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1. Disinhibition in dementia related to reduced morphometric similarity of cognitive control network.

Author

Jenkins, Lisanne, Heywood, Ashley, Gupta, Sonya, Kouchakidivkolaei, Maryam, Sridhar, Jaiashre, Rogalski, Emily, Weintraub, Sandra, Popuri, Karteek, Wang, Lei, and Rosen, Howard

Subjects
Alzheimer’s dementia, MRI, behavioural variant frontotemporal dementia, disinhibition, morphometric similarity networks
Abstract

Disinhibition is one of the most distressing and difficult to treat neuropsychiatric symptoms of dementia. It involves socially inappropriate behaviours, such as hypersexual comments, inappropriate approaching of strangers and excessive jocularity. Disinhibition occurs in multiple dementia syndromes, including behavioural variant frontotemporal dementia, and dementia of the Alzheimers type. Morphometric similarity networks are a relatively new method for examining brain structure and can be used to calculate measures of network integrity on large scale brain networks and subnetworks such as the salience network and cognitive control network. In a cross-sectional study, we calculated morphometric similarity networks to determine whether disinhibition in behavioural variant frontotemporal dementia (n = 75) and dementia of the Alzheimers type (n = 111) was associated with reduced integrity of these networks independent of diagnosis. We found that presence of disinhibition, measured by the Neuropsychiatric Inventory Questionnaire, was associated with reduced global efficiency of the cognitive control network in both dementia of the Alzheimers type and behavioural variant frontotemporal dementia. Future research should replicate this transdiagnostic finding in other dementia diagnoses and imaging modalities, and investigate the potential for intervention at the level of the cognitive control network to target disinhibition.

Published
2024

2. Predictors of Cognitive Change in Parkinson Disease

Author

Gasca-Salas, Carmen, Duff-Canning, Sarah, McArthur, Eric, Armstrong, Melissa J, Fox, Susan, Meaney, Christopher A, Tang-Wai, David F, Gill, David, Eslinger, Paul J, Zadikoff, Cindy, Marshall, Fred J, Mapstone, Mark, Chou, Kelvin L, Persad, Carol, Litvan, Irene, Mast, Benjamin T, Gerstenecker, Adam T, Weintraub, Sandra, and Marras, Connie

Subjects
Psychology, Applied and Developmental Psychology, Dementia, Neurodegenerative, Acquired Cognitive Impairment, Alzheimer's Disease, Behavioral and Social Science, Aging, Neurosciences, Mental Health, Brain Disorders, Parkinson's Disease, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aetiology, 2.1 Biological and endogenous factors, Neurological, Humans, Follow-Up Studies, Parkinson Disease, Cognitive Dysfunction, Cognition, Neuropsychological Tests, cognitive dysfunction, dementia, Parkinson disease, neuropsychological tests, longitudinal studies, Clinical Sciences, Cognitive Sciences, Geriatrics, Clinical sciences, Biological psychology
Abstract

BackgroundMild cognitive impairment is common in Parkinson disease (PD-MCI). However, instability in this clinical diagnosis and variability in rates of progression to dementia raises questions regarding its utility for longitudinal tracking and prediction of cognitive change in PD. We examined baseline neuropsychological test and cognitive diagnosis predictors of cognitive change in PD.MethodsPersons with PD, without dementia PD (N=138) underwent comprehensive neuropsychological assessment at baseline and were followed up to 2 years. Level II Movement Disorder Society criteria for PD-MCI and PD dementia (PDD) were applied annually. Composite global and domain cognitive z -scores were calculated based on a 10-test neuropsychological battery.ResultsBaseline diagnosis of PD-MCI was not associated with a change in global cognitive z -scores. Lower baseline attention and higher executive domain z -scores were associated with greater global cognitive z -score worsening regardless of cognitive diagnosis. Worse baseline domain z -scores in the attention and language domains were associated with progression to MCI or PDD, whereas higher baseline scores in all cognitive domains except executive function were associated with clinical and psychometric reversion to "normal" cognition.ConclusionsLower scores on cognitive tests of attention were predictive of worse global cognition over 2 years of follow-up in PD, and lower baseline attention and language scores were associated with progression to MCI or PDD. However, PD-MCI diagnosis per se was not predictive of cognitive decline over 2 years. The association between higher executive domain z -scores and greater global cognitive worsening is probably a spurious result.

Published
2023

3. Network Connectivity Alterations across the MAPT Mutation Clinical Spectrum

Author

Zhang, Liwen, Flagan, Taru M, Häkkinen, Suvi, Chu, Stephanie A, Brown, Jesse A, Lee, Alex J, Pasquini, Lorenzo, Mandelli, Maria Luisa, Gorno‐Tempini, Maria Luisa, Sturm, Virginia E, Yokoyama, Jennifer S, Appleby, Brian S, Cobigo, Yann, Dickerson, Bradford C, Domoto‐Reilly, Kimiko, Geschwind, Daniel H, Ghoshal, Nupur, Graff‐Radford, Neill R, Grossman, Murray, Hsiung, Ging‐Yuek Robin, Huey, Edward D, Kantarci, Kejal, Lago, Argentina Lario, Litvan, Irene, Mackenzie, Ian R, Mendez, Mario F, Onyike, Chiadi U, Ramos, Eliana Marisa, Roberson, Erik D, Tartaglia, Maria Carmela, Toga, Arthur W, Weintraub, Sandra, Wszolek, Zbigniew K, 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, the ARTFL LEFFTDS ALLFTD

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Dementia, Brain Disorders, Alzheimer's Disease Related Dementias (ADRD), Clinical Research, Frontotemporal Dementia (FTD), Mental Health, Alzheimer's Disease, Rare Diseases, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Acquired Cognitive Impairment, Neurodegenerative, Biomedical Imaging, 2.1 Biological and endogenous factors, Aetiology, Neurological, Humans, Cross-Sectional Studies, tau Proteins, Brain, Mutation, Gray Matter, Magnetic Resonance Imaging, Frontotemporal Dementia, Biomarkers, ARTFL/LEFFTDS/ALLFTD Consortia, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveMicrotubule-associated protein tau (MAPT) mutations cause frontotemporal lobar degeneration, and novel biomarkers are urgently needed for early disease detection. We used task-free functional magnetic resonance imaging (fMRI) mapping, a promising biomarker, to analyze network connectivity in symptomatic and presymptomatic MAPT mutation carriers.MethodsWe compared cross-sectional fMRI data between 17 symptomatic and 39 presymptomatic carriers and 81 controls with (1) seed-based analyses to examine connectivity within networks associated with the 4 most common MAPT-associated clinical syndromes (ie, salience, corticobasal syndrome, progressive supranuclear palsy syndrome, and default mode networks) and (2) whole-brain connectivity analyses. We applied K-means clustering to explore connectivity heterogeneity in presymptomatic carriers at baseline. Neuropsychological measures, plasma neurofilament light chain, and gray matter volume were compared at baseline and longitudinally between the presymptomatic subgroups defined by their baseline whole-brain connectivity profiles.ResultsSymptomatic and presymptomatic carriers had connectivity disruptions within MAPT-syndromic networks. Compared to controls, presymptomatic carriers showed regions of connectivity alterations with age. Two presymptomatic subgroups were identified by clustering analysis, exhibiting predominantly either whole-brain hypoconnectivity or hyperconnectivity at baseline. At baseline, these two presymptomatic subgroups did not differ in neuropsychological measures, although the hypoconnectivity subgroup had greater plasma neurofilament light chain levels than controls. Longitudinally, both subgroups showed visual memory decline (vs controls), yet the subgroup with baseline hypoconnectivity also had worsening verbal memory and neuropsychiatric symptoms, and extensive bilateral mesial temporal gray matter decline.InterpretationNetwork connectivity alterations arise as early as the presymptomatic phase. Future studies will determine whether presymptomatic carriers' baseline connectivity profiles predict symptomatic conversion. ANN NEUROL 2023;94:632-646.

Published
2023

4. LATE-NC risk alleles (in TMEM106B, GRN, and ABCC9 genes) among persons with African ancestry.

Author

Katsumata, Yuriko, Fardo, David W, Shade, Lincoln MP, Bowen, James D, Crane, Paul K, Jarvik, Gail P, Keene, C Dirk, Larson, Eric B, McCormick, Wayne C, McCurry, Susan M, Mukherjee, Shubhabrata, Kowall, Neil W, McKee, Ann C, Honig, Robert A, Lawrence, S, Vonsattel, Jean Paul, Williamson, Jennifer, Small, Scott, Burke, James R, Hulette, Christine M, Welsh-Bohmer, Kathleen A, Gearing, Marla, Lah, James J, Levey, Allan I, Wingo, Thomas S, Apostolova, Liana G, Farlow, Martin R, Ghetti, Bernardino, Saykin, Andrew J, Spina, Salvatore, Albert, Marilyn S, Lyketsos, Constantine G, Troncoso, Juan C, Frosch, Matthew P, Green, Robert C, Growdon, John H, Hyman, Bradley T, Tanzi, Rudolph E, Potter, Huntington, Dickson, Dennis W, Ertekin-Taner, Nilufer, Graff-Radford, Neill R, Parisi, Joseph E, Petersen, Ronald C, Duara, Ranjan, Buxbaum, Joseph D, Goate, Alison M, Sano, Mary, Masurkar, Arjun V, Wisniewski, Thomas, Bigio, Eileen H, Mesulam, Marsel, Weintraub, Sandra, Vassar, Robert, Kaye, Jeffrey A, Quinn, Joseph F, Woltjer, Randall L, Barnes, Lisa L, Bennett, David A, Schneider, Julie A, Yu, Lei, Henderson, Victor, Fallon, Kenneth B, Harrell, Lindy E, Marson, Daniel C, Roberson, Erik D, DeCarli, Charles, Jin, Lee-Way, Olichney, John M, Kim, Ronald, LaFerla, Frank M, Monuki, Edwin, Head, Elizabeth, Sultzer, David, Geschwind, Daniel H, Vinters, Harry V, Chesselet, Marie-Francoise, Galasko, Douglas R, Brewer, James B, Boxer, Adam, Karydas, Anna, Kramer, Joel H, Miller, Bruce L, Rosen, Howard J, Seeley, William W, Burns, Jeffrey M, Swerdlow, Russell H, Abner, Erin, Van Eldik, Linda J, Albin, Roger L, Lieberman, Andrew P, Paulson, Henry L, Arnold, Steven E, Trojanowski, John Q, Van Deerlin, Vivianna M, Hamilton, Ronald L, Kamboh, M Ilyas, Lopez, Oscar L, and Becker, James T

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Brain Disorders, Neurodegenerative, Alzheimer's Disease, Acquired Cognitive Impairment, Prevention, Aging, Minority Health, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Health Disparities, Genetics, 2.1 Biological and endogenous factors, Aetiology, Humans, Alleles, Polymorphism, Single Nucleotide, Alzheimer Disease, TDP-43 Proteinopathies, Progranulins, Membrane Proteins, Nerve Tissue Proteins, Sulfonylurea Receptors, Alzheimer’s Disease Genetics Consortium, KCNMB2, Diversity, Epidemiology, FTLD, Genome-Wide Association Studies, KATP, Neurology & Neurosurgery, Clinical sciences
Abstract

Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE neuropathologic changes (LATE-NC) in diverse populations. The defining neuropathologic feature of LATE-NC is TDP-43 proteinopathy, often with comorbid hippocampal sclerosis (HS). In terms of genetic risk factors, LATE-NC and/or HS are associated with single nucleotide variants (SNVs) in 3 genes-TMEM106B (rs1990622), GRN (rs5848), and ABCC9 (rs1914361 and rs701478). We evaluated these 3 genes in convenience samples of individuals of African ancestry. The allele frequencies of the LATE-associated alleles were significantly different between persons of primarily African (versus European) ancestry: In persons of African ancestry, the risk-associated alleles for TMEM106B and ABCC9 were less frequent, whereas the risk allele in GRN was more frequent. We performed an exploratory analysis of data from African-American subjects processed by the Alzheimer's Disease Genomics Consortium, with a subset of African-American participants (n = 166) having corroborating neuropathologic data through the National Alzheimer's Coordinating Center (NACC). In this limited-size sample, the ABCC9/rs1914361 SNV was associated with HS pathology. More work is required concerning the genetic factors influencing non-Alzheimer disease pathology such as LATE-NC in diverse cohorts.

Published
2023

5. 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

6. Differential Vulnerability of Hippocampal Subfields in Primary Age-Related Tauopathy and Chronic Traumatic Encephalopathy.

Author

Farrell, Kurt, Iida, Megan A, Cherry, Jonathan D, Casella, Alicia, Stein, Thor D, Bieniek, Kevin F, Walker, Jamie M, Richardson, Timothy E, White, Charles L, Alvarez, Victor E, Huber, Bertrand R, Dickson, Dennis W, Insausti, Ricardo, Dams-O'Connor, Kristen, Vonsattel, Jean-Paul, Teich, Andy F, Gearing, Marla, Glass, Jonathan, Troncoso, Juan C, Frosch, Matthew P, Hyman, Bradley T, Murray, Melissa E, Attems, Johannes, Flanagan, Margaret E, Mao, Qinwen, Mesulam, M-Marsel, Weintraub, Sandra, Woltjer, Randy L, Pham, Thao, Kofler, Julia, Schneider, Julie A, Yu, Lei, Purohit, Dushyant P, Haroutunian, Vahram, Hof, Patrick R, Gandy, Sam, Sano, Mary, Beach, Thomas G, Poon, Wayne, Kawas, Claudia H, Corrada, María M, Rissman, Robert A, Metcalf, Jeff, Shuldberg, Sara, Salehi, Bahar, Nelson, Peter T, Trojanowski, John Q, Lee, Edward B, Wolk, David A, McMillan, Corey T, Keene, C Dirk, Latimer, Caitlin S, Montine, Thomas J, Kovacs, Gabor G, Lutz, Mirjam I, Fischer, Peter, Perrin, Richard J, Cairns, Nigel J, McKee, Ann C, and Crary, John F

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Frontotemporal Dementia (FTD), Acquired Cognitive Impairment, Aging, Brain Disorders, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Chronic Traumatic Encephalopathy, Hippocampus, Humans, Neurofibrillary Tangles, Tauopathies, tau Proteins, Chronic traumatic encephalopathy, Primary age-related tauopathy, Repetitive head impacts, Tauopathy, Part Working Group, Neurology & Neurosurgery, Clinical sciences
Abstract

Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive mild head impacts characterized by perivascular hyperphosphorylated tau (p-tau) in neurofibrillary tangles (NFTs) and neurites in the depths of the neocortical sulci. In moderate to advanced CTE, NFTs accumulate in the hippocampus, potentially overlapping neuroanatomically with primary age-related tauopathy (PART), an age-related tauopathy characterized by Alzheimer disease-like tau pathology in the hippocampus devoid of amyloid plaques. We measured p-tau burden using positive-pixel counts on immunohistochemically stained and neuroanatomically segmented hippocampal tissue. Subjects with CTE had a higher total p-tau burden than PART subjects in all sectors (p = 0.005). Within groups, PART had significantly higher total p-tau burden in CA1/subiculum compared to CA3 (p = 0.02) and CA4 (p = 0.01) and total p-tau burden in CA2 trended higher than CA4 (p = 0.06). In CTE, total p-tau burden in CA1/subiculum was significantly higher than in the dentate gyrus; and CA2 also trended higher than dentate gyrus (p = 0.01, p = 0.06). When controlling for p-tau burden across the entire hippocampus, CA3 and CA4 had significantly higher p-tau burden in CTE than PART (p

Published
2022

7. Emergency Department Care Transitions for Patients With Cognitive Impairment: A Scoping Review

Author

Gettel, Cameron J, Falvey, Jason R, Gifford, Angela, Hoang, Ly, Christensen, Leslie A, Hwang, Ula, Shah, Manish N, Network, The GEAR 2 0-ADC, Aggarawal, Neelum, Allore, Heather, Amy, Aloysi, Belleville, Michael, Bellolio, M Fernanda, Betz, Marian, Biese, Kevin, Brandt, Cynthia, Bruursema, Stacey, Carnahan, Ryan, Carpenter, Christopher, Carr, David, Chin-Hansen, Jennie, Daven, Morgan, Degesys, Nida, Dresden, M Scott, Dussetschleger, Jeffrey, Ellenbogen, Michael, Falvey, Jason, Foster, Beverley, Gettel, Cameron, Gilmore-Bykovskyi, Andrea, Goldberg, Elizabeth, Han, Jin, Hardy, James, Hastings, S Nicole, Hirshon, Jon Mark, Hogan, Tess, Hung, William, Isaacs, Eric, Jaspal, Naveena, Jobe, Deb, Johnson, Jerry, Kelly, Kathleen, Kennedy, Maura, Kind, Amy, Leggett, Jesseca, Malone, Michael, Moccia, Michelle, Moreno, Monica, Morrow-Howell, Nancy, Nowroozpoor, Armin, Ohuabunwa, Ugochi, Oiyemhonian, Brenda, Perry, William, Prusaczk, Beth, Resendez, Jason, Rising, Kristen, Sano, Mary, Savage, Bob, Shah, Manish, Suyama, Joe, Swartzberg, Jeremy, Taylor, Zachary, Vaishal, Tolia, Vann, Allan, Webb, Teresa, and Weintraub, Sandra

Subjects
Emergency Care, Brain Disorders, Clinical Research, Health Services, Behavioral and Social Science, Aging, Management of diseases and conditions, 7.1 Individual care needs, Mental health, Good Health and Well Being, Aged, Cognitive Dysfunction, Emergency Service, Hospital, Geriatric Assessment, House Calls, Humans, Patient Transfer, GEAR 2.0-ADC Network, Care transitions, cognitive impairment, emergency department, patient-centered outcomes, Clinical Sciences, Nursing, Public Health and Health Services, Geriatrics
Abstract

ObjectivesWe aimed to describe emergency department (ED) care transition interventions delivered to older adults with cognitive impairment, identify relevant patient-centered outcomes, and determine priority research areas for future investigation.DesignSystematic scoping review.Setting and participantsED patients with cognitive impairment and/or their care partners.MethodsInformed by the clinical questions, we conducted systematic electronic searches of medical research databases for relevant publications following published guidelines. The results were presented to a stakeholder group representing ED-based and non-ED-based clinicians, individuals living with cognitive impairment, care partners, and advocacy organizations. After discussion, they voted on potential research areas to prioritize for future investigations.ResultsFrom 3848 publications identified, 78 eligible studies underwent full text review, and 10 articles were abstracted. Common ED-to-community care transition interventions for older adults with cognitive impairment included interdisciplinary geriatric assessments, home visits from medical personnel, and telephone follow-ups. Intervention effects were mixed, with improvements observed in 30-day ED revisit rates but most largely ineffective at promoting connections to outpatient care or improving secondary outcomes such as physical function. Outcomes identified as important to adults with cognitive impairment and their care partners included care coordination between providers and inclusion of care partners in care management within the ED setting. The highest priority research area for future investigation identified by stakeholders was identifying strategies to tailor ED-to-community care transitions for adults living with cognitive impairment complicated by other vulnerabilities such as social isolation or economic disadvantage.Conclusions and implicationsThis scoping review identified key gaps in ED-to-community care transition interventions delivered to older adults with cognitive impairment. Combined with a stakeholder assessment and prioritization, it identified relevant patient-centered outcomes and clarifies priority areas for future investigation to improve ED care for individuals with impaired cognition, an area of critical need given the current population trends.

Published
2022

9. 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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10. Correction: Italian adaptation of the Uniform Data Set Neuropsychological Test Battery (I‑UDSNB 1.0): development and normative data

Author

Conca, Francesca, Esposito, Valentina, Rundo, Francesco, Quaranta, Davide, Muscio, Cristina, Manenti, Rosa, Caruso, Giulia, Lucca, Ugo, Galbussera, Alessia Antonella, Di Tella, Sonia, Baglio, Francesca, L’Abbate, Federica, Canu, Elisa, Catania, Valentina, Filippi, Massimo, Mattavelli, Giulia, Poletti, Barbara, Silani, Vincenzo, Lodi, Raffaele, De Matteis, Maddalena, Maserati, Michelangelo Stanzani, Arighi, Andrea, Rotondo, Emanuela, Tanzilli, Antonio, Pace, Andrea, Garramone, Federica, Cavaliere, Carlo, Pardini, Matteo, Rizzetto, Cristiano, Sorbi, Sandro, Perri, Roberta, Tiraboschi, Pietro, Canessa, Nicola, Cotelli, Maria, Ferri, Raffaele, Weintraub, Sandra, Marra, Camillo, Tagliavini, Fabrizio, Catricalà, Eleonora, and Cappa, Stefano Francesco

Published
2023
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11. 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

12. 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

13. Demographic, clinical, biomarker, and neuropathological correlates of posterior cortical atrophy: an international cohort study and individual participant data meta-analysis

Author

Abdi, Zeinab, Agosta, Federica, Ahmed, Samrah, Alcolea, Daniel, Allen, Isabel Elaine, Allinson, Kieren S.J., Apostolova, Liana G., Arighi, Andrea, Balasa, Mircea, Barkhof, Frederik, Best, John, Boon, Baayla D., Brandt, Katherine D., Brosch, Jared, Burrell, James, Butler, Christopher R., Calandri, Ismael, Caminiti, Silvia Paola, Canu, Elisa, Carrillo, Maria C., Caso, Francesca, Chapleau, Marianne, Chrem Mendez, Patricio, Chu, Min, Crutch, Sebastian, Cordato, Nicholas, Costa, Ana Sofia, Cui, Yue, Dickerson, Bradford, Dickson, Dennis W., Duara, Ranjan, Dubois, Bruno, Eldaief, Mark, Farlow, Martin, Fenoglio, Chiara, Filippi, Massimo, Fliessbach, Klaus, Formaglio, Maïté, Fortea, Juan, Fox, Nick, Foxe, David, Tilikete, Caroline Froment, Frosch, Matthew P., Fumagalli, Giorgio Giulio, Galasko, Douglas, Galimberti, Daniela, Garat, Oscar, Giardinieri, Giulia, Graff-Radford, Jonathan, Graff-Radford, Neill R., Grinberg, Lea, Groot, Colin, Hake, Ann Marie, Hansson, Oskar, Headley, Alison, Hernandez, Micaela, Hochberg, Daisy, Hodges, John R., Hof, Patrick R., Holton, Janice, Hromas, Gabrielle, Gala, Ignacio Illán, Irwin, David J., Jaunmuktane, Zane, Jing, Donglai, Josephs, Keith, Kagerer, Sonja M., Kasuga, Kensaku, Kong, Yu, Kövari, Enikö, Lacombe-Thibault, Mégane, Lleó, Alberto, Laforce, Robert, La Joie, Renaud, Lashley, Tammaryn, Leger, Gabriel, Levin, Netta, Levy, Richard, Liu, Yang, Liu, Li, Lladó Plarrumaní, Albert, Lucente, Diane E., Machulda, Mary M., Magnani, Giuseppe, Magnin, Eloi, Malpetti, Maura, Matthews, Brandy, McGinnis, Scott, Mendez, Mario F., Mesulam, Marsel, Migliaccio, Raffaella, Miklitz, Carolin, Miller, Zachary A., Montembeault, Maxime, Murray, Melissa E., Mundada, Nidhi, Nemes, Sara, Nestor, Peter J., Ocal, Dilek, Ossenkoppele, Rik, Paterson, Ross, Pelak, Victoria, Perani, Daniela, Phillips, Jeffrey, Piguet, Olivier, Pijnenburg, Yolande, Putcha, Deepti, Quimby, Megan, Rabinovici, Gil D., Reetz, Kathrin, Rein, Netaniel, Revesz, Tamas, Rezaii, Neguine, Rodriguez-Porcel, Federico, Rogalski, Emily, Rowe, James B., Ryan, Natalie, Sanchez-Valle, Raquel, Sacchi, Luca, Santos-Santos, Miguel Ángel, Schott, Jonathan M., Seeley, William, Sherman, Janet, Spina, Salvatore, Stomrud, Erik, Sullivan, A. Campbell, Tanner, Jeremy, Tideman, Pontus, Tokutake, Takayoshi, Tondo, Giacomo, Touroutoglou, Alexandra, Tousi, Babak, Vandenberghe, Rik, van der Flier, Wiesje, Walker, Jamie M., Weintraub, Sandra, Whitwell, Jennifer L., Wolk, David A., Wong, Bonnie, Wu, Liyong, Xie, Kexin, Yong, Keir, Apostolova, Liana, Boon, Baayla D C, Grinberg, Lea T, Irwin, David J, Josephs, Keith A, Mendez, Mario F, Mendez, Patricio Chrem, Miller, Zachary A, Murray, Melissa E, Nemes, Sára, Schott, Jonathan M, Sullivan, A Campbell, Walker, Jamie, Whitwell, Jennifer L, Wolk, David A, and Rabinovici, Gil D

Published
2024
Full Text
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14. Genome-wide association study and functional validation implicates JADE1 in tauopathy

Author

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

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

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

Published
2022

15. Alzheimer's polygenic hazard score in SuperAgers: SuperGenes or SuperResilience?

Author

Spencer, Barbara E, Banks, Sarah J, Dale, Anders M, Brewer, James B, Makowski‐Woidan, Beth, Weintraub, Sandra, Mesulam, M‐Marsel, Geula, Changiz, and Rogalski, Emily

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Research, Brain Disorders, Acquired Cognitive Impairment, Neurodegenerative, Dementia, Alzheimer's Disease, Aging, Aetiology, 2.1 Biological and endogenous factors, Neurological, aging, Alzheimer's disease, dementia, episodic memory, polygenic risk, resilience, resistance, successful aging, Clinical sciences, Biological psychology
Abstract

IntroductionSuperAgers are individuals over age 80 with superior episodic memory, at a level consistent with individuals 20 to 30 years their junior and who seem to show resistance to age-related neurofibrillary degeneration. Here we examine whether low genetic risk for Alzheimer's disease (AD) contributes to SuperAgers' unusually high episodic memory performance in advanced age.MethodsThe AD polygenic hazard score (PHS) was calculated for each SuperAger and cognitively normal participant and compared between groups.ResultsA total of 37 SuperAgers (73% female, mean [standard deviation] 82.7 [2.8] years old) and 35 controls (54% female, 83.7 [4.3] years old) were included. There was no significant difference in the AD PHS between SuperAgers and cognitively normal controls.DiscussionUnusually successful cognitive aging cannot be simply explained by low polygenic risk for AD as assessed by common genetic variants. However, rare variants and common protective genetic factors may contribute to resistance or resilience.HighlightsSuperAging cannot be simply explained by low polygenic risk for Alzheimer's disease.Rare variants and common protective genetic factors may contribute to SuperAging.A protective factors polygenic score may uncover mechanisms for SuperAging.

Published
2022

16. Demographic and psychosocial factors associated with the decision to learn mutation status in familial frontotemporal dementia and the impact of disclosure on mood

Author

Bajorek, Lynn P, Kiekhofer, Rachel, Hall, Matthew, Taylor, Joanne, Lucente, Diane E, Brushaber, Danielle, Appleby, Brian, Coppolla, Giovanni, Bordelon, Yvette M, Botha, Hugo, Dickerson, Brad C, Dickson, Dennis W, Domoto‐Reilly, Kimiko, Fagan, Anne M, Fields, Julie A, Fong, Jamie C, Foroud, Tatiana M, Forsberg, Leah K, Galasko, Doug R, Gavrilova, Ralitza H, Geschwind, Daniel H, Ghoshal, Nupur, Goldman, Jill, Graff‐Radford, Neill R, Graff‐Radford, Jonathan, Grant, Ian, Grossman, Murray, Heuer, Hilary W, Hsiung, Ging‐Yuek Robin, Huang, Eric J, Huey, Edward D, Irwin, David J, Jones, David T, Kantarci, Kejal, Kornak, John, Kremers, Walter K, Lapid, Maria I, Leger, Gabriel C, Litvan, Irene, Ljubenkov, Peter A, Mackenzie, Ian R, Masdeu, Joseph C, McMillan, Corey, Mendez, Mario, Miller, Bruce L, Miyagawa, Toji, Onyike, Chiadi U, Pascual, Belen, Pedraza, Otto, Petrucelli, Leonard, Rademakers, Rosa, Ramos, Eliana Marisa, Rankin, Katherine P, Rascovsky, Katya, Rexach, Jessica E, Ritter, Aaron, Roberson, Erik D, Savica, Rodolfo, Rojas, Julio C, Seeley, William W, Tartaglia, Maria Carmela, Toga, Arthur W, Weintraub, Sandra, Wong, Bonnie, Wszolek, Zbigniew, Vandevrede, Lawren, Boeve, Bradley F, Boxer, Adam L, Rosen, Howard J, Staffaroni, Adam M, and Consortium, ALLFTD

Subjects
Clinical Trials and Supportive Activities, Aging, Dementia, Genetics, Neurodegenerative, Clinical Research, Prevention, Acquired Cognitive Impairment, Mental Health, Depression, Brain Disorders, Clinical Sciences, Neurosciences, Geriatrics
Abstract

BACKGROUND: Up to 30% of frontotemporal dementia (FTD) cases are due to known pathogenic mutations (f-FTD). Little is known about the factors that predict who will choose to learn their results. Upcoming clinical trials in f-FTD may require disclosure prior to enrollment, even before symptom onset, and thus characterizing this sample is important. Furthermore, understanding the mood impacts of genetic disclosure may guide genetic counseling practice. METHOD: F-FTD participants (n=568) from families with a known pathogenic mutation (MAPT, C9orf72, GRN) were enrolled through the ARTFL/LEFFTDS Longitudinal FTD Study (ALLFTD) and provided the opportunity for disclosure. Independent-sample t-tests compared demographic and psychosocial factors between participants who did and did not receive their results. In participants who were asymptomatic at baseline and follow up (n=199,177 with follow-up), linear mixed effects modeling was used to investigate pre- to post-disclosure changes in the 15-item Geriatric Depression Scale (GDS). RESULT: Of participants from families with a known pathogenic genetic mutation, 47% received genetic disclosure. Of the asymptomatic subset (n=386), 36% know their mutation status. Of these asymptomatic learners, 46% received disclosure through the study, and the remainder learned their genetic status prior to study enrollment. None of the analyzed demographic or psychosocial factors (i.e., sex, age, education, having children) differed between learners and non-learners (p's > 0.05). In the longitudinal analysis of asymptomatic participants, learners showed a pre- to post-increase of 0.31 GDS points/year (95%CI: -0.08, 0.69, p = 0.12), whereas non-learners showed a slight decline (-0.15 points/year, 95%CI: -0.36, 0.06, p = 0.16). This difference between slopes was statistically significant (0.46, 95%CI: 0.02, 0.89, p=0.04) but represents a small clinical effect. In asymptomatic learners, slopes did not differ based on mutation status (0.28, 95%CI: -0.66, 1.20, p=0.55). Conclusions were based on the estimates and full range of confidence intervals. CONCLUSION: The majority of asymptomatic research participants do not know their genetic status, which will be a consideration for clinical trials that require disclosure. No considered demographic factors were strongly associated with the decision to receive disclosure. The findings suggest that disclosure in asymptomatic participants has minimal impact on depressive symptoms regardless of genetic results.

Published
2021

17. 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

18. 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

20. Genome-wide association study and functional validation implicates JADE1 in tauopathy

Author

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

Subjects
Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Genetics, Dementia, Alzheimer's Disease, Frontotemporal Dementia (FTD), Brain Disorders, Neurosciences, Biotechnology, Neurodegenerative, Aging, Acquired Cognitive Impairment, Aetiology, 2.1 Biological and endogenous factors, Neurological
Abstract

AbstractPrimary age-related tauopathy (PART) is a neurodegenerative tauopathy with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) deposition in plaques. The pathogenesis of PART is unknown, but evidence suggests it is associated with genes that promote tau pathology as well as others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n=647) using Braak neurofibrillary tangle stage as a quantitative trait adjusting for sex, age, genotyping platform, and principal components. We found significant associations with some candidate loci associated with AD and progressive supranuclear palsy, a primary tauopathy (SLC24A4, MS4A6A, HS3ST1, MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brain from tauopathies containing isoforms with four microtubule-binding domain repeats (4R) and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation revealed a direct and specific binding of JADE1 protein to tau containing four (4R) and no N-terminal inserts (0N4R) in post-mortem human PART brain tissue. Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a mediator of neurofibrillary degeneration.

Published
2021

21. Recognition memory and divergent cognitive profiles in prodromal genetic frontotemporal dementia.

Author

Barker, Megan S, Manoochehri, Masood, Rizer, Sandra J, Appleby, Brian S, Brushaber, Danielle, Dev, Sheena I, Devick, Katrina L, Dickerson, Bradford C, Fields, Julie A, Foroud, Tatiana M, Forsberg, Leah K, Galasko, Douglas R, Ghoshal, Nupur, Graff-Radford, Neill R, Grossman, Murray, Heuer, Hilary W, Hsiung, Ging-Yuek, Kornak, John, Litvan, Irene, Mackenzie, Ian R, Mendez, Mario F, Pascual, Belen, Rankin, Katherine P, Rascovsky, Katya, Staffaroni, Adam M, Tartaglia, Maria Carmela, Weintraub, Sandra, Wong, Bonnie, Boeve, Bradley F, Boxer, Adam L, Rosen, Howard J, Goldman, Jill, Huey, Edward D, Cosentino, Stephanie, and ALLFTD consortium

Subjects
ALLFTD consortium, Humans, Pick Disease of the Brain, Cognition, Neuropsychological Tests, Heterozygote, Mutation, Frontotemporal Dementia, Progranulins, Behavioral variant frontotemporal dementia, Episodic memory, Genetic frontotemporal dementia, Neuropsychology, Prodromal disease, Behavioral variant frontotemporal, dementia, Frontotemporal Dementia (FTD), Alzheimer's Disease, Rare Diseases, Alzheimer's Disease Related Dementias (ADRD), Behavioral and Social Science, Dementia, Neurosciences, Genetics, Aging, Acquired Cognitive Impairment, Brain Disorders, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Genetic Testing, Basic Behavioral and Social Science, 2.1 Biological and endogenous factors, Neurological, Mental health, Experimental Psychology, Psychology, Cognitive Sciences
Abstract

Although executive dysfunction is the characteristic cognitive marker of behavioral variant frontotemporal dementia (bvFTD), episodic memory deficits are relatively common, and may be present even during the prodromal disease phase. In a cohort of mutation carriers with mild behavioral and/or cognitive symptoms consistent with prodromal bvFTD, we aimed to investigate patterns of performance on an abbreviated list learning task, with a particular focus on recognition memory. We further aimed to characterize the cognitive prodromes associated with the three major genetic causes of frontotemporal dementia, as emerging evidence suggests there may be subtle differences in cognitive profiles among carriers of different genetic mutations. Participants included 57 carriers of a pathogenic mutation in microtubule-associated protein tau (MAPT, N = 23), or progranulin (GRN, N = 15), or a or a hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72, N = 19), with mild cognitive and/or behavioral symptoms consistent with prodromal bvFTD. Familial non-carriers were included as controls (N = 143). All participants completed a comprehensive neuropsychological examination, including an abbreviated list learning test assessing episodic memory recall and recognition. MAPT mutation carriers performed worse than non-carriers in terms of list recall, and had difficulty discriminating targets from distractors on the recognition memory task, primarily due to the endorsement of distractors as targets. MAPT mutation carriers also showed nonverbal episodic memory and semantic memory dysfunction (object naming). GRN mutation carriers were variable in performance and overall the most dysexecutive. Slowed psychomotor speed was evident in C9orf72 repeat expansion carriers. Identifying the earliest cognitive indicators of bvFTD is of critical clinical and research importance. List learning may be a sensitive cognitive marker for incipient dementia in MAPT and potentially a subset of GRN carriers. Our results highlight that distinct cognitive profiles may be evident in carriers of the three disease-causing genes during the prodromal disease stage.

Published
2021

22. 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

23. Early Selective Vulnerability of the CA2 Hippocampal Subfield in Primary Age-Related Tauopathy (vol 80, nlaa153, 2021)

Author

Walker, Jamie M, Richardson, Timothy E, Farrell, Kurt, Iida, Megan A, Foong, Chan, Shang, Ping, Attems, Johannes, Ayalon, Gai, Beach, Thomas G, Bigio, Eileen H, Budson, Andrew, Cairns, Nigel J, Corrada, Maria, Cortes, Etty, Dickson, Dennis W, Fischer, Peter, Flanagan, Margaret E, Franklin, Erin, Gearing, Marla, Glass, Jonathan, Hansen, Lawrence A, Haroutunian, Vahram, Hof, Patrick R, Honig, Lawrence, Kawas, Claudia, Keene, C Dirk, Kofler, Julia, Kovacs, Gabor G, Lee, Edward B, Lutz, Mirjam I, Mao, Qinwen, Masliah, Eliezer, McKee, Ann C, McMillan, Corey T, Mesulam, M Marsel, Murray, Melissa, Nelson, Peter T, Perrin, Richard, Pham, Thao, Poon, Wayne, Dushyant, P Purohit, Rissman, Robert A, Sakai, Kenji, Sano, Mary, Schneider, Julie A, Stein, Thor D, Teich, Andrew F, Trojanowski, John Q, Troncoso, Juan C, Vonsattel, Jean-Paul, Weintraub, Sandra, Wolk, David A, Woltjer, Randall L, Yamada, Masahito, Yu, Lei, White, Charles L, and Crary, John F

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Neurology & Neurosurgery, Clinical sciences
Published
2021

24. 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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25. Uniform data set language measures for bvFTD and PPA diagnosis and monitoring

Author

Staffaroni, Adam M, Weintraub, Sandra, Rascovsky, Katya, Rankin, Katherine P, Taylor, Jack, Fields, Julie A, Casaletto, Kaitlin B, Hillis, Argye E, Lukic, Sladjana, Gorno‐Tempini, Maria Luisa, Heuer, Hilary, Teylan, Merilee A, Kukull, Walter A, Miller, Bruce L, Boeve, Bradley F, Rosen, Howard J, Boxer, Adam L, and Kramer, Joel H

Subjects
Biological Psychology, Psychology, Alzheimer's Disease Related Dementias (ADRD), Aging, Clinical Research, Neurodegenerative, Neurosciences, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Rare Diseases, Clinical Trials and Supportive Activities, Aphasia, Frontotemporal Dementia (FTD), Dementia, clinical trials, cognition, differential diagnosis, endpoints, frontotemporal dementia, FTLD module, longitudinal, neuropsychology, primary progressive aphasia, speech, Genetics, Biological psychology
Abstract

IntroductionThe Frontotemporal Lobar Degeneration Module (FTLD-MOD) includes a neuropsychological battery designed to assess the clinical features of FTLD, although much is unknown about its utility. We investigated FTLD-MOD and Uniform Data Set 3.0 (UDS) language tests for differential diagnosis and disease monitoring.MethodsLinear regressions compared baseline performances in 1655 National Alzheimer's Coordinating Center participants (behavioral variant frontotemporal dementia (bvFTD, n = 612), semantic variant primary progressive aphasia (svPPA, n = 168), non-fluent/agrammatic variant PPA (nfvPPA, n = 168), logopenic variant PPA (lvPPA, n = 109), and controls (n = 581)). Sample sizes to detect treatment effects were estimated using longitudinal data.ResultsAmong PPAs, the FTLD-MOD language tasks and UDS Multilingual Naming Test accurately discriminated svPPA. Number Span Forward best discriminated lvPPA; Phonemic:Semantic Fluency ratio was excellent for nfvPPA classification. UDS fluency and naming measures required the smallest sample size to detect meaningful change.DiscussionThe FTLD-MOD and UDS differentiated among PPA subtypes. UDS 3.0 measures performed best for longitudinal monitoring.

Published
2021

26. 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

27. Parkinson disease with mild cognitive impairment: Domain‐specific cognitive complaints predict dementia

Author

Gasca‐Salas, Carmen, Duff‐Canning, Sarah, Armstrong, Melissa J, Eslinger, Paul J, Schneider, Ruth B, Kennedy, Nancy, Chou, Kelvin L, Persad, Carol, Litvan, Irene, Weintraub, Sandra, and Marras, Connie

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Parkinson's Disease, Alzheimer's Disease, Mental Health, Aging, Acquired Cognitive Impairment, Clinical Research, Neurodegenerative, Behavioral and Social Science, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Dementia, Mental health, Neurological, Aged, Aged, 80 and over, Cohort Studies, Disease Progression, Female, Humans, Male, Middle Aged, Neuropsychological Tests, Parkinson Disease, Retrospective Studies, Symptom Assessment, cognitive complaint, dementia, mild cognitive impairment, Parkinson ' s disease, Parkinson´s disease, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundThe presence of subjective cognitive complaints (SCC) as a predictor of cognitive impairment in Parkinson´s disease (PD) has shown conflicting results. Most previous studies only assessed complaints in the memory domain. We investigate the association of SCCs across cognitive domains with development of mild cognitive impairment (PD-MCI) and dementia (PDD) in PD and to assess agreement between SCCs and objective cognitive impairments in this population.MethodsThis is a retrospective analysis of a prospective cohort study. Participants were enrolled at six North-American movement disorders centers. They underwent neuropsychological and non-cognitive clinical evaluations, including the modified Neurobehavioral Inventory to elicit SCC (rated by each patient and independently by their close contact (CC)). Associations between SCCs and development of future cognitive impairment were assessed. Agreement between SCCs and objective impairment within the same domain was also calculated.ResultsOf 138 included PD patients, 42% fulfilled criteria for PD-MCI. None of the NBI items predicted development of cognitive impairment after one and two years in PD with normal cognition. In PD-MCI patients, SCCs related to attention predicted dementia at year one. CC ratings of SCCs related to memory and language problems predicted PDD in PD-MCI patients. According to CC reported patients' complaints, there was a significant agreement between SCCs and objective cognitive test scores on attention.ConclusionsEliciting SCCs including cognitive domains other than memory is crucial for a complete evaluation, including both patient and CC report. Memory, language, and especially attention SCCs in PD-MCI may predict progression to dementia.

Published
2020

28. 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

29. Plasma neurofilament light chain levels reflect caregiver burden and social cognition measures in familial frontotemporal lobar degeneration (FTLD)

Author

Heuer, Hilary W, Rojas, Julio C, Toller, Gianina, Rankin, Katherine, Brushaber, Danielle, Appleby, Brian, Bordelon, Yvette M, Dickerson, Brad C, Kimiko, Domoto‐Reilly, Faber, Kelley, Foroud, Tatiana M, Forsberg, Leah K, Ghoshal, Nupur, Grant, Ian, Graff‐Radford, Neill R, Grossman, Murray, Hsiung, Ging‐Yuek Robin, Huey, Edward D, Karydas, Anna M, Kaufer, Daniel, Kerwin, Diana R, Lagone, Emma, Litvan, Irene, Ljubenkov, Peter A, Mackenzie, Ian R, Mendez, Mario F, Miller, Bruce L, Onyike, Chiadi U, Ramos, Eliana Marisa, Rascovsky, Katya, Roberson, Erik D, Tartaglia, Carmela, Weintraub, Sandra, Boeve, Bradley F, Rosen, Howard J, and Boxer, Adam L

Subjects
Neurodegenerative, Clinical Trials and Supportive Activities, Acquired Cognitive Impairment, Genetics, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, Neurosciences, Dementia, Clinical Research, Brain Disorders, Behavioral and Social Science, Neurological, Geriatrics, Clinical Sciences
Published
2020

30. 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

31. 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

32. 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

33. Clinical and volumetric changes with increasing functional impairment in familial frontotemporal lobar degeneration.

Author

Olney, Nicholas T, Ong, Elise, Goh, Sheng-Yang M, Bajorek, Lynn, Dever, Reilly, Staffaroni, Adam M, Cobigo, Yann, Bock, Meredith, Chiang, Kevin, Ljubenkov, Peter, Kornak, John, Heuer, Hilary W, Wang, Ping, Rascovsky, Katya, Wolf, Amelia, Appleby, Brian, Bove, Jessica, Bordelon, Yvette, Brannelly, Patrick, Brushaber, Danielle, Caso, Christine, Coppola, Giovanni, Dickerson, Bradford C, Dickinson, Susan, Domoto-Reilly, Kimiko, Faber, Kelly, Ferrall, Jessica, Fields, Julie, Fishman, Ann, Fong, Jamie, Foroud, Tatiana, Forsberg, Leah K, Gearhart, Debra J, Ghazanfari, Behnaz, Ghoshal, Nupur, Goldman, Jill, Graff-Radford, Jonathan, Graff-Radford, Neill R, Grant, Ian, Grossman, Murray, Haley, Dana, Hsiung, Gingyuek, Huey, Edward D, Irwin, David J, Jones, David T, Kantarci, Kejal, Karydas, Anna M, Kaufer, Daniel, Kerwin, Diana, Knopman, David S, Kramer, Joel H, Kraft, Ruth, Kremers, Walter, Kukull, Walter, Lapid, Maria I, Litvan, Irene, Mackenzie, Ian R, Maldonado, Miranda, Manoochehri, Masood, McGinnis, Scott M, McKinley, Emily C, Mendez, Mario F, Miller, Bruce L, Onyike, Chiadi, Pantelyat, Alex, Pearlman, Rodney, Petrucelli, Len, Potter, Madeleine, Rademakers, Rosa, Ramos, Eliana M, Rankin, Katherine P, Roberson, Erik D, Rogalski, Emily, Sengdy, Pheth, Shaw, Leslie M, Syrjanen, Jeremy, Tartaglia, M Carmela, Tatton, Nadine, Taylor, Joanne, Toga, Arthur, Trojanowski, John Q, Weintraub, Sandra, Wong, Bonnie, Wszolek, Zbigniew, Boxer, Adam L, Boeve, Brad F, Rosen, Howard J, and ARTFL and LEFFTDS consortia

Subjects
ARTFL and LEFFTDS consortia, Temporal Lobe, Humans, Atrophy, Genetic Predisposition to Disease, tau Proteins, Magnetic Resonance Imaging, Longitudinal Studies, Neuropsychological Tests, Image Processing, Computer-Assisted, Middle Aged, Female, Male, Frontotemporal Lobar Degeneration, C9orf72 Protein, Progranulins, C9ORF72, Familial, Frontotemporal lobar degeneration, GRN, Genetic, MAPT, Frontotemporalobar degeneration, Neurodegenerative, Behavioral and Social Science, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease Related Dementias (ADRD), Biomedical Imaging, Aging, Alzheimer's Disease, Clinical Trials and Supportive Activities, Acquired Cognitive Impairment, Dementia, Clinical Research, Brain Disorders, Neurosciences, Rare Diseases, Frontotemporal Dementia (FTD), 2.1 Biological and endogenous factors, Neurological, Geriatrics, Clinical Sciences
Abstract

IntroductionThe Advancing Research and Treatment in Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects longitudinal studies were designed to describe the natural history of familial-frontotemporal lobar degeneration due to autosomal dominant mutations.MethodsWe examined cognitive performance, behavioral ratings, and brain volumes from the first time point in 320 MAPT, GRN, and C9orf72 family members, including 102 non-mutation carriers, 103 asymptomatic carriers, 43 mildly/questionably symptomatic carriers, and 72 carriers with dementia.ResultsAsymptomatic carriers showed similar scores on all clinical measures compared with noncarriers but reduced frontal and temporal volumes. Those with mild/questionable impairment showed decreased verbal recall, fluency, and Trail Making Test performance and impaired mood and self-monitoring. Dementia was associated with impairment in all measures. All MAPT carriers with dementia showed temporal atrophy, but otherwise, there was no single cognitive test or brain region that was abnormal in all subjects.DiscussionImaging changes appear to precede clinical changes in familial-frontotemporal lobar degeneration, but specific early clinical and imaging changes vary across individuals.

Published
2020

34. Individualized atrophy scores predict dementia onset in familial frontotemporal lobar degeneration.

Author

Staffaroni, Adam M, Cobigo, Yann, Goh, Sheng-Yang M, Kornak, John, Bajorek, Lynn, Chiang, Kevin, Appleby, Brian, Bove, Jessica, Bordelon, Yvette, Brannelly, Patrick, Brushaber, Danielle, Caso, Christina, Coppola, Giovanni, Dever, Reilly, Dheel, Christina, Dickerson, Bradford C, Dickinson, Susan, Dominguez, Sophia, Domoto-Reilly, Kimiko, Faber, Kelly, Ferrall, Jessica, Fields, Julie A, Fishman, Ann, Fong, Jamie, Foroud, Tatiana, Forsberg, Leah K, Gavrilova, Ralitza, Gearhart, Debra, Ghazanfari, Behnaz, Ghoshal, Nupur, Goldman, Jill, Graff-Radford, Jonathan, Graff-Radford, Neill, Grant, Ian, Grossman, Murray, Haley, Dana, Heuer, Hilary W, Hsiung, Ging-Yuek, Huey, Edward D, Irwin, David J, Jones, David T, Jones, Lynne, Kantarci, Kejal, Karydas, Anna, Kaufer, Daniel I, Kerwin, Diana R, Knopman, David S, Kraft, Ruth, Kramer, Joel H, Kremers, Walter K, Kukull, Walter A, Litvan, Irene, Ljubenkov, Peter A, Lucente, Diane, Lungu, Codrin, Mackenzie, Ian R, Maldonado, Miranda, Manoochehri, Masood, McGinnis, Scott M, McKinley, Emily, Mendez, Mario F, Miller, Bruce L, Multani, Namita, Onyike, Chiadi, Padmanabhan, Jaya, Pantelyat, Alex, Pearlman, Rodney, Petrucelli, Len, Potter, Madeline, Rademakers, Rosa, Ramos, Eliana Marisa, Rankin, Katherine P, Rascovsky, Katya, Roberson, Erik D, Rogalski, Emily, Sengdy, Pheth, Shaw, Leslie M, Syrjanen, Jeremy, Tartaglia, M Carmela, Tatton, Nadine, Taylor, Joanne, Toga, Arthur, Trojanowski, John Q, Weintraub, Sandra, Wang, Ping, Wong, Bonnie, Wszolek, Zbigniew, Boxer, Adam L, Boeve, Brad F, Rosen, Howard J, and ARTFL/LEFFTDS consortium

Subjects
ARTFL/LEFFTDS consortium, Brain, Humans, Atrophy, Genetic Predisposition to Disease, tau Proteins, Magnetic Resonance Imaging, Neuropsychological Tests, Mutation, Image Processing, Computer-Assisted, Middle Aged, Female, Male, Frontotemporal Dementia, C9orf72 Protein, Progranulins, Frontotemporal dementia, Genetics, Magnetic resonance imaging, TDP-43, Tau, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Frontotemporal Dementia (FTD), Dementia, Brain Disorders, Neurosciences, Acquired Cognitive Impairment, Prevention, Alzheimer's Disease, Rare Diseases, Aging, Neurodegenerative, Neurological, Geriatrics, Clinical Sciences
Abstract

IntroductionSome models of therapy for neurodegenerative diseases envision starting treatment before symptoms develop. Demonstrating that such treatments are effective requires accurate knowledge of when symptoms would have started without treatment. Familial frontotemporal lobar degeneration offers a unique opportunity to develop predictors of symptom onset.MethodsWe created dementia risk scores in 268 familial frontotemporal lobar degeneration family members by entering covariate-adjusted standardized estimates of brain atrophy into a logistic regression to classify asymptomatic versus demented participants. The score's predictive value was tested in a separate group who were followed up longitudinally (stable vs. converted to dementia) using Cox proportional regressions with dementia risk score as the predictor.ResultsCross-validated logistic regression achieved good separation of asymptomatic versus demented (accuracy = 90%, SE = 0.06). Atrophy scores predicted conversion from asymptomatic or mildly/questionably symptomatic to dementia (HR = 1.51, 95% CI: [1.16,1.98]).DiscussionIndividualized quantification of baseline brain atrophy is a promising predictor of progression in asymptomatic familial frontotemporal lobar degeneration mutation carriers.

Published
2020

35. Differentiating among stages of cognitive impairment in aging: Version 3 of the Uniform Data Set (UDS) neuropsychological test battery and MoCA index scores

Author

Dodge, Hiroko H, Goldstein, Felicia C, Wakim, Nicole I, Gefen, Tamar, Teylan, Merilee, Chan, Kwun CG, Kukull, Walter A, Barnes, Lisa L, Giordani, Bruno, Hughes, Timothy M, Kramer, Joel H, Loewenstein, David A, Marson, Daniel C, Mungas, Dan M, Mattek, Nora, Sachs, Bonnie C, Salmon, David P, Willis‐Parker, Monica, Welsh‐Bohmer, Kathleen A, Wild, Katherine V, Morris, John C, Weintraub, Sandra, and Center, Alzheimer's Coordinating

Subjects
Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Neurosciences, Brain Disorders, Neurodegenerative, Alzheimer's Disease, Acquired Cognitive Impairment, Clinical Research, Aging, differentiating CDR, National Alzheimer's Coordinating Center Uniform Data Set, optimal cut-point, racial differences, receiver-operating characteristic area under the curve, validity, National Alzheimer's Coordinating Center, optimal cut‐point, receiver‐operating characteristic area under the curve
Abstract

IntroductionFederally funded Alzheimer's Disease Centers in the United States have been using a standardized neuropsychological test battery as part of the National Alzheimer's Coordinating Center Uniform Data Set (UDS) since 2005. Version 3 (V3) of the UDS replaced the previous version (V2) in 2015. We compared V2 and V3 neuropsychological tests with respect to their ability to distinguish among the Clinical Dementia Rating (CDR) global scores of 0, 0.5, and 1.MethodsFirst, we matched participants receiving V2 tests (V2 cohort) and V3 tests (V3 cohort) in their cognitive functions using tests common to both versions. Then, we compared receiver-operating characteristic (ROC) area under the curve in differentiating CDRs for the remaining tests.ResultsSome V3 tests performed better than V2 tests in differentiating between CDR 0.5 and 0, but the improvement was limited to Caucasian participants.DiscussionFurther efforts to improve the ability for early identification of cognitive decline among diverse racial groups are required.

Published
2020

36. The longitudinal evaluation of familial frontotemporal dementia subjects protocol: Framework and methodology

Author

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

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease Related Dementias (ADRD), Neurosciences, Dementia, Brain Disorders, Rare Diseases, Alzheimer's Disease, Acquired Cognitive Impairment, Genetics, Aging, Neurodegenerative, Clinical Trials and Supportive Activities, Frontotemporal Dementia (FTD), Neurological, Adult, C9orf72 Protein, Female, Frontotemporal Dementia, Genetic Predisposition to Disease, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Neuropsychological Tests, tau Proteins, C9orf72, Frontotemporal dementia, GRN, MAPT, Tau, TDP-43, LEFFTDS Consortium, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionIt is important to establish the natural history of familial frontotemporal lobar degeneration (f-FTLD) and provide clinical and biomarker data for planning these studies, particularly in the asymptomatic phase.MethodsThe Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects protocol was designed to enroll and follow at least 300 subjects for more than at least three annual visits who are members of kindreds with a mutation in one of the three most common f-FTLD genes-microtubule-associated protein tau, progranulin, or chromosome 9 open reading frame 72.ResultsWe present the theoretical considerations of f-FTLD and the aims/objectives of this protocol. We also describe the design and methodology for evaluating and rating subjects, in which detailed clinical and neuropsychological assessments are performed, biofluid samples are collected, and magnetic resonance imaging scans are performed using a standard protocol.DiscussionThese data and samples, which are available to interested investigators worldwide, will facilitate planning for upcoming disease-modifying therapeutic trials in f-FTLD.

Published
2020

37. Assessment of executive function declines in presymptomatic and mildly symptomatic familial frontotemporal dementia: NIH-EXAMINER as a potential clinical trial endpoint.

Author

Staffaroni, Adam M, Bajorek, Lynn, Casaletto, Kaitlin B, Cobigo, Yann, Goh, Sheng-Yang M, Wolf, Amy, Heuer, Hilary W, Elahi, Fanny M, Ljubenkov, Peter A, Dever, Reilly, Kornak, John, Appleby, Brian, Bove, Jessica, Bordelon, Yvette, Brannelly, Patrick, Brushaber, Danielle, Caso, Christina, Coppola, Giovanni, Dheel, Christina, Dickerson, Bradford C, Dickinson, Susan, Dominguez, Sophia, Domoto-Reilly, Kimiko, Faber, Kelly, Ferrall, Jessica, Fields, Julie A, Fishman, Ann, Fong, Jamie, Foroud, Tatiana, Forsberg, Leah K, Gavrilova, Ralitza, Gearhart, Debra, Ghazanfari, Behnaz, Ghoshal, Nupur, Goldman, Jill, Graff-Radford, Jonathan, Graff-Radford, Neill, Grant, Ian, Grossman, Murray, Haley, Dana, Hsiung, Ging-Yuek, Huey, Edward D, Irwin, David J, Jones, David T, Jones, Lynne, Kantarci, Kejal, Karydas, Anna, Kaufer, Daniel I, Kerwin, Diana R, Knopman, David S, Kraft, Ruth, Kremers, Walter K, Kukull, Walter A, Litvan, Irene, Lucente, Diane, Lungu, Codrin, Mackenzie, Ian R, Maldonado, Miranda, Manoochehri, Masood, McGinnis, Scott M, McKinley, Emily, Mendez, Mario F, Miller, Bruce L, Multani, Namita, Onyike, Chiadi, Padmanabhan, Jaya, Pantelyat, Alex, Pearlman, Rodney, Petrucelli, Len, Potter, Madeline, Rademakers, Rosa, Ramos, Eliana Marisa, Rankin, Katherine P, Rascovsky, Katya, Roberson, Erik D, Rogalski, Emily, Sengdy, Pheth, Shaw, Leslie M, Syrjanen, Jeremy, Tartaglia, M Carmela, Tatton, Nadine, Taylor, Joanne, Toga, Arthur, Trojanowski, John Q, Weintraub, Sandra, Wang, Ping, Wong, Bonnie, Wszolek, Zbigniew, Boxer, Adam L, Boeve, Brad F, Kramer, Joel H, Rosen, Howard J, and ARTFL/LEFFTDS consortium

Subjects
ARTFL/LEFFTDS consortium, Humans, Disease Progression, Magnetic Resonance Imaging, Longitudinal Studies, Neuropsychological Tests, Mutation, Middle Aged, Female, Male, Executive Function, Frontotemporal Dementia, Biomarkers, C9orf72 Protein, Behavioral variant, Cognition, Corticobasal syndrome, Fluency, Genetic, Inhibition, Neuropsychology, Nonfluent variant, Primary progressive aphasia, Progranulin, Progressive supranuclear palsy, Semantic variant, Set-shifting, Tau, Working memory, Clinical Sciences, Neurosciences, Geriatrics
Abstract

IntroductionIdentifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD) is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression.MethodsNinety-three mutation carriers with no symptoms or minimal/questionable symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34; Clinical Dementia Rating scale plus NACC FTLD Module < 1) and 78 noncarriers enrolled through Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects studies completed the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) and the UDS neuropsychological battery. Linear mixed-effects models were used to identify group differences in cognition at baseline and longitudinally. We examined associations between cognition, clinical functioning, and magnetic resonance imaging volumes.ResultsNIH-EXAMINER scores detected baseline and differences in slopes between carriers and noncarriers, even in carriers with a baseline Clinical Dementia Rating scale plus NACC FTLD Module = 0. NIH-EXAMINER declines were associated with worsening clinical symptoms and brain volume loss.DiscussionThe NIH-EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint.

Published
2020

38. Utility of the global CDR® plus NACC FTLD rating and development of scoring rules: 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, Howard J, Boeve, Bradley F, Appleby, Brian, Bordelon, Yvette, Bove, Jessica, Brannelly, Patrick, Caso, Christina, Coppola, Giovanni, Dever, Reilly, Dheel, Christina, Dickerson, Bradford, Dickinson, Susan, Dominguez, Sophia, Domoto‐Reilly, Kimiko, Faber, Kelley, Ferrell, Jessica, Fishman, Ann, Fong, Jamie, Foroud, Tatiana, Gavrilova, Ralitza, Gearhart, Debra, Ghazanfari, Behnaz, Ghoshal, Nupur, Goldman, Jill S, Graff‐Radford, Jonathan, Graff‐Radford, Neill, Grant, Ian, Grossman, Murray, Haley, Dana, Hsiung, Robin, Huey, Edward, Irwin, David, Jones, David, Jones, Lynne, Kantarci, Kejal, Karydas, Anna, Kaufer, Daniel, Kerwin, Diana, Kraft, Ruth, Kramer, Joel, Kukull, Walter, Litvan, Irene, Lucente, Diane, Lungu, Codrin, Mackenzie, Ian, Maldonado, Miranda, Manoochehri, Masood, McGinnis, Scott, McKinley, Emily, Mendez, Mario F, Miller, Bruce, Multani, Namita, Onyike, Chiadi, Padmanabhan, Jaya, Pantelyat, Alexander, Pearlman, Rodney, Petrucelli, Leonard, Potter, Madeline, Rademakers, Rosa, Ramos, Eliana M, Rankin, Kate, Rascovsky, Katya, Roberson, Erik D, Rogalski, Emily, Sengdy, Pheth, Shaw, Leslie, Tartaglia, Maria C, Tatton, Nadine, Taylor, Joanne, Toga, Arthur, Trojanowski, John Q, Wang, Ping, Weintraub, Sandra, Wong, Bonnie, and Wszolek, Zbigniew

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Psychology, Dementia, Frontotemporal Dementia (FTD), Neurosciences, Neurodegenerative, Acquired Cognitive Impairment, Clinical Trials and Supportive Activities, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Brain Disorders, Aged, Aphasia, Primary Progressive, Cross-Sectional Studies, Female, Frontotemporal Lobar Degeneration, Humans, Male, Mental Status and Dementia Tests, Middle Aged, behavior, comportment, personality, CDR, CDR plus NACC FTLD, frontotemporal lobar degeneration, global rating, language, CDR®, behavior, comportment, and personality, Clinical Sciences, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionWe created global rating scoring rules for the CDR® plus NACC FTLD to detect and track early frontotemporal lobar degeneration (FTLD) and to conduct clinical trials in FTLD.MethodsThe CDR plus NACC FTLD rating was applied to 970 sporadic and familial participants from the baseline visit of Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS). Each of the eight domains of the CDR plus NACC FTLD was equally weighed in determining the global score. An interrater reliability study was completed for 40 participants.ResultsThe CDR plus NACC FTLD showed very good interrater reliability. It was especially useful in detecting clinical features of mild non-fluent/agrammatic variant primary progressive aphasia participants.DiscussionThe global CDR plus NACC FTLD score could be an attractive outcome measure for clinical trials in symptomatic FTLD, and may be useful in natural history studies and clinical trials in FTLD spectrum disorders.

Published
2020

39. Genetic screening of a large series of North American sporadic and familial frontotemporal dementia cases

Author

Ramos, Eliana Marisa, Dokuru, Deepika Reddy, Van Berlo, Victoria, Wojta, Kevin, Wang, Qing, Huang, Alden Y, Deverasetty, Sandeep, Qin, Yue, van Blitterswijk, Marka, Jackson, Jazmyne, Appleby, Brian, Bordelon, Yvette, Brannelly, Patrick, Brushaber, Danielle E, Dickerson, Bradford, Dickinson, Susan, Domoto‐Reilly, Kimiko, Faber, Kelley, Fields, Julie, Fong, Jamie, Foroud, Tatiana, Forsberg, Leah K, Gavrilova, Ralitza, Ghoshal, Nupur, Goldman, Jill, Graff‐Radford, Jonathan, Graff‐Radford, Neill, Grant, Ian, Grossman, Murray, Heuer, Hilary W, Hsiung, Ging‐Yuek R, Huey, Edward, Irwin, David, Kantarci, Kejal, Karydas, Anna, Kaufer, Daniel, Kerwin, Diana, Knopman, David, Kornak, John, Kramer, Joel H, Kremers, Walter, Kukull, Walter, Litvan, Irene, Ljubenkov, Peter, Lungu, Codrin, Mackenzie, Ian, Mendez, Mario F, Miller, Bruce L, Onyike, Chiadi, Pantelyat, Alexander, Pearlman, Rodney, Petrucelli, Len, Potter, Madeline, Rankin, Katherine P, Rascovsky, Katya, Roberson, Erik D, Rogalski, Emily, Shaw, Leslie, Syrjanen, Jeremy, Tartaglia, Maria Carmela, Tatton, Nadine, Taylor, Joanne, Toga, Arthur, Trojanowski, John Q, Weintraub, Sandra, Wong, Bonnie, Wszolek, Zbigniew, Rademakers, Rosa, Boeve, Brad F, Rosen, Howard J, Boxer, Adam L, consortium, on behalf of the ARTFL LEFFTDS, and Coppola, Giovanni

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Neurodegenerative, Frontotemporal Dementia (FTD), Genetics, Alzheimer's Disease, Human Genome, Prevention, Rare Diseases, Aging, Brain Disorders, Clinical Research, Acquired Cognitive Impairment, Genetic Testing, Alzheimer's Disease Related Dementias (ADRD), Aetiology, 2.1 Biological and endogenous factors, Neurological, C9orf72 Protein, Female, Frontotemporal Dementia, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Progranulins, tau Proteins, C9orf72, familial, frontotemporal dementia, GRN, MAPT, sporadic, ARTFL/LEFFTDS consortium, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionThe Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) consortia are two closely connected studies, involving multiple North American centers that evaluate both sporadic and familial frontotemporal dementia (FTD) participants and study longitudinal changes.MethodsWe screened the major dementia-associated genes in 302 sporadic and 390 familial (symptomatic or at-risk) participants enrolled in these studies.ResultsAmong the sporadic patients, 16 (5.3%) carried chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), and progranulin (GRN) pathogenic variants, whereas in the familial series we identified 207 carriers from 146 families. Of interest, one patient was found to carry a homozygous C9orf72 expansion, while another carried both a C9orf72 expansion and a GRN pathogenic variant. We also identified likely pathogenic variants in the TAR DNA binding protein (TARDBP), presenilin 1 (PSEN1), and valosin containing protein (VCP) genes, and a subset of variants of unknown significance in other rare FTD genes.DiscussionOur study reports the genetic characterization of a large FTD series and supports an unbiased sequencing screen, irrespective of clinical presentation or family history.

Published
2020

40. Nonlinear Z-score modeling for improved detection of cognitive abnormality.

Author

Kornak, John, Fields, Julie, Kremers, Walter, Farmer, Sara, Heuer, Hilary W, Forsberg, Leah, Brushaber, Danielle, Rindels, Amy, Dodge, Hiroko, Weintraub, Sandra, Besser, Lilah, Appleby, Brian, Bordelon, Yvette, Bove, Jessica, Brannelly, Patrick, Caso, Christina, Coppola, Giovanni, Dever, Reilly, Dheel, Christina, Dickerson, Bradford, Dickinson, Susan, Dominguez, Sophia, Domoto-Reilly, Kimiko, Faber, Kelley, Ferrall, Jessica, Fishman, Ann, Fong, Jamie, Foroud, Tatiana, Gavrilova, Ralitza, Gearhart, Deb, Ghazanfari, Behnaz, Ghoshal, Nupur, Goldman, Jill, Graff-Radford, Jonathan, Graff-Radford, Neill, Grant, Ian M, Grossman, Murray, Haley, Dana, Hsiao, John, Hsiung, Robin, Huey, Edward D, Irwin, David, Jones, David, Jones, Lynne, Kantarci, Kejal, Karydas, Anna, Kaufer, Daniel, Kerwin, Diana, Knopman, David, Kraft, Ruth, Kramer, Joel, Kukull, Walter, Lapid, Maria, Litvan, Irene, Ljubenkov, Peter, Lucente, Diane, Lungu, Codrin, Mackenzie, Ian, Maldonado, Miranda, Manoochehri, Masood, McGinnis, Scott, McKinley, Emily, Mendez, Mario, Miller, Bruce, Multani, Namita, Onyike, Chiadi, Padmanabhan, Jaya, Pantelyat, Alexander, Pearlman, Rodney, Petrucelli, Len, Potter, Madeline, Rademakers, Rosa, Ramos, Eliana Marisa, Rankin, Katherine, Rascovsky, Katya, Roberson, Erik D, Rogalski-Miller, Emily, Sengdy, Pheth, Shaw, Les, Staffaroni, Adam M, Sutherland, Margaret, Syrjanen, Jeremy, Tartaglia, Carmela, Tatton, Nadine, Taylor, Joanne, Toga, Arthur, Trojanowski, John, Wang, Ping, Wong, Bonnie, Wszolek, Zbigniew, Boeve, Brad, Boxer, Adam, Rosen, Howard, and ARTFL/LEFFTDS Consortium

Subjects
ARTFL/LEFFTDS Consortium, Generalized additive models, Heterogenous variance modeling, Neuropsychological testing scores, Nonlinear Z-score correction, Shape constrained additive models, Genetics, Neurosciences
Abstract

IntroductionConventional Z-scores are generated by subtracting the mean and dividing by the standard deviation. More recent methods linearly correct for age, sex, and education, so that these "adjusted" Z-scores better represent whether an individual's cognitive performance is abnormal. Extreme negative Z-scores for individuals relative to this normative distribution are considered indicative of cognitive deficiency.MethodsIn this article, we consider nonlinear shape constrained additive models accounting for age, sex, and education (correcting for nonlinearity). Additional shape constrained additive models account for varying standard deviation of the cognitive scores with age (correcting for heterogeneity of variance).ResultsCorrected Z-scores based on nonlinear shape constrained additive models provide improved adjustment for age, sex, and education, as indicated by higher adjusted-R2.DiscussionNonlinearly corrected Z-scores with respect to age, sex, and education with age-varying residual standard deviation allow for improved detection of non-normative extreme cognitive scores.

Published
2019

41. Tracking white matter degeneration in asymptomatic and symptomatic MAPT mutation carriers

Author

Chen, Qin, Boeve, Bradley F, Schwarz, Christopher G, Reid, Robert, Tosakulwong, Nirubol, Lesnick, Timothy G, Bove, Jessica, Brannelly, Patrick, Brushaber, Danielle, Coppola, Giovanni, Dheel, Christina, Dickerson, Bradford C, Dickinson, Susan, Faber, Kelley, Fields, Julie, Fong, Jamie, Foroud, Tatiana, Forsberg, Leah, Gavrilova, Ralitza H, Gearhart, Debra, Ghoshal, Nupur, Goldman, Jill, Graff-Radford, Jonathan, Graff-Radford, Neill R, Grossman, Murray, Haley, Dana, Heuer, Hilary W, Hsiung, Ging-Yuek R, Huey, Edward, Irwin, David J, Jack, Clifford R, Jones, David T, Jones, Lynne, Karydas, Anna M, Knopman, David S, Kornak, John, Kramer, Joel, Kremers, Walter, Kukull, Walter A, Lapid, Maria, Lucente, Diane, Lungu, Codrin, Mackenzie, Ian RA, Manoochehri, Masood, McGinnis, Scott, Miller, Bruce L, Pearlman, Rodney, Petrucelli, Leonard, Potter, Madeline, Rademakers, Rosa, Ramos, Eliana M, Rankin, Katherine P, Rascovsky, Katya, Sengdy, Pheth, Shaw, Leslie, Syrjanen, Jeremy, Tatton, Nadine, Taylor, Joanne, Toga, Arthur W, Trojanowski, John, Weintraub, Sandra, Wong, Bonnie, Boxer, Adam L, Rosen, Howie, Wszolek, Zbigniew, Kantarci, Kejal, and Consortium, LEFFTDS

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Dementia, Neurodegenerative, Aging, Acquired Cognitive Impairment, Biomedical Imaging, Neurosciences, Clinical Trials and Supportive Activities, Clinical Research, Brain Disorders, 2.1 Biological and endogenous factors, Adult, Aged, Diffusion Magnetic Resonance Imaging, Diffusion Tensor Imaging, Disease Progression, Female, Frontotemporal Dementia, Gray Matter, Heterozygote, Humans, Male, Middle Aged, Mutation, Neurodegenerative Diseases, Neuropsychological Tests, White Matter, tau Proteins, Diffusion tensor image, MAPT, Asymptomatic, Frontotemporal dementia, Longitudinal, LEFFTDS Consortium, Neurology & Neurosurgery, Biological psychology
Abstract

Our aim was to investigate the patterns and trajectories of white matter (WM) diffusion abnormalities in microtubule-associated protein tau (MAPT) mutations carriers. We studied 22 MAPT mutation carriers (12 asymptomatic, 10 symptomatic) and 20 noncarriers from 8 families, who underwent diffusion tensor imaging (DTI) and a subset (10 asymptomatic, 6 symptomatic MAPT mutation carriers, and 10 noncarriers) were followed annually (median = 4 years). Cross-sectional and longitudinal changes in mean diffusivity (MD) and fractional anisotropy were analyzed. Asymptomatic MAPT mutation carriers had higher MD in entorhinal WM, which propagated to the limbic tracts and frontotemporal projections in the symptomatic stage compared with noncarriers. Reduced fractional anisotropy and increased MD in the entorhinal WM were associated with the proximity to estimated and actual age of symptom onset. The annualized change of entorhinal MD on serial DTI was accelerated in MAPT mutation carriers compared with noncarriers. Entorhinal WM diffusion abnormalities precede the symptom onset and track with disease progression in MAPT mutation carriers. Our cross-sectional and longitudinal data showed a potential clinical utility for DTI to track neurodegenerative disease progression for MAPT mutation carriers in clinical trials.

Published
2019

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

Author

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

Published
2024
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43. P2‐314: THE MULTIDOMAIN IMPAIRMENT RATING (MIR) SCALE: INITIAL RELIABILITY DATA ON A MULTIDIMENSIONAL SCALE DESIGNED FOR FTLD SPECTRUM DISORDERS

Author

Forsberg, Leah K, Boeve, Bradley F, Boxer, Adam L, Rosen, Howard J, Kornak, John, Heuer, Hilary W, Fields, Julie A, Brushaber, Danielle, Machulda, Mary M, Sturm, Virginia, Staffaroni, Adam M, Ljubenkov, Peter A, Denver, Reilly, Ong, Elise, Appleby, Brian, Bordelon, Yvette M, Brannelly, Patrick, Coppola, Giovanni, Dickerson, Brad C, Dickinson, Susan, Kimiko, Domoto-Reilly, Faber, Kelley, Fong, Jamie, Foroud, Tatiana M, Gavrilova, Ralitza H, Gearhart, Debra, Ghoshal, Nupur, Goldman, Jill, Graff-Radford, Jonathan, Graff-Radford, Neil R, Grossman, Murray, Hsiung, Ging-Yuek Robin, Huey, Edward D, Irwin, David, Jones, David T, Kantarci, Kejal, Karydas, Anna M, Kaufer, Daniel, Kerwin, Diana R, Knopman, David S, Kraft, Ruth A, Kramer, Joel H, Kremers, Walter K, Kukull, Walter A, Litvan, Irene, Lucente, Diane E, Lungu, Codrin, Mackenzie, Ian R, McGinnis, Scott M, Mendez, Mario F, Miller, Bruce L, Onyike, Chiadi U, Pantelyat, Alex, Pearlman, Rodney, Petrucelli, Leonard, Potter, Madeline, Rademakers, Rosa, Ramos, Eliana Marisa, Rankin, Katherine, Rascovsky, Katya, Roberson, Erik D, Rogalski, Emily J, Shaw, Leslie M, Sutherland, Marg, Syrjanen, Jeremy, Tartaglia, Carmela, Tatton, Nadine, Taylor, Joanne, Toga, Arthur W, Trojanowski, John Q, Weintraub, Sandra, Wong, Bonnie, and Wszolek, Zbigniew

Subjects
Clinical Sciences, Neurosciences, Geriatrics
Published
2019

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

Author

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

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

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

Published
2019

45. Genetic screen in a large series of patients with primary progressive aphasia

Author

Ramos, Eliana Marisa, Dokuru, Deepika Reddy, Van Berlo, Victoria, Wojta, Kevin, Wang, Qing, Huang, Alden Y, Miller, Zachary A, Karydas, Anna M, Bigio, Eileen H, Rogalski, Emily, Weintraub, Sandra, Rader, Benjamin, Miller, Bruce L, Gorno‐Tempini, Maria Luisa, Mesulam, Marek‐Marsel, and Coppola, Giovanni

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Dementia, Alzheimer's Disease Related Dementias (ADRD), Aging, Genetics, Frontotemporal Dementia (FTD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, Brain Disorders, Neurodegenerative, Acquired Cognitive Impairment, Clinical Research, Aphasia, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Aphasia, Primary Progressive, C9orf72 Protein, Cohort Studies, DNA-Binding Proteins, Female, Frontotemporal Dementia, Humans, Male, Middle Aged, Mutation, Progranulins, Primary progressive aphasia, C9orf72, GRN, TARDBP, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionPrimary progressive aphasia (PPA) is a neurological syndrome, associated with both frontotemporal dementia and Alzheimer's disease, in which progressive language impairment emerges as the most salient clinical feature during the initial stages of disease.MethodsWe screened the main genes associated with Alzheimer's disease and frontotemporal dementia for pathogenic and risk variants in a cohort of 403 PPA cases.ResultsIn this case series study, 14 (3.5%) cases carried (likely) pathogenic variants: four C9orf72 expansions, nine GRN, and one TARDBP mutation. Rare risk variants, TREM2 R47H and MAPT A152T, were associated with a three- to seven-fold increase in risk for PPA.DiscussionOur results show that while pathogenic variants within the most common dementia genes were rarely associated with PPA, these were found almost exclusively in GRN and C9orf72, suggesting that PPA is more TDP43- than tau-related in our series. This is consistent with the finding that PPA frequency in dominantly inherited dementias is the highest in kindreds with GRN variants.

Published
2019

46. Responsiveness to Change of the Montreal Cognitive Assessment, Mini-Mental State Examination, and SCOPA-Cog in Non-Demented Patients with Parkinson’s Disease

Author

Faust-Socher, Achinoam, Duff-Canning, Sarah, Grabovsky, Arthur, Armstrong, Melissa J, Rothberg, Brandon, Eslinger, Paul J, Meaney, Christopher A, Schneider, Ruth B, Tang-Wai, David F, Fox, Susan H, Zadikoff, Cindy, Kennedy, Nancy, Chou, Kelvin L, Persad, Carol, Litvan, Irene, Mast, Benjamin T, Gerstenecker, Adam T, Weintraub, Sandra, Reginold, William, and Marras, Connie

Subjects
Parkinson's Disease, Clinical Research, Neurosciences, Behavioral and Social Science, Acquired Cognitive Impairment, Neurodegenerative, Dementia, Mental Health, Brain Disorders, Aging, Neurological, Aged, Aged, 80 and over, Cognition, Cognitive Dysfunction, Disease Progression, Female, Humans, Male, Mental Status and Dementia Tests, Middle Aged, Neuropsychological Tests, Parkinson Disease, ROC Curve, Reproducibility of Results, Sensitivity and Specificity, Mild cognitive impairment, Responsiveness, Parkinson's disease, Cognitive decline, Parkinson’s disease, Clinical Sciences, Cognitive Sciences, Geriatrics
Abstract

BackgroundClinical monitoring of patients with Parkinson's disease (PD) for cognitive decline is an important element of care. The Montreal Cognitive Assessment (MoCA) has been proposed to be a sensitive tool for assessing cognitive impairment in PD. The aim of our study was to compare the responsiveness of the MoCA to decline in cognition to the responsiveness of the Mini Mental State Examination (MMSE) and the Scales for Outcomes of Parkinson's disease-cognition (SCOPA-Cog).MethodsPD patients without dementia were enrolled at 6 North American movement disorders centers between 2008 and 2011. Participants received annual evaluations including the MoCA, MMSE, and SCOPA-Cog followed by formal neuropsychological testing. The gold standard for change in cognition was defined as the change on the neuropsychological test scores over the annual assessments. The Reliable Change Method was used to provide an estimate of the probability that a given difference score would be obtained by chance. The sensitivity of the MoCA, MMSE, and SCOPA-Cog to change was quantified using receiver operating characteristics (ROC) curves.ResultsOne hundred seventeen patients were included in the analysis. Participants were followed at mean intervals of 11 ± 2 months for a median of 2 (maximum 5) visits. According to the reliable change index, 56 intervals of cognitive testing showed a decline in global cognition. ROC analysis of change in MoCA, MMSE, and SCOPA-Cog global scores compared to gold standard testing found an area under the curve (AUC) of 0.55 (95% CI 0.48-0.62), 0.56 (0.48-0.63), and 0.63 (0.55-0.70) respectively. There were no significant differences in the AUCs across the tests. The sensitivity of the MoCA, MMSE, and SCOPA-Cog to change at various thresholds for decline in scores reached a maximum of 71% for a cut-off of 1 point change on the SCOPA-Cog.ConclusionUsing neuropsychological testing as a gold standard comparator, the performance of the MoCA, MMSE, and SCOPA-Cog for detecting decline in non-demented PD patients over a 1-year interval is poor. This has implications for clinical practice; stable scores may not be taken as reassurance of the absence of cognitive decline.

Published
2019

49. Italian adaptation of the Uniform Data Set Neuropsychological Test Battery (I-UDSNB 1.0): development and normative data

Author

Conca, Francesca, Esposito, Valentina, Rundo, Francesco, Quaranta, Davide, Muscio, Cristina, Manenti, Rosa, Caruso, Giulia, Lucca, Ugo, Galbussera, Alessia Antonella, Di Tella, Sonia, Baglio, Francesca, L’Abbate, Federica, Canu, Elisa, Catania, Valentina, Filippi, Massimo, Mattavelli, Giulia, Poletti, Barbara, Silani, Vincenzo, Lodi, Raffaele, De Matteis, Maddalena, Stanzani Maserati, Michelangelo, Arighi, Andrea, Rotondo, Emanuela, Tanzilli, Antonio, Pace, Andrea, Garramone, Federica, Cavaliere, Carlo, Pardini, Matteo, Rizzetto, Cristiano, Sorbi, Sandro, Perri, Roberta, Tiraboschi, Pietro, Canessa, Nicola, Cotelli, Maria, Ferri, Raffaele, Weintraub, Sandra, Marra, Camillo, Tagliavini, Fabrizio, Catricalà, Eleonora, and Cappa, Stefano Francesco

Published
2022
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50. Comprehensive cross-sectional and longitudinal analyses of plasma neurofilament light across FTD spectrum disorders

Author

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, 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., and Petrucelli, Leonard

Published
2022
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