan R, Czabotar, Peter E, D’Angiolella, Vincenzo, Daugaard, Mads, Dawson, Ted M, Dawson, Valina L, De Maria, Ruggero, De Strooper, Bart, Debatin, Klaus-Michael, Deberardinis, Ralph J, Degterev, Alexei, Del Sal, Giannino, Deshmukh, Mohanish, Di Virgilio, Francesco, Diederich, Marc, Dixon, Scott J, Dynlacht, Brian D, El-Deiry, Wafik S, Elrod, John W, Engeland, Kurt, Fimia, Gian Maria, Galassi, Claudia, Ganini, Carlo, Garcia-Saez, Ana J, Garg, Abhishek D, Garrido, Carmen, Gavathiotis, Evripidis, Gerlic, Motti, Ghosh, Sourav, Green, Douglas R, Greene, Lloyd A, Gronemeyer, Hinrich, Häcker, Georg, Hajnóczky, György, Hardwick, J Marie, Haupt, Ygal, He, Sudan, Heery, David M, Hengartner, Michael O, Hetz, Claudio, Hildeman, David A, Ichijo, Hidenori, Inoue, Satoshi, Jäättelä, Marja, Janic, Ana, Joseph, Bertrand, Jost, Philipp J, and Kanneganti, Thirumala-Devi

Subjects
Biochemistry and Cell Biology, Biological Sciences, Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Good Health and Well Being, Animals, Humans, Apoptosis, Cell Death, Caspases, Carcinogenesis, Mammals, Medical and Health Sciences, Biochemistry & Molecular Biology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.

Published
2023

8. Atp7b-dependent choroid plexus dysfunction causes transient copper deficit and metabolic changes in the developing mouse brain

Author

Washington-Hughes, Clorissa L, Roy, Shubhrajit, Seneviratne, Herana Kamal, Karuppagounder, Senthilkumar S, Morel, Yulemni, Jones, Jace W, Zak, Alex, Xiao, Tong, Boronina, Tatiana N, Cole, Robert N, Bumpus, Namandjé N, Chang, Christopher J, Dawson, Ted M, and Lutsenko, Svetlana

Subjects
Biochemistry and Cell Biology, Biological Sciences, Neurosciences, Neurodegenerative, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Underpinning research, Aetiology, Neurological, Mice, Animals, Copper-Transporting ATPases, Copper, Choroid Plexus, Menkes Kinky Hair Syndrome, Brain, Copper-transporting ATPases, Genetics, Developmental Biology
Abstract

Copper (Cu) has a multifaceted role in brain development, function, and metabolism. Two homologous Cu transporters, Atp7a (Menkes disease protein) and Atp7b (Wilson disease protein), maintain Cu homeostasis in the tissue. Atp7a mediates Cu entry into the brain and activates Cu-dependent enzymes, whereas the role of Atp7b is less clear. We show that during postnatal development Atp7b is necessary for normal morphology and function of choroid plexus (ChPl). Inactivation of Atp7b causes reorganization of ChPl' cytoskeleton and cell-cell contacts, loss of Slc31a1 from the apical membrane, and a decrease in the length and number of microvilli and cilia. In ChPl lacking Atp7b, Atp7a is upregulated but remains intracellular, which limits Cu transport into the brain and results in significant Cu deficit, which is reversed only in older animals. Cu deficiency is associated with down-regulation of Atp7a in locus coeruleus and catecholamine imbalance, despite normal expression of dopamine-β-hydroxylase. In addition, there are notable changes in the brain lipidome, which can be attributed to inhibition of diacylglyceride-to-phosphatidylethanolamine conversion. These results identify the new role for Atp7b in developing brain and identify metabolic changes that could be exacerbated by Cu chelation therapy.

Published
2023

9. ADP‐ribosyltransferases, an update on function and nomenclature

Author

Lüscher, Bernhard, Ahel, Ivan, Altmeyer, Matthias, Ashworth, Alan, Bai, Peter, Chang, Paul, Cohen, Michael, Corda, Daniela, Dantzer, Françoise, Daugherty, Matthew D, Dawson, Ted M, Dawson, Valina L, Deindl, Sebastian, Fehr, Anthony R, Feijs, Karla LH, Filippov, Dmitri V, Gagné, Jean‐Philippe, Grimaldi, Giovanna, Guettler, Sebastian, Hoch, Nicolas C, Hottiger, Michael O, Korn, Patricia, Kraus, W Lee, Ladurner, Andreas, Lehtiö, Lari, Leung, Anthony KL, Lord, Christopher J, Mangerich, Aswin, Matic, Ivan, Matthews, Jason, Moldovan, George‐Lucian, Moss, Joel, Natoli, Gioacchino, Nielsen, Michael L, Niepel, Mario, Nolte, Friedrich, Pascal, John, Paschal, Bryce M, Pawłowski, Krzysztof, Poirier, Guy G, Smith, Susan, Timinszky, Gyula, Wang, Zhao‐Qi, Yélamos, José, Yu, Xiaochun, Zaja, Roko, and Ziegler, Mathias

Subjects
Biochemistry and Cell Biology, Biological Sciences, Infectious Diseases, Emerging Infectious Diseases, Genetics, Underpinning research, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, 1.1 Normal biological development and functioning, Generic health relevance, ADP Ribose Transferases, Protein Biosynthesis, Adenosine Diphosphate Ribose, Adenosine Diphosphate, ADP-ribosylation, MARylation, PARP, PARylation, posttranslational modification, Medicinal and Biomolecular Chemistry, Medical Biochemistry and Metabolomics, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medical biochemistry and metabolomics, Medicinal and biomolecular chemistry
Abstract

ADP-ribosylation, a modification of proteins, nucleic acids, and metabolites, confers broad functions, including roles in stress responses elicited, for example, by DNA damage and viral infection and is involved in intra- and extracellular signaling, chromatin and transcriptional regulation, protein biosynthesis, and cell death. ADP-ribosylation is catalyzed by ADP-ribosyltransferases (ARTs), which transfer ADP-ribose from NAD+ onto substrates. The modification, which occurs as mono- or poly-ADP-ribosylation, is reversible due to the action of different ADP-ribosylhydrolases. Importantly, inhibitors of ARTs are approved or are being developed for clinical use. Moreover, ADP-ribosylhydrolases are being assessed as therapeutic targets, foremost as antiviral drugs and for oncological indications. Due to the development of novel reagents and major technological advances that allow the study of ADP-ribosylation in unprecedented detail, an increasing number of cellular processes and pathways are being identified that are regulated by ADP-ribosylation. In addition, characterization of biochemical and structural aspects of the ARTs and their catalytic activities have expanded our understanding of this protein family. This increased knowledge requires that a common nomenclature be used to describe the relevant enzymes. Therefore, in this viewpoint, we propose an updated and broadly supported nomenclature for mammalian ARTs that will facilitate future discussions when addressing the biochemistry and biology of ADP-ribosylation. This is combined with a brief description of the main functions of mammalian ARTs to illustrate the increasing diversity of mono- and poly-ADP-ribose mediated cellular processes.

Published
2022

10. Genetic evaluation of dementia with Lewy bodies implicates distinct disease subgroups.

Author

Kaivola, Karri, Shah, Zalak, Chia, Ruth, Black, Sandra E, Gan-Or, Ziv, Keith, Julia, Masellis, Mario, Rogaeva, Ekaterina, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Calvo, Andrea, Canosa, Antonio, Chio, Adriano, Logroscino, Giancarlo, Mora, Gabriele, Krüger, Reijko, May, Patrick, Alcolea, Daniel, Clarimon, Jordi, Fortea, Juan, Gonzalez-Aramburu, Isabel, Infante, Jon, Lage, Carmen, Lleó, Alberto, Pastor, Pau, Sanchez-Juan, Pascual, Brett, Francesca, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Gentleman, Steve, Hardy, John A, Hodges, Angela K, Love, Seth, McKeith, Ian G, Morris, Christopher M, Morris, Huw R, Palmer, Laura, Pickering-Brown, Stuart, Ryten, Mina, Thomas, Alan J, Troakes, Claire, Albert, Marilyn S, Barrett, Matthew J, Beach, Thomas G, Bekris, Lynn M, Bennett, David A, Boeve, Bradley F, Dalgard, Clifton L, Dawson, Ted M, Dickson, Dennis W, Faber, Kelley, Ferman, Tanis, Ferrucci, Luigi, Flanagan, Margaret E, Foroud, Tatiana M, Ghetti, Bernardino, Gibbs, J Raphael, Goate, Alison, Goldstein, David S, Graff-Radford, Neill R, Kaufmann, Horacio, Kukull, Walter A, Leverenz, James B, Mao, Qinwen, Masliah, Eliezer, Monuki, Edwin, Newell, Kathy L, Palma, Jose Alberto, Pletnikova, Olga, Renton, Alan E, Resnick, Susan M, Rosenthal, Liana S, Ross, Owen A, Scherzer, Clemens R, Serrano, Geidy E, Shakkottai, Vikram G, Sidransky, Ellen, Tanaka, Toshiko, Topol, Eric, Torkamani, Ali, Troncoso, Juan C, Woltjer, Randy, Wszolek, Zbigniew K, and Scholz, Sonja W

Subjects
Genetics, Lewy Body Dementia, Neurodegenerative, Aging, Brain Disorders, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Alzheimer's Disease, Acquired Cognitive Impairment, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Alzheimer Disease, Apolipoprotein E4, Genome-Wide Association Study, Humans, Lewy Body Disease, alpha-Synuclein, International LBD Genomics Consortium, APOE, Alzheimer’s disease, co-pathology, dementia with Lewy bodies, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

The APOE locus is strongly associated with risk for developing Alzheimer's disease and dementia with Lewy bodies. In particular, the role of the APOE ε4 allele as a putative driver of α-synuclein pathology is a topic of intense debate. Here, we performed a comprehensive evaluation in 2466 dementia with Lewy bodies cases versus 2928 neurologically healthy, aged controls. Using an APOE-stratified genome-wide association study approach, we found that GBA is associated with risk for dementia with Lewy bodies in patients without APOE ε4 (P = 6.58 × 10-9, OR = 3.41, 95% CI = 2.25-5.17), but not with dementia with Lewy bodies with APOE ε4 (P = 0.034, OR = 1.87, 95%, 95% CI = 1.05-3.37). We then divided 495 neuropathologically examined dementia with Lewy bodies cases into three groups based on the extent of concomitant Alzheimer's disease co-pathology: pure dementia with Lewy bodies (n = 88), dementia with Lewy bodies with intermediate Alzheimer's disease co-pathology (n = 66) and dementia with Lewy bodies with high Alzheimer's disease co-pathology (n = 341). In each group, we tested the association of the APOE ε4 against the 2928 neurologically healthy controls. Our examination found that APOE ε4 was associated with dementia with Lewy bodies + Alzheimer's disease (P = 1.29 × 10-32, OR = 4.25, 95% CI = 3.35-5.39) and dementia with Lewy bodies + intermediate Alzheimer's disease (P = 0.0011, OR = 2.31, 95% CI = 1.40-3.83), but not with pure dementia with Lewy bodies (P = 0.31, OR = 0.75, 95% CI = 0.43-1.30). In conclusion, although deep clinical data were not available for these samples, our findings do not support the notion that APOE ε4 is an independent driver of α-synuclein pathology in pure dementia with Lewy bodies, but rather implicate GBA as the main risk gene for the pure dementia with Lewy bodies subgroup.

Published
2022

14. Safety, tolerability, and efficacy of NLY01 in early untreated Parkinson's disease: a randomised, double-blind, placebo-controlled trial

Author

McGarry, Andrew, Rosanbalm, Shane, Leinonen, Mika, Olanow, C Warren, To, Dennis, Bell, Adam, Lee, Daniel, Chang, Jamie, Dubow, Jordan, Dhall, Rohit, Burdick, Daniel, Parashos, Sotirios, Feuerstein, Jeanne, Quinn, Joseph, Pahwa, Rajesh, Afshari, Mitra, Ramirez-Zamora, Aldolfo, Chou, Kelvin, Tarakad, Arjun, Luca, Corneliu, Klos, Kevin, Bordelon, Yvette, St Hiliare, Marie-Helene, Shprecher, David, Lee, Seulki, Dawson, Ted M, Roschke, Viktor, and Kieburtz, Karl

Published
2024
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15. Semantic fluency and processing speed are reduced in non-cognitively impaired participants with Parkinson’s disease

Author

Cholerton, Brenna A, Poston, Kathleen L, Yang, Laurice, Rosenthal, Liana S, Dawson, Ted M, Pantelyat, Alexander, Edwards, Karen L, Tian, Lu, Quinn, Joseph F, Chung, Kathryn A, Hiller, Amie L, Hu, Shu-Ching, Montine, Thomas J, and Zabetian, Cyrus P

Subjects
Biological Psychology, Psychology, Acquired Cognitive Impairment, Neurosciences, Behavioral and Social Science, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Neurodegenerative, Clinical Trials and Supportive Activities, Parkinson's Disease, Brain Disorders, Aging, Neurological, Cognition, Cognitive Dysfunction, Humans, Neuropsychological Tests, Parkinson Disease, Semantics, cognition, healthy volunteers, neuropsychological assessment, Parkinson's disease, Parkinson’s disease, Cognitive Sciences, Experimental Psychology, Biological psychology, Clinical and health psychology, Cognitive and computational psychology
Abstract

Introduction: Parkinson's disease (PD) is associated with a range of cognitive deficits. Few studies have carefully examined the subtle impacts of PD on cognition among patients who do not meet formal criteria for MCI or dementia. The aim of the current study was thus to describe the impact of PD on cognition in those without cognitive impairment in a well-characterized cohort.Methods: Non-cognitively impaired participants (122 with PD, 122 age- and sex-matched healthy volunteers) underwent extensive cognitive testing. Linear regression analyses compared diagnostic group performance across cognitive measures. For cognitive tasks that were significantly different between groups, additional analyses examined group differences restricting the group inclusion to PD participants with mild motor symptoms or disease duration less than 10 years.Results: Processing speed and semantic verbal fluency were significantly lower in the PD group (B = -3.77, 95% CIs [-5.76 to -1.77], p

Published
2021

16. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

Author

Chia, Ruth, Sabir, Marya S, Bandres-Ciga, Sara, Saez-Atienzar, Sara, Reynolds, Regina H, Gustavsson, Emil, Walton, Ronald L, Ahmed, Sarah, Viollet, Coralie, Ding, Jinhui, Makarious, Mary B, Diez-Fairen, Monica, Portley, Makayla K, Shah, Zalak, Abramzon, Yevgeniya, Hernandez, Dena G, Blauwendraat, Cornelis, Stone, David J, Eicher, John, Parkkinen, Laura, Ansorge, Olaf, Clark, Lorraine, Honig, Lawrence S, Marder, Karen, Lemstra, Afina, St George-Hyslop, Peter, Londos, Elisabet, Morgan, Kevin, Lashley, Tammaryn, Warner, Thomas T, Jaunmuktane, Zane, Galasko, Douglas, Santana, Isabel, Tienari, Pentti J, Myllykangas, Liisa, Oinas, Minna, Cairns, Nigel J, Morris, John C, Halliday, Glenda M, Van Deerlin, Vivianna M, Trojanowski, John Q, Grassano, Maurizio, Calvo, Andrea, Mora, Gabriele, Canosa, Antonio, Floris, Gianluca, Bohannan, Ryan C, Brett, Francesca, Gan-Or, Ziv, Geiger, Joshua T, Moore, Anni, May, Patrick, Krüger, Rejko, Goldstein, David S, Lopez, Grisel, Tayebi, Nahid, Sidransky, Ellen, Norcliffe-Kaufmann, Lucy, Palma, Jose-Alberto, Kaufmann, Horacio, Shakkottai, Vikram G, Perkins, Matthew, Newell, Kathy L, Gasser, Thomas, Schulte, Claudia, Landi, Francesco, Salvi, Erika, Cusi, Daniele, Masliah, Eliezer, Kim, Ronald C, Caraway, Chad A, Monuki, Edwin S, Brunetti, Maura, Dawson, Ted M, Rosenthal, Liana S, Albert, Marilyn S, Pletnikova, Olga, Troncoso, Juan C, Flanagan, Margaret E, Mao, Qinwen, Bigio, Eileen H, Rodríguez-Rodríguez, Eloy, Infante, Jon, Lage, Carmen, González-Aramburu, Isabel, Sanchez-Juan, Pascual, Ghetti, Bernardino, Keith, Julia, Black, Sandra E, Masellis, Mario, Rogaeva, Ekaterina, Duyckaerts, Charles, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Barrett, Matthew J, Tilley, Bension S, Gentleman, Steve, Logroscino, Giancarlo, and Serrano, Geidy E

Subjects
Biological Sciences, Genetics, Human Genome, Alzheimer's Disease Related Dementias (ADRD), Prevention, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, Aging, Dementia, Brain Disorders, Acquired Cognitive Impairment, Lewy Body Dementia, Biotechnology, Parkinson's Disease, Neurosciences, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adaptor Proteins, Signal Transducing, Alzheimer Disease, Case-Control Studies, Gene Expression Profiling, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Glucosylceramidase, Humans, Lewy Body Disease, Nuclear Proteins, Parkinson Disease, Polymorphism, Single Nucleotide, Tumor Suppressor Proteins, alpha-Synuclein, American Genome Center, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Published
2021

18. Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias

Author

Soltis, Anthony R., Viollet, Coralie, Sukumar, Gauthaman, Alba, Camille, Lott, Nathaniel, McGrath Martinez, Elisa, Tuck, Meila, Singh, Jatinder, Bacikova, Dagmar, Zhang, Xijun, Hupalo, Daniel N., Adeleye, Adelani, Wilkerson, Matthew D., Pollard, Harvey B., Dalgard, Clifton L., Black, Sandra E., Gan-Or, Ziv, Keith, Julia, Masellis, Mario, Rogaeva, Ekaterina, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Calvo, Andrea, Canosa, Antonio, Chio, Adriano, Logroscino, Giancarlo, Mora, Gabriele, Krüger, Reijko, May, Patrick, Alcolea, Daniel, Clarimon, Jordi, Fortea, Juan, Gonzalez-Aramburu, Isabel, Infante, Jon, Lage, Carmen, Lleó, Alberto, Pastor, Pau, Sanchez-Juan, Pascual, Brett, Francesca, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Gentleman, Steve, Hardy, John A., Hodges, Angela K., Love, Seth, McKeith, Ian G., Morris, Christopher M., Morris, Huw R., Palmer, Laura, Pickering-Brown, Stuart, Ryten, Mina, Thomas, Alan J., Troakes, Claire, Albert, Marilyn S., Barrett, Matthew J., Beach, Thomas G., Bekris, Lynn M., Bennett, David A., Boeve, Bradley F., Dawson, Ted M., Dickson, Dennis W., Faber, Kelley, Ferman, Tanis, Ferrucci, Luigi, Flanagan, Margaret E., Foroud, Tatiana M., Ghetti, Bernardino, Gibbs, J. Raphael, Goate, Alison, Goldstein, David S., Graff-Radford, Neill R., Kaufmann, Horacio, Kukull, Walter A., Leverenz, James B., Lopez, Grisel, Mao, Qinwen, Masliah, Eliezer, Monuki, Edwin, Newell, Kathy L., Palma, Jose-Alberto, Perkins, Matthew, Pletnikova, Olga, Renton, Alan E., Resnick, Susan M., Rosenthal, Liana S., Ross, Owen A., Scherzer, Clemens R., Serrano, Geidy E., Shakkottai, Vikram G., Sidransky, Ellen, Tanaka, Toshiko, Tayebi, Nahid, Topol, Eric, Torkamani, Ali, Troncoso, Juan C., Woltjer, Randy, Wszolek, Zbigniew K., Scholz, Sonja W., Baloh, Robert H., Bowser, Robert, Broach, James, Camu, William, Chiò, Adriano, Cooper-Knock, John, Drepper, Carsten, Drory, Vivian E., Dunckley, Travis L., Feldman, Eva, Fratta, Pietro, Gerhard, Glenn, Gibson, Summer B., Glass, Jonathan D., Harms, Matthew B., Heiman-Patterson, Terry D., Jansson, Lilja, Kirby, Janine, Kwan, Justin, Laaksovirta, Hannu, Landers, John E., Landi, Francesco, Le Ber, Isabelle, Lumbroso, Serge, MacGowan, Daniel J.L., Maragakis, Nicholas J., Mouzat, Kevin, Myllykangas, Liisa, Orrell, Richard W., Ostrow, Lyle W., Pamphlett, Roger, Pioro, Erik, Pulst, Stefan M., Ravits, John M., Robberecht, Wim, Rothstein, Jeffrey D., Sendtner, Michael, Shaw, Pamela J., Sidle, Katie C., Simmons, Zachary, Stein, Thor, Stone, David J., Tienari, Pentti J., Traynor, Bryan J., Valori, Miko, Van Damme, Philip, Van Deerlin, Vivianna M., Van Den Bosch, Ludo, Zinman, Lorne, Kaivola, Karri, Chia, Ruth, Ding, Jinhui, Rasheed, Memoona, Fujita, Masashi, Menon, Vilas, Walton, Ronald L., Collins, Ryan L., Billingsley, Kimberley, Brand, Harrison, Talkowski, Michael, Zhao, Xuefang, Dewan, Ramita, Stark, Ali, Ray, Anindita, Solaiman, Sultana, Alvarez Jerez, Pilar, Malik, Laksh, Tienari, Pentti, Mazzini, Letizia, D'Alfonso, Sandra, Moglia, Cristina, and De Jager, Philip L.

Published
2023
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19. Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly

Author

Serey-Gaut, Margaux, Cortes, Marisol, Makrythanasis, Periklis, Suri, Mohnish, Taylor, Alexander M.R., Sullivan, Jennifer A., Asleh, Ayat N., Mitra, Jaba, Dar, Mohamad A., McNamara, Amy, Shashi, Vandana, Dugan, Sarah, Song, Xiaofei, Rosenfeld, Jill A., Cabrol, Christelle, Iwaszkiewicz, Justyna, Zoete, Vincent, Pehlivan, Davut, Akdemir, Zeynep Coban, Roeder, Elizabeth R., Littlejohn, Rebecca Okashah, Dibra, Harpreet K., Byrd, Philip J., Stewart, Grant S., Geckinli, Bilgen B., Posey, Jennifer, Westman, Rachel, Jungbluth, Chelsy, Eason, Jacqueline, Sachdev, Rani, Evans, Carey-Anne, Lemire, Gabrielle, VanNoy, Grace E., O’Donnell-Luria, Anne, Mau-Them, Frédéric Tran, Juven, Aurélien, Piard, Juliette, Nixon, Cheng Yee, Zhu, Ying, Ha, Taekjip, Buckley, Michael F., Thauvin, Christel, Essien Umanah, George K., Van Maldergem, Lionel, Lupski, James R., Roscioli, Tony, Dawson, Valina L., Dawson, Ted M., and Antonarakis, Stylianos E.

Published
2023
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21. Gut-Initiated Alpha Synuclein Fibrils Drive Parkinson's Disease Phenotypes: Temporal Mapping of non-Motor Symptoms and REM Sleep Behavior Disorder

Author

Dautan, Daniel, primary, Paslawski, Wojciech, additional, Montejo, Sergio, additional, Doyon, Daniel, additional, Marangiu, Roberta, additional, Kaplitt, Michael G, additional, Chen, Rong, additional, Dawson, Valina L., additional, Zhang, Xiaoqun, additional, Dawson, Ted M., additional, and Svenningsson, Per, additional

Published
2024
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22. CYFIP1 Dosages Exhibit Divergent Behavioral Impact via Diametric Regulation of NMDA Receptor Complex Translation in Mouse Models of Psychiatric Disorders

Author

Kim, Nam-Shik, Ringeling, Francisca Rojas, Zhou, Ying, Nguyen, Ha Nam, Temme, Stephanie J., Lin, Yu-Ting, Eacker, Stephen, Dawson, Valina L., Dawson, Ted M., Xiao, Bo, Hsu, Kuei-sen, Canzar, Stefan, Li, Weidong, Worley, Paul, Christian, Kimberly M., Yoon, Ki-Jun, Song, Hongjun, and Ming, Guo-li

Published
2022
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26. Sex differences in progression to mild cognitive impairment and dementia in Parkinson's disease

Author

Cholerton, Brenna, Johnson, Catherine O, Fish, Brian, Quinn, Joseph F, Chung, Kathryn A, Peterson-Hiller, Amie L, Rosenthal, Liana S, Dawson, Ted M, Albert, Marilyn S, Hu, Shu-Ching, Mata, Ignacio F, Leverenz, James B, Poston, Kathleen L, Montine, Thomas J, Zabetian, Cyrus P, and Edwards, Karen L

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Aging, Parkinson's Disease, Neurodegenerative, Dementia, Behavioral and Social Science, Acquired Cognitive Impairment, Clinical Research, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Neurosciences, Neurological, Adult, Aged, Aged, 80 and over, Cognitive Dysfunction, Disease Progression, Female, Humans, Longitudinal Studies, Male, Middle Aged, Parkinson Disease, Sex Characteristics, Sex Factors, Parkinson's disease, Cognition, Mild cognitive impairment, Sex differences, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences, Biological psychology
Abstract

INTRODUCTION:Identification of factors associated with progression of cognitive symptoms in Parkinson's disease (PD) is important for treatment planning, clinical care, and design of future clinical trials. The current study sought to identify whether prediction of cognitive progression is aided by examining baseline cognitive features, and whether this differs according to stage of cognitive disease. METHODS:Participants with PD in the Pacific Udall Center Clinical Consortium who had longitudinal data available and were nondemented at baseline were included in the study (n = 418). Logistic and Cox regression models were utilized to examine the relationship between cognitive, demographic, and clinical variables with risk and time to progression from no cognitive impairment to mild cognitive impairment (PD-MCI) or dementia (PDD), and from PD-MCI to PDD. RESULTS:Processing speed (OR = 1.05, p = 0.009) and working memory (OR = 1.01, p = 0.03) were associated with conversion to PDD among those with PD-MCI at baseline, over and above demographic variables. Conversely, the primary predictive factor in the transition from no cognitive impairment to PD-MCI or PDD was male sex (OR = 4.47, p = 0.004), and males progressed more rapidly than females (p = 0.01). Further, among females with shorter disease duration, progression was slower than for their male counterparts, and poor baseline performance on semantic verbal fluency was associated with shorter time to cognitive impairment in females but not in males. CONCLUSIONS:This study provides evidence for sex differences in the progression to cognitive impairment in PD, while specific cognitive features become more important indicators of progression with impending conversion to PDD.

Published
2018

27. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

Author

Galluzzi, Lorenzo, Vitale, Ilio, Aaronson, Stuart A, Abrams, John M, Adam, Dieter, Agostinis, Patrizia, Alnemri, Emad S, Altucci, Lucia, Amelio, Ivano, Andrews, David W, Annicchiarico-Petruzzelli, Margherita, Antonov, Alexey V, Arama, Eli, Baehrecke, Eric H, Barlev, Nickolai A, Bazan, Nicolas G, Bernassola, Francesca, Bertrand, Mathieu JM, Bianchi, Katiuscia, Blagosklonny, Mikhail V, Blomgren, Klas, Borner, Christoph, Boya, Patricia, Brenner, Catherine, Campanella, Michelangelo, Candi, Eleonora, Carmona-Gutierrez, Didac, Cecconi, Francesco, Chan, Francis K-M, Chandel, Navdeep S, Cheng, Emily H, Chipuk, Jerry E, Cidlowski, John A, Ciechanover, Aaron, Cohen, Gerald M, Conrad, Marcus, Cubillos-Ruiz, Juan R, Czabotar, Peter E, D’Angiolella, Vincenzo, Dawson, Ted M, Dawson, Valina L, De Laurenzi, Vincenzo, De Maria, Ruggero, Debatin, Klaus-Michael, DeBerardinis, Ralph J, Deshmukh, Mohanish, Di Daniele, Nicola, Di Virgilio, Francesco, Dixit, Vishva M, Dixon, Scott J, Duckett, Colin S, Dynlacht, Brian D, El-Deiry, Wafik S, Elrod, John W, Fimia, Gian Maria, Fulda, Simone, García-Sáez, Ana J, Garg, Abhishek D, Garrido, Carmen, Gavathiotis, Evripidis, Golstein, Pierre, Gottlieb, Eyal, Green, Douglas R, Greene, Lloyd A, Gronemeyer, Hinrich, Gross, Atan, Hajnoczky, Gyorgy, Hardwick, J Marie, Harris, Isaac S, Hengartner, Michael O, Hetz, Claudio, Ichijo, Hidenori, Jäättelä, Marja, Joseph, Bertrand, Jost, Philipp J, Juin, Philippe P, Kaiser, William J, Karin, Michael, Kaufmann, Thomas, Kepp, Oliver, Kimchi, Adi, Kitsis, Richard N, Klionsky, Daniel J, Knight, Richard A, Kumar, Sharad, Lee, Sam W, Lemasters, John J, Levine, Beth, Linkermann, Andreas, Lipton, Stuart A, Lockshin, Richard A, López-Otín, Carlos, Lowe, Scott W, Luedde, Tom, Lugli, Enrico, MacFarlane, Marion, Madeo, Frank, Malewicz, Michal, Malorni, Walter, and Manic, Gwenola

Subjects
Biochemistry and Cell Biology, Biological Sciences, Animals, Cell Death, Humans, Lysosomes, Mitochondrial Membrane Transport Proteins, Mitochondrial Permeability Transition Pore, Necrosis, Medical and Health Sciences, Biochemistry & Molecular Biology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

Published
2018

28. Opportunities for the repurposing of PARP inhibitors for the therapy of non‐oncological diseases

Author

Berger, Nathan A, Besson, Valerie C, Boulares, A Hamid, Bürkle, Alexander, Chiarugi, Alberto, Clark, Robert S, Curtin, Nicola J, Cuzzocrea, Salvatore, Dawson, Ted M, Dawson, Valina L, Haskó, György, Liaudet, Lucas, Moroni, Flavio, Pacher, Pál, Radermacher, Peter, Salzman, Andrew L, Snyder, Solomon H, Soriano, Francisco Garcia, Strosznajder, Robert P, Sümegi, Balázs, Swanson, Raymond A, and Szabo, Csaba

Subjects
Orphan Drug, Brain Disorders, Neurosciences, Rare Diseases, Lung, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Good Health and Well Being, Acute Disease, Animals, Chronic Disease, Drug Repositioning, Humans, Poly(ADP-ribose) Polymerase Inhibitors, Pharmacology and Pharmaceutical Sciences, Pharmacology & Pharmacy
Abstract

The recent clinical availability of the PARP inhibitor olaparib (Lynparza) opens the door for potential therapeutic repurposing for non-oncological indications. Considering (a) the preclinical efficacy data with PARP inhibitors in non-oncological diseases and (b) the risk-benefit ratio of treating patients with a compound that inhibits an enzyme that has physiological roles in the regulation of DNA repair, we have selected indications, where (a) the severity of the disease is high, (b) the available therapeutic options are limited, and (c) the duration of PARP inhibitor administration could be short, to provide first-line options for therapeutic repurposing. These indications are as follows: acute ischaemic stroke; traumatic brain injury; septic shock; acute pancreatitis; and severe asthma and severe acute lung injury. In addition, chronic, devastating diseases, where alternative therapeutic options cannot halt disease development (e.g. Parkinson's disease, progressive multiple sclerosis or severe fibrotic diseases), should also be considered. We present a preclinical and clinical action plan for the repurposing of PARP inhibitors.Linked articlesThis article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.

Published
2018

29. Intracellular Signaling

Author

Thompson, John W., primary, Xu, Jinchong, additional, Dawson, Valina L., additional, Perez-Pinzon, Miguel A., additional, and Dawson, Ted M., additional

Published
2022
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30. Contributors

Author

Adams, Harold P., primary, Adeoye, Opeolu, additional, Albers, Gregory W., additional, Alexandrov, Andrei V., additional, Amin-Hanjani, Sepideh, additional, An, Hongyu, additional, Anderson, Craig S., additional, Anrather, Josef, additional, Aparicio, Hugo J., additional, Arai, Ken, additional, Aronowski, Jaroslaw, additional, Atchaneeyasakul, Kunakorn, additional, Audebert, Heinrich, additional, Auer, Roland N., additional, Awad, Issam A., additional, Ay, Hakan, additional, Baltan, Selva, additional, Balu, Ramani, additional, Behbahani, Mandana, additional, Benavente, Oscar R., additional, Bershad, Eric M., additional, Berthaud, Jimmy V., additional, Blackburn, Spiros L., additional, Bonati, Leo H., additional, Bösel, Julian, additional, Bousser, Marie Germaine, additional, Broderick, Joseph P., additional, Brown, Martin M., additional, Brown, Wendy, additional, Brust, John C.M., additional, Bushnell, Cheryl, additional, Canhão, Patrícia, additional, Caplan, Louis R., additional, Carrión-Penagos, Julián, additional, Castellanos, Mar, additional, Caunca, Michelle R., additional, Chabriat, Hugues, additional, Chamorro, Angel, additional, Chen, Jieli, additional, Chen, Jun, additional, Chopp, Michael, additional, Christorforids, Greg, additional, Connolly, E. Sander, additional, Cramer, Steven C., additional, Cucchiara, Brett L., additional, Czap, Alexandra L., additional, Dannenbaum, Mark J., additional, Davis, Patricia H., additional, Dawson, Ted M., additional, Dawson, Valina L., additional, Day, Arthur L., additional, De Silva, T. Michael, additional, de Sousa, Diana Aguiar, additional, Del Brutto, Victor J., additional, del Zoppo, Gregory J., additional, Derdeyn, Colin P., additional, Di Tullio, Marco R., additional, Diener, Hans Christoph, additional, Diringer, Michael N., additional, Dobkin, Bruce H., additional, Dzialowski, Imanuel, additional, Elkind, Mitchell S.V., additional, Elm, Jordan, additional, Feigin, Valery L., additional, Ferro, José Manuel, additional, Field, Thalia S., additional, Fischer, Marlene, additional, Fornage, Myriam, additional, Furie, Karen L., additional, Garcia-Bonilla, Lidia, additional, Giannotta, Steven L., additional, Gobin, Y. Pierre, additional, Goldberg, Mark P., additional, Goldstein, Larry B., additional, Gonzales, Nicole R., additional, Greer, David M., additional, Grotta, James C., additional, Guo, Ruiming, additional, Gutierrez, Jose, additional, Harmel, Peter, additional, Howard, George, additional, Howard, Virginia J., additional, Hwang, Jee-Yeon, additional, Iadecola, Costantino, additional, Jahan, Reza, additional, Jickling, Glen C., additional, Joutel, Anne, additional, Kasner, Scott E., additional, Katan, Mira, additional, Kellner, Christopher P., additional, Khan, Muhib, additional, Kidwell, Chelsea S., additional, Kim, Helen, additional, Kim, Jong S., additional, Kircher, Charles E., additional, Krings, Timo, additional, Krishnamurthi, Rita V., additional, Kurth, Tobias, additional, Lansberg, Maarten G., additional, Levy, Elad I., additional, Liebeskind, David S., additional, Liew, Sook-Lei, additional, Lin, David J., additional, Lisle, Benjamin, additional, Lo, Eng H., additional, Lyden, Patrick D., additional, Maki, Takakuni, additional, Maragkos, Georgios A., additional, Marosfoi, Miklos, additional, McCullough, Louise D., additional, Meckler, Jason M., additional, Meschia, James Frederick, additional, Messé, Steven R., additional, Mocco, J, additional, Mokin, Maxim, additional, Mooney, Michael A., additional, Morgenstern, Lewis B., additional, Moskowitz, Michael A., additional, Mullen, Michael T., additional, Nägel, Steffen, additional, Nedergaard, Maiken, additional, Neira, Justin A., additional, Newman, Sarah, additional, Nicholson, Patrick J., additional, Norrving, Bo, additional, O’Donnell, Martin, additional, Ofengeim, Dimitry, additional, Ogata, Jun, additional, Ogilvy, Christopher S., additional, Orrù, Emanuele, additional, Ortega-Gutiérrez, Santiago, additional, Padrick, Matthew Maximillian, additional, Parsha, Kaushik, additional, Parsons, Mark, additional, Patel, Neil V., additional, Patel, Virendra I., additional, Pawlikowska, Ludmila, additional, Pérez, Adriana, additional, Perez-Pinzon, Miguel A., additional, Picard, John M., additional, Polster, Sean P., additional, Powers, William J., additional, Puetz, Volker, additional, Putaala, Jukka, additional, Rabinovich, Margarita, additional, Ransom, Bruce R., additional, Roa, Jorge A., additional, Rosenberg, Gary A., additional, Rossitto, Christina P., additional, Rundek, Tatjana, additional, Russin, Jonathan J., additional, Sacco, Ralph L., additional, Safouris, Apostolos, additional, Samaniego, Edgar A., additional, Sansing, Lauren H., additional, Satani, Nikunj, additional, Sattenberg, Ronald J., additional, Saver, Jeffrey L., additional, Savitz, Sean I., additional, Schmidt, Christian, additional, Seshadri, Sudha, additional, Sharma, Vijay K., additional, Sharp, Frank R., additional, Sheth, Kevin N., additional, Siddiqi, Omar K., additional, Singhal, Aneesh B., additional, Sobey, Christopher G., additional, Sommer, Clemens J., additional, Spetzler, Robert F., additional, Stapleton, Christopher J., additional, Strickland, Ben A., additional, Su, Hua, additional, Suarez, José I., additional, Takayama, Hiroo, additional, Tarsia, Joseph, additional, Tatlisumak, Turgut, additional, Thomas, Ajith J., additional, Thompson, John W., additional, Tsivgoulis, Georgios, additional, Tournier-Lasserve, Elizabeth, additional, Vidal, Gabriel, additional, Wakhloo, Ajay K., additional, Weksler, Babette B., additional, Willey, Joshua Z., additional, Wintermark, Max, additional, Wong, Lawrence K.S., additional, Xi, Guohua, additional, Xu, Jinchong, additional, Yaghi, Shadi, additional, Yamaguchi, Takenori, additional, Yang, Tuo, additional, Yasaka, Masahiro, additional, Zahuranec, Darin B., additional, Zhang, Feng, additional, Zhang, John H., additional, Zheng, Zhitong, additional, Zukin, R. Suzanne, additional, and Zweifler, Richard M., additional

Published
2022
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32. Brainstem Pathologies Correlate With Depression and Psychosis in Parkinson's Disease

Author

Fischer, Nicole Mercado, Hinkle, Jared T., Perepezko, Kate, Bakker, Catherine C., Morris, Meaghan, Broen, Martinus P.G., Butala, Ankur, Dawson, Ted M., Leentjens, Albert F.G., Mari, Zoltan, Marvel, Cherie L., Mills, Kelly A., Rosenthal, Liana S., Shepard, Melissa D., Pantelyat, Alexander, Bakker, Arnold, Pletnikova, Olga, Troncoso, Juan C., Wang, Jiangxia, and Pontone, Gregory M.

Published
2021
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33. Seeking progress in disease modification in Parkinson disease

Author

Lungu, Codrin, Cedarbaum, Jesse M., Dawson, Ted M., Dorsey, E. Ray, Faraco, Carlos, Federoff, Howard J., Fiske, Brian, Fox, Robert, Goldfine, Andrew M., Kieburtz, Karl, Macklin, Eric A., Matthews, Helen, Rafaloff, Gary, Saunders-Pullman, Rachel, Schor, Nina F., Schwarzschild, Michael A., Sieber, Beth-Anne, Simuni, Tanya, Surmeier, Dalton J., Tamiz, Amir, Werner, Milton H., Wright, Clinton B., and Wyse, Richard

Published
2021
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36. Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease

Author

Davis, Marie Y, Johnson, Catherine O, Leverenz, James B, Weintraub, Daniel, Trojanowski, John Q, Chen-Plotkin, Alice, Van Deerlin, Vivianna M, Quinn, Joseph F, Chung, Kathryn A, Peterson-Hiller, Amie L, Rosenthal, Liana S, Dawson, Ted M, Albert, Marilyn S, Goldman, Jennifer G, Stebbins, Glenn T, Bernard, Bryan, Wszolek, Zbigniew K, Ross, Owen A, Dickson, Dennis W, Eidelberg, David, Mattis, Paul J, Niethammer, Martin, Yearout, Dora, Hu, Shu-Ching, Cholerton, Brenna A, Smith, Megan, Mata, Ignacio F, Montine, Thomas J, Edwards, Karen L, and Zabetian, Cyrus P

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Dementia, Neurodegenerative, Acquired Cognitive Impairment, Clinical Research, Genetics, Aging, Brain Disorders, Parkinson's Disease, Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Cognitive Dysfunction, Disease Progression, Female, Glucosylceramidase, Humans, Longitudinal Studies, Male, Middle Aged, Mutation, Parkinson Disease, Polymorphism, Genetic
Abstract

ImportanceParkinson disease (PD) is heterogeneous in symptom manifestation and rate of progression. Identifying factors that influence disease progression could provide mechanistic insight, improve prognostic accuracy, and elucidate novel therapeutic targets.ObjectiveTo determine whether GBA mutations and the E326K polymorphism modify PD symptom progression.Design, setting, and participantsThe entire GBA coding region was screened for mutations and E326K in 740 patients with PD enrolled at 7 sites from the PD Cognitive Genetics Consortium. Detailed longitudinal motor and cognitive assessments were performed with patients in the on state.Main outcomes and measuresLinear regression was used to test for an association between GBA genotype and motor progression, with the Movement Disorder Society-sponsored version of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) score at the last assessment as the outcome and GBA genotype as the independent variable, with adjustment for levodopa equivalent dose, sex, age, disease duration, MDS-UPDRS III score at the first assessment, duration of follow-up, and site. Similar methods were used to examine the association between genotype and tremor and postural instability and gait difficulty (PIGD) scores. To examine the effect of GBA genotype on cognitive progression, patients were classified into those with conversion to mild cognitive impairment or dementia during the study (progression) and those without progression. The association between GBA genotype and progression status was then tested using logistic regression, adjusting for sex, age, disease duration, duration of follow-up, years of education, and site.ResultsOf the total sample of 733 patients who underwent successful genotyping, 226 (30.8%) were women and 507 (69.2%) were men (mean [SD] age, 68.1 [8.8] years). The mean (SD) duration of follow-up was 3.0 (1.7) years. GBA mutations (β = 4.65; 95% CI, 1.72-7.58; P = .002), E326K (β = 3.42; 95% CI, 0.66-6.17; P = .02), and GBA variants combined as a single group (β = 4.01; 95% CI, 1.95-6.07; P = 1.5 × 10-4) were associated with a more rapid decline in MDS-UPDRS III score. Combined GBA variants (β = 0.38; 95% CI, 0.23-0.53; P = .01) and E326K (β = 0.64; 95% CI, 0.43-0.86; P = .002) were associated with faster progression in PIGD scores, but not in tremor scores. A significantly higher proportion of E326K carriers (10 of 21 [47.6%]; P = .01) and GBA variant carriers (15 of 39 [38.5%]; P = .04) progressed to mild cognitive impairment or dementia.Conclusions and relevanceGBA variants predict a more rapid progression of cognitive dysfunction and motor symptoms in patients with PD, with a greater effect on PIGD than tremor. Thus, GBA variants influence the heterogeneity in symptom progression observed in PD.

Published
2016

37. Twelve Years of Drug Prioritization to Help Accelerate Disease Modification Trials in Parkinson's Disease: The International Linked Clinical Trials Initiative.

Author

Wyse, Richard K., Isaacs, Tom, Barker, Roger A., Cookson, Mark R., Dawson, Ted M., Devos, David, Dexter, David T., Duffen, Joy, Federoff, Howard, Fiske, Brian, Foltynie, Thomas, Fox, Susan, Greenamyre, J. Timothy, Kieburtz, Karl, Kordower, Jeffrey H., Krainc, Dimitri, Matthews, Helen, Moore, Darren J., Mursaleen, Leah, and Schwarzschild, Michael A.

Subjects
PARKINSON'S disease, CLINICAL trials, MEDICAL charities, MOVEMENT disorders, MEDICAL research
Abstract

In 2011, the UK medical research charity Cure Parkinson's set up the international Linked Clinical Trials (iLCT) committee to help expedite the clinical testing of potentially disease modifying therapies for Parkinson's disease (PD). The first committee meeting was held at the Van Andel Institute in Grand Rapids, Michigan in 2012. This group of PD experts has subsequently met annually to assess and prioritize agents that may slow the progression of this neurodegenerative condition, using a systematic approach based on preclinical, epidemiological and, where possible, clinical data. Over the last 12 years, 171 unique agents have been evaluated by the iLCT committee, and there have been 21 completed clinical studies and 20 ongoing trials associated with the initiative. In this review, we briefly outline the iLCT process as well as the clinical development and outcomes of some of the top prioritized agents. We also discuss a few of the lessons that have been learnt, and we conclude with a perspective on what the next decade may bring, including the introduction of multi-arm, multi-stage clinical trial platforms and the possibility of combination therapies for PD. [ABSTRACT FROM AUTHOR]

Published
2024
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38. Blocking the Self-Destruct Program of Dopamine Neurons through Macrophage Migration Inhibitory Factor Nuclease Inhibition.

Author

Patel, Jaimin, Dawson, Valina L., and Dawson, Ted M.

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative condition that pathognomonically involves the death of dopaminergic neurons in the substantia nigra pars compacta, resulting in a myriad of motor and nonmotor symptoms. Given the insurmountable burden of this disease on the population and healthcare system, significant efforts have been put forth toward generating disease modifying therapies. This class of treatments characteristically alters disease course, as opposed to current strategies that focus on managing symptoms. Previous literature has implicated the cell death pathway known as parthanatos in PD progression. Inhibition of this pathway by targeting poly (ADP)-ribose polymerase 1 (PARP1) prevents neurodegeneration in a model of idiopathic PD. However, PARP1 has a vast repertoire of functions within the body, increasing the probability of side effects with the long-term treatment likely necessary for clinically significant neuroprotection. Recent work culminated in the development of a novel agent targeting the macrophage migration inhibitory factor (MIF) nuclease domain, also named parthanatos-associated apoptosis-inducing factor nuclease (PAAN). This nuclease activity specifically executes the terminal step in parthanatos. Parthanatos-associated apoptosis-inducing factor nuclease inhibitor-1 was neuroprotective in multiple preclinical mouse models of PD. This piece will focus on contextualizing this discovery, emphasizing its significance, and discussing its potential implications for parthanatos-directed treatment. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Published
2024
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39. GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease

Author

Mata, Ignacio F, Leverenz, James B, Weintraub, Daniel, Trojanowski, John Q, Chen-Plotkin, Alice, Van Deerlin, Vivianna M, Ritz, Beate, Rausch, Rebecca, Factor, Stewart A, Wood-Siverio, Cathy, Quinn, Joseph F, Chung, Kathryn A, Peterson-Hiller, Amie L, Goldman, Jennifer G, Stebbins, Glenn T, Bernard, Bryan, Espay, Alberto J, Revilla, Fredy J, Devoto, Johnna, Rosenthal, Liana S, Dawson, Ted M, Albert, Marilyn S, Tsuang, Debby, Huston, Haley, Yearout, Dora, Hu, Shu-Ching, Cholerton, Brenna A, Montine, Thomas J, Edwards, Karen L, and Zabetian, Cyrus P

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Parkinson's Disease, Genetics, Basic Behavioral and Social Science, Aging, Neurodegenerative, Clinical Research, Acquired Cognitive Impairment, Brain Disorders, Behavioral and Social Science, Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Cognition Disorders, Female, Genetic Association Studies, Genotype, Glucosylceramidase, Humans, Male, Middle Aged, Neuropsychological Tests, Parkinson Disease, Polymorphism, Single Nucleotide, Severity of Illness Index, United States, cognition, GBA, neuropsychological tests, visuospatial, working memory, Human Movement and Sports Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundLoss-of-function mutations in the GBA gene are associated with more severe cognitive impairment in PD, but the nature of these deficits is not well understood and whether common GBA polymorphisms influence cognitive performance in PD is not yet known.MethodsWe screened the GBA coding region for mutations and the E326K polymorphism in 1,369 PD patients enrolled at eight sites from the PD Cognitive Genetics Consortium. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised), working memory/executive function (Letter-Number Sequencing Test and Trail Making Test A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation), and global cognitive function (MoCA). We used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates and accounted for multiple testing using Bonferroni's corrections.ResultsMutation carriers (n = 60; 4.4%) and E326K carriers (n = 65; 4.7%) had a higher prevalence of dementia (mutations, odds ratio = 5.1; P = 9.7 × 10(-6) ; E326K, odds ratio = 6.4; P = 5.7 × 10(-7) ) and lower performance on Letter-Number Sequencing (mutations, corrected P[Pc ] = 9.0 × 10(-4) ; E326K, Pc  = 0.036), Trail Making B-A (mutations, Pc  = 0.018; E326K, Pc  = 0.018), and Benton Judgment of Line Orientation (mutations, Pc  = 0.0045; E326K, Pc  = 0.0013).ConclusionsBoth GBA mutations and E326K are associated with a distinct cognitive profile characterized by greater impairment in working memory/executive function and visuospatial abilities in PD patients. The discovery that E326K negatively impacts cognitive performance approximately doubles the proportion of PD patients we now recognize are at risk for more severe GBA-related cognitive deficits.

Published
2016

40. α-Synuclein pathology disrupts mitochondrial function in dopaminergic and cholinergic neurons at-risk in Parkinson’s disease

Author

Geibl, Fanni F., primary, Henrich, Martin T., additional, Xie, Zhong, additional, Zampese, Enrico, additional, Tkatch, Tatiana, additional, Wokosin, David L., additional, Nasiri, Elena, additional, Grotmann, Constantin A., additional, Dawson, Valina L., additional, Dawson, Ted M., additional, Chandel, Navdeep S., additional, Oertel, Wolfgang H., additional, and Surmeier, D. James, additional

Published
2023
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42. Enhanced mTORC1 signaling and protein synthesis in pathologic α-synuclein cellular and animal models of Parkinson’s disease

Author

Khan, Mohammed Repon, primary, Yin, Xiling, additional, Kang, Sung-Ung, additional, Mitra, Jaba, additional, Wang, Hu, additional, Ryu, Taekyung, additional, Brahmachari, Saurav, additional, Karuppagounder, Senthilkumar S., additional, Kimura, Yasuyoshi, additional, Jhaldiyal, Aanishaa, additional, Kim, Hyun Hee, additional, Gu, Hao, additional, Chen, Rong, additional, Redding-Ochoa, Javier, additional, Troncoso, Juan, additional, Na, Chan Hyun, additional, Ha, Taekjip, additional, Dawson, Valina L., additional, and Dawson, Ted M., additional

Published
2023
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45. Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson’s disease

Author

Kam, Tae-In, Mao, Xiaobo, Park, Hyejin, Chou, Shih-Ching, Karuppagounder, Senthilkumar S., Umanah, George Essien, Yun, Seung Pil, Brahmachari, Saurav, Panicker, Nikhil, Chen, Rong, Andrabi, Shaida A., Qi, Chen, Poirier, Guy G., Pletnikova, Olga, Troncoso, Juan C., Bekris, Lynn M., Leverenz, James B., Pantelyat, Alexander, Ko, Han Seok, Rosenthal, Liana S., Dawson, Ted M., and Dawson, Valina L.

Published
2018

46. AIF3 splicing switch triggers neurodegeneration

Author

Liu, Shuiqiao, Zhou, Mi, Ruan, Zhi, Wang, Yanan, Chang, Calvin, Sasaki, Masayuki, Rajaram, Veena, Lemoff, Andrew, Nambiar, Kalyani, Wang, Jennifer E., Hatanpaa, Kimmo J., Luo, Weibo, Dawson, Ted M., Dawson, Valina L., and Wang, Yingfei

Published
2021
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49. Cognitive profile of LRRK2-related Parkinson's disease.

Author

Srivatsal, Sindhu, Cholerton, Brenna, Leverenz, James B, Wszolek, Zbigniew K, Uitti, Ryan J, Dickson, Dennis W, Weintraub, Daniel, Trojanowski, John Q, Van Deerlin, Vivianna M, Quinn, Joseph F, Chung, Kathryn A, Peterson, Amie L, Factor, Stewart A, Wood-Siverio, Cathy, Goldman, Jennifer G, Stebbins, Glenn T, Bernard, Bryan, Ritz, Beate, Rausch, Rebecca, Espay, Alberto J, Revilla, Fredy J, Devoto, Johnna, Rosenthal, Liana S, Dawson, Ted M, Albert, Marilyn S, Mata, Ignacio F, Hu, Shu-Ching, Montine, Kathleen S, Johnson, Catherine, Montine, Thomas J, Edwards, Karen L, Zhang, Jing, and Zabetian, Cyrus P

Subjects
Humans, Parkinson Disease, Cohort Studies, Cross-Sectional Studies, Cognition Disorders, Mental Status Schedule, Neuropsychological Tests, Mutation, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Protein Serine-Threonine Kinases, LRRK2, Parkinson's disease, cognition, neuropsychological tests, working memory, Genetic Testing, Genetics, Acquired Cognitive Impairment, Neurosciences, Dementia, Parkinson's Disease, Brain Disorders, Aging, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Good Health and Well Being, Clinical Sciences, Human Movement and Sports Sciences, Neurology & Neurosurgery
Abstract

BackgroundIncreasing evidence suggests that genetic factors play a role in the variability associated with cognitive performance in Parkinson's disease (PD). Mutations in the LRRK2 gene are the most common cause of monogenic PD; however, the cognitive profile of LRRK2-related PD is not well-characterized.MethodsA cohort of 1,447 PD patients enrolled in the PD Cognitive Genetics Consortium was screened for LRRK2 mutations and completed detailed cognitive testing. Associations between mutation carrier status and cognitive test scores were assessed using linear regression models.ResultsLRRK2 mutation carriers (n = 29) demonstrated better performance on the Mini Mental State Examination (P = 0.03) and the Letter-Number Sequencing Test (P = 0.005). A smaller proportion of LRRK2 carriers were demented (P = 0.03).ConclusionsOur cross-sectional study demonstrates better performance on certain cognitive tests, as well as lower rates of dementia in LRRK2-related PD. Future longitudinal studies are needed to determine whether LRRK2 mutation carriers exhibit slower cognitive decline. © 2015 International Parkinson and Movement Disorder Society.

Published
2015

50. PARK10 is a major locus for sporadic neuropathologically confirmed Parkinson disease

Author

Beecham, Gary W, Dickson, Dennis W, Scott, William K, Martin, Eden R, Schellenberg, Gerard, Nuytemans, Karen, Larson, Eric B, Buxbaum, Joseph D, Trojanowski, John Q, Van Deerlin, Vivianna M, Hurtig, Howard I, Mash, Deborah C, Beach, Thomas G, Troncoso, Juan C, Pletnikova, Olga, Frosch, Matthew P, Ghetti, Bernardino, Foroud, Tatiana M, Honig, Lawrence S, Marder, Karen, Vonsattel, Jean Paul, Goldman, Samuel M, Vinters, Harry V, Ross, Owen A, Wszolek, Zbigniew K, Wang, Liyong, Dykxhoorn, Derek M, Pericak-Vance, Margaret A, Montine, Thomas J, Leverenz, James B, Dawson, Ted M, and Vance, Jeffery M

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Genetics, Brain Disorders, Aging, Neurodegenerative, Prevention, Human Genome, Parkinson's Disease, Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Aged, 80 and over, Chromosomes, Human, Pair 1, Female, Genetic Loci, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Parkinson Disease, Polymorphism, Single Nucleotide, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo minimize pathologic heterogeneity in genetic studies of Parkinson disease (PD), the Autopsy-Confirmed Parkinson Disease Genetics Consortium conducted a genome-wide association study using both patients with neuropathologically confirmed PD and controls.MethodsFour hundred eighty-four cases and 1,145 controls met neuropathologic diagnostic criteria, were genotyped, and then imputed to 3,922,209 variants for genome-wide association study analysis.ResultsA small region on chromosome 1 was strongly associated with PD (rs10788972; p = 6.2 × 10(-8)). The association peak lies within and very close to the maximum linkage peaks of 2 prior positive linkage studies defining the PARK10 locus. We demonstrate that rs10788972 is in strong linkage disequilibrium with rs914722, the single nucleotide polymorphism defining the PARK10 haplotype previously shown to be significantly associated with age at onset in PD. The region containing the PARK10 locus was significantly reduced from 10.6 megabases to 100 kilobases and contains 4 known genes: TCEANC2, TMEM59, miR-4781, and LDLRAD1.ConclusionsWe confirm the association of a PARK10 haplotype with the risk of developing idiopathic PD. Furthermore, we significantly reduce the size of the PARK10 region. None of the candidate genes in the new PARK10 region have been previously implicated in the biology of PD, suggesting new areas of potential research. This study strongly suggests that reducing pathologic heterogeneity may enhance the application of genetic association studies to PD.

Published
2015

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