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1. Investigation of the genetic aetiology of Lewy body diseases with and without dementia

Author

Wu, Lesley Yue, Real, Raquel, Martinez-Carrasco, Alejandro, Chia, Ruth, Lawton, Michael A, Shoai, Maryam, Bresner, Catherine, Blauwendraat, Cornelis, Singleton, Andrew B, Ryten, Mina, Abramzon, Yevgeniya, Ahmed, Sarah, Alba, Camille, Albert, Marilyn S, Bacikova, Dagmar, Barrett, Matthew J, Beach, Thomas G, Bennett, David A, Besser, Lilah M, Bigio, Eileen H, Boeve, Bradley F, Bohannan, Ryan C, Caraway, Chad A, Palma, Jose-Alberto, Dalgard, Clifton L, Dickson, Dennis, Ding, Jinhui, Faber, Kelley, Ferman, Tanis, Ferrucci, Luigi, Flanagan, Margaret E, Foroud, Tatiana M, Ghetti, Bernardino, Gibbs, J Raphael, Goate, Alison, Goldstein, David, Graff-Radford, Neill R, Hu, Heng-Chen, Hupalo, Daniel, Kaiser, Scott M, Kaufmann, Horacio, Kim, Ronald C, Klein, Gregory, Kukull, Walter, Kuzma, Amanda, Leverenz, James, Lopez, Grisel, Mao, Qinwen, Martinez-McGrath, Elisa, Masliah, Eliezer, Monuki, Ed, Newell, Kathy L, Norcliffe-Kaufmann, Lucy, Perkins, Matthew, Pletnikova, Olga, Renton, Alan E, Resnick, Susan M, Ross, Owen A, Sabir, Marya S, Scherzer, Clemens R, Scholz, Sonja W, Serrano, Geidy, Shakkotai, Vikram, Sidransky, Ellen, Tanaka, Toshiko, Tayebi, Nahid, Traynor, Bryan J, Troncoso, Juan C, Viollet, Coralie, Walton, Ronald L, Woltjer, Randy, Wszolek, Zbigniew K, Black, Sandra E, Gan-Or, Ziv, Keith, Julia, Masellis, Mario, Rogaeva, Ekaterina, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Ferrari, Raffaele, Gentleman, Steve, Hardy, John A, Hodges, Angela K, Love, Seth, McKeith, Ian, Morris, Christopher M, Morris, Huw R, Palmer, Laura, Pickering-Brown, Stuart, Reynolds, Regina H, Thomas, Alan J, Tilley, Bension S, Troakes, Claire, Brett, Francesca, Brice, Alexis, and Duyckaerts, Charles

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Neurodegenerative, Genetics, Prevention, Aging, Lewy Body Dementia, Brain Disorders, Dementia, Alzheimer's Disease Related Dementias (ADRD), Parkinson's Disease, Human Genome, Acquired Cognitive Impairment, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 2.1 Biological and endogenous factors, Neurological, International Lewy Body Dementia Genomics Consortium, APOE, Lewy body diseases, dementia, genome-wide association studies, Clinical sciences, Biological psychology
Abstract

Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be the key to understanding disease pathways and, ultimately, therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7804 patients of European ancestry from Tracking Parkinson's, The Oxford Discovery Cohort, and Accelerating Medicine Partnership-Parkinson's Disease Initiative. We conducted a discrete phenotype genome-wide association study comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk allele rs429358 tagging APOEe4 increases the odds of developing dementia, and that rs7668531 near the MMRN1 and SNCA-AS1 genes and an intronic variant rs17442721 tagging LRRK2 G2019S on chromosome 12 are protective against dementia. These results should be validated in autopsy-confirmed cases in future studies.

Published
2024

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

Author

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

Subjects
Biological Sciences, Genetics, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Acquired Cognitive Impairment, Frontotemporal Dementia (FTD), Rare Diseases, Neurosciences, Dementia, Human Genome, Brain Disorders, Biotechnology, Aging, Alzheimer's Disease Related Dementias (ADRD), Alzheimer's Disease, 2.1 Biological and endogenous factors, Neurological, Progressive Supranuclear Palsy, Whole-Genome Sequencing, Genome-Wide Association Study, Structural Variants, Apolipoprotein E, P. S. P. genetics study group, Humans, Supranuclear Palsy, Progressive, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Aged, Aged, 80 and over, Middle Aged, Female, Male, Whole Genome Sequencing, Clinical Sciences, Neurology & Neurosurgery, Biochemistry and cell biology
Abstract

BackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs).MethodIn this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed.ResultsOur analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10-3) in PSP.ConclusionsThrough WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Published
2024

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

Author

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

Published
2024
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5. 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

6. Aβ efflux impairment and inflammation linked to cerebrovascular accumulation of amyloid-forming amylin secreted from pancreas

Author

Verma, Nirmal, Velmurugan, Gopal Viswanathan, Winford, Edric, Coburn, Han, Kotiya, Deepak, Leibold, Noah, Radulescu, Laura, Despa, Sanda, Chen, Kuey C, Van Eldik, Linda J, Nelson, Peter T, Wilcock, Donna M, Jicha, Gregory A, Stowe, Ann M, Goldstein, Larry B, Powel, David K, Walton, Jeffrey H, Navedo, Manuel F, Nystoriak, Matthew A, Murray, Andrew J, Biessels, Geert Jan, Troakes, Claire, Zetterberg, Henrik, Hardy, John, Lashley, Tammaryn, and Despa, Florin

Subjects
Biochemistry and Cell Biology, Biological Sciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Acquired Cognitive Impairment, Alzheimer's Disease, Neurosciences, Brain Disorders, Dementia, Aging, Aetiology, 2.1 Biological and endogenous factors, Neurological, Humans, Rats, Animals, Islet Amyloid Polypeptide, Alzheimer Disease, Amyloid beta-Peptides, Amyloidogenic Proteins, Pancreas, Inflammation, Biological sciences, Biomedical and clinical sciences
Abstract

Impairment of vascular pathways of cerebral β-amyloid (Aβ) elimination contributes to Alzheimer disease (AD). Vascular damage is commonly associated with diabetes. Here we show in human tissues and AD-model rats that bloodborne islet amyloid polypeptide (amylin) secreted from the pancreas perturbs cerebral Aβ clearance. Blood amylin concentrations are higher in AD than in cognitively unaffected persons. Amyloid-forming amylin accumulates in circulating monocytes and co-deposits with Aβ within the brain microvasculature, possibly involving inflammation. In rats, pancreatic expression of amyloid-forming human amylin indeed induces cerebrovascular inflammation and amylin-Aβ co-deposits. LRP1-mediated Aβ transport across the blood-brain barrier and Aβ clearance through interstitial fluid drainage along vascular walls are impaired, as indicated by Aβ deposition in perivascular spaces. At the molecular level, cerebrovascular amylin deposits alter immune and hypoxia-related brain gene expression. These converging data from humans and laboratory animals suggest that altering bloodborne amylin could potentially reduce cerebrovascular amylin deposits and Aβ pathology.

Published
2023

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

Author

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

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

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

Published
2022

8. 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

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

Author

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

Published
2024
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12. Tau deposition patterns are associated with functional connectivity in primary tauopathies

Author

Franzmeier, Nicolai, Brendel, Matthias, Beyer, Leonie, Slemann, Luna, Kovacs, Gabor G, Arzberger, Thomas, Kurz, Carolin, Respondek, Gesine, Lukic, Milica J, Biel, Davina, Rubinski, Anna, Frontzkowski, Lukas, Hummel, Selina, Müller, Andre, Finze, Anika, Palleis, Carla, Joseph, Emanuel, Weidinger, Endy, Katzdobler, Sabrina, Song, Mengmeng, Biechele, Gloria, Kern, Maike, Scheifele, Maximilian, Rauchmann, Boris-Stephan, Perneczky, Robert, Rullman, Michael, Patt, Marianne, Schildan, Andreas, Barthel, Henryk, Sabri, Osama, Rumpf, Jost J, Schroeter, Matthias L, Classen, Joseph, Villemagne, Victor, Seibyl, John, Stephens, Andrew W, Lee, Edward B, Coughlin, David G, Giese, Armin, Grossman, Murray, McMillan, Corey T, Gelpi, Ellen, Molina-Porcel, Laura, Compta, Yaroslau, van Swieten, John C, Laat, Laura Donker, Troakes, Claire, Al-Sarraj, Safa, Robinson, John L, Xie, Sharon X, Irwin, David J, Roeber, Sigrun, Herms, Jochen, Simons, Mikael, Bartenstein, Peter, Lee, Virginia M, Trojanowski, John Q, Levin, Johannes, Höglinger, Günter, and Ewers, Michael

Subjects
Biochemistry and Cell Biology, Biological Sciences, Acquired Cognitive Impairment, Rare Diseases, Brain Disorders, Pick's Disease, Alzheimer's Disease, Dementia, Frontotemporal Dementia (FTD), Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Aging, Alzheimer's Disease Related Dementias (ADRD), Biomedical Imaging, Aetiology, 2.1 Biological and endogenous factors, Neurological, Brain, Humans, Magnetic Resonance Imaging, Supranuclear Palsy, Progressive, Tauopathies, tau Proteins
Abstract

Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies, including cortico-basal degeneration and progressive supranuclear palsy. Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4-repeat tauopathies, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assess whether connectivity is associated with 4R-tau deposition patterns by combining resting-state fMRI connectomics with both 2nd generation 18F-PI-2620 tau-PET in 46 patients with clinically diagnosed 4-repeat tauopathies and post-mortem cell-type-specific regional tau assessments from two independent progressive supranuclear palsy patient samples (n = 97 and n = 96). We find that inter-regional connectivity is associated with higher inter-regional correlation of both tau-PET and post-mortem tau levels in 4-repeat tauopathies. In regional cell-type specific post-mortem tau assessments, this association is stronger for neuronal than for astroglial or oligodendroglial tau, suggesting that connectivity is primarily associated with neuronal tau accumulation. Using tau-PET we find further that patient-level tau patterns are associated with the connectivity of subcortical tau epicenters. Together, the current study provides combined in vivo tau-PET and histopathological evidence that brain connectivity is associated with tau deposition patterns in 4-repeat tauopathies.

Published
2022

16. Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Author

Dewan, Ramita, Chia, Ruth, Ding, Jinhui, Hickman, Richard A, Stein, Thor D, Abramzon, Yevgeniya, Ahmed, Sarah, Sabir, Marya S, Portley, Makayla K, Tucci, Arianna, Ibáñez, Kristina, Shankaracharya, FNU, Keagle, Pamela, Rossi, Giacomina, Caroppo, Paola, Tagliavini, Fabrizio, Waldo, Maria L, Johansson, Per M, Nilsson, Christer F, Rowe, James B, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Jabbari, Edwin, Viollet, Coralie, Glass, Jonathan D, Singleton, Andrew B, Silani, Vincenzo, Ross, Owen A, Ryten, Mina, Torkamani, Ali, Tanaka, Toshiko, Ferrucci, Luigi, Resnick, Susan M, Pickering-Brown, Stuart, Brady, Christopher B, Kowal, Neil, Hardy, John A, Van Deerlin, Vivianna, Vonsattel, Jean Paul, Harms, Matt, Morris, Christopher M, Ferrari, Raffaele, Landers, John E, Chiò, Adriano, Gibbs, Jesse Raphael, Dalgard, Clifton L, Scholz, Sonja W, Traynor, Bryan J, Adeleye, Adelani, Alba, Camille, Bacikova, Dagmar, Hupalo, Daniel N, Martinez, Elisa McGrath, Pollard, Harvey B, Sukumar, Gauthaman, Soltis, Anthony R, Tuck, Meila, Zhang, Xijun, Wilkerson, Matthew D, Smith, Bradley N, Ticozzi, Nicola, Fallini, Claudia, Gkazi, Athina Soragia, Topp, Simon D, Kost, Jason, Scotter, Emma L, Kenna, Kevin P, Miller, Jack W, Tiloca, Cinzia, Vance, Caroline, Danielson, Eric W, Troakes, Claire, Colombrita, Claudia, Al-Sarraj, Safa, Lewis, Elizabeth A, King, Andrew, Calini, Daniela, Pensato, Viviana, Castellotti, Barbara, de Belleroche, Jacqueline, Baas, Frank, Asbroek, Anneloor LMA ten, Sapp, Peter C, McKenna-Yasek, Diane, McLaughlin, Russell L, Polak, Meraida, Asress, Seneshaw, Esteban-Pérez, Jesús, Muñoz-Blanco, José Luis, Stevic, Zorica, D’Alfonso, Sandra, Mazzini, Letizia, Comi, Giacomo P, Del Bo, Roberto, Ceroni, Mauro, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, and van Rheenen, Wouter

Subjects
Genetics, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Research, Neurodegenerative, Acquired Cognitive Impairment, Dementia, Frontotemporal Dementia (FTD), Alzheimer's Disease Related Dementias (ADRD), ALS, Rare Diseases, Brain Disorders, Neurosciences, Huntington's Disease, 2.1 Biological and endogenous factors, Aetiology, Neurological, Amyotrophic Lateral Sclerosis, DNA Repeat Expansion, Frontotemporal Dementia, Humans, Huntingtin Protein, Mutation, Whole Genome Sequencing, American Genome Center, FALS Sequencing Consortium, Genomics England Research Consortium, International ALS/FTD Genomics Consortium, International FTD Genetics Consortium, International LBD Genomics Consortium, NYGC ALS Consortium, PROSPECT Consortium, amyotrophic lateral sclerosis, frontotemporal dementia, huntingtin, repeat expansions, whole-genome sequencing, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Published
2021

17. 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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18. Distribution patterns of tau pathology in progressive supranuclear palsy

Author

Kovacs, Gabor G, Lukic, Milica Jecmenica, Irwin, David J, Arzberger, Thomas, Respondek, Gesine, Lee, Edward B, Coughlin, David, Giese, Armin, Grossman, Murray, Kurz, Carolin, McMillan, Corey T, Gelpi, Ellen, Compta, Yaroslau, van Swieten, John C, Laat, Laura Donker, Troakes, Claire, Al-Sarraj, Safa, Robinson, John L, Roeber, Sigrun, Xie, Sharon X, Lee, Virginia M-Y, Trojanowski, John Q, and Höglinger, Günter U

Subjects
Biomedical and Clinical Sciences, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Rare Diseases, Acquired Cognitive Impairment, Aging, Alzheimer's Disease, Frontotemporal Dementia (FTD), Dementia, Neurodegenerative, Brain Disorders, Underpinning research, 1.1 Normal biological development and functioning, Neurological, Aged, Brain, Cohort Studies, Female, Humans, Male, Middle Aged, Supranuclear Palsy, Progressive, tau Proteins, Coiled body, Neurofibrillary tangle, Progressive supranuclear palsy, Propagation, Richardson syndrome, Sequential involvement, Stage, Tau, Tauopathy, Tufted astrocyte, Clinical Sciences, Neurology & Neurosurgery
Abstract

Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We used conditional probability and logistic regression to model the sequential distribution of tau pathologies across different brain regions. Tau pathology uniformly predominates in the neurons of the pallido-nigro-luysian axis in different clinical subtypes. However, clinical subtypes are distinguished not only by total tau load but rather cell-type (neuronal versus glial) specific vulnerability patterns of brain regions suggesting distinct dynamics or circuit-specific segregation of propagation of tau pathologies. For Richardson syndrome (n = 81) we recognize six sequential steps of involvement of brain regions by the combination of cellular tau pathologies. This is translated to six stages for the practical neuropathological diagnosis by the evaluation of the subthalamic nucleus, globus pallidus, striatum, cerebellum with dentate nucleus, and frontal and occipital cortices. This system can be applied to further clinical subtypes by emphasizing whether they show caudal (cerebellum/dentate nucleus) or rostral (cortical) predominant, or both types of pattern. Defining cell-specific stages of tau pathology helps to identify preclinical or early-stage cases for the better understanding of early pathogenic events, has implications for understanding the clinical subtype-specific dynamics of disease-propagation, and informs tau-neuroimaging on distribution patterns.

Published
2020

19. Validation of the movement disorder society criteria for the diagnosis of 4-repeat tauopathies.

Author

Respondek, Gesine, Grimm, Max-Joseph, Piot, Ines, Arzberger, Thomas, Compta, Yaroslau, Englund, Elisabet, Ferguson, Leslie, Gelpi, Ellen, Roeber, Sigrun, Giese, Armin, Grossman, Murray, Irwin, David, Meissner, Wassilios, Nilsson, Christer, Pantelyat, Alexander, Rajput, Alex, van Swieten, John, Troakes, Claire, and Höglinger, Günter

Subjects
Four-repeat tauopathies, corticobasal degeneration, diagnostic criteria, progressive supranuclear palsy, Aged, Brain, Female, Humans, Male, Middle Aged, Multiple System Atrophy, Parkinson Disease, Parkinsonian Disorders, Supranuclear Palsy, Progressive, Tauopathies
Abstract

BACKGROUND: The Movement Disorder Society criteria for progressive supranuclear palsy introduced the category probable 4-repeat (4R)-tauopathy for joint clinical diagnosis of progressive supranuclear palsy and corticobasal degeneration. OBJECTIVES: To validate the accuracy of these clinical criteria for probable 4R-tauopathy to predict underlying 4R-tauopathy pathology. METHODS: Diagnostic accuracy for 4R-tauopathies according to the established criteria was estimated retrospectively in autopsy-confirmed patients with progressive supranuclear palsy and corticobasal degeneration (grouped as 4R-tauopathies), and Parkinsons disease, multiple system atrophy, and frontotemporal lobar degeneration (grouped as non-4R-tauopathies). RESULTS: We identified 250 cases with progressive supranuclear palsy (N = 195) and corticobasal degeneration (N = 55) and with and non-4R-tauopathies (N = 161). Sensitivity and specificity of probable 4R-tauopathy was 10% and 99% in the first year and 59% and 88% at final record. CONCLUSIONS: The new diagnostic category probable 4R-tauopathy showed high specificity and may be suitable for the recruitment of patients with progressive supranuclear palsy and corticobasal degeneration into therapeutic trials targeting 4R-tauopathy. The low sensitivity underpins the need for diagnostic biomarkers. © 2019 International Parkinson and Movement Disorder Society.

Published
2020

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

Author

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

Subjects
Biomedical and Clinical Sciences, Neurosciences, Genetics, Rare Diseases, Acquired Cognitive Impairment, Aging, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), ALS, Neurodegenerative, Alzheimer's Disease Related Dementias (ADRD), Frontotemporal Dementia (FTD), Dementia, Stem Cell Research, 2.1 Biological and endogenous factors, Aetiology, Neurological, Alzheimer Disease, Amyotrophic Lateral Sclerosis, Autophagy, Basal Ganglia Diseases, Brain, C9orf72 Protein, Frontotemporal Dementia, Humans, Neurodegenerative Diseases, Parkinson Disease, Parkinsonian Disorders, Neurodegeneration, Corticobasal degeneration, C9orf72 repeat expansion, Parkinsonism, Clinical Sciences, Neurology & Neurosurgery
Abstract

Microsatellite repeat expansion disease loci can exhibit pleiotropic clinical and biological effects depending on repeat length. Large expansions in C9orf72 (100s-1000s of units) are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). However, whether intermediate expansions also contribute to neurodegenerative disease is not well understood. Several studies have identified intermediate repeats in Parkinson's disease patients, but the association was not found in autopsy-confirmed cases. We hypothesized that intermediate C9orf72 repeats are a genetic risk factor for corticobasal degeneration (CBD), a neurodegenerative disease that can be clinically similar to Parkinson's but has distinct tau protein pathology. Indeed, intermediate C9orf72 repeats were significantly enriched in autopsy-proven CBD (n = 354 cases, odds ratio = 3.59, p = 0.00024). While large C9orf72 repeat expansions are known to decrease C9orf72 expression, intermediate C9orf72 repeats result in increased C9orf72 expression in human brain tissue and CRISPR/cas9 knockin iPSC-derived neural progenitor cells. In contrast to cases of FTD/ALS with large C9orf72 expansions, CBD with intermediate C9orf72 repeats was not associated with pathologic RNA foci or dipeptide repeat protein aggregates. Knock-in cells with intermediate repeats exhibit numerous changes in gene expression pathways relating to vesicle trafficking and autophagy. Additionally, overexpression of C9orf72 without the repeat expansion leads to defects in autophagy under nutrient starvation conditions. These results raise the possibility that therapeutic strategies to reduce C9orf72 expression may be beneficial for the treatment of CBD.

Published
2019

22. How to apply the movement disorder society criteria for diagnosis of progressive supranuclear palsy.

Author

Grimm, Max-Joseph, Respondek, Gesine, Stamelou, Maria, Arzberger, Thomas, Ferguson, Leslie, Gelpi, Ellen, Giese, Armin, Grossman, Murray, Irwin, David J, Pantelyat, Alexander, Rajput, Alex, Roeber, Sigrun, van Swieten, John C, Troakes, Claire, Antonini, Angelo, Bhatia, Kailash P, Colosimo, Carlo, van Eimeren, Thilo, Kassubek, Jan, Levin, Johannes, Meissner, Wassilios G, Nilsson, Christer, Oertel, Wolfgang H, Piot, Ines, Poewe, Werner, Wenning, Gregor K, Boxer, Adam, Golbe, Lawrence I, Josephs, Keith A, Litvan, Irene, Morris, Huw R, Whitwell, Jennifer L, Compta, Yaroslau, Corvol, Jean-Christophe, Lang, Anthony E, Rowe, James B, Höglinger, Günter U, and Movement Disorder Society-endorsed PSP Study Group

Subjects
Movement Disorder Society-endorsed PSP Study Group, Brain, Humans, Parkinsonian Disorders, Supranuclear Palsy, Progressive, Ocular Motility Disorders, Sensation Disorders, Autopsy, Retrospective Studies, Cohort Studies, Adult, Aged, Aged, 80 and over, Middle Aged, Societies, Medical, Female, Male, Postural Balance, Cognitive Dysfunction, autopsy, diversity, phenotype, progressive supranuclear palsy, Brain Disorders, Pediatric, Neurosciences, Rare Diseases, Clinical Research, Perinatal Period - Conditions Originating in Perinatal Period, 4.2 Evaluation of markers and technologies, Neurology & Neurosurgery, Clinical Sciences, Human Movement and Sports Sciences
Abstract

BackgroundThe Movement Disorder Society criteria for progressive supranuclear palsy define diagnostic allocations, stratified by certainty levels and clinical predominance types. We aimed to study the frequency of ambiguous multiple allocations and to develop rules to eliminate them.MethodsWe retrospectively collected standardized clinical data by chart review in a multicenter cohort of autopsy-confirmed patients with progressive supranuclear palsy, to classify them by diagnostic certainty level and predominance type and to identify multiple allocations.ResultsComprehensive data were available from 195 patients. More than one diagnostic allocation occurred in 157 patients (80.5%). On average, 5.4 allocations were possible per patient. We developed four rules for Multiple Allocations eXtinction (MAX). They reduced the number of patients with multiple allocations to 22 (11.3%), and the allocations per patient to 1.1.ConclusionsThe proposed MAX rules help to standardize the application of the Movement Disorder Society criteria for progressive supranuclear palsy. © 2019 International Parkinson and Movement Disorder Society.

Published
2019

23. Genome-wide DNA methylation profiling identifies convergent molecular signatures associated with idiopathic and syndromic autism in post-mortem human brain tissue

Author

Wong, Chloe CY, Smith, Rebecca G, Hannon, Eilis, Ramaswami, Gokul, Parikshak, Neelroop N, Assary, Elham, Troakes, Claire, Poschmann, Jeremie, Schalkwyk, Leonard C, Sun, Wenjie, Prabhakar, Shyam, Geschwind, Daniel H, and Mill, Jonathan

Subjects
Human Genome, Neurosciences, Intellectual and Developmental Disabilities (IDD), Autism, Genetics, Pediatric, Mental Health, Brain Disorders, Aetiology, 1.1 Normal biological development and functioning, Underpinning research, 2.1 Biological and endogenous factors, Mental health, Neurological, Autistic Disorder, Case-Control Studies, Cerebellum, DNA Methylation, Epigenome, Female, Gene Ontology, Gene Regulatory Networks, Genome, Human, Humans, Immune System, Male, Neural Pathways, Prefrontal Cortex, Synaptic Transmission, Temporal Lobe, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Autism spectrum disorder (ASD) encompasses a collection of complex neuropsychiatric disorders characterized by deficits in social functioning, communication and repetitive behaviour. Building on recent studies supporting a role for developmentally moderated regulatory genomic variation in the molecular aetiology of ASD, we quantified genome-wide patterns of DNA methylation in 223 post-mortem tissues samples isolated from three brain regions [prefrontal cortex, temporal cortex and cerebellum (CB)] dissected from 43 ASD patients and 38 non-psychiatric control donors. We identified widespread differences in DNA methylation associated with idiopathic ASD (iASD), with consistent signals in both cortical regions that were distinct to those observed in the CB. Individuals carrying a duplication on chromosome 15q (dup15q), representing a genetically defined subtype of ASD, were characterized by striking differences in DNA methylationacross a discrete domain spanning an imprinted gene cluster within the duplicated region. In addition to the dramatic cis-effects on DNA methylation observed in dup15q carriers, we identified convergent methylomic signatures associated with both iASD and dup15q, reflecting the findings from previous studies of gene expression and H3K27ac. Cortical co-methylation network analysis identified a number of co-methylated modules significantly associated with ASD that are enriched for genomic regions annotated to genes involved in the immune system, synaptic signalling and neuronal regulation. Our study represents the first systematic analysis of DNA methylation associated with ASD across multiple brain regions, providing novel evidence for convergent molecular signatures associated with both idiopathic and syndromic autism.

Published
2019

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

Author

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

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

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

Published
2019

29. Impact of Magnetic Resonance Imaging Markers on the Diagnostic Performance of the International Parkinson and Movement Disorder Society Multiple System Atrophy Criteria.

Author

Jensen, Ida, Heine, Johanne, Ruf, Viktoria C., Compta, Yaroslau, Porcel, Laura Molina, Troakes, Claire, Vamanu, Albert, Downes, Sophia, Irwin, David, Cohen, Jesse, Lee, Edward B., Nilsson, Christer, Englund, Elisabet, Nemati, Mojtaba, Katzdobler, Sabrina, Levin, Johannes, Pantelyat, Alex, Seemiller, Joseph, Berger, Stephen, and van Swieten, John

Abstract

Background: Multiple system atrophy is a neurodegenerative disease with α‐synuclein aggregation in glial cytoplasmic inclusions, leading to dysautonomia, parkinsonism, and cerebellar ataxia. Objective: The aim of this study was to validate the accuracy of the International Parkinson and Movement Disorder Society Multiple System Atrophy clinical diagnostic criteria, particularly considering the impact of the newly introduced brain magnetic resonance imaging (MRI) markers. Methods: Diagnostic accuracy of the clinical diagnostic criteria for multiple system atrophy was estimated retrospectively in autopsy‐confirmed patients with multiple system atrophy, Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. Results: We identified a total of 240 patients. Sensitivity of the clinically probable criteria was moderate at symptom onset but improved with disease duration (year 1: 9%, year 3: 39%, final ante mortem record: 77%), whereas their specificity remained consistently high (99%–100% throughout). Sensitivity of the clinically established criteria was low during the first 3 years (1%–9%), with mild improvement at the final ante mortem record (22%), whereas specificity remained high (99%–100% throughout). When MRI features were excluded from the clinically established criteria, their sensitivity increased considerably (year 1: 3%, year 3: 22%, final ante mortem record: 48%), and their specificity was not compromised (99%–100% throughout). Conclusions: The International Parkinson and Movement Disorder Society multiple system atrophy diagnostic criteria showed consistently high specificity and low to moderate sensitivity throughout the disease course. The MRI markers for the clinically established criteria reduced their sensitivity without improving specificity. Combining clinically probable and clinically established criteria, but disregarding MRI features, yielded the best sensitivity with excellent specificity and may be most appropriate to select patients for therapeutic trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Published
2024
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30. MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study

Author

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

Published
2024
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31. Which ante mortem clinical features predict progressive supranuclear palsy pathology?

Author

Respondek, Gesine, Kurz, Carolin, Arzberger, Thomas, Compta, Yaroslau, Englund, Elisabet, Ferguson, Leslie W, Gelpi, Ellen, Giese, Armin, Irwin, David J, Meissner, Wassilios G, Nilsson, Christer, Pantelyat, Alexander, Rajput, Alex, van Swieten, John C, Troakes, Claire, Josephs, Keith A, Lang, Anthony E, Mollenhauer, Brit, Müller, Ulrich, Whitwell, Jennifer L, Antonini, Angelo, Bhatia, Kailash P, Bordelon, Yvette, Corvol, Jean‐Christophe, Colosimo, Carlo, Dodel, Richard, Grossman, Murray, Kassubek, Jan, Krismer, Florian, Levin, Johannes, Lorenzl, Stefan, Morris, Huw, Nestor, Peter, Oertel, Wolfgang H, Rabinovici, Gil D, Rowe, James B, van Eimeren, Thilo, Wenning, Gregor K, Boxer, Adam, Golbe, Lawrence I, Litvan, Irene, Stamelou, Maria, Höglinger, Günter U, and Group, for the Movement Disorder Society‐Endorsed PSP Study

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Brain Disorders, Dementia, Alzheimer's Disease Related Dementias (ADRD), Pick's Disease, Rare Diseases, Acquired Cognitive Impairment, Neurodegenerative, Neurosciences, Aging, Parkinson's Disease, Frontotemporal Dementia (FTD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aetiology, 2.1 Biological and endogenous factors, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Neurological, Humans, Supranuclear Palsy, Progressive, Progressive supranuclear palsy, clinical features, diagnosis, clinico-pathological series, systematic review, Movement Disorder Society-Endorsed PSP Study Group, Clinical Sciences, Human Movement and Sports Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundProgressive supranuclear palsy (PSP) is a neuropathologically defined disease presenting with a broad spectrum of clinical phenotypes.ObjectiveTo identify clinical features and investigations that predict or exclude PSP pathology during life, aiming at an optimization of the clinical diagnostic criteria for PSP.MethodsWe performed a systematic review of the literature published since 1996 to identify clinical features and investigations that may predict or exclude PSP pathology. We then extracted standardized data from clinical charts of patients with pathologically diagnosed PSP and relevant disease controls and calculated the sensitivity, specificity, and positive predictive value of key clinical features for PSP in this cohort.ResultsOf 4166 articles identified by the database inquiry, 269 met predefined standards. The literature review identified clinical features predictive of PSP, including features of the following 4 functional domains: ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction. No biomarker or genetic feature was found reliably validated to predict definite PSP. High-quality original natural history data were available from 206 patients with pathologically diagnosed PSP and from 231 pathologically diagnosed disease controls (54 corticobasal degeneration, 51 multiple system atrophy with predominant parkinsonism, 53 Parkinson's disease, 73 behavioral variant frontotemporal dementia). We identified clinical features that predicted PSP pathology, including phenotypes other than Richardson's syndrome, with varying sensitivity and specificity.ConclusionsOur results highlight the clinical variability of PSP and the high prevalence of phenotypes other than Richardson's syndrome. The features of variant phenotypes with high specificity and sensitivity should serve to optimize clinical diagnosis of PSP. © 2017 International Parkinson and Movement Disorder Society.

Published
2017

32. Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria.

Author

Höglinger, Günter U, Respondek, Gesine, Stamelou, Maria, Kurz, Carolin, Josephs, Keith A, Lang, Anthony E, Mollenhauer, Brit, Müller, Ulrich, Nilsson, Christer, Whitwell, Jennifer L, Arzberger, Thomas, Englund, Elisabet, Gelpi, Ellen, Giese, Armin, Irwin, David J, Meissner, Wassilios G, Pantelyat, Alexander, Rajput, Alex, van Swieten, John C, Troakes, Claire, Antonini, Angelo, Bhatia, Kailash P, Bordelon, Yvette, Compta, Yaroslau, Corvol, Jean-Christophe, Colosimo, Carlo, Dickson, Dennis W, Dodel, Richard, Ferguson, Leslie, Grossman, Murray, Kassubek, Jan, Krismer, Florian, Levin, Johannes, Lorenzl, Stefan, Morris, Huw R, Nestor, Peter, Oertel, Wolfgang H, Poewe, Werner, Rabinovici, Gil, Rowe, James B, Schellenberg, Gerard D, Seppi, Klaus, van Eimeren, Thilo, Wenning, Gregor K, Boxer, Adam L, Golbe, Lawrence I, Litvan, Irene, and Movement Disorder Society-endorsed PSP Study Group

Subjects
Movement Disorder Society-endorsed PSP Study Group, Humans, Supranuclear Palsy, Progressive, Societies, Medical, Practice Guidelines as Topic, clinical diagnostic criteria, consensus-based, evidence-based, progressive supranuclear palsy, Brain Disorders, Neurosciences, Neurological, Clinical Sciences, Human Movement and Sports Sciences, Neurology & Neurosurgery
Abstract

BackgroundPSP is a neuropathologically defined disease entity. Clinical diagnostic criteria, published in 1996 by the National Institute of Neurological Disorders and Stroke/Society for PSP, have excellent specificity, but their sensitivity is limited for variant PSP syndromes with presentations other than Richardson's syndrome.ObjectiveWe aimed to provide an evidence- and consensus-based revision of the clinical diagnostic criteria for PSP.MethodsWe searched the PubMed, Cochrane, Medline, and PSYCInfo databases for articles published in English since 1996, using postmortem diagnosis or highly specific clinical criteria as the diagnostic standard. Second, we generated retrospective standardized clinical data from patients with autopsy-confirmed PSP and control diseases. On this basis, diagnostic criteria were drafted, optimized in two modified Delphi evaluations, submitted to structured discussions with consensus procedures during a 2-day meeting, and refined in three further Delphi rounds.ResultsDefined clinical, imaging, laboratory, and genetic findings serve as mandatory basic features, mandatory exclusion criteria, or context-dependent exclusion criteria. We identified four functional domains (ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction) as clinical predictors of PSP. Within each of these domains, we propose three clinical features that contribute different levels of diagnostic certainty. Specific combinations of these features define the diagnostic criteria, stratified by three degrees of diagnostic certainty (probable PSP, possible PSP, and suggestive of PSP). Clinical clues and imaging findings represent supportive features.ConclusionsHere, we present new criteria aimed to optimize early, sensitive, and specific clinical diagnosis of PSP on the basis of currently available evidence. © 2017 International Parkinson and Movement Disorder Society.

Published
2017

34. Genetic determinants of survival in progressive supranuclear palsy: a genome-wide association study

Author

Mok, Kin Y., Murphy, David P., Al-Sarraj, Safa, Troakes, Claire, Gentleman, Steve M., Allinson, Kieren S.J., Jaunmuktane, Zane, Holton, Janice L., Lees, Andrew J., Morris, Christopher M., Compta, Yaroslau, Gelpi, Ellen, van Swieten, John C., Rajput, Alex, Ferguson, Leslie, Cookson, Mark R., Gibbs, J. Raphael, Blauwendraat, Cornelis, Ding, Jinhui, Chia, Ruth, Traynor, Bryan J., Pantelyat, Alexander, Viollet, Coralie, Pletnikova, Olga, Troncoso, Juan C., Rosenthal, Liana S., Boxer, Adam L., Respondek, Gesine, Arzberger, Thomas, Roeber, Sigrun, Giese, Armin, Burn, David J., Pavese, Nicola, Gerhard, Alexander, Kobylecki, Christopher, Leigh, P. Nigel, Church, Alistair, T.M. Hu, Michele, Jabbari, Edwin, Koga, Shunsuke, Valentino, Rebecca R, Reynolds, Regina H, Ferrari, Raffaele, Tan, Manuela M X, Rowe, James B, Dalgard, Clifton L, Scholz, Sonja W, Dickson, Dennis W, Warner, Thomas T, Revesz, Tamas, Höglinger, Günter U, Ross, Owen A, Ryten, Mina, Hardy, John, Shoai, Maryam, and Morris, Huw R

Published
2021
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36. 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, Serrano, Geidy E., Beach, Thomas G., McKeith, Ian G., Thomas, Alan J., Attems, Johannes, Morris, Christopher M., Palmer, Laura, Love, Seth, Troakes, Claire, Al-Sarraj, Safa, Hodges, Angela K., Aarsland, Dag, Klein, Gregory, Kaiser, Scott M., Woltjer, Randy, Pastor, Pau, Bekris, Lynn M., Leverenz, James B., Besser, Lilah M., Kuzma, Amanda, Renton, Alan E., Goate, Alison, Bennett, David A., Scherzer, Clemens R., Morris, Huw R., Ferrari, Raffaele, Albani, Diego, Pickering-Brown, Stuart, Faber, Kelley, Kukull, Walter A., Morenas-Rodriguez, Estrella, Lleó, Alberto, Fortea, Juan, Alcolea, Daniel, Clarimon, Jordi, Nalls, Mike A., Ferrucci, Luigi, Resnick, Susan M., Tanaka, Toshiko, Foroud, Tatiana M., Graff-Radford, Neill R., Wszolek, Zbigniew K., Ferman, Tanis, Boeve, Bradley F., Hardy, John A., Topol, Eric J., Torkamani, Ali, Singleton, Andrew B., Ryten, Mina, Dickson, Dennis W., Chiò, Adriano, Ross, Owen A., Gibbs, J. Raphael, Dalgard, Clifton L., Traynor, Bryan J., and Scholz, Sonja W.

Published
2021
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37. Tau‐mediated synaptic dysfunction is coupled with HCN channelopathy.

Author

Goniotaki, Despoina, Tamagnini, Francesco, Biasetti, Luca, Rumpf, Svenja‐Lotta, Troakes, Claire, Pollack, Saskia J., Ukwesa, Shalom, Sun, Haoyue, Kraev, Igor, Serpell, Louise C., Noble, Wendy, Staras, Kevin, and Hanger, Diane P.

Abstract

INTRODUCTION: In tauopathies, altered tau processing correlates with impairments in synaptic density and function. Changes in hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels contribute to disease‐associated abnormalities in multiple neurodegenerative diseases. METHODS: To investigate the link between tau and HCN channels, we performed histological, biochemical, ultrastructural, and functional analyses of hippocampal tissues from Alzheimer's disease (AD), age‐matched controls, Tau35 mice, and/or Tau35 primary hippocampal neurons. RESULTS: Expression of specific HCN channels is elevated in post mortem AD hippocampus. Tau35 mice develop progressive abnormalities including increased phosphorylated tau, enhanced HCN channel expression, decreased dendritic branching, reduced synapse density, and vesicle clustering defects. Tau35 primary neurons show increased HCN channel expression enhanced hyperpolarization‐induced membrane voltage "sag" and changes in the frequency and kinetics of spontaneous excitatory postsynaptic currents. DISCUSSION: Our findings are consistent with a model in which pathological changes in tauopathies impact HCN channels to drive network‐wide structural and functional synaptic deficits. Highlights: Hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels are functionally linked to the development of tauopathy.Expression of specific HCN channels is elevated in the hippocampus in Alzheimer's disease and the Tau35 mouse model of tauopathy.Increased expression of HCN channels in Tau35 mice is accompanied by hyperpolarization‐induced membrane voltage "sag" demonstrating a detrimental effect of tau abnormalities on HCN channel function.Tau35 expression alters synaptic organization, causing a loosened vesicle clustering phenotype in Tau35 mice. [ABSTRACT FROM AUTHOR]

Published
2024
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38. Transmembrane and coiled‐coil 2 associates with Alzheimer's disease pathology in the human brain.

Author

Hopkins, Paul C. R., Troakes, Claire, King, Andrew, and Tear, Guy

Subjects
*AMYLOID beta-protein precursor, *ALZHEIMER'S disease, *TEMPORAL lobe, *AMYLOID plaque, *APOLIPOPROTEIN E
Abstract

Transmembrane and coiled‐coil 2 (TMCC2) is a human orthologue of the Drosophila gene dementin, mutant alleles of which cause neurodegeneration with features of Alzheimer's disease (AD). TMCC2 and Dementin further have an evolutionarily conserved interaction with the amyloid protein precursor (APP), a protein central to AD pathogenesis. To investigate if human TMCC2 might also participate in mechanisms of neurodegeneration, we examined TMCC2 expression in late onset AD human brain and age‐matched controls, familial AD cases bearing a mutation in APP Val717, and Down syndrome AD. Consistent with previous observations of complex formation between TMCC2 and APP in the rat brain, the dual immunocytochemistry of control human temporal cortex showed highly similar distributions of TMCC2 and APP. In late onset AD cases stratified by APOE genotype, TMCC2 immunoreactivity was associated with dense core senile plaques and adjacent neuronal dystrophies, but not with Aβ surrounding the core, diffuse Aβ plaques or tauopathy. In Down syndrome AD, we observed in addition TMCC2‐immunoreactive and methoxy‐X04‐positive pathological features that were morphologically distinct from those seen in the late onset and familial AD cases, suggesting enhanced pathological alteration of TMCC2 in Down syndrome AD. At the protein level, western blots of human brain extracts revealed that human brain‐derived TMCC2 exists as at least three isoforms, the relative abundance of which varied between the temporal gyrus and cerebellum and was influenced by APOE and/or dementia status. Our findings thus implicate human TMCC2 in AD via its interactions with APP, its association with dense core plaques, as well as its alteration in Down syndrome AD. [ABSTRACT FROM AUTHOR]

Published
2024
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44. The Psychiatric Risk Gene NT5C2 Regulates Adenosine Monophosphate-Activated Protein Kinase Signaling and Protein Translation in Human Neural Progenitor Cells

Author

Duarte, Rodrigo R.R., Bachtel, Nathaniel D., Côtel, Marie-Caroline, Lee, Sang H., Selvackadunco, Sashika, Watson, Iain A., Hovsepian, Gary A., Troakes, Claire, Breen, Gerome D., Nixon, Douglas F., Murray, Robin M., Bray, Nicholas J., Eleftherianos, Ioannis, Vernon, Anthony C., Powell, Timothy R., and Srivastava, Deepak P.

Published
2019
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47. Interaction of amisulpride with GLUT1 at the blood-brain barrier. Relevance to Alzheimer’s disease

Author

Boyanova, Sevda T., primary, Lloyd-Morris, Ethlyn, additional, Corpe, Christopher, additional, Rahman, Khondaker Miraz, additional, Farag, Doaa B., additional, Page, Lee K., additional, Wang, Hao, additional, Fleckney, Alice L., additional, Gatt, Ariana, additional, Troakes, Claire, additional, Vizcay-Barrena, Gema, additional, Fleck, Roland, additional, Reeves, Suzanne J., additional, and Thomas, Sarah A., additional

Published
2023
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48. 53. INTEGRATING HUMAN ENDOGENOUS RETROVIRUSES IN TRANSCRIPTOME-WIDE ASSOCIATION STUDIES HIGHLIGHTS NOVEL RISK FACTORS FOR MAJOR PSYCHIATRIC CONDITIONS

Author

Powell, Timothy, primary, Duarte, Rodrigo Rafagnin, additional, Pain, Oliver, additional, Bendall, Matthew, additional, de Mulder Rougvie, Miguel, additional, Marston, Jez, additional, Selvackadunco, Sashika, additional, Troakes, Claire, additional, O'Reilly, Paul, additional, Srivastava, Deepak, additional, and Nixon, Douglas, additional

Published
2023
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49. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study

Author

Pottier, Cyril, Zhou, Xiaolai, Perkerson, Ralph B, III, Baker, Matt, Jenkins, Gregory D, Serie, Daniel J, Ghidoni, Roberta, Benussi, Luisa, Binetti, Giuliano, López de Munain, Adolfo, Zulaica, Miren, Moreno, Fermin, Le Ber, Isabelle, Pasquier, Florence, Hannequin, Didier, Sánchez-Valle, Raquel, Antonell, Anna, Lladó, Albert, Parsons, Tammee M, Finch, NiCole A, Finger, Elizabeth C, Lippa, Carol F, Huey, Edward D, Neumann, Manuela, Heutink, Peter, Synofzik, Matthis, Wilke, Carlo, Rissman, Robert A, Slawek, Jaroslaw, Sitek, Emilia, Johannsen, Peter, Nielsen, Jørgen E, Ren, Yingxue, van Blitterswijk, Marka, DeJesus-Hernandez, Mariely, Christopher, Elizabeth, Murray, Melissa E, Bieniek, Kevin F, Evers, Bret M, Ferrari, Camilla, Rollinson, Sara, Richardson, Anna, Scarpini, Elio, Fumagalli, Giorgio G, Padovani, Alessandro, Hardy, John, Momeni, Parastoo, Ferrari, Raffaele, Frangipane, Francesca, Maletta, Raffaele, Anfossi, Maria, Gallo, Maura, Petrucelli, Leonard, Suh, EunRan, Lopez, Oscar L, Wong, Tsz H, van Rooij, Jeroen G J, Seelaar, Harro, Mead, Simon, Caselli, Richard J, Reiman, Eric M, Noel Sabbagh, Marwan, Kjolby, Mads, Nykjaer, Anders, Karydas, Anna M, Boxer, Adam L, Grinberg, Lea T, Grafman, Jordan, Spina, Salvatore, Oblak, Adrian, Mesulam, M-Marsel, Weintraub, Sandra, Geula, Changiz, Hodges, John R, Piguet, Olivier, Brooks, William S, Irwin, David J, Trojanowski, John Q, Lee, Edward B, Josephs, Keith A, Parisi, Joseph E, Ertekin-Taner, Nilüfer, Knopman, David S, Nacmias, Benedetta, Piaceri, Irene, Bagnoli, Silvia, Sorbi, Sandro, Gearing, Marla, Glass, Jonathan, Beach, Thomas G, Black, Sandra E, Masellis, Mario, Rogaeva, Ekaterina, Vonsattel, Jean-Paul, Honig, Lawrence S, Kofler, Julia, Bruni, Amalia C, Snowden, Julie, Mann, David, Pickering-Brown, Stuart, Diehl-Schmid, Janine, Winkelmann, Juliane, Galimberti, Daniela, Graff, Caroline, Öijerstedt, Linn, Troakes, Claire, Al-Sarraj, Safa, Cruchaga, Carlos, Cairns, Nigel J, Rohrer, Jonathan D, Halliday, Glenda M, Kwok, John B, van Swieten, John C, White, Charles L, III, Ghetti, Bernardino, Murell, Jill R, Mackenzie, Ian R A, Hsiung, Ging-Yuek R, Borroni, Barbara, Rossi, Giacomina, Tagliavini, Fabrizio, Wszolek, Zbigniew K, Petersen, Ronald C, Bigio, Eileen H, Grossman, Murray, Van Deerlin, Vivianna M, Seeley, William W, Miller, Bruce L, Graff-Radford, Neill R, Boeve, Bradley F, Dickson, Dennis W, Biernacka, Joanna M, and Rademakers, Rosa

Published
2018
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50. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author

Logullo, Francesco O., Simone, Isabella, Logroscino, Giancarlo, Salvi, Fabrizio, Bartolomei, Ilaria, Borghero, Giuseppe, Murru, Maria Rita, Costantino, Emanuela, Pani, Carla, Puddu, Roberta, Caredda, Carla, Piras, Valeria, Tranquilli, Stefania, Cuccu, Stefania, Corongiu, Daniela, Melis, Maurizio, Milia, Antonio, Marrosu, Francesco, Marrosu, Maria Giovanna, Floris, Gianluca, Cannas, Antonino, Capasso, Margherita, Caponnetto, Claudia, Mancardi, Gianluigi, Origone, Paola, Mandich, Paola, Conforti, Francesca L., Cavallaro, Sebastiano, Mora, Gabriele, Marinou, Kalliopi, Sideri, Riccardo, Penco, Silvana, Mosca, Lorena, Lunetta, Christian, Pinter, Giuseppe Lauria, Corbo, Massimo, Riva, Nilo, Carrera, Paola, Volanti, Paolo, Mandrioli, Jessica, Fini, Nicola, Fasano, Antonio, Tremolizzo, Lucio, Arosio, Alessandro, Ferrarese, Carlo, Trojsi, Francesca, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Piccirillo, Giovanni, Femiano, Cinzia, Ticca, Anna, Ortu, Enzo, La Bella, Vincenzo, Spataro, Rossella, Colletti, Tiziana, Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Marangi, Giuseppe, Santarelli, Marialuisa, Petrucci, Antonio, Pugliatti, Maura, Pirisi, Angelo, Parish, Leslie D., Occhineri, Patrizia, Giannini, Fabio, Battistini, Stefania, Ricci, Claudia, Benigni, Michele, Cau, Tea B., Loi, Daniela, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Barberis, Marco, Restagno, Gabriella, Casale, Federico, Marrali, Giuseppe, Fuda, Giuseppe, Ossola, Irene, Cammarosano, Stefania, Canosa, Antonio, Ilardi, Antonio, Manera, Umberto, Grassano, Maurizio, Tanel, Raffaella, Pisano, Fabrizio, Harms, Matthew B., Goldstein, David B., Shneider, Neil A., Goutman, Stephen, Simmons, Zachary, Miller, Timothy M., Chandran, Siddharthan, Pal, Suvankar, Manousakis, Georgios, Appel, Stanley H., Simpson, Ericka, Wang, Leo, Baloh, Robert H., Gibson, Summer, Bedlack, Richard, Lacomis, David, Sareen, Dhruv, Sherman, Alexander, Bruijn, Lucie, Penny, Michelle, Allen, Andrew S., Appel, Stanley, Bedlack, Richard S., Boone, Braden E., Brown, Robert, Carulli, John P., Chesi, Alessandra, Chung, Wendy K., Cirulli, Elizabeth T., Cooper, Gregory M., Couthouis, Julien, Day-Williams, Aaron G., Dion, Patrick A., Gitler, Aaron D., Glass, Jonathan D., Han, Yujun, Harris, Tim, Hayes, Sebastian D., Jones, Angela L., Keebler, Jonathan, Krueger, Brian J., Lasseigne, Brittany N., Levy, Shawn E., Lu, Yi-Fan, Maniatis, Tom, McKenna-Yasek, Diane, Myers, Richard M., Petrovski, Slavé, Pulst, Stefan M., Raphael, Alya R., Ravits, John M., Ren, Zhong, Rouleau, Guy A., Sapp, Peter C., Sims, Katherine B., Staropoli, John F., Waite, Lindsay L., Wang, Quanli, Wimbish, Jack R., Xin, Winnie W., Phatnani, Hemali, Kwan, Justin, Broach, James R., Arcila-Londono, Ximena, Lee, Edward B., Van Deerlin, Vivianna M., Fraenkel, Ernest, Ostrow, Lyle W., Baas, Frank, Zaitlen, Noah, Berry, James D., Malaspina, Andrea, Fratta, Pietro, Cox, Gregory A., Thompson, Leslie M., Finkbeiner, Steve, Dardiotis, Efthimios, Hornstein, Eran, MacGowan, Daniel J., Heiman-Patterson, Terry, Hammell, Molly G., Patsopoulos, Nikolaos A., Dubnau, Joshua, Nath, Avindra, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia, LeNail, Alexander, Lima, Leandro, Rothstein, Jeffrey D., Svendsen, Clive N., Van Eyk, Jenny, Maragakis, Nicholas J., Kolb, Stephen J., Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J. Paul, Wu, Gang, Rampersaud, Evadnie, Wuu, Joanne, Rademakers, Rosa, Züchner, Stephan, Schule, Rebecca, McCauley, Jacob, Hussain, Sumaira, Cooley, Anne, Wallace, Marielle, Clayman, Christine, Barohn, Richard, Statland, Jeffrey, Ravits, John, Swenson, Andrea, Jackson, Carlayne, Trivedi, Jaya, Khan, Shaida, Katz, Jonathan, Jenkins, Liberty, Burns, Ted, Gwathmey, Kelly, Caress, James, McMillan, Corey, Elman, Lauren, Pioro, Erik, Heckmann, Jeannine, So, Yuen, Walk, David, Maiser, Samuel, Zhang, Jinghui, Silani, Vincenzo, Ticozzi, Nicola, Gellera, Cinzia, Ratti, Antonia, Taroni, Franco, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P., Sorarù, Gianni, Cereda, Cristina, D’Alfonso, Sandra, Corrado, Lucia, De Marchi, Fabiola, Corti, Stefania, Ceroni, Mauro, Mazzini, Letizia, Siciliano, Gabriele, Filosto, Massimiliano, Inghilleri, Maurizio, Peverelli, Silvia, Colombrita, Claudia, Poletti, Barbara, Maderna, Luca, Del Bo, Roberto, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, Pensato, Viviana, Castellotti, Barbara, Camu, William, Mouzat, Kevin, Lumbroso, Serge, Corcia, Philippe, Meininger, Vincent, Besson, Gérard, Lagrange, Emmeline, Clavelou, Pierre, Guy, Nathalie, Couratier, Philippe, Vourch, Patrick, Danel, Véronique, Bernard, Emilien, Lemasson, Gwendal, Al Kheifat, Ahmad, Al-Chalabi, Ammar, Andersen, Peter, Basak, A. Nazli, Blair, Ian P., Chio, Adriano, Cooper-Knock, Jonathan, de Carvalho, Mamede, Dekker, Annelot, Drory, Vivian, Redondo, Alberto Garcia, Gotkine, Marc, Hardiman, Orla, Hide, Winston, Iacoangeli, Alfredo, Glass, Jonathan, Kenna, Kevin, Kiernan, Matthew, Kooyman, Maarten, Landers, John, McLaughlin, Russell, Middelkoop, Bas, Mill, Jonathan, Neto, Miguel Mitne, Moisse, Mattieu, Pardina, Jesus Mora, Morrison, Karen, Newhouse, Stephen, Pinto, Susana, Pulit, Sara, Robberecht, Wim, Shatunov, Aleksey, Shaw, Pamela, Shaw, Chris, Sproviero, William, Tazelaar, Gijs, van Damme, Philip, van den Berg, Leonard, van der Spek, Rick, van Eijk, Kristel, van Es, Michael, van Rheenen, Wouter, van Vugt, Joke, Veldink, Jan, Weber, Markus, Williams, Kelly L., Zatz, Mayana, Bauer, Denis C., Twine, Natalie A., Nicolas, Aude, Kenna, Kevin P., Renton, Alan E., Faghri, Faraz, Chia, Ruth, Dominov, Janice A., Kenna, Brendan J., Nalls, Mike A., Keagle, Pamela, Rivera, Alberto M., Murphy, Natalie A., van Vugt, Joke J.F.A., Geiger, Joshua T., Van der Spek, Rick A., Pliner, Hannah A., Shankaracharya, Smith, Bradley N., Topp, Simon D., Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D., Kenna, Aoife, Messina, Sonia, Simone, Isabella L., Ferrucci, Luigi, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C., Wyman, Stacia K., LeNail, Alex, Van Eyk, Jennifer E., Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W., Sidle, Katie C., Hardy, John, Singleton, Andrew B., Johnson, Janel O., Arepalli, Sampath, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, ten Asbroek, Anneloor L.M.A., Muñoz-Blanco, José Luis, Hernandez, Dena G., Ding, Jinhui, Gibbs, J. Raphael, Scholz, Sonja W., Floeter, Mary Kay, Campbell, Roy H., Landi, Francesco, Bowser, Robert, MacGowan, Daniel J.L., Kirby, Janine, Pioro, Erik P., Pamphlett, Roger, Broach, James, Gerhard, Glenn, Dunckley, Travis L., Brady, Christopher B., Kowall, Neil W., Troncoso, Juan C., Le Ber, Isabelle, Heiman-Patterson, Terry D., Kamel, Freya, Van Den Bosch, Ludo, Strom, Tim M., Meitinger, Thomas, Van Eijk, Kristel R., Moisse, Matthieu, McLaughlin, Russell L., Van Es, Michael A., Boylan, Kevin B., Van Blitterswijk, Marka, Morrison, Karen E., Mora, Jesús S., Drory, Vivian E., Shaw, Pamela J., Turner, Martin R., Talbot, Kevin, Fifita, Jennifer A., Nicholson, Garth A., Esteban-Pérez, Jesús, García-Redondo, Alberto, Rogaeva, Ekaterina, Zinman, Lorne, Cooper-Knock, Johnathan, Brice, Alexis, Goutman, Stephen A., Feldman, Eva L., Gibson, Summer B., Van Damme, Philip, Ludolph, Albert C., Andersen, Peter M., Weishaupt, Jochen H., Trojanowski, John Q., Brown, Robert H., Jr., van den Berg, Leonard H., Veldink, Jan H., Stone, David J., Tienari, Pentti, Chiò, Adriano, Shaw, Christopher E., Traynor, Bryan J., and Landers, John E.

Published
2018
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