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1. Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia.

Author

Manzoni, Claudia, Kia, Demis, Ferrari, Raffaele, Leonenko, Ganna, Costa, Beatrice, Saba, Valentina, Jabbari, Edwin, Tan, Manuela, Albani, Diego, Alvarez, Victoria, Alvarez, Ignacio, Andreassen, Ole, Angiolillo, Antonella, Arighi, Andrea, Baker, Matt, Benussi, Luisa, Bessi, Valentina, Binetti, Giuliano, Blackburn, Daniel, Boada, Merce, Boeve, Bradley, Borrego-Ecija, Sergi, Borroni, Barbara, Bråthen, Geir, Brooks, William, Bruni, Amalia, Caroppo, Paola, Bandres-Ciga, Sara, Clarimon, Jordi, Colao, Rosanna, Cruchaga, Carlos, Danek, Adrian, de Boer, Sterre, de Rojas, Itziar, di Costanzo, Alfonso, Dickson, Dennis, Diehl-Schmid, Janine, Dobson-Stone, Carol, Dols-Icardo, Oriol, Donizetti, Aldo, Dopper, Elise, Durante, Elisabetta, Ferrari, Camilla, Forloni, Gianluigi, Frangipane, Francesca, Fratiglioni, Laura, Kramberger, Milica, Galimberti, Daniela, Gallucci, Maurizio, García-González, Pablo, Ghidoni, Roberta, Giaccone, Giorgio, Graff, Caroline, Graff-Radford, Neill, Grafman, Jordan, Halliday, Glenda, Hernandez, Dena, Hjermind, Lena, Hodges, John, Holloway, Guy, Huey, Edward, Illán-Gala, Ignacio, Josephs, Keith, Knopman, David, Kristiansen, Mark, Kwok, John, Leber, Isabelle, Leonard, Hampton, Libri, Ilenia, Lleo, Alberto, Mackenzie, Ian, Madhan, Gaganjit, Maletta, Raffaele, Marquié, Marta, Maver, Ales, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce, Morris, Christopher, Morris, Huw, Nacmias, Benedetta, Newton, Judith, Nielsen, Jørgen, Nilsson, Christer, Novelli, Valeria, Padovani, Alessandro, Pal, Suvankar, Pasquier, Florence, Pastor, Pau, Perneczky, Robert, Peterlin, Borut, Petersen, Ronald, Piguet, Olivier, Pijnenburg, Yolande, Puca, Annibale, Rademakers, Rosa, Rainero, Innocenzo, Reus, Lianne, Richardson, Anna, and Riemenschneider, Matthias

Subjects
Humans, Frontotemporal Dementia, tau Proteins, Genome-Wide Association Study, Apolipoproteins E, Male, Female, Genetic Predisposition to Disease, Aged, Polymorphism, Single Nucleotide, Genetic Loci, Middle Aged, Case-Control Studies, Myelin Proteins
Abstract

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10-12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10-12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10-8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.

Published
2024

3. RECOVER-NEURO: study protocol for a multi-center, multi-arm, phase 2, randomized, active comparator trial evaluating three interventions for cognitive dysfunction in post-acute sequelae of SARS-CoV-2 infection (PASC)

Author

Knopman, David S., Laskowitz, Daniel T., Koltai, Deborah C., Charvet, Leigh E., Becker, Jacqueline H., Federman, Alex D., Wisnivesky, Juan, Mahncke, Henry, Van Vleet, Thomas M., Bateman, Lucinda, Kim, Dong-Yun, O’Steen, Ashley, James, Melissa, Silverstein, Adam, Lokhnygina, Yuliya, Rich, Jennifer, Feger, Bryan J., and Zimmerman, Kanecia O.

Published
2024
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4. Influences of amyloid-β and tau on white matter neurite alterations in dementia with Lewy bodies

Author

Mak, Elijah, Reid, Robert I., Przybelski, Scott A., Lesnick, Timothy G., Schwarz, Christopher G., Senjem, Matthew L., Raghavan, Sheelakumari, Vemuri, Prashanthi, Jack, Jr, Clifford R., Min, Hoon Ki, Jain, Manoj K., Miyagawa, Toji, Forsberg, Leah K., Fields, Julie A., Savica, Rodolfo, Graff-Radford, Jonathan, Jones, David T., Botha, Hugo, St. Louis, Erik K., Knopman, David S., Ramanan, Vijay K., Dickson, Dennis W., Graff-Radford, Neill R., Ferman, Tanis J., Petersen, Ronald C., Lowe, Val J., Boeve, Bradley F., O’Brien, John T., and Kantarci, Kejal

Published
2024
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5. HDGFL2 cryptic proteins report presence of TDP-43 pathology in neurodegenerative diseases

Author

Calliari, Anna, Daughrity, Lillian M., Albagli, Ellen A., Castellanos Otero, Paula, Yue, Mei, Jansen-West, Karen, Islam, Naeyma N., Caulfield, Thomas, Rawlinson, Bailey, DeTure, Michael, Cook, Casey, Graff-Radford, Neill R., Day, Gregory S., Boeve, Bradley F., Knopman, David S., Petersen, Ronald C., Josephs, Keith A., Oskarsson, Björn, Gitler, Aaron D., Dickson, Dennis W., Gendron, Tania F., Prudencio, Mercedes, Ward, Michael E., Zhang, Yong-Jie, and Petrucelli, Leonard

Published
2024
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6. Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance

Author

Mei, Hao, Simino, Jeannette, Li, Lianna, Jiang, Fan, Bis, Joshua C., Davies, Gail, Hill, W David, Xia, Charley, Gudnason, Vilmundur, Yang, Qiong, Lahti, Jari, Smith, Jennifer A., Kirin, Mirna, De Jager, Philip, Armstrong, Nicola J., Ghanbari, Mohsen, Kolcic, Ivana, Moran, Christopher, Teumer, Alexander, Sargurupremraj, Murali, Mahmud, Shamsed, Fornage, Myriam, Zhao, Wei, Satizabal, Claudia L., Polasek, Ozren, Räikkönen, Katri, Liewald, David C., Homuth, Georg, Callisaya, Michele, Mather, Karen A., Windham, B. Gwen, Zemunik, Tatijana, Palotie, Aarno, Pattie, Alison, van der Auwera, Sandra, Thalamuthu, Anbupalam, Knopman, David S., Rudan, Igor, Starr, John M., Wittfeld, Katharina, Kochan, Nicole A., Griswold, Michael E., Vitart, Veronique, Brodaty, Henry, Gottesman, Rebecca, Cox, Simon R., Psaty, Bruce M., Boerwinkle, Eric, Chasman, Daniel I., Grodstein, Francine, Sachdev, Perminder S., Srikanth, Velandai, Hayward, Caroline, Wilson, James F., Eriksson, Johan G., Kardia, Sharon L. R., Grabe, Hans J., Bennett, David A., Ikram, M. Arfan, Deary, Ian J., van Duijn, Cornelia M., Launer, Lenore, Fitzpatrick, Annette L., Seshadri, Sudha, Bressler, Jan, Debette, Stephanie, and Mosley, Jr, Thomas H.

Published
2024
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7. Abundant transcriptomic alterations in the human cerebellum of patients with a C9orf72 repeat expansion

Author

Udine, Evan, DeJesus-Hernandez, Mariely, Tian, Shulan, das Neves, Sofia Pereira, Crook, Richard, Finch, NiCole A., Baker, Matthew C., Pottier, Cyril, Graff-Radford, Neill R., Boeve, Bradley F., Petersen, Ronald C., Knopman, David S., Josephs, Keith A., Oskarsson, Björn, Da Mesquita, Sandro, Petrucelli, Leonard, Gendron, Tania F., Dickson, Dennis W., Rademakers, Rosa, and van Blitterswijk, Marka

Published
2024
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8. Physical Activity and Trajectory of Cognitive Change in Older Persons: Mayo Clinic Study of Aging

Author

Krell-Roesch, Janina, primary, Syrjanen, Jeremy A., additional, Bezold, Jelena, additional, Trautwein, Sandra, additional, Barisch-Fritz, Bettina, additional, Boes, Klaus, additional, Woll, Alexander, additional, Forzani, Erica, additional, Kremers, Walter K., additional, Machulda, Mary M., additional, Mielke, Michelle M., additional, Knopman, David S., additional, Petersen, Ronald C., additional, Vassilaki, Maria, additional, and Geda, Yonas E., additional

Published
2024
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9. Network structure and transcriptomic vulnerability shape atrophy in frontotemporal dementia

Author

Shafiei, Golia, Bazinet, Vincent, Dadar, Mahsa, Manera, Ana L, Collins, D Louis, Dagher, Alain, Borroni, Barbara, Sanchez-Valle, Raquel, Moreno, Fermin, Laforce, Robert, Graff, Caroline, Synofzik, Matthis, Galimberti, Daniela, Rowe, James B, Masellis, Mario, Tartaglia, Maria Carmela, Finger, Elizabeth, Vandenberghe, Rik, de Mendonça, Alexandre, Tagliavini, Fabrizio, Santana, Isabel, Butler, Chris, Gerhard, Alex, Danek, Adrian, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Jiskoot, Lize C, Seelaar, Harro, van Swieten, John C, Rohrer, Jonathan D, Misic, Bratislav, Ducharme, Simon, Initiative, Frontotemporal Lobar Degeneration Neuroimaging, Rosen, Howard, Dickerson, Bradford C, Domoto-Reilly, Kimoko, Knopman, David, Boeve, Bradley F, Boxer, Adam L, Kornak, John, Miller, Bruce L, Seeley, William W, Gorno-Tempini, Maria-Luisa, McGinnis, Scott, Mandelli, Maria Luisa, Initiative, GENetic Frontotemporal dementia, Esteve, Aitana Sogorb, Nelson, Annabel, Bouzigues, Arabella, Heller, Carolin, Greaves, Caroline V, Cash, David, Thomas, David L, Todd, Emily, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J, Nicholas, Jennifer, Samra, Kiran, Russell, Lucy L, Bocchetta, Martina, Shafei, Rachelle, Convery, Rhian S, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, van der Ende, Emma, Poos, Jackie, Papma, Janne M, Giannini, Lucia, and van Minkelen, Rick

Subjects
Biomedical and Clinical Sciences, Health Sciences, Psychology, Acquired Cognitive Impairment, Dementia, Aging, Neurodegenerative, Frontotemporal Dementia (FTD), Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Alzheimer's Disease, Aetiology, 2.1 Biological and endogenous factors, Neurological, Humans, Frontotemporal Dementia, Transcriptome, Brain, Pick Disease of the Brain, Atrophy, Connectome, Magnetic Resonance Imaging, Neuropsychological Tests, Frontotemporal Lobar Degeneration Neuroimaging Initiative, GENetic Frontotemporal dementia Initiative, connectome, disease epicentre, frontotemporal dementia, gene expression, network spreading, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences
Abstract

Connections among brain regions allow pathological perturbations to spread from a single source region to multiple regions. Patterns of neurodegeneration in multiple diseases, including behavioural variant of frontotemporal dementia (bvFTD), resemble the large-scale functional systems, but how bvFTD-related atrophy patterns relate to structural network organization remains unknown. Here we investigate whether neurodegeneration patterns in sporadic and genetic bvFTD are conditioned by connectome architecture. Regional atrophy patterns were estimated in both genetic bvFTD (75 patients, 247 controls) and sporadic bvFTD (70 patients, 123 controls). First, we identified distributed atrophy patterns in bvFTD, mainly targeting areas associated with the limbic intrinsic network and insular cytoarchitectonic class. Regional atrophy was significantly correlated with atrophy of structurally- and functionally-connected neighbours, demonstrating that network structure shapes atrophy patterns. The anterior insula was identified as the predominant group epicentre of brain atrophy using data-driven and simulation-based methods, with some secondary regions in frontal ventromedial and antero-medial temporal areas. We found that FTD-related genes, namely C9orf72 and TARDBP, confer local transcriptomic vulnerability to the disease, modulating the propagation of pathology through the connectome. Collectively, our results demonstrate that atrophy patterns in sporadic and genetic bvFTD are jointly shaped by global connectome architecture and local transcriptomic vulnerability, providing an explanation as to how heterogenous pathological entities can lead to the same clinical syndrome.

Published
2023

10. A data‐driven examination of apathy and depressive symptoms in dementia with independent replication

Author

Da Silva, Miguel Vasconcelos, Melendez‐Torres, Gerardo Javier, Ismail, Zahinoor, Testad, Ingelin, Ballard, Clive, Creese, Byron, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jack, Clifford R, Jagust, William, Trojanowki, John Q, Toga, Arthur W, Beckett, Laurel, Green, Robert C, Saykin, Andrew J, Morris, John, Shaw, Leslie M, Liu, Enchi, Montine, Tom, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Jiminez, Gus, Harvey, Danielle, Bernstein, Matthew, Fox, Nick, Thompson, Paul, Schuff, Norbert, DeCArli, Charles, Borowski, Bret, Gunter, Jeff, Senjem, Matt, Vemuri, Prashanthi, Jones, David, Kantarci, Kejal, Ward, Chad, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Landau, Susan, Cairns, Nigel J, Householder, Erin, Reinwald, Lisa Taylor, Lee, Virginia, Korecka, Magdalena, Figurski, Michal, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kelley, Faber, Kim, Sungeun, Nho, Kwangsik, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Carter, Raina, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Beccera, Mauricio, Teodoro, Liberty, Spann, Bryan M, Brewer, James, Van der Swag, Helen, Fleisher, Adam, Heidebrink, Judith L, Lord, Joanne L, Mason, Sara S, Albers, Colleen S, Knopman, David, Johnson, Kris, Doody, Rachelle S, Meyer, Javier Villanueva, Chowdhury, Munir, Rountree, Susan, Dang, Mimi, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Ances, Beau, Morris, John C, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, and Oliver, Angela

Subjects
Clinical and Health Psychology, Biomedical and Clinical Sciences, Psychology, Brain Disorders, Mental Health, Depression, Mental Illness, Mental health, Alzheimer's Disease Neuroimaging Initiative, apathy, dementia, depression, latent class analysis, Genetics, Neurosciences, Biological psychology
Abstract

Apathy is one of the most common neuropsychiatric symptoms (NPS) and is associated with poor clinical outcomes. Research that helps define the apathy phenotype is urgently needed, particularly for clinical and biomarker studies. We used latent class analysis (LCA) with two independent cohorts to understand how apathy and depression symptoms co-occur statistically. We further explored the relationship between latent class membership, demographics, and the presence of other NPS. The LCA identified a four-class solution (no symptoms, apathy, depression, and combined apathy/depression), reproducible over both cohorts, providing robust support for an apathy syndrome distinct from depression and confirming that an apathy/depression syndrome exists, supported by the model fit test with the four-class solution scores evidencing better fitting (Bayesian information criterion adjusted and entropy R 2). Using a data-driven method, we show distinct and statistically meaningful co-occurrence of apathy and depressive symptoms. There was evidence that these classes have different clinical associations, which may help inform diagnostic categories for research studies and clinical practice.HighlightsWe found four classes: no symptoms, apathy, depression and apathy/depression.Apathy conferred a higher probability for agitation.Apathy diagnostic criteria should include accompanying neuropsychiatric symptoms.

Published
2023

11. GPT-D: Inducing Dementia-related Linguistic Anomalies by Deliberate Degradation of Artificial Neural Language Models

Author

Li, Changye, Knopman, David, Xu, Weizhe, Cohen, Trevor, and Pakhomov, Serguei

Subjects
Computer Science - Computation and Language
Abstract

Deep learning (DL) techniques involving fine-tuning large numbers of model parameters have delivered impressive performance on the task of discriminating between language produced by cognitively healthy individuals, and those with Alzheimer's disease (AD). However, questions remain about their ability to generalize beyond the small reference sets that are publicly available for research. As an alternative to fitting model parameters directly, we propose a novel method by which a Transformer DL model (GPT-2) pre-trained on general English text is paired with an artificially degraded version of itself (GPT-D), to compute the ratio between these two models' \textit{perplexities} on language from cognitively healthy and impaired individuals. This technique approaches state-of-the-art performance on text data from a widely used "Cookie Theft" picture description task, and unlike established alternatives also generalizes well to spontaneous conversations. Furthermore, GPT-D generates text with characteristics known to be associated with AD, demonstrating the induction of dementia-related linguistic anomalies. Our study is a step toward better understanding of the relationships between the inner workings of generative neural language models, the language that they produce, and the deleterious effects of dementia on human speech and language characteristics., Comment: This paper has been accepted by ACL 2022

Published
2022

12. Temporal order of clinical and biomarker changes in familial frontotemporal dementia

Author

Staffaroni, Adam M, Quintana, Melanie, Wendelberger, Barbara, Heuer, Hilary W, Russell, Lucy L, Cobigo, Yann, Wolf, Amy, Goh, Sheng-Yang Matt, Petrucelli, Leonard, Gendron, Tania F, Heller, Carolin, Clark, Annie L, Taylor, Jack Carson, Wise, Amy, Ong, Elise, Forsberg, Leah, Brushaber, Danielle, Rojas, Julio C, VandeVrede, Lawren, Ljubenkov, Peter, Kramer, Joel, Casaletto, Kaitlin B, Appleby, Brian, Bordelon, Yvette, Botha, Hugo, Dickerson, Bradford C, Domoto-Reilly, Kimiko, Fields, Julie A, Foroud, Tatiana, Gavrilova, Ralitza, Geschwind, Daniel, Ghoshal, Nupur, Goldman, Jill, Graff-Radford, Jonathon, Graff-Radford, Neill, Grossman, Murray, Hall, Matthew G. H, Hsiung, Ging-Yuek, Huey, Edward D, Irwin, David, Jones, David T, Kantarci, Kejal, Kaufer, Daniel, Knopman, David, Kremers, Walter, Lago, Argentina Lario, Lapid, Maria I, Litvan, Irene, Lucente, Diane, Mackenzie, Ian R, Mendez, Mario F, Mester, Carly, Miller, Bruce L, Onyike, Chiadi U, Rademakers, Rosa, Ramanan, Vijay K, Ramos, Eliana Marisa, Rao, Meghana, Rascovsky, Katya, Rankin, Katherine P, Roberson, Erik D, Savica, Rodolfo, Tartaglia, M. Carmela, Weintraub, Sandra, Wong, Bonnie, Cash, David M, Bouzigues, Arabella, Swift, Imogen J, Peakman, Georgia, Bocchetta, Martina, Todd, Emily G, Convery, Rhian S, Rowe, James B, Borroni, Barbara, Galimberti, Daniela, Tiraboschi, Pietro, Masellis, Mario, Finger, Elizabeth, van Swieten, John C, Seelaar, Harro, Jiskoot, Lize C, Sorbi, Sandro, Butler, Chris R, Graff, Caroline, Gerhard, Alexander, Langheinrich, Tobias, Laforce, Robert, Sanchez-Valle, Raquel, de Mendonça, Alexandre, Moreno, Fermin, Synofzik, Matthis, Vandenberghe, Rik, Ducharme, Simon, Le Ber, Isabelle, Levin, Johannes, Danek, Adrian, Otto, Markus, Pasquier, Florence, Santana, Isabel, and Kornak, John

Published
2022

13. Differences in Motor Features of C9orf72, MAPT, or GRN Variant Carriers With Familial Frontotemporal Lobar Degeneration.

Author

Tipton, Philip Wade, Deutschlaender, Angela B, Savica, Rodolfo, Heckman, Michael G, Brushaber, Danielle E, Dickerson, Bradford C, Gavrilova, Ralitza H, Geschwind, Daniel H, Ghoshal, Nupur, Graff-Radford, Jonathan, Graff-Radford, Neill R, Grossman, Murray, Hsiung, Ging-Yuek R, Huey, Edward D, Irwin, David John, Jones, David T, Knopman, David S, McGinnis, Scott M, Rademakers, Rosa, Ramos, Eliana Marisa, Forsberg, Leah K, Heuer, Hilary W, Onyike, Chiadi, Tartaglia, Carmela, Domoto-Reilly, Kimiko, Roberson, Erik D, Mendez, Mario F, Litvan, Irene, Appleby, Brian S, Grant, Ian, Kaufer, Daniel, Boxer, Adam L, Rosen, Howard J, Boeve, Brad F, and Wszolek, Zbigniew K

Subjects
C9orf72 Protein: genetics, Frontotemporal Dementia: diagnosis, genetics, Frontotemporal Lobar Degeneration: genetics, Granulins: genetics, Humans, Mutation: genetics, Progranulins: genetics, Quality of Life, Supranuclear Palsy, Progressive, tau Proteins: genetics
Abstract

Familial frontotemporal lobar degeneration (f-FTLD) is a phenotypically heterogeneous spectrum of neurodegenerative disorders most often caused by variants within chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), or granulin (GRN). The phenotypic association with each of these genes is incompletely understood. We hypothesized that the frequency of specific clinical features would correspond with different genes.We screened the Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS)/ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium for symptomatic carriers of pathogenic variants in C9orf72, MAPT, or GRN. We assessed for clinical differences among these 3 groups based on data recorded as part of a detailed neurologic examination, the Progressive Supranuclear Palsy Rating Scale, Progressive Supranuclear Palsy-Quality of Life Rating Scale, Unified Parkinson's Disease Rating Scale Part III (motor items), and the Amyotrophic Lateral Sclerosis Functional Rating Scale, revised version. Data were analyzed using Kruskal-Wallis and Wilcoxon rank-sum tests and Fisher exact test.We identified 184 symptomatic participants who had a single pathogenic variant in C9orf72 (n = 88), MAPT (n = 53), or GRN (n = 43). Motor symptom age at onset was earliest in the MAPT participants followed by C9orf72, whereas the GRN pathogenic variant carriers developed symptoms later. C9orf72 participants more often had fasciculations, muscle atrophy, and weakness, whereas parkinsonism was less frequent. Vertical oculomotor abnormalities were more common in the MAPT cohort, whereas apraxia and focal limb dystonia occurred more often in participants with GRN variants.We present a large comparative study of motor features in C9orf72, MAPT, and GRN pathogenic variant carriers with symptomatic f-FTLD. Our findings demonstrate characteristic phenotypic differences corresponding with specific gene variants that increase our understanding of the genotype-phenotype relationship in this complex spectrum of neurodegenerative disorders.NCT02365922, NCT02372773, and NCT04363684.

Published
2022

14. Alzheimer Disease Cerebrospinal Fluid Biomarkers in a Tertiary Neurology Practice

Author

Li, Wentao, Petersen, Ronald C., Algeciras-Schimnich, Alicia, Cogswell, Petrice M., Bornhorst, Joshua A., Kremers, Walter K., Boeve, Bradley F., Jones, David T., Botha, Hugo, Ramanan, Vijay K., Knopman, David S., Savica, Rodolfo, Josephs, Keith A., Cliatt-Brown, Christine, Andersen, Emerlee, Day, Gregory S., Graff-Radford, Neill R., Ertekin-Taner, Nilüfer, Lachner, Christian, Wicklund, Meredith, van Harten, Argonde, Woodruff, Bryan K., Caselli, Richard J., and Graff-Radford, Jonathan

Published
2024
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15. Frequency of LATE neuropathologic change across the spectrum of Alzheimer’s disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts

Author

Nelson, Peter T, Brayne, Carol, Flanagan, Margaret E, Abner, Erin L, Agrawal, Sonal, Attems, Johannes, Castellani, Rudolph J, Corrada, Maria M, Cykowski, Matthew D, Di, Jing, Dickson, Dennis W, Dugger, Brittany N, Ervin, John F, Fleming, Jane, Graff-Radford, Jonathan, Grinberg, Lea T, Hokkanen, Suvi RK, Hunter, Sally, Kapasi, Alifiya, Kawas, Claudia H, Keage, Hannah AD, Keene, C Dirk, Kero, Mia, Knopman, David S, Kouri, Naomi, Kovacs, Gabor G, Labuzan, Sydney A, Larson, Eric B, Latimer, Caitlin S, Leite, Renata EP, Matchett, Billie J, Matthews, Fiona E, Merrick, Richard, Montine, Thomas J, Murray, Melissa E, Myllykangas, Liisa, Nag, Sukriti, Nelson, Ruth S, Neltner, Janna H, Nguyen, Aivi T, Petersen, Ronald C, Polvikoski, Tuomo, Reichard, R Ross, Rodriguez, Roberta D, Suemoto, Claudia K, Wang, Shih-Hsiu J, Wharton, Stephen B, White, Lon, and Schneider, Julie A

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Research, Alzheimer's Disease, Acquired Cognitive Impairment, Aging, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Alzheimer's Disease Related Dementias (ADRD), Dementia, Behavioral and Social Science, 2.1 Biological and endogenous factors, Aetiology, Neurological, Aged, 80 and over, Alzheimer Disease, Amyloid, Autopsy, DNA-Binding Proteins, Frontotemporal Dementia, Humans, Male, Nervous System Diseases, Plaque, Amyloid, ADRD, Tau, NFT, Nondemented, Oldest-old, Epidemiology, APOE, ROS-MAP, Vantaa 85+, HAAS, CFAS, CC75C, The 90+study, ACT, VITA, Nun study, Biobank for aging studies, Mayo clinic study of aging, The 90 + study, Vantaa 85 + , Clinical Sciences, Neurology & Neurosurgery
Abstract

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheimer's disease neuropathologic change (ADNC) are each associated with substantial cognitive impairment in aging populations. However, the prevalence of LATE-NC across the full range of ADNC remains uncertain. To address this knowledge gap, neuropathologic, genetic, and clinical data were compiled from 13 high-quality community- and population-based longitudinal studies. Participants were recruited from United States (8 cohorts, including one focusing on Japanese-American men), United Kingdom (2 cohorts), Brazil, Austria, and Finland. The total number of participants included was 6196, and the average age of death was 88.1 years. Not all data were available on each individual and there were differences between the cohorts in study designs and the amount of missing data. Among those with known cognitive status before death (n = 5665), 43.0% were cognitively normal, 14.9% had MCI, and 42.4% had dementia-broadly consistent with epidemiologic data in this age group. Approximately 99% of participants (n = 6125) had available CERAD neuritic amyloid plaque score data. In this subsample, 39.4% had autopsy-confirmed LATE-NC of any stage. Among brains with "frequent" neuritic amyloid plaques, 54.9% had comorbid LATE-NC, whereas in brains with no detected neuritic amyloid plaques, 27.0% had LATE-NC. Data on LATE-NC stages were available for 3803 participants, of which 25% had LATE-NC stage > 1 (associated with cognitive impairment). In the subset of individuals with Thal Aβ phase = 0 (lacking detectable Aβ plaques), the brains with LATE-NC had relatively more severe primary age-related tauopathy (PART). A total of 3267 participants had available clinical data relevant to frontotemporal dementia (FTD), and none were given the clinical diagnosis of definite FTD nor the pathological diagnosis of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In the 10 cohorts with detailed neurocognitive assessments proximal to death, cognition tended to be worse with LATE-NC across the full spectrum of ADNC severity. This study provided a credible estimate of the current prevalence of LATE-NC in advanced age. LATE-NC was seen in almost 40% of participants and often, but not always, coexisted with Alzheimer's disease neuropathology.

Published
2022

16. Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate

Author

Mishra, Aniket, Duplaà, Cécile, Vojinovic, Dina, Suzuki, Hideaki, Sargurupremraj, Muralidharan, Zilhão, Nuno R, Li, Shuo, Bartz, Traci M, Jian, Xueqiu, Zhao, Wei, Hofer, Edith, Wittfeld, Katharina, Harris, Sarah E, van der Auwera-Palitschka, Sandra, Luciano, Michelle, Bis, Joshua C, Adams, Hieab HH, Satizabal, Claudia L, Gottesman, Rebecca F, Gampawar, Piyush G, Bülow, Robin, Weiss, Stefan, Yu, Miao, Bastin, Mark E, Lopez, Oscar L, Vernooij, Meike W, Beiser, Alexa S, Völker, Uwe, Kacprowski, Tim, Soumare, Aicha, Smith, Jennifer A, Knopman, David S, Morris, Zoe, Zhu, Yicheng, Rotter, Jerome I, Dufouil, Carole, Hernández, Maria Valdés, Maniega, Susana Muñoz, Lathrop, Mark, Boerwinkle, Erik, Schmidt, Reinhold, Ihara, Masafumi, Mazoyer, Bernard, Yang, Qiong, Joutel, Anne, Tournier-Lasserve, Elizabeth, Launer, Lenore J, Deary, Ian J, Mosley, Thomas H, Amouyel, Philippe, DeCarli, Charles S, Psaty, Bruce M, Tzourio, Christophe, Kardia, Sharon LR, Grabe, Hans J, Teumer, Alexander, van Duijn, Cornelia M, Schmidt, Helena, Wardlaw, Joanna M, Ikram, M Arfan, Fornage, Myriam, Gudnason, Vilmundur, Seshadri, Sudha, Matthews, Paul M, Longstreth, William T, Couffinhal, Thierry, and Debette, Stephanie

Subjects
Epidemiology, Health Sciences, Acquired Cognitive Impairment, Genetics, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Stroke, Neurosciences, Human Genome, Biotechnology, Clinical Research, Dementia, Aging, 2.1 Biological and endogenous factors, Aetiology, Neurological, Cardiovascular, Animals, Brain Ischemia, Cerebral Small Vessel Diseases, Endothelial Cells, Genome-Wide Association Study, Mice, cerebral small vessel disease, endothelial cells, GWAS, TRIM47, whole-exome association study, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5' UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer's disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work.

Published
2022

17. Sensitivity of the Social Behavior Observer Checklist to Early Symptoms of Patients With Frontotemporal Dementia.

Author

Toller, Gianina, Cobigo, Yann, Ljubenkov, Peter A, Appleby, Brian S, Dickerson, Bradford C, Domoto-Reilly, Kimiko, Fong, Jamie C, Forsberg, Leah K, Gavrilova, Ralitza H, Ghoshal, Nupur, Heuer, Hilary W, Knopman, David S, Kornak, John, Lapid, Maria I, Litvan, Irene, Lucente, Diane E, Mckenzie, Ian R, McGinnis, Scott M, Miller, Bruce L, Pedraza, Otto, Rojas, Julio C, Staffaroni, Adam M, Wong, Bonnie, Wszolek, Zbigniew K, Boeve, Brad F, Boxer, Adam L, Rosen, Howard J, Rankin, Katherine P, and ALLFTD research consortium

Subjects
ALLFTD research consortium, Social Behavior Observer Checklist, behavior, behavioral variant frontotemporal dementia, clinical trials, neurodegenerative disease, social cognition, Aging, Acquired Cognitive Impairment, Brain Disorders, Neurodegenerative, Clinical Research, Dementia, Behavioral and Social Science, Frontotemporal Dementia (FTD), Alzheimer's Disease, Clinical Trials and Supportive Activities, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Rare Diseases, Neurosciences, Basic Behavioral and Social Science, Prevention, Neurological, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Background and objectivesChanges in social behavior are common symptoms of frontotemporal lobar degeneration (FTLD) and Alzheimer's disease syndromes. For early identification of individual patients and differential diagnosis, sensitive clinical measures are required that are able to assess patterns of behaviors and detect syndromic differences in both asymptomatic and symptomatic stages. We investigated whether the examiner-based Social Behavior Observer Checklist (SBOCL) is sensitive to early behavior changes and reflects disease severity within and between neurodegenerative syndromes.MethodsAsymptomatic individuals and neurodegenerative disease patients were selected from the multisite ALLFTD cohort study. In a sample of participants with at least one timepoint of SBOCL data, we investigated whether the Disorganized, Reactive, and Insensitive subscales of the SBOCL change as a function of disease stage within and between these syndromes. In a longitudinal subsample with both SBOCL and neuroimaging data, we examined whether change over time on each subscale corresponds to progressive gray matter atrophy.Results1082 FTLD mutation carriers and non-carriers were enrolled (282 asymptomatic, 341 behavioral variant frontotemporal dementia, 114 semantic and 95 non-fluent variant primary progressive aphasia, 137 progressive supranuclear palsy, 113 Alzheimer's clinical syndrome). The Disorganized score increased between asymptomatic to very mild (p=0.016, estimate=-1.10, 95%CI=[-1.99, -0.22]), very mild to mild (p=0.013, -1.17, [-2.08, -0.26]), and mild to moderate/severe (p

Published
2022

18. The neurophysiological brain-fingerprint of Parkinson’s disease

Author

Breitner, John, Poirier, Judes, Baillet, Sylvain, Bellec, Pierre, Bohbot, Véronique, Chakravarty, Mallar, Collins, Louis, Etienne, Pierre, Evans, Alan, Gauthier, Serge, Hoge, Rick, Ituria-Medina, Yasser, Multhaup, Gerhard, Münter, Lisa-Marie, Rajah, Natasha, Rosa-Neto, Pedro, Soucy, Jean-Paul, Vachon-Presseau, Etienne, Villeneuve, Sylvia, Amouyel, Philippe, Appleby, Melissa, Ashton, Nicholas, Auld, Daniel, Ayranci, Gülebru, Bedetti, Christophe, Beland, Marie-Lise, Blennow, Kaj, Westman, Ann Brinkmalm, Cuello, Claudio, Dadar, Mahsa, Daoust, Leslie-Ann, Das, Samir, Dauar-Tedeschi, Marina, De Beaumont, Louis, Dea, Doris, Descoteaux, Maxime, Dufour, Marianne, Farzin, Sarah, Ferdinand, Fabiola, Fonov, Vladimir, Gonneaud, Julie, Kat, Justin, Kazazian, Christina, Labonté, Anne, Lafaille-Magnan, Marie-Elyse, Lalancette, Marc, Lambert, Jean-Charles, Leoutsakos, Jeannie-Marie, Mahar, Laura, Mathieu, Axel, McSweeney, Melissa, Meyer, Pierre-François, Miron, Justin, Near, Jamie, NewboldFox, Holly, Nilsson, Nathalie, Orban, Pierre, Picard, Cynthia, Binette, Alexa Pichet, Poline, Jean-Baptiste, Rabipour, Sheida, Salaciak, Alyssa, Settimi, Matthew, Subramaniapillai, Sivaniya, Tam, Angela, Tardif, Christine, Théroux, Louise, Tremblay-Mercier, Jennifer, Tullo, Stephanie, Ulku, Irem, Vallée, Isabelle, Zetterberg, Henrik, Nair, Vasavan, Pruessner, Jens, Aisen, Paul, Anthal, Elena, Barkun, Alan, Beaudry, Thomas, Benbouhoud, Fatiha, Brandt, Jason, Carmo, Leopoldina, Carrier, Charles Edouard, Cheewakriengkrai, Laksanun, Courcot, Blandine, Couture, Doris, Craft, Suzanne, Dansereau, Christian, Debacker, Clément, Desautels, René, Dubuc, Sylvie, Duclair, Guerda, Eisenberg, Mark, El-Khoury, Rana, Faubert, Anne-Marie, Fontaine, David, Frappier, Josée, Frenette, Joanne, Gagné, Guylaine, Gervais, Valérie, Giles, Renuka, Gordon, Renee, Jack, Clifford, Jutras, Benoit, Khachaturian, Zaven, Knopman, David, Kostopoulos, Penelope, Lapalme, Félix, Lee, Tanya, Lepage, Claude, Leppert, Illana, Madjar, Cécile, Maillet, David, Maltais, Jean-Robert, Mathotaarachchi, Sulantha, Mayrand, Ginette, Michaud, Diane, Montine, Thomas, Morris, John, Pagé, Véronique, Pascoal, Tharick, Peillieux, Sandra, Petkova, Mirela, Pogossova, Galina, Rioux, Pierre, Sager, Mark, Saint-Fort, Eunice Farah, Savard, Mélissa, Sperling, Reisa, Tabrizi, Shirin, Tariot, Pierre, Teigner, Eduard, Thomas, Ronald, Toussaint, Paule-Joanne, Tuwaig, Miranda, Venugopalan, Vinod, Verfaillie, Sander, Vogel, Jacob, Wan, Karen, Wang, Seqian, Yu, Elsa, Beaulieu-Boire, Isabelle, Blanchet, Pierre, Bogard, Sarah, Bouchard, Manon, Chouinard, Sylvain, Cicchetti, Francesca, Cloutier, Martin, Dagher, Alain, Degroot, Clotilde, Desautels, Alex, Dion, Marie Hélène, Drouin-Ouellet, Janelle, Dufresne, Anne-Marie, Dupré, Nicolas, Duquette, Antoine, Durcan, Thomas, Fellows, Lesley K., Fon, Edward, Gagnon, Jean-François, Gan-Or, Ziv, Genge, Angela, Jodoin, Nicolas, Karamchandani, Jason, Lafontaine, Anne-Louise, Langlois, Mélanie, Leveille, Etienne, Lévesque, Martin, Melmed, Calvin, Monchi, Oury, Montplaisir, Jacques, Panisset, Michel, Parent, Martin, Pham-An, Minh-Thy, Postuma, Ronald, Pourcher, Emmanuelle, Rao, Trisha, Rivest, Jean, Rouleau, Guy, Sharp, Madeleine, Soland, Valérie, Sidel, Michael, Wing Sun, Sonia Lai, Thiel, Alexander, Vitali, Paolo, da Silva Castanheira, Jason, Wiesman, Alex I., Hansen, Justine Y., and Misic, Bratislav

Published
2024
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19. 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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20. TDP-43-regulated cryptic RNAs accumulate in Alzheimer’s disease brains

Author

Estades Ayuso, Virginia, Pickles, Sarah, Todd, Tiffany, Yue, Mei, Jansen-West, Karen, Song, Yuping, González Bejarano, Jesús, Rawlinson, Bailey, DeTure, Michael, Graff-Radford, Neill R., Boeve, Bradley F., Knopman, David S., Petersen, Ronald C., Dickson, Dennis W., Josephs, Keith A., Petrucelli, Leonard, and Prudencio, Mercedes

Published
2023
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21. Frontotemporal lobar degeneration

Author

Grossman, Murray, Seeley, William W., Boxer, Adam L., Hillis, Argye E., Knopman, David S., Ljubenov, Peter A., Miller, Bruce, Piguet, Olivier, Rademakers, Rosa, Whitwell, Jennifer L., Zetterberg, Henrik, and van Swieten, John C.

Published
2023
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22. Proposed research criteria for prodromal behavioural variant frontotemporal dementia

Author

Barker, Megan S, Gottesman, Reena T, Manoochehri, Masood, Chapman, Silvia, Appleby, Brian S, Brushaber, Danielle, Devick, Katrina L, Dickerson, Bradford C, Domoto-Reilly, Kimiko, Fields, Julie A, Forsberg, Leah K, Galasko, Douglas R, Ghoshal, Nupur, Goldman, Jill, Graff-Radford, Neill R, Grossman, Murray, Heuer, Hilary W, Hsiung, Ging-Yuek, Knopman, David S, Kornak, John, Litvan, Irene, Mackenzie, Ian R, Masdeu, Joseph C, Mendez, Mario F, Pascual, Belen, Staffaroni, Adam M, Tartaglia, Maria Carmela, Boeve, Bradley F, Boxer, Adam L, Rosen, Howard J, Rankin, Katherine P, Cosentino, Stephanie, Rascovsky, Katya, Huey, Edward D, Foroud, Tatiana, Kaufer, Daniel, Kremers, Walter, Leger, Gabriel, Onyike, Chiadi, Ritter, Aaron, Roberson, Erik D, and Weintraub, Sandra

Subjects
Clinical and Health Psychology, Psychology, Behavioral and Social Science, Dementia, Neurosciences, Alzheimer's Disease, Rare Diseases, Frontotemporal Dementia (FTD), Acquired Cognitive Impairment, Aging, Brain Disorders, Prevention, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Research, Alzheimer's Disease Related Dementias (ADRD), Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Alzheimer Disease, Biomarkers, Frontotemporal Dementia, Frontotemporal Lobar Degeneration, Humans, Neuropsychological Tests, behavioural variant frontotemporal dementia, prodromal, mild behavioural impairment, mild cognitive impairment, criteria, ALLFTD Consortium, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences
Abstract

At present, no research criteria exist for the diagnosis of prodromal behavioural variant frontotemporal dementia (bvFTD), though early detection is of high research importance. Thus, we sought to develop and validate a proposed set of research criteria for prodromal bvFTD, termed 'mild behavioural and/or cognitive impairment in bvFTD' (MBCI-FTD). Participants included 72 participants deemed to have prodromal bvFTD; this comprised 55 carriers of a pathogenic mutation known to cause frontotemporal lobar degeneration, and 17 individuals with autopsy-confirmed frontotemporal lobar degeneration. All had mild behavioural and/or cognitive changes, as judged by an evaluating clinician. Based on extensive clinical workup, the prodromal bvFTD group was divided into a Development Group (n = 22) and a Validation Group (n = 50). The Development Group was selected to be the subset of the prodromal bvFTD group for whom we had the strongest longitudinal evidence of conversion to bvFTD, and was used to develop the MBCI-FTD criteria. The Validation Group was the remainder of the prodromal bvFTD group and was used as a separate sample on which to validate the criteria. Familial non-carriers were included as healthy controls (n = 165). The frequencies of behavioural and neuropsychiatric features, neuropsychological deficits, and social cognitive dysfunction in the prodromal bvFTD Development Group and healthy controls were assessed. Based on sensitivity and specificity analyses, seven core features were identified: apathy without moderate-severe dysphoria, behavioural disinhibition, irritability/agitation, reduced empathy/sympathy, repetitive behaviours (simple and/or complex), joviality/gregariousness, and appetite changes/hyperorality. Supportive features include a neuropsychological profile of impaired executive function or naming with intact orientation and visuospatial skills, reduced insight for cognitive or behavioural changes, and poor social cognition. Three core features or two core features plus one supportive feature are required for the diagnosis of possible MBCI-FTD; probable MBCI-FTD requires imaging or biomarker evidence, or a pathogenic genetic mutation. The proposed MBCI-FTD criteria correctly classified 95% of the prodromal bvFTD Development Group, and 74% of the prodromal bvFTD Validation Group, with a false positive rate of

Published
2022

23. Comprehensive cross-sectional and longitudinal analyses of plasma neurofilament light across FTD spectrum disorders

Author

Gendron, Tania F, Heckman, Michael G, White, Launia J, Veire, Austin M, Pedraza, Otto, Burch, Alexander R, Bozoki, Andrea C, Dickerson, Bradford C, Domoto-Reilly, Kimiko, Foroud, Tatiana, Forsberg, Leah K, Galasko, Douglas R, Ghoshal, Nupur, Graff-Radford, Neill R, Grossman, Murray, Heuer, Hilary W, Huey, Edward D, Hsiung, Ging-Yuek R, Irwin, David J, Kaufer, Daniel I, Leger, Gabriel C, Litvan, Irene, Masdeu, Joseph C, Mendez, Mario F, Onyike, Chiadi U, Pascual, Belen, Ritter, Aaron, Roberson, Erik D, Rojas, Julio C, Tartaglia, Maria Carmela, Wszolek, Zbigniew K, Rosen, Howard, Boeve, Bradley F, Boxer, Adam L, consortium, ALLFTD, Appleby, Brian S, Barmada, Sami, Bordelon, Yvette, Botha, Hugo, Brushaber, Danielle, Clark, David, Coppola, Giovanni, Darby, Ryan, Devick, Katrina, Dickson, Dennis, Faber, Kelley, Fagan, Anne, Fields, Julie A, Gavrilova, Ralitza, Geschwind, Daniel, Goldman, Jill, Graff-Radford, Jonathon, Grant, Ian, Jones, David T, Kantarci, Kejal, Kerwin, Diana, Knopman, David S, Kornak, John, Kremers, Walter, Lapid, Maria, Lago, Argentina Lario, Ljubenkov, Peter, Lucente, Diane, Mackenzie, Ian R, McGinnis, Scott, Mester, Carly, Miller, Bruce L, Pressman, Peter, Rademakers, Rosa, Ramanan, Vijay K, Ramos, E Marisa, Rankin, Katherine P, Rao, Meghana, Rascovsky, Katya, Savica, Rodolfo, Seeley, William, Staffaroni, Adam M, Syrjanen, Jeremy, Taylor, Jack, VandeVrede, Lawren, Weintraub, Sandra, Wong, Bonnie, and Petrucelli, Leonard

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Rare Diseases, Dementia, Brain Disorders, Prevention, Acquired Cognitive Impairment, Neurodegenerative, Frontotemporal Dementia (FTD), 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Good Health and Well Being, Cross-Sectional Studies, Frontotemporal Dementia, Humans, Intermediate Filaments, Neurofilament Proteins, Pick Disease of the Brain, Syndrome, ALLFTD consortium, Richardson’s syndrome, behavioral variant frontotemporal dementia, biomarker, corticobasal syndrome, neurofilament light, plasma, presymptomatic, primary progressive aphasia, progressive supranuclear palsy, Biomedical and clinical sciences
Abstract

Frontotemporal dementia (FTD) therapy development is hamstrung by a lack of susceptibility, diagnostic, and prognostic biomarkers. Blood neurofilament light (NfL) shows promise as a biomarker, but studies have largely focused only on core FTD syndromes, often grouping patients with different diagnoses. To expedite the clinical translation of NfL, we avail ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources and conduct a comprehensive investigation of plasma NfL across FTD syndromes and in presymptomatic FTD mutation carriers. We find plasma NfL is elevated in all studied syndromes, including mild cases; increases in presymptomatic mutation carriers prior to phenoconversion; and associates with indicators of disease severity. By facilitating the identification of individuals at risk of phenoconversion, and the early diagnosis of FTD, plasma NfL can aid in participant selection for prevention or early treatment trials. Moreover, its prognostic utility would improve patient care, clinical trial efficiency, and treatment outcome estimations.

Published
2022

24. TDP-43 represses cryptic exon inclusion in the FTD–ALS gene UNC13A

Author

Ma, X Rosa, Prudencio, Mercedes, Koike, Yuka, Vatsavayai, Sarat C, Kim, Garam, Harbinski, Fred, Briner, Adam, Rodriguez, Caitlin M, Guo, Caiwei, Akiyama, Tetsuya, Schmidt, H Broder, Cummings, Beryl B, Wyatt, David W, Kurylo, Katherine, Miller, Georgiana, Mekhoubad, Shila, Sallee, Nathan, Mekonnen, Gemechu, Ganser, Laura, Rubien, Jack D, Jansen-West, Karen, Cook, Casey N, Pickles, Sarah, Oskarsson, Björn, Graff-Radford, Neill R, Boeve, Bradley F, Knopman, David S, Petersen, Ronald C, Dickson, Dennis W, Shorter, James, Myong, Sua, Green, Eric M, Seeley, William W, Petrucelli, Leonard, and Gitler, Aaron D

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Rare Diseases, Stem Cell Research - Nonembryonic - Human, Dementia, Neurosciences, Brain Disorders, Acquired Cognitive Impairment, Human Genome, Stem Cell Research, Neurodegenerative, ALS, 2.1 Biological and endogenous factors, Aetiology, Neurological, Amyotrophic Lateral Sclerosis, DNA-Binding Proteins, Exons, Frontotemporal Dementia, Genome-Wide Association Study, Humans, Motor Neurons, Nerve Tissue Proteins, General Science & Technology
Abstract

A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord1. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing2-4. Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies5,6, but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon-splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harbouring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (UNC13A genetic variants), and loss of TDP-43 function.

Published
2022

26. Neurite-based white matter alterations in MAPT mutation carriers: A multi-shell diffusion MRI study in the ALLFTD consortium

Author

Corriveau-Lecavalier, Nick, Tosakulwong, Nirubol, Lesnick, Timothy G., Fought, Angela J., Reid, Robert I., Schwarz, Christopher G., Senjem, Matthew L., Jack, Clifford R., Jr., Jones, David T., Vemuri, Prashanthi, Rademakers, Rosa, Ramos, Eliana Marisa, Geschwind, Daniel H., Knopman, David S., Botha, Hugo, Savica, Rodolfo, Graff-Radford, Jonathan, Ramanan, Vijay K., Fields, Julie A., Graff-Radford, Neill, Wszolek, Zbigniew, Forsberg, Leah K., Petersen, Ronald C., Heuer, Hilary W., Boxer, Adam L., Rosen, Howard J., Boeve, Bradley F., and Kantarci, Kejal

Published
2024
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27. Associations of Pulmonary Function with MRI Brain Volumes: A Coordinated Multi-Study Analysis

Author

Frenzel, Stefan, Bis, Joshua C, Gudmundsson, Elias F, O’Donnell, Adrienne, Simino, Jeannette, Yaqub, Amber, Bartz, Traci M, Brusselle, Guy GO, Bülow, Robin, DeCarli, Charles S, Ewert, Ralf, Gharib, Sina A, Ghosh, Saptaparni, Gireud-Goss, Monica, Gottesman, Rebecca F, Ikram, M Arfan, Knopman, David S, Launer, Lenore J, London, Stephanie J, Longstreth, WT, Lopez, Oscar L, van Lent, Debora Melo, O’Connor, George, Satizabal, Claudia L, Shrestha, Srishti, Sigurdsson, Sigurdur, Stubbe, Beate, Talluri, Rajesh, Vasan, Ramachandran S, Vernooij, Meike W, Völzke, Henry, Wiggins, Kerri L, Yu, Bing, Beiser, Alexa S, Gudnason, Vilmundur, Mosley, Thomas, Psaty, Bruce M, Wolters, Frank J, Grabe, Hans J, and Seshadri, Sudha

Subjects
Brain Disorders, Lung, Neurosciences, Clinical Research, Aging, Humans, Aged, Forced Expiratory Volume, Cross-Sectional Studies, Magnetic Resonance Imaging, Brain, Dementia, epidemiology, magnetic resonance imaging, respiratory function tests, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

BackgroundPrevious studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent.ObjectiveTo study the cross-sectional associations of pulmonary function with structural brain variables.MethodsData from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses.ResultsFEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume.ConclusionIn cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.

Published
2022

28. Gearing up for the future: Exploring facilitators and barriers to inform clinical trial design in frontotemporal lobar degeneration

Author

Banga, Yasmin B, Lai, Yujung, Kim, Priscilla, Boeve, Bradley F, Boxer, Adam L, Rosen, Howard J, Forsberg, Leah K, Heuer, Hilary W, Brushaber, Danielle, Appleby, Brian, Biernacka, Joanna M, Bordelon, Yvette M, Botha, Hugo, Bozoki, Andrea C, Brannelly, Patrick, Dickerson, Brad C, Dickinson, Susan, Dickson, Dennis W, Domoto‐Reilly, Kimiko, Faber, Kelley, Fagan, Anne M, Fields, Julie A, Fishman, Ann, Foroud, Tatiana M, Galasko, Doug R, Gavrilova, Ralitza H, Gendron, Tania F, Geschwind, Daniel H, Ghoshal, Nupur, Goldman, Jill, Graff‐Radford, Jonathan, Graff‐Radford, Neill R, Grant, Ian, Grossman, Murray, Hsiung, Ging‐Yuek Robin, Huang, Eric J, Huey, Edward D, Irwin, David J, Jones, David T, Kantarci, Kejal, Karydas, Anna M, Kaufer, Daniel, Knopman, David S, Kramer, Joel H, Kremers, Walter K, Kornak, John, Kukull, Walter A, Lagone, Emma, Leger, Gabriel C, Litvan, Irene, Ljubenkov, Peter A, Lucente, Diane E, Mackenzie, Ian R, Manoochehri, Masood, Masdeu, Joseph C, McGinnis, Scott, Mendez, Mario F, Miller, Bruce L, Miyagawa, Toji, Nelson, Kevin M, Onyike, Chiadi U, Pantelyat, Alex, Pascual, Belen, Pearlman, Rodney, Petrucelli, Leonard, Pottier, Cyril P, Rademakers, Rosa, Ramos, Eliana Marisa, Rankin, Katherine P, Rascovsky, Katya, Rexach, Jessica E, Ritter, Aaron, Roberson, Erik D, Rojas, Julio C, Sabbagh, Marwan N, Salmon, David P, Savica, Rodolfo, Seeley, William W, Staffaroni, Adam M, Syrjanen, Jeremy A, Tartaglia, Maria Carmela, Tatton, Nadine, Taylor, Jack C, Toga, Arthur W, Weintraub, Sandra, Wheaton, Diana, Wong, Benjamin, Wszolek, Zbigniew, and Consortium, ALLFTD

Subjects
Frontotemporal Dementia (FTD), Rare Diseases, Behavioral and Social Science, Neurodegenerative, Acquired Cognitive Impairment, Basic Behavioral and Social Science, Brain Disorders, Clinical Research, Dementia, Aging, Biomedical Imaging, Clinical Trials and Supportive Activities, Neurological, Clinical Sciences, Neurosciences, Geriatrics
Abstract

BACKGROUND: Frontotemporal lobar degeneration (FTLD) refers to a group of neurodegenerative conditions, affecting the frontal and/or temporal lobes. Ongoing research has provided insight into developing clinical trials for FTLD and key clinical measures such as structural MRI. To inform clinical trial design and optimize participation, it is imperative to explore facilitators and barriers for potential candidates. OBJECTIVE: The objective of this study is to explore facilitators and barriers to participating in future clinical trials for FTLD. METHODS: Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) are observational studies focused on characterizing FTLD syndromes in preparation for clinical trials. The 584 participants enrolled across 18 research sites in the United States and Canada completed a survey assessing interest in clinical trial participation. RESULTS: 29% of respondents self-reported as patients (63±10 years), 26% self-reported as caregivers answering on behalf of patients (65±10 years), and 45% self-reported as healthy but at risk for FTLD (48±14 years). Travel reimbursement was the most common factor reported to positively influence participation (≧66%), with the healthy but at risk group showing the strongest endorsement (83%). Cost and time involved in travel were possible barriers for about half of the patients (48%) and healthy but at risk respondents (53%). The respondents value receiving feedback on the study findings (≧80%) and being informed of their individual disease progression (≧75%). Particularly, keeping participation confidential was very important for the healthy but at risk group (62%). In regard to research assessments, most participants demonstrated a high interest in physical and neurological exams at a research center (≧87%) whereas only half were interested in doing more invasive procedures such as the lumbar puncture (≧52%). Overall, respondents showed a positive attitude and support for research participation (≧77%) and trusted that their health information would remain confidential in a clinical trial (≧53%). CONCLUSIONS: Favorable attitudes and interest towards medical research exist among participants. To optimize participation, clinical trials should allocate funding for travel and involve participants in feedback about study results and their disease progression. Alternatives to invasive assessments may increase participation.

Published
2021

29. Presymptomatic and symptomatic MAPT mutation carriers feature functional connectivity alterations

Author

Zhang, Liwen, Flagan, Taru M, Chu, Stephanie A, Häkkinen, Suvi, Brown, Jesse A, Lee, Alex Jihun, Pasquini, Lorenzo, Mandelli, Maria Luisa, Tempini, Maria Luisa Gorno, Appleby, Brian, Dickerson, Brad C, Domoto‐Reilly, Kimiko, Geschwind, Daniel H, Ghoshal, Nupur, Graff‐Radford, Neill R, Grossman, Murray, Hsiung, Ging‐Yuek Robin, Huey, Edward D, Kantarci, Kejal, Karydas, Anna M, Kaufer, Daniel, Knopman, David S, Litvan, Irene, Mackenzie, Ian R, Mendez, Mario, Onyike, Chiadi U, Ramos, Eliana Marisa, Roberson, Erik D, Trataglia, Maria Carmela, Toga, Arthur W, Weintraub, Sandra, Forsberg, Leah K, Heuer, Hilary W, Boeve, Bradley F, Boxer, Adam L, Rosen, Howard J, Miller, Bruce L, Seeley, William W, Lee, Suzee E, and Consortia, ARTFL LEFFTDS

Subjects
Brain Disorders, Clinical Research, Neurodegenerative, Biomedical Imaging, Rare Diseases, Neurosciences, Dementia, Acquired Cognitive Impairment, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurological, Clinical Sciences, Geriatrics
Published
2021

30. Plasma amyloid β levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: A genome‐wide association study in over 12,000 non‐demented participants

Author

Damotte, Vincent, van der Lee, Sven J, Chouraki, Vincent, Grenier‐Boley, Benjamin, Simino, Jeannette, Adams, Hieab, Tosto, Giuseppe, White, Charles, Terzikhan, Natalie, Cruchaga, Carlos, Knol, Maria J, Li, Shuo, Schraen, Susanna, Grove, Megan L, Satizabal, Claudia, Amin, Najaf, Berr, Claudine, Younkin, Steven, Initiative, Alzheimer's Disease Neuroimaging, Gottesman, Rebecca F, Buée, Luc, Beiser, Alexa, Knopman, David S, Uitterlinden, Andre, DeCarli, Charles, Bressler, Jan, DeStefano, Anita, Dartigues, Jean‐François, Yang, Qiong, Boerwinkle, Eric, Tzourio, Christophe, Fornage, Myriam, Ikram, M Arfan, Amouyel, Philippe, de Jager, Phil, Reitz, Christiane, Mosley, Thomas H, Lambert, Jean‐Charles, Seshadri, Sudha, and van Duijn, Cornelia M

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Brain Disorders, Alzheimer's Disease, Dementia, Prevention, Genetics, Aging, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Neurological, Alzheimer Disease, Amyloid, Amyloid Precursor Protein Secretases, Amyloid beta-Protein Precursor, Apolipoproteins E, Aspartic Acid Endopeptidases, Brain, Genome-Wide Association Study, Healthy Volunteers, Humans, Positron-Emission Tomography, Presenilin-2, Alzheimer&apos, s disease, APOE, APP, BACE1, endophenotype, genetic epidemiology, genome&#8209, wide association study, plasma amyloid beta levels, plasma biomarkers, preclinical biomarkers, PSEN2, Alzheimer's Disease Neuroimaging Initiative, Alzheimer's disease, genome-wide association study, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionThere is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures.MethodsWe included 12,369 non-demented participants from eight population-based studies. Imputed genetic data and measured plasma Aβ1-40, Aβ1-42 levels and Aβ1-42/Aβ1-40 ratio were used to perform genome-wide association studies, and gene-based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk.ResultsSingle-variant analysis identified associations with apolipoprotein E (APOE) for Aβ1-42 and Aβ1-42/Aβ1-40 ratio, and BACE1 for Aβ1-40. Gene-based analysis of Aβ1-40 additionally identified associations for APP, PSEN2, CCK, and ZNF397. There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition.DiscussionIdentification of variants near/in known major Aβ-processing genes strengthens the relevance of plasma-Aβ levels as an endophenotype of AD.

Published
2021

32. Assessing network degeneration and phenotypic heterogeneity in genetic frontotemporal lobar degeneration by decoding FDG-PET

Author

Corriveau-Lecavalier, Nick, Barnard, Leland R., Przybelski, Scott A., Gogineni, Venkatsampath, Botha, Hugo, Graff-Radford, Jonathan, Ramanan, Vijay K., Forsberg, Leah K., Fields, Julie A., Machulda, Mary M., Rademakers, Rosa, Gavrilova, Ralitza H., Lapid, Maria I., Boeve, Bradley F., Knopman, David S., Lowe, Val J., Petersen, Ronald C., Jack, Clifford R., Kantarci, Kejal, and Jones, David T.

Published
2024
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33. Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration

Author

Rojas, Julio C, Wang, Ping, Staffaroni, Adam M, Heller, Carolin, Cobigo, Yann, Wolf, Amy, Goh, Sheng-Yang M, Ljubenkov, Peter A, Heuer, Hilary W, Fong, Jamie C, Taylor, Joanne B, Veras, Eliseo, Song, Linan, Jeromin, Andreas, Hanlon, David, Yu, Lili, Khinikar, Arvind, Sivasankaran, Rajeev, Kieloch, Agnieszka, Valentin, Marie-Anne, Karydas, Anna M, Mitic, Laura L, Pearlman, Rodney, Kornak, John, Kramer, Joel H, Miller, Bruce L, Kantarci, Kejal, Knopman, David S, Graff-Radford, Neill, Petrucelli, Leonard, Rademakers, Rosa, Irwin, David J, Grossman, Murray, Ramos, Eliana Marisa, Coppola, Giovanni, Mendez, Mario F, Bordelon, Yvette, Dickerson, Bradford C, Ghoshal, Nupur, Huey, Edward D, Mackenzie, Ian R, Appleby, Brian S, Domoto-Reilly, Kimiko, Hsiung, Ging-Yuek R, Toga, Arthur W, Weintraub, Sandra, Kaufer, Daniel I, Kerwin, Diana, Litvan, Irene, Onyike, Chiadikaobi U, Pantelyat, Alexander, Roberson, Erik D, Tartaglia, Maria C, Foroud, Tatiana, Chen, Weiping, Czerkowicz, Julie, Graham, Danielle L, van Swieten, John C, Borroni, Barbara, Sanchez-Valle, Raquel, Moreno, Fermin, Laforce, Robert, Graff, Caroline, Synofzik, Matthis, Galimberti, Daniela, Rowe, James B, Masellis, Mario, Finger, Elizabeth, Vandenberghe, Rik, de Mendonça, Alexandre, Tagliavini, Fabrizio, Santana, Isabel, Ducharme, Simon, Butler, Chris R, Gerhard, Alexander, Levin, Johannes, Danek, Adrian, Otto, Markus, Sorbi, Sandro, Cash, David M, Convery, Rhian S, Bocchetta, Martina, Foiani, Martha, Greaves, Caroline V, Peakman, Georgia, Russell, Lucy, Swift, Imogen, Todd, Emily, Rohrer, Jonathan D, Boeve, Bradley F, Rosen, Howard J, Boxer, Adam L, and consortia, on behalf of the ALLFTD and GENFI

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Neurodegenerative, Genetics, Prevention, Dementia, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Research, Alzheimer's Disease, Frontotemporal Dementia (FTD), Aging, Acquired Cognitive Impairment, Clinical Trials and Supportive Activities, 2.1 Biological and endogenous factors, Aetiology, Adult, Aged, Aged, 80 and over, Biomarkers, Cohort Studies, Disease Progression, Female, Frontotemporal Lobar Degeneration, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neurofilament Proteins, Predictive Value of Tests, Young Adult, ALLFTD and GENFI consortia, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveWe tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression.MethodsBaseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. C9orf72, GRN, and MAPT mutation carriers and noncarriers from the same families were classified by disease severity (asymptomatic, prodromal, and full phenotype) using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed-effect models related NfL to clinical variables.ResultsIn both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL, p = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, p = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers.ConclusionsPlasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression and is a potential tool to select participants for prevention clinical trials.Trial registration informationClinicalTrials.gov Identifier: NCT02372773 and NCT02365922.Classification of evidenceThis study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.

Published
2021

34. Circular-SWAT for deep learning based diagnostic classification of Alzheimer's disease: application to metabolome data

Author

Kaddurah-Daouk, Rima, Kueider-Paisley, Alexandra, Doraiswamy, P. Murali, Blach, Colette, Moseley, Arthur, Thompson, Will, St John-Williams, Lisa, Mahmoudiandehkhordi, Siamak, Tenenbaum, Jessica, Welsh-Balmer, Kathleen, Plassman, Brenda, Saykin, Andrew J., Nho, Kwangsik, Risacher, Shannon L., Kastenmüller, Gabi, Arnold, Matthias, Han, Xianlin, Baillie, Rebecca, Knight, Rob, Dorrestein, Pieter, Brewer, James, Mayer, Emeran, Labus, Jennifer, Baldi, Pierre, Gupta, Arpana, Fiehn, Oliver, Barupal, Dinesh, Meikle, Peter, Mazmanian, Sarkis, Rader, Dan, Kling, Mitchel, Shaw, Leslie, Trojanowski, John, van Duijin, Cornelia, Nevado-Holgado, Alejo, Bennett, David, Krishnan, Ranga, Keshavarzian, Ali, Vogt, Robin, Ikram, Arfan, Hankemeier, Thomas, Thiele, Ines, Price, Nathan, Funk, Cory, Baloni, Priyanka, Jia, Wei, Wishart, David, Brinton, Roberta, Chang, Rui, Farrer, Lindsay, Au, Rhoda, Qiu, Wendy, Würtz, Peter, Koal, Therese, Mangravite, Lara, Krumsiek, Jan, Suhre, Karsten, Newman, John, Moreno, Herman, Foroud, Tatania, Sacks, Frank, Jansson, Janet, Weiner, Michael W., Aisen, Paul, Petersen, Ronald, Jack, Clifford R., Jr., Jagust, William, Trojanowki, John Q., Toga, Arthur W., Beckett, Laurel, Green, Robert C., Morris, John C., Perrin, Richard J., Shaw, Leslie M., Khachaturian, Zaven, Carrillo, Maria, Potter, William, Barnes, Lisa, Bernard, Marie, Gonzalez, Hector, Ho, Carole, Hsiao, John K., Jackson, Jonathan, Masliah, Eliezer, Masterman, Donna, Okonkwo, Ozioma, Perrin, Richard, Ryan, Laurie, Silverberg, Nina, Fleisher, Adam, Sacrey, Diana Truran, Fockler, Juliet, Conti, Cat, Veitch, Dallas, Neuhaus, John, Jin, Chengshi, Nosheny, Rachel, Ashford, Miriam, Flenniken, Derek, Kormos, Adrienne, Montine, Tom, Rafii, Michael, Raman, Rema, Jimenez, Gustavo, Donohue, Michael, Gessert, Devon, Salazar, Jennifer, Zimmerman, Caileigh, Cabrera, Yuliana, Walter, Sarah, Miller, Garrett, Coker, Godfrey, Clanton, Taylor, Hergesheimer, Lindsey, Smith, Stephanie, Adegoke, Olusegun, Mahboubi, Payam, Moore, Shelley, Pizzola, Jeremy, Shaffer, Elizabeth, Sloan, Brittany, Harvey, Danielle, Forghanian-Arani, Arvin, Borowski, Bret, Ward, Chad, Schwarz, Christopher, Jones, David, Gunter, Jeff, Kantarci, Kejal, Senjem, Matthew, Vemuri, Prashanthi, Reid, Robert, Fox, Nick C., Malone, Ian, Thompson, Paul, Thomopoulos, Sophia I., Nir, Talia M., Jahanshad, Neda, DeCarli, Charles, Knaack, Alexander, Fletcher, Evan, Tosun-Turgut, Duygu, Chen, Stephanie Rossi, Choe, Mark, Crawford, Karen, Yushkevich, Paul A., Das, Sandhitsu, Koeppe, Robert A., Reiman, Eric M., Chen, Kewei, Mathis, Chet, Landau, Susan, Cairns, Nigel J., Householder, Erin, Franklin, Erin, Bernhardt, Haley, Taylor-Reinwald, Lisa, Korecka, Magdalena, Figurski, Michal, Neu, Scott, Apostolova, Liana G., Shen, Li, Foroud, Tatiana M., Nudelman, Kelly, Faber, Kelley, Wilmes, Kristi, Thal, Leon, Silbert, Lisa C., Lind, Betty, Crissey, Rachel, Kaye, Jeffrey A., Carter, Raina, Dolen, Sara, Quinn, Joseph, Schneider, Lon S., Pawluczyk, Sonia, Becerra, Mauricio, Teodoro, Liberty, Dagerman, Karen, Spann, Bryan M., Vanderswag, Helen, Ziolkowski, Jaimie, Heidebrink, Judith L., Zbizek-Nulph, Lisa, Lord, Joanne L., Mason, Sara S., Albers, Colleen S., Knopman, David, Johnson, Kris, Villanueva-Meyer, Javier, Pavlik, Valory, Pacini, Nathaniel, Lamb, Ashley, Kass, Joseph S., Doody, Rachelle S., Shibley, Victoria, Chowdhury, Munir, Rountree, Susan, Dang, Mimi, Stern, Yaakov, Honig, Lawrence S., Mintz, Akiva, Ances, Beau, Winkfield, David, Carroll, Maria, Stobbs-Cucchi, Georgia, Oliver, Angela, Creech, Mary L., Mintun, Mark A., Schneider, Stacy, Geldmacher, David, Love, Marissa Natelson, Griffith, Randall, Clark, David, Brockington, John, Marson, Daniel, Grossman, Hillel, Goldstein, Martin A., Greenberg, Jonathan, Mitsis, Effie, Shah, Raj C., Lamar, Melissa, Samuels, Patricia, Duara, Ranjan, Greig-Custo, Maria T., Rodriguez, Rosemarie, Albert, Marilyn, Onyike, Chiadi, Farrington, Leonie, Rudow, Scott, Brichko, Rottislav, Kielb, Stephanie, Smith, Amanda, Raj, Balebail Ashok, Fargher, Kristin, Sadowski, Martin, Wisniewski, Thomas, Shulman, Melanie, Faustin, Arline, Rao, Julia, Castro, Karen M., Ulysse, Anaztasia, Chen, Shannon, Sheikh, Mohammed O., Singleton-Garvin, Jamika, Petrella, JeffreyR., James, Olga, Wong, Terence Z., Borges-Neto, Salvador, Karlawish, Jason H., Wolk, David A., Vaishnavi, Sanjeev, Clark, Christopher M., Arnold, Steven E., Smith, Charles D., Jicha, Gregory A., Raslau, Flavius D., Lopez, Oscar L., Oakley, MaryAnn, Simpson, Donna M., Porsteinsson, Anton P., Martin, Kim, Kowalski, Nancy, Keltz, Melanie, Goldstein, Bonnie S., Makino, Kelly M., Ismail, M. Saleem, Brand, Connie, Thai, Gaby, Pierce, Aimee, Yanez, Beatriz, Sosa, Elizabeth, Witbracht, Megan, Kelley, Brendan, Nguyen, Trung, Womack, Kyle, Mathews, Dana, Quiceno, Mary, Levey, Allan I., Lah, James J., Hajjar, Ihab, Cellar, Janet S., Burns, Jeffrey M., Swerdlow, Russell H., Brooks, William M., Silverman, Daniel H.S., Kremen, Sarah, Apostolova, Liana, Tingus, Kathleen, Lu, Po H., Bartzokis, George, Woo, Ellen, Teng, Edmond, Graff-Radford, Neill R., Parfitt, Francine, Poki-Walker, Kim, Farlow, Martin R., Hake, Ann Marie, Matthews, Brandy R., Brosch, Jared R., Herring, Scott, van, Christopher H., Mecca, Adam P., Good, Susan P., MacAvoy, Martha G., Carson, Richard E., Varma, Pradeep, Chertkow, Howard, Vaitekunis, Susan, Hosein, Chris, Black, Sandra, Stefanovic, Bojana, Heyn, Chris (Chinthaka), Robin Hsiung, Ging-Yuek, Kim, Ellen, Mudge, Benita, Sossi, Vesna, Feldman, Howard, Assaly, Michele, Finger, Elizabeth, Pasternak, Stephen, Rachinsky, Irina, Kertesz, Andrew, Drost, Dick, Rogers, John, Grant, Ian, Muse, Brittanie, Rogalski, Emily, Robson, Jordan, Mesulam, M.-Marsel, Kerwin, Diana, Wu, Chuang-Kuo, Johnson, Nancy, Lipowski, Kristine, Weintraub, Sandra, Bonakdarpour, Borna, Pomara, Nunzio, Hernando, Raymundo, Sarrael, Antero, Rosen, Howard J., Miller, Bruce L., Perry, David, Turner, Raymond Scott, Johnson, Kathleen, Reynolds, Brigid, MCCann, Kelly, Poe, Jessica, Sperling, Reisa A., Johnson, Keith A., Marshall, Gad A., Yesavage, Jerome, Taylor, Joy L., Chao, Steven, Coleman, Jaila, White, Jessica D., Lane, Barton, Rosen, Allyson, Tinklenberg, Jared, Belden, Christine M., Atri, Alireza, Clark, Kelly A., Zamrini, Edward, Sabbagh, Marwan, Killiany, Ronald, Stern, Robert, Mez, Jesse, Kowall, Neil, Budson, Andrew E., Obisesan, Thomas O., Ntekim, Oyonumo E., Wolday, Saba, Khan, Javed I., Nwulia, Evaristus, Nadarajah, Sheeba, Lerner, Alan, Ogrocki, Paula, Tatsuoka, Curtis, Fatica, Parianne, Maillard, Pauline, Olichney, John, Carmichael, Owen, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Borrie, Michael, Lee, T.-Y., Bartha, Dr Rob, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M., Perrin, Allison, Burke, Anna, Scharre, Douglas W., Kataki, Maria, Tarawneh, Rawan, Hart, David, Zimmerman, Earl A., Celmins, Dzintra, Miller, Delwyn D., BolesPonto, Laura L., Smith, Karen Ekstam, Koleva, Hristina, Shim, Hyungsub, Nam, Ki Won, Schultz, Susan K., Williamson, Jeff D., Craft, Suzanne, Cleveland, Jo, Yang, Mia, Sink, Kaycee M., Ott, Brian R., Drake, Jonathan, Tremont, Geoffrey, Daiello, Lori A., Drake, Jonathan D., Ritter, Aaron, Bernick, Charles, Munic, Donna, O'Connelll, Abigail, Mintzer, Jacobo, Wiliams, Arthur, Masdeu, Joseph, Shi, Jiong, Garcia, Angelica, Newhouse, Paul, Potkin, Steven, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Kittur, Smita, Pearlson, Godfrey D., Blank, Karen, Anderson, Karen, Flashman, Laura A., Seltzer, Marc, Hynes, Mary L., Santulli, Robert B., Relkin, Norman, Chiang, Gloria, Lee, Athena, Lin, Michael, Ravdin, Lisa, Petersen, Ron, Neylan, Thomas, Grafman, Jordan, Danowski, Sarah, Nguyen-Barrera, Catherine, Hayes, Jacqueline, Finley, Shannon, Bernstein, Matthew, Senjem, Matt, Foster, Norm, Kim, Sungeun, Sood, Ajay, Blanchard, Kimberly S., Fleischman, Debra, Arfanakis, Konstantinos, Varon, Daniel, Greig, Maria T., Petrella, Jeffrey R., Goldstein, Bonnie, Martin, Kimberly S., Reist, Christopher, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Rosen, Howard, Marshall, Gad, Peskind, Elaine R., Petrie, Eric C., Li, Gail, Mackin, Scott, Jimenez-Maggiora, Gustavo, Drake, Erin, Donohue, Mike, Nelson, Craig, Bickford, David, Butters, Meryl, Zmuda, Michelle, Reyes, Denise, Faber, Kelley M., Nudelman, Kelly N., Au, Yiu Ho, Scherer, Kelly, Catalinotto, Daniel, Stark, Samuel, Ong, Elise, Fernandez, Dariella, Jo, Taeho, Kim, Junpyo, Bice, Paula, Huynh, Kevin, Wang, Tingting, Meikle, Peter J., and Giles, Corey

Published
2023
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35. Hearing intervention versus health education control to reduce cognitive decline in older adults with hearing loss in the USA (ACHIEVE): a multicentre, randomised controlled trial

Author

Lin, Frank R, Pike, James R, Albert, Marilyn S, Arnold, Michelle, Burgard, Sheila, Chisolm, Theresa, Couper, David, Deal, Jennifer A, Goman, Adele M, Glynn, Nancy W, Gmelin, Theresa, Gravens-Mueller, Lisa, Hayden, Kathleen M, Huang, Alison R, Knopman, David, Mitchell, Christine M, Mosley, Thomas, Pankow, James S, Reed, Nicholas S, Sanchez, Victoria, Schrack, Jennifer A, Windham, B Gwen, and Coresh, Josef

Published
2023
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37. Brain volumetric deficits in MAPT mutation carriers: a multisite study

Author

Chu, Stephanie A, Flagan, Taru M, Staffaroni, Adam M, Jiskoot, Lize C, Deng, Jersey, Spina, Salvatore, Zhang, Liwen, Sturm, Virginia E, Yokoyama, Jennifer S, Seeley, William W, Papma, Janne M, Geschwind, Dan H, Rosen, Howard J, Boeve, Bradley F, Boxer, Adam L, Heuer, Hilary W, Forsberg, Leah K, Brushaber, Danielle E, Grossman, Murray, Coppola, Giovanni, Dickerson, Bradford C, Bordelon, Yvette M, Faber, Kelley, Feldman, Howard H, Fields, Julie A, Fong, Jamie C, Foroud, Tatiana, Gavrilova, Ralitza H, Ghoshal, Nupur, Graff‐Radford, Neill R, Hsiung, Ging‐Yuek Robin, Huey, Edward D, Irwin, David J, Kantarci, Kejal, Kaufer, Daniel I, Karydas, Anna M, Knopman, David S, Kornak, John, Kramer, Joel H, Kukull, Walter A, Lapid, Maria I, Litvan, Irene, Mackenzie, Ian RA, Mendez, Mario F, Miller, Bruce L, Onyike, Chiadi U, Pantelyat, Alexander Y, Rademakers, Rosa, Ramos, Eliana Marisa, Roberson, Erik D, Tartaglia, Maria Carmela, Tatton, Nadine A, Toga, Arthur W, Vetor, Ashley, Weintraub, Sandra, Wong, Bonnie, Wszolek, Zbigniew K, Consortium, the ARTFL LEFFTDS, Van Swieten, John C, and Lee, Suzee E

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Psychology, Aging, Rare Diseases, Acquired Cognitive Impairment, Neurosciences, Neurodegenerative, Dementia, Frontotemporal Dementia (FTD), Brain Disorders, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adult, Aged, Brain, Female, Frontotemporal Dementia, Heterozygote, Humans, Male, Middle Aged, Mutation, tau Proteins, ARTFL/LEFFTDS Consortium, Clinical Sciences, Clinical and health psychology
Abstract

ObjectiveMAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach.MethodsWe studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers' clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson's disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype.ResultsSymptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers.InterpretationA subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.

Published
2021

39. Cerebral small vessel disease genomics and its implications across the lifespan.

Author

Sargurupremraj, Muralidharan, Suzuki, Hideaki, Jian, Xueqiu, Sarnowski, Chloé, Evans, Tavia E, Bis, Joshua C, Eiriksdottir, Gudny, Sakaue, Saori, Terzikhan, Natalie, Habes, Mohamad, Zhao, Wei, Armstrong, Nicola J, Hofer, Edith, Yanek, Lisa R, Hagenaars, Saskia P, Kumar, Rajan B, van den Akker, Erik B, McWhirter, Rebekah E, Trompet, Stella, Mishra, Aniket, Saba, Yasaman, Satizabal, Claudia L, Beaudet, Gregory, Petit, Laurent, Tsuchida, Ami, Zago, Laure, Schilling, Sabrina, Sigurdsson, Sigurdur, Gottesman, Rebecca F, Lewis, Cora E, Aggarwal, Neelum T, Lopez, Oscar L, Smith, Jennifer A, Valdés Hernández, Maria C, van der Grond, Jeroen, Wright, Margaret J, Knol, Maria J, Dörr, Marcus, Thomson, Russell J, Bordes, Constance, Le Grand, Quentin, Duperron, Marie-Gabrielle, Smith, Albert V, Knopman, David S, Schreiner, Pamela J, Evans, Denis A, Rotter, Jerome I, Beiser, Alexa S, Maniega, Susana Muñoz, Beekman, Marian, Trollor, Julian, Stott, David J, Vernooij, Meike W, Wittfeld, Katharina, Niessen, Wiro J, Soumaré, Aicha, Boerwinkle, Eric, Sidney, Stephen, Turner, Stephen T, Davies, Gail, Thalamuthu, Anbupalam, Völker, Uwe, van Buchem, Mark A, Bryan, R Nick, Dupuis, Josée, Bastin, Mark E, Ames, David, Teumer, Alexander, Amouyel, Philippe, Kwok, John B, Bülow, Robin, Deary, Ian J, Schofield, Peter R, Brodaty, Henry, Jiang, Jiyang, Tabara, Yasuharu, Setoh, Kazuya, Miyamoto, Susumu, Yoshida, Kazumichi, Nagata, Manabu, Kamatani, Yoichiro, Matsuda, Fumihiko, Psaty, Bruce M, Bennett, David A, De Jager, Philip L, Mosley, Thomas H, Sachdev, Perminder S, Schmidt, Reinhold, Warren, Helen R, Evangelou, Evangelos, Trégouët, David-Alexandre, International Network against Thrombosis (INVENT) Consortium, International Headache Genomics Consortium (IHGC), Ikram, Mohammad A, Wen, Wei, DeCarli, Charles, Srikanth, Velandai K, Jukema, J Wouter, Slagboom, Eline P, and Kardia, Sharon LR

Subjects
International Network against Thrombosis (INVENT) Consortium, International Headache Genomics Consortium, Humans, Alzheimer Disease, Hypertension, Medical History Taking, Risk Assessment, Risk Factors, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Stroke, Genome-Wide Association Study, Young Adult, Diffusion Tensor Imaging, Genetic Loci, Mendelian Randomization Analysis, Cerebral Small Vessel Diseases, White Matter, and over
Abstract

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.

Published
2020

40. Studying the natural history of frontotemporal lobar degeneration (FTLD): The ARTFL LEFFTDS longitudinal FTLD (ALLFTD) protocol

Author

Boeve, Bradley F, Boxer, Adam L, Rosen, Howard J, Forsberg, Leah K, Heuer, Hilary W, Brushaber, Danielle, Appleby, Brian, Biernacka, Joanna M, Bordelon, Yvette M, Botha, Hugo, Brannelly, Patrick, Dickerson, Brad C, Dickson, Dennis W, Kimiko, Domoto‐Reilly, Faber, Kelley, Fagan, Anne, Fields, Julie A, Fishman, Ann, Foroud, Tatiana M, Galasko, Doug R, Gavrilova, Ralitza H, Gendron, Tania F, Geschwind, Daniel H, Ghoshal, Nupur, Goldman, Jill, Graff‐Radford, Jonathan, Graff‐Radford, Neill R, Grant, Ian, Grossman, Murray, Hsiung, Ging‐Yuek Robin, Huang, Eric J, Huey, Edward, Irwin, David J, Jones, David T, Kantarci, Kejal, Karydas, Anna M, Kaufer, Daniel, Knopman, David S, Kramer, Joel H, Kremers, Walter K, Kornak, John, Kukull, Walter A, Lagone, Emma, Leger, Gabriel C, Litvan, Irene, Ljubenkov, Peter A, Lucente, Diane E, Mackenzie, Ian R, Manoochehri, Masood, Masdeu, Joseph C, McGinnis, Scott, Mendez, Mario F, Miller, Bruce L, Miyagawa, Toji, Nelson, Kevin M, Onyike, Chiadi U, Pantelyat, Alex, Pascual, Belen, Pearlman, Rodney, Petrucelli, Leonard, Rademakers, Rosa, Ramos, Eliana Marisa, Rankin, Katherine, Rascovsky, Katya, Rexach, Jessica E, Ritter, Aaron, Roberson, Erik D, Rojas, Julio C, Sabbagh, Marwan N, Salmon, David P, Savica, Rodolfo, Seeley, William W, Staffaroni, Adam M, Syrjanen, Jeremy, Tartaglia, Carmela, Tatton, Nadine, Taylor, Joanne, Toga, Arthur W, Weintraub, Sandra, Wheaton, Diana, Wong, Bonnie, and Wszolek, Zbigniew

Subjects
Brain Disorders, Rare Diseases, Acquired Cognitive Impairment, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Trials and Supportive Activities, Clinical Research, Frontotemporal Dementia (FTD), Alzheimer's Disease Related Dementias (ADRD), Genetics, Neurosciences, Dementia, 2.1 Biological and endogenous factors, Geriatrics, Clinical Sciences
Published
2020

42. How Good is Artificial Intelligence at Automatically Answering Consumer Questions Related to Alzheimer's Disease?

Author

Soundararajan, Krishna B., Fu, Sunyang, Carlson, Luke A., Smith, Rebecca A., Knopman, David S., Liu, Hongfang, and Wang, Yanshan

Subjects
Computer Science - Information Retrieval, Computer Science - Computation and Language
Abstract

Alzheimer's Disease (AD) is the most common type of dementia, comprising 60-80% of cases. There were an estimated 5.8 million Americans living with Alzheimer's dementia in 2019, and this number will almost double every 20 years. The total lifetime cost of care for someone with dementia is estimated to be $350,174 in 2018, 70% of which is associated with family-provided care. Most family caregivers face emotional, financial and physical difficulties. As a medium to relieve this burden, online communities in social media websites such as Twitter, Reddit, and Yahoo! Answers provide potential venues for caregivers to search relevant questions and answers, or post questions and seek answers from other members. However, there are often a limited number of relevant questions and responses to search from, and posted questions are rarely answered immediately. Due to recent advancement in Artificial Intelligence (AI), particularly Natural Language Processing (NLP), we propose to utilize AI to automatically generate answers to AD-related consumer questions posted by caregivers and evaluate how good AI is at answering those questions. To the best of our knowledge, this is the first study in the literature applying and evaluating AI models designed to automatically answer consumer questions related to AD.

Published
2019

43. Prioritization of Drug Targets for Neurodegenerative Diseases by Integrating Genetic and Proteomic Data From Brain and Blood

Author

Ferrari, Raffaele, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Ramasamy, Adaikalavan, Kwok, John B.J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J., Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R.A., Hsiung, Ging-Yuek R., Mann, David M.A., Grafman, Jordan, Morris, Christopher M., Attems, Johannes, Griffiths, Timothy D., McKeith, Ian G., Thomas, Alan J., Pietrini, P., Huey, Edward D., Wassermann, Eric M., Baborie, Atik, Jaros, Evelyn, Tierney, Michael C., Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C.M., Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., van der Zee, Julie, Deschamps, William, Van Langenhove, Tim, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F., Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E., Hjermind, Lena E., Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Richardson, Anna, Gerhard, Alexander, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, van Swieten, John C., Dopper, Elise G.P., Seelaar, Harro, Pijnenburg, Yolande A.L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebert, Florence, Kapogiannis, Dimitrios, Ferrucci, Luigi, Pickering-Brown, Stuart, Singleton, Andrew B., Hardy, John, Momeni, Parastoo, Ge, Yi-Jun, Ou, Ya-Nan, Deng, Yue-Ting, Wu, Bang-Sheng, Yang, Liu, Zhang, Ya-Ru, Chen, Shi-Dong, Huang, Yu-Yuan, Dong, Qiang, Tan, Lan, and Yu, Jin-Tai

Published
2023
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44. Quality of life and caregiver burden in familial frontotemporal lobar degeneration: Analyses of symptomatic and asymptomatic individuals within the LEFFTDS cohort

Author

Gentry, Melanie T, Lapid, Maria I, Syrjanen, Jeremy, Calvert, Kendrick, Hughes, Samantha, Brushaber, Danielle, Kremers, Walter, Bove, Jessica, Brannelly, Patrick, Coppola, Giovanni, Dheel, Christina, Dickerson, Bradley, Dickinson, Susan, Faber, Kelley, Fields, Julie, Fong, Jamie, Foroud, Tatiana, Forsberg, Leah, Gavrilova, Ralitza, Gearhart, Deb, Ghoshal, Nupur, Goldman, Jill, Graff‐Radford, Jonathan, Graff‐Radford, Neill, Grossman, Murray, Haley, Dana, Heuer, Hilary, Hsiung, Ging‐Yuek, Huey, Edward, Irwin, David, Jones, David, Jones, Lynne, Kantarci, Kejal, Karydas, Anna, Knopman, David, Kornak, John, Kramer, Joel, Kukull, Walter, Lucente, Diane, Lungu, Codrin, Mackenzie, Ian, Manoochehri, Masood, McGinnis, Scott, Miller, Bruce, Pearlman, Rodney, Petrucelli, Len, Potter, Madeline, Rademakers, Rosa, Ramos, Eliana Marisa, Rankin, Katherine, Rascovsky, Katya, Sengdy, Pheth, Shaw, Leslie, Tatton, Nadine, Taylor, Joanne, Toga, Arthur, Trojanowski, John, Weintraub, Sandra, Wong, Bonnie, Wszolek, Zbigniew, Boeve, Bradley F, Boxer, Adam, Rosen, Howard, and Consortium, the LEFFTDS

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Aging, Acquired Cognitive Impairment, Frontotemporal Dementia (FTD), Behavioral and Social Science, Brain Disorders, Clinical Research, Neurodegenerative, Alzheimer's Disease, Adolescent, Adult, Aged, Aged, 80 and over, Caregivers, Cohort Studies, Cost of Illness, Female, Frontotemporal Lobar Degeneration, Humans, Longitudinal Studies, Male, Middle Aged, Quality of Life, Young Adult, C9orf72, frontotemporal dementia, GRN, MAPT, quality of life, tau, TDP-43, LEFFTDS Consortium, Geriatrics, Clinical sciences, Biological psychology
Abstract

ObjectiveThe Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects evaluates familial frontotemporal lobar degeneration (FTLD) kindreds with MAPT, GRN, or C9orf72 mutations. Objectives were to examine whether health-related quality of life (HRQoL) correlates with clinical symptoms and caregiver burden, and whether self-rated and informant-rated HRQoL would correlate with each other.MethodsIndividuals were classified using the Clinical Dementia Rating (CDR® ) Scale plus National Alzheimer's Coordinating Center (NACC) FTLD. HRQoL was measured with DEMQOL and DEMQOL-proxy; caregiver burden with the Zarit Burden Interview (ZBI). For analysis, Pearson correlations and weighted kappa statistics were calculated.ResultsThe cohort of 312 individuals included symptomatic and asymptomatic individuals. CDR® plus NACC FTLD was negatively correlated with DEMQOL (r = -0.20, P = .001), as were ZBI and DEMQOL (r = -0.22, P = .0009). There was fair agreement between subject and informant DEMQOL (κ = 0.36, P

Published
2020

45. Longitudinal structural and metabolic changes in frontotemporal dementia.

Author

Bejanin, Alexandre, Tammewar, Gautam, Marx, Gabe, Cobigo, Yann, Iaccarino, Leonardo, Kornak, John, Staffaroni, Adam M, Dickerson, Bradford C, Boeve, Bradley F, Knopman, David S, Gorno-Tempini, Marilu, Miller, Bruce L, Jagust, William J, Boxer, Adam L, Rosen, Howard J, and Rabinovici, Gil D

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Brain Disorders, Biomedical Imaging, Frontotemporal Dementia (FTD), Dementia, Neurodegenerative, Acquired Cognitive Impairment, Aging, Clinical Research, Alzheimer's Disease, Aphasia, Neurosciences, Rare Diseases, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Atrophy, Cerebral Cortex, Disease Progression, Female, Fluorodeoxyglucose F18, Frontotemporal Dementia, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Neuroimaging, Neuropsychological Tests, Positron-Emission Tomography, Radiopharmaceuticals, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo compare the sensitivity of structural MRI and 18F-fludeoxyglucose PET (18FDG-PET) to detect longitudinal changes in frontotemporal dementia (FTD).MethodsThirty patients with behavioral variant FTD (bvFTD), 7 with nonfluent/agrammatic variant primary progressive aphasia (nfvPPA), 16 with semantic variant primary progressive aphasia (svPPA), and 43 cognitively normal controls underwent 2-4 MRI and 18FDG-PET scans (total scans/visit = 270) as part of the Frontotemporal Lobar Degeneration Neuroimaging Initiative study. Linear mixed-effects models were carried out voxel-wise and in regions of interest to identify areas showing decreased volume or metabolism over time in patients as compared to controls.ResultsAt baseline, patients with bvFTD showed bilateral temporal, dorsolateral, and medial prefrontal atrophy/hypometabolism that extended with time into adjacent structures and parietal lobe. In nfvPPA, baseline atrophy/hypometabolism in supplementary motor cortex extended with time into left greater than right precentral, dorsolateral, and dorsomedial prefrontal cortex. In svPPA, baseline atrophy/hypometabolism encompassed the anterior temporal and medial prefrontal cortex and longitudinal changes were found in temporal, orbitofrontal, and lateral parietal cortex. Across syndromes, there was substantial overlap in the brain regions showing volume and metabolism loss. Even though the pattern of metabolic decline was more extensive, metabolic changes were also more variable and sample size estimates were similar or higher for 18FDG-PET compared to MRI.ConclusionOur findings demonstrated the sensitivity of 18FDG-PET and structural MRI for tracking disease progression in FTD. Both modalities showed highly overlapping patterns of longitudinal change and comparable sample size estimates to detect longitudinal changes in future clinical trials.

Published
2020

46. Revised Self-Monitoring Scale: A potential endpoint for frontotemporal dementia clinical trials.

Author

Toller, Gianina, Ranasinghe, Kamalini, Cobigo, Yann, Staffaroni, Adam, Appleby, Brian, Brushaber, Danielle, Coppola, Giovanni, Dickerson, Bradford, Domoto-Reilly, Kimiko, Fields, Julie, Fong, Jamie, Forsberg, Leah, Ghoshal, Nupur, Graff-Radford, Neill, Grossman, Murray, Heuer, Hilary, Hsiung, Gink-Yuek, Huey, Edward, Irwin, David, Kantarci, Kejal, Kaufer, Daniel, Kerwin, Diana, Knopman, David, Kornak, John, Kramer, Joel, Litvan, Irene, Mackenzie, Ian, Mendez, Mario, Miller, Bruce, Rademakers, Rosa, Ramos, Eliana, Rascovsky, Katya, Roberson, Erik, Syrjanen, Jeremy, Tartaglia, Carmela, Weintraub, Sandra, Boeve, Brad, Boxer, Adam, Rosen, Howard, and Rankin, Katherine

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Neurodegenerative, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Trials and Supportive Activities, Aging, Brain Disorders, Clinical Research, Dementia, Alzheimer's Disease, Neurosciences, Adult, Aged, Caregivers, Clinical Trials as Topic, Expressed Emotion, Facial Expression, Female, Frontotemporal Dementia, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Reproducibility of Results, Self-Management, Surveys and Questionnaires, ARTFL/LEFFTDS Consortium, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo investigate whether the Revised Self-Monitoring Scale (RSMS), an informant measure of socioemotional sensitivity, is a potential clinical endpoint for treatment trials for patients with behavioral variant frontotemporal dementia (bvFTD).MethodsWe investigated whether RSMS informant ratings reflected disease severity in 475 participants (71 bvFTD mutation+, 154 bvFTD mutation-, 12 behavioral mild cognitive impairment [MCI] mutation+, 98 asymptomatic mutation+, 140 asymptomatic mutation-). In a subset of 62 patients (20 bvFTD mutation+, 35 bvFTD mutation-, 7 MCI mutation+) who had at least 2 time points of T1-weighted images available on the same 3T scanner, we examined longitudinal changes in RSMS score over time and its correspondence to progressive gray matter atrophy.ResultsRSMS score showed a similar pattern in mutation carriers and noncarriers, with significant drops at each stage of progression from asymptomatic to very mild, mild, moderate, and severe disease (F 4,48 = 140.10, p < 0.001) and a significant slope of decline over time in patients with bvFTD (p = 0.004, 95% confidence interval [CI] -1.90 to -0.23). More rapid declines on the RSMS corresponded to faster gray matter atrophy predominantly in the salience network (SN), and RSMS score progression best predicted thalamic volume in very mild and mild disease stages of bvFTD. Higher RSMS score predicted more caregiver burden (p < 0.001, 95% CI -0.30 to -0.11).ConclusionsThe RSMS is sensitive to progression of both socioemotional symptoms and SN atrophy in patients with bvFTD and corresponds directly to caregiver burden. The RSMS may be useful in both neurologic practice and clinical trials aiming to treat behavioral symptoms of patients with bvFTD.

Published
2020

47. Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

Author

van der Lee, Sven J, Conway, Olivia J, Jansen, Iris, Carrasquillo, Minerva M, Kleineidam, Luca, van den Akker, Erik, Hernández, Isabel, van Eijk, Kristel R, Stringa, Najada, Chen, Jason A, Zettergren, Anna, Andlauer, Till FM, Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E, Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J, Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A, Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, van Berckel, Bart NM, Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank), IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia), Netherlands Brain Bank (NBB), Boeve, Bradley F, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel JT, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande AL, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild IA, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, and Clarimón, Jordi

Subjects
DESGESCO, EADB, IFGC, IPDGC, RiMod-FTD, Netherlands Brain Bank, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Acquired Cognitive Impairment, Brain Disorders, Neurodegenerative, Alzheimer's Disease, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Aging, Parkinson's Disease, Genetics, 2.1 Biological and endogenous factors, Neurological, Neurology & Neurosurgery, Clinical Sciences
Abstract

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.

Published
2020

48. Trajectory of lobar atrophy in asymptomatic and symptomatic GRN mutation carriers: a longitudinal MRI study

Author

Chen, Qin, Boeve, Bradley F, Senjem, Matthew, Tosakulwong, Nirubol, Lesnick, Timothy, Brushaber, Danielle, Dheel, Christina, Fields, Julie, Forsberg, Leah, Gavrilova, Ralitza, Gearhart, Debra, Graff-Radford, Jonathan, Graff-Radford, Neill, Jack, Clifford R, Jones, David, Knopman, David, Kremers, Walter K, Lapid, Maria, Rademakers, Rosa, Ramos, Eliana Marisa, Syrjanen, Jeremy, Boxer, Adam L, Rosen, Howie, Wszolek, Zbigniew K, and Kantarci, Kejal

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Brain Disorders, Biomedical Imaging, Neurosciences, Alzheimer's Disease Related Dementias (ADRD), Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Frontotemporal Dementia (FTD), Dementia, Acquired Cognitive Impairment, Neurodegenerative, Neurological, Adult, Asymptomatic Diseases, Atrophy, Female, Frontotemporal Lobar Degeneration, Heterozygote, Humans, Loss of Function Mutation, Magnetic Resonance Imaging, Male, Middle Aged, Progranulins, Temporal Lobe, Young Adult, Magnetic resonance image, GRN, Asymptomatic, Frontotemporal dementia, Longitudinal, Neurology & Neurosurgery, Biological psychology
Abstract

Loss-of-function mutations in the progranulin gene (GRN) are one of the major causes of familial frontotemporal lobar degeneration. Our objective was to determine the rates and trajectories of lobar cortical atrophy from longitudinal structural magnetic resonance imaging in both asymptomatic and symptomatic GRN mutation carriers. Individuals in this study were from the ADRC and LEFFTDS studies at the Mayo Clinic. We identified 13 GRN mutation carriers (8 asymptomatic, 5 symptomatic) and noncarriers (n = 10) who had at least 2 serial T1-weighted structural magnetic resonance images and were followed annually with a median of 3 years (range 1.0-9.8 years). Longitudinal changes in lobar cortical volume were analyzed using the tensor-based morphometry with symmetric normalization (TBM-SyN) algorithm. Linear mixed-effect models were used to model cortical volume change over time among 3 groups. The annual rates of frontal (p < 0.05) and parietal (p < 0.01) lobe cortical atrophy were higher in asymptomatic GRN mutation carriers than noncarriers. The symptomatic GRN mutation carriers also had increased rates of atrophy in the frontal (p < 0.01) and parietal lobe (p < 0.01) cortices than noncarriers. In addition, greater rates of cortical atrophy were observed in the temporal lobe cortices of symptomatic GRN mutation carriers than noncarriers (p < 0.001). We found that a decline in frontal and parietal lobar cortical volume occurs in asymptomatic GRN mutation carriers and continues in the symptomatic GRN mutation carriers, whereas an increased rate of temporal lobe cortical atrophy is observed only in symptomatic GRN mutation carriers. This sequential pattern of cortical involvement in GRN mutation carriers has important implications for using imaging biomarkers of neurodegeneration as an outcome measure in potential treatment trials involving GRN mutation carriers.

Published
2020

49. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study.

Author

Moore, Katrina M, Nicholas, Jennifer, Grossman, Murray, McMillan, Corey T, Irwin, David J, Massimo, Lauren, Van Deerlin, Vivianna M, Warren, Jason D, Fox, Nick C, Rossor, Martin N, Mead, Simon, Bocchetta, Martina, Boeve, Bradley F, Knopman, David S, Graff-Radford, Neill R, Forsberg, Leah K, Rademakers, Rosa, Wszolek, Zbigniew K, van Swieten, John C, Jiskoot, Lize C, Meeter, Lieke H, Dopper, Elise Gp, Papma, Janne M, Snowden, Julie S, Saxon, Jennifer, Jones, Matthew, Pickering-Brown, Stuart, Le Ber, Isabelle, Camuzat, Agnès, Brice, Alexis, Caroppo, Paola, Ghidoni, Roberta, Pievani, Michela, Benussi, Luisa, Binetti, Giuliano, Dickerson, Bradford C, Lucente, Diane, Krivensky, Samantha, Graff, Caroline, Öijerstedt, Linn, Fallström, Marie, Thonberg, Håkan, Ghoshal, Nupur, Morris, John C, Borroni, Barbara, Benussi, Alberto, Padovani, Alessandro, Galimberti, Daniela, Scarpini, Elio, Fumagalli, Giorgio G, Mackenzie, Ian R, Hsiung, Ging-Yuek R, Sengdy, Pheth, Boxer, Adam L, Rosen, Howie, Taylor, Joanne B, Synofzik, Matthis, Wilke, Carlo, Sulzer, Patricia, Hodges, John R, Halliday, Glenda, Kwok, John, Sanchez-Valle, Raquel, Lladó, Albert, Borrego-Ecija, Sergi, Santana, Isabel, Almeida, Maria Rosário, Tábuas-Pereira, Miguel, Moreno, Fermin, Barandiaran, Myriam, Indakoetxea, Begoña, Levin, Johannes, Danek, Adrian, Rowe, James B, Cope, Thomas E, Otto, Markus, Anderl-Straub, Sarah, de Mendonça, Alexandre, Maruta, Carolina, Masellis, Mario, Black, Sandra E, Couratier, Philippe, Lautrette, Geraldine, Huey, Edward D, Sorbi, Sandro, Nacmias, Benedetta, Laforce, Robert, Tremblay, Marie-Pier L, Vandenberghe, Rik, Damme, Philip Van, Rogalski, Emily J, Weintraub, Sandra, Gerhard, Alexander, Onyike, Chiadi U, Ducharme, Simon, Papageorgiou, Sokratis G, Ng, Adeline Su Lyn, Brodtmann, Amy, Finger, Elizabeth, and Guerreiro, Rita

Subjects
FTD Prevention Initiative, Humans, Disease Progression, tau Proteins, Retrospective Studies, Cohort Studies, Family, Age of Onset, Phenotype, Mutation, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Frontotemporal Dementia, C9orf72 Protein, Progranulins, Clinical Research, Rare Diseases, Dementia, Aging, Brain Disorders, Genetic Testing, Neurodegenerative, Neurosciences, Alzheimer's Disease Related Dementias (ADRD), Prevention, Genetics, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 2.1 Biological and endogenous factors, Neurological, Neurology & Neurosurgery, Clinical Sciences
Abstract

BackgroundFrontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72.MethodsIn this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried.FindingsData were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0·45 between individual and parental age at onset, r=0·63 between individual and mean family age at onset, r=0·58 between individual and parental age at death, and r=0·69 between individual and mean family age at death) than in either the C9orf72 group (r=0·32 individual and parental age at onset, r=0·36 individual and mean family age at onset, r=0·38 individual and parental age at death, and r=0·40 individual and mean family age at death) or the GRN group (r=0·22 individual and parental age at onset, r=0·18 individual and mean family age at onset, r=0·22 individual and parental age at death, and r=0·32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35-62, for age at onset; 61%, 47-73, for age at death), and even more by family membership (66%, 56-75, for age at onset; 74%, 65-82, for age at death). In the GRN group, only 2% (0-10) of the variability of age at onset and 9% (3-21) of that of age of death was explained by the specific mutation, whereas 14% (9-22) of the variability of age at onset and 20% (12-30) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11-26) of the variability of age at onset and 19% (12-29) of that of age at death.InterpretationOur study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates.FundingUK Medical Research Council, National Institute for Health Research, and Alzheimer's Society.

Published
2020

50. Use of the CDR® plus NACC FTLD in mild FTLD: Data from the ARTFL/LEFFTDS consortium.

Author

Miyagawa, Toji, Brushaber, Danielle, Syrjanen, Jeremy, Kremers, Walter, Fields, Julie, Forsberg, Leah K, Heuer, Hilary W, Knopman, David, Kornak, John, Boxer, Adam, Rosen, Howie, Boeve, Bradley, and ARTFL/LEFFTDS Consortium

Subjects
ARTFL/LEFFTDS Consortium, Humans, Cross-Sectional Studies, Behavior, Language, Personality, Adult, Aged, Middle Aged, Female, Frontotemporal Lobar Degeneration, Frontotemporal Dementia, Mental Status and Dementia Tests, CDR®, Comportment and personality, Frontotemporal dementia, Frontotemporal lobar degeneration, NACC FTLD Module, Primary progressive aphasia, CDR, Primary progressive aphasia Language, Neurodegenerative, Acquired Cognitive Impairment, Alzheimer's Disease Related Dementias (ADRD), Clinical Research, Frontotemporal Dementia (FTD), Rare Diseases, Dementia, Behavioral and Social Science, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Aging, Geriatrics, Clinical Sciences
Abstract

IntroductionBehavior/Comportment/Personality (BEHAV) and Language (LANG) domains were added to the Clinical Dementia Rating (CDR®) for improving evaluation of patients with frontotemporal lobar degeneration (FTLD) (CDR® plus NACC FTLD).MethodsWe analyzed the CDR® plus NACC FTLD among participants from the baseline visit of the Advancing Research and Treatment for Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects Consortium.ResultsThe CDR® plus NACC FTLD was able to detect early symptoms in the mildly impaired participants who were rated as CDR® sum of boxes (CDR®-SB) = 0. The CDR®-SB was not sensitive, particularly in participants with mild nonfluent/agrammatic primary progressive aphasia. Participants with familial and sporadic behavioral variant FTD exhibited similar CDR® plus NACC FTLD profiles except that language impairment was more frequent in participants with mild sporadic behavioral variant FTD. Adding the BEHAV and/or LANG domains to the CDR®-SB significantly enhanced discriminatory power in differentiating among the FTLD spectrum disorders.DiscussionThe BEHAV and LANG domains enable the CDR® plus NACC FTLD to capture early symptomatology of FTLD.

Published
2020

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