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1. Examining Associations Between Smartphone Use and Clinical Severity in Frontotemporal Dementia: Proof-of-Concept Study

Author

Paolillo, Emily W, Casaletto, Kaitlin B, Clark, Annie L, Taylor, Jack C, Heuer, Hilary W, Wise, Amy B, Dhanam, Sreya, Sanderson-Cimino, Mark, Saloner, Rowan, Kramer, Joel H, Kornak, John, Kremers, Walter, Forsberg, Leah, Appleby, Brian, Bayram, Ece, Bozoki, Andrea, Brushaber, Danielle, Darby, R Ryan, Day, Gregory S, Dickerson, Bradford C, Domoto-Reilly, Kimiko, Elahi, Fanny, Fields, Julie A, Ghoshal, Nupur, Graff-Radford, Neill, Hall, Matthew GH, Honig, Lawrence S, Huey, Edward D, Lapid, Maria I, Litvan, Irene, Mackenzie, Ian R, Masdeu, Joseph C, Mendez, Mario F, Mester, Carly, Miyagawa, Toji, Naasan, Georges, Pascual, Belen, Pressman, Peter, Ramos, Eliana Marisa, Rankin, Katherine P, Rexach, Jessica, Rojas, Julio C, VandeVrede, Lawren, Wong, Bonnie, Wszolek, Zbigniew K, Boeve, Bradley F, Rosen, Howard J, Boxer, Adam L, Staffaroni, Adam M, and Consortium, ALLFTD

Subjects
Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Neurosciences, Frontotemporal Dementia (FTD), Clinical Research, Alzheimer's Disease, Neurodegenerative, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease Related Dementias (ADRD), Behavioral and Social Science, Aging, Mental Health, Dementia, Basic Behavioral and Social Science, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Neurological, Mental health, Humans, Female, Male, Middle Aged, Frontotemporal Dementia, Smartphone, Aged, Severity of Illness Index, Proof of Concept Study, Adult, Longitudinal Studies, Neuropsychological Tests, Mobile Applications, digital, technology, remote, monitoring, cognition, neuropsychology, cognitive impairment, neurodegenerative, screening, clinical trials, mobile phone, ALLFTD Consortium, Clinical sciences, Biomedical engineering, Health services and systems
Abstract

BackgroundFrontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged

Published
2024

2. 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

3. Plasma inflammation for predicting phenotypic conversion and clinical progression of autosomal dominant frontotemporal lobar degeneration.

Author

Asken, Breton, Ljubenkov, Peter, Staffaroni, Adam, Casaletto, Kaitlin, Masdeu, Joseph, Mendez, Mario, Pascual, Belen, Pressman, Peter, Tartaglia, Maria, Kremers, Walter, Forsberg, Leah, Boeve, Brad, Boxer, Adam, Rosen, Howie, Kramer, Joel, Kornak, John, Heuer, Hilary, Shigenaga, Judy, Appleby, Brian, Bozoki, Andrea, Domoto-Reilly, Kimiko, Ghoshal, Nupur, Huey, Edward, Cobigo, Yann, Rojas-Rodriguez, Julio, Rankin, Katherine, Litvan, Irene, and Vandevrede, Lawren

Subjects
CLINICAL NEUROLOGY, FRONTOTEMPORAL DEMENTIA, Humans, C9orf72 Protein, Disease Progression, Frontotemporal Dementia, Frontotemporal Lobar Degeneration, Inflammation, Interleukin-6, Mutation, tau Proteins, Tumor Necrosis Factor-alpha
Abstract

BACKGROUND: Measuring systemic inflammatory markers may improve clinical prognosis and help identify targetable pathways for treatment in patients with autosomal dominant forms of frontotemporal lobar degeneration (FTLD). METHODS: We measured plasma concentrations of IL-6, TNFα and YKL-40 in pathogenic variant carriers (MAPT, C9orf72, GRN) and non-carrier family members enrolled in the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium. We evaluated associations between baseline plasma inflammation and rate of clinical and neuroimaging changes (linear mixed effects models with standardised (z) outcomes). We compared inflammation between asymptomatic carriers who remained clinically normal (asymptomatic non-converters) and those who became symptomatic (asymptomatic converters) using area under the curve analyses. Discrimination accuracy was compared with that of plasma neurofilament light chain (NfL). RESULTS: We studied 394 participants (non-carriers=143, C9orf72=117, GRN=62, MAPT=72). In MAPT, higher TNFα was associated with faster functional decline (B=0.12 (0.02, 0.22), p=0.02) and temporal lobe atrophy. In C9orf72, higher TNFα was associated with faster functional decline (B=0.09 (0.03, 0.16), p=0.006) and cognitive decline (B=-0.16 (-0.22, -0.10), p

Published
2023

4. Feasibility and acceptability of remote smartphone cognitive testing in frontotemporal dementia research

Author

Taylor, Jack Carson, Heuer, Hilary W, Clark, Annie L, Wise, Amy B, Manoochehri, Masood, Forsberg, Leah, Mester, Carly, Rao, Meghana, Brushaber, Daniell, Kramer, Joel, Welch, Ariane E, Kornak, John, Kremers, Walter, Appleby, Brian, Dickerson, Bradford C, Domoto‐Reilly, Kimiko, Fields, Julie A, Ghoshal, Nupur, Graff‐Radford, Neill, Grossman, Murray, Hall, Matthew GH, Huey, Edward D, Irwin, David, Lapid, Maria I, Litvan, Irene, Mackenzie, Ian R, Masdeu, Joseph C, Mendez, Mario F, Nevler, Naomi, Onyike, Chiadi U, Pascual, Belen, Pressman, Peter, Rankin, Katherine P, Ratnasiri, Buddhika, Rojas, Julio C, Tartaglia, Maria Carmela, Wong, Bonnie, Gorno‐Tempini, Maria Luisa, Boeve, Bradley F, Rosen, Howard J, Boxer, Adam L, and Staffaroni, Adam M

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Frontotemporal Dementia (FTD), Behavioral and Social Science, Brain Disorders, Dementia, Aging, Neurodegenerative, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Research, Rare Diseases, Neurological, adherence, digital technology, smartphone, cognition, neuropsychology, frontotemporal lobar degeneration, primary progressive aphasia, Genetics, Biological psychology
Abstract

IntroductionRemote smartphone assessments of cognition, speech/language, and motor functioning in frontotemporal dementia (FTD) could enable decentralized clinical trials and improve access to research. We studied the feasibility and acceptability of remote smartphone data collection in FTD research using the ALLFTD Mobile App (ALLFTD-mApp).MethodsA diagnostically mixed sample of 214 participants with FTD or from familial FTD kindreds (asymptomatic: CDR®+NACC-FTLD = 0 [N = 101]; prodromal: 0.5 [N = 49]; symptomatic ≥1 [N = 51]; not measured [N = 13]) were asked to complete ALLFTD-mApp tests on their smartphone three times within 12 days. They completed smartphone familiarity and participation experience surveys.ResultsIt was feasible for participants to complete the ALLFTD-mApp on their own smartphones. Participants reported high smartphone familiarity, completed ∼ 70% of tasks, and considered the time commitment acceptable (98% of respondents). Greater disease severity was associated with poorer performance across several tests.DiscussionThese findings suggest that the ALLFTD-mApp study protocol is feasible and acceptable for remote FTD research.HighlightsThe ALLFTD Mobile App is a smartphone-based platform for remote, self-administered data collection.The ALLFTD Mobile App consists of a comprehensive battery of surveys and tests of executive functioning, memory, speech and language, and motor abilities.Remote digital data collection using the ALLFTD Mobile App was feasible in a multicenter research consortium that studies FTD. Data was collected in healthy controls and participants with a range of diagnoses, particularly FTD spectrum disorders.Remote digital data collection was well accepted by participants with a variety of diagnoses.

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

Author

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

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

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

Published
2022

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

Author

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

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

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

Published
2022

8. 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

9. 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

10. Fluid and Tissue Biomarkers of Lewy Body Dementia: Report of an LBDA Symposium

Author

Scott, Gregory D, Arnold, Moriah R, Beach, Thomas G, Gibbons, Christopher H, Kanthasamy, Anumantha G, Lebovitz, Russell M, Lemstra, Afina W, Shaw, Leslie M, Teunissen, Charlotte E, Zetterberg, Henrik, Taylor, Angela S, Graham, Todd C, Boeve, Bradley F, Gomperts, Stephen N, Graff-Radford, Neill R, Moussa, Charbel, Poston, Kathleen L, Rosenthal, Liana S, Sabbagh, Marwan N, Walsh, Ryan R, Weber, Miriam T, Armstrong, Melissa J, Bang, Jee A, Bozoki, Andrea C, Domoto-Reilly, Kimiko, Duda, John E, Fleisher, Jori E, Galasko, Douglas R, Galvin, James E, Goldman, Jennifer G, Holden, Samantha K, Honig, Lawrence S, Huddleston, Daniel E, Leverenz, James B, Litvan, Irene, Manning, Carol A, Marder, Karen S, Pantelyat, Alexander Y, Pelak, Victoria S, Scharre, Douglas W, Sha, Sharon J, Shill, Holly A, Mari, Zoltan, Quinn, Joseph F, and Irwin, David J

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Alzheimer's Disease Related Dementias (ADRD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, Aging, Dementia, Brain Disorders, Acquired Cognitive Impairment, Lewy Body Dementia, Parkinson's Disease, Neurodegenerative, Neurological, cerebrospinal fluid, alpha-synuclein, skin biopsy, seeded aggregation assays, tau, amyloid, Lewy body dementia, LBDA biomarker symposium, Clinical sciences, Biological psychology
Abstract

The Lewy Body Dementia Association (LBDA) held a virtual event, the LBDA Biofluid/Tissue Biomarker Symposium, on January 25, 2021, to present advances in biomarkers for Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLBs) and Parkinson's disease dementia (PDD). The meeting featured eight internationally known scientists from Europe and the United States and attracted over 200 scientists and physicians from academic centers, the National Institutes of Health, and the pharmaceutical industry. Methods for confirming and quantifying the presence of Lewy body and Alzheimer's pathology and novel biomarkers were discussed.

Published
2022

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. Lewy Body Dementia Association’s Research Centers of Excellence Program: Inaugural Meeting Proceedings

Author

Peterson, Bethany, Armstrong, Melissa, Galasko, Douglas, Galvin, James E, Goldman, Jennifer, Irwin, David, Paulson, Henry, Kaufer, Daniel, Leverenz, James, Lunde, Angela, McKeith, Ian G, Siderowf, Andrew, Taylor, Angela, Amodeo, Katherine, Barrett, Matt, Domoto-Reilly, Kimiko, Duda, John, Gomperts, Stephen, Graff-Radford, Neill, Holden, Samantha, Honig, Lawrence, Huddleston, Daniel, Lippa, Carol, Litvan, Irene, Manning, Carol, Marder, Karen, Moussa, Charbel, Onyike, Chiadi, Pagan, Fernando, Pantelyat, Alexander, Pelak, Victoria, Poston, Kathleen, Quinn, Joseph, Richard, Irene, Rosenthal, Liana S, Sabbagh, Marwan, Scharre, Douglas, Sha, Sharon, Shill, Holly, Torres-Yaghi, Yasar, Christie, Tina, Graham, Todd, Richards, Ian, Koehler, Mike, and Boeve, Brad

Subjects
Health Services and Systems, Health Sciences, Dementia, Alzheimer's Disease, Prevention, Brain Disorders, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Parkinson's Disease, Alzheimer's Disease Related Dementias (ADRD), Clinical Research, Aging, Acquired Cognitive Impairment, Lewy Body Dementia, Neurological, Biomedical Research, Clinical Trials as Topic, Congresses as Topic, Humans, Lewy Body Disease, New Orleans, Lewy body dementia, Lewy Body Dementia Association, Parkinson's disease dementia, Parkinson’s disease dementia, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
Abstract

The first Lewy Body Dementia Association (LBDA) Research Centers of Excellence (RCOE) Investigator's meeting was held on December 14, 2017, in New Orleans. The program was established to increase patient access to clinical experts on Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), and to create a clinical trials-ready network. Four working groups (WG) were created to pursue the LBDA RCOE aims: (1) increase access to high-quality clinical care, (2) increase access to support for people living with LBD and their caregivers, (3) increase knowledge of LBD among medical and allied (or other) professionals, and (4) create infrastructure for a clinical trials-ready network as well as resources to advance the study of new therapeutics.

Published
2019

24. 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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25. Study protocol for the Functional Communication Checklist for people living with primary progressive aphasia.

Author

Gallée, Jeanne, Cartwright, Jade, Henry, Maya L., Mooney, Aimee, Stark, Brielle C., Volkmer, Anna, Nakano, Connie, Fredericksen, Rob J., Domoto-Reilly, Kimiko, and Crane, Paul K.

Subjects
PATIENT autonomy, COMMUNICATIVE competence, RESEARCH protocols, MEDICAL protocols, MEDICAL research
Abstract

This study protocol describes the development of the first instrument of functional communication for people living with primary progressive aphasia (PPA), with future applications to other progressive conditions, with expert validation, item-level reliability analyses, input from partners in research, and outcomes. Progressive conditions like PPA require monitoring, and as such, re-assessment. Re-assessment poses the high risk of being burdensome, destructive, and of little use to the patient. As such, there is a significant need to establish a validated and reliable measure that (1) poses minimal patient burden and (2) captures communication ability in a strengths-based manner for both clinical and research purposes. A strengths-based approach to assessment is widely recognized as the optimal way to promote patient autonomy, minimize harm, and implement functional treatment protocols and strategies. To date, there are no strengths-based assessment tools that were developed for people living with PPA nor ways to efficiently document functional communication performance. This study protocol outlines our work to address this gap in clinical practice and research. [ABSTRACT FROM AUTHOR]

Published
2024
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28. Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration

Author

Saloner, Rowan, primary, Staffaroni, Adam, additional, Dammer, Eric, additional, Johnson, Erik C.B., additional, Paolillo, Emily, additional, Wise, Amy, additional, Heuer, Hilary, additional, Forsberg, Leah, additional, Lago, Argentina Lario, additional, Webb, Julia, additional, Vogel, Jacob, additional, Santillo, Alexander, additional, Hansson, Oskar, additional, Kramer, Joel, additional, Miller, Bruce, additional, Li, Jingyao, additional, Loureiro, Joseph, additional, Sivasankaran, Rajeev, additional, Worringer, Kathleen, additional, Seyfried, Nicholas, additional, Yokoyama, Jennifer, additional, Seeley, William, additional, Spina, Salvatore, additional, Grinberg, Lea, additional, VandeVrede, Lawren, additional, Ljubenkov, Peter, additional, Bayram, Ece, additional, Bozoki, Andrea, additional, Brushaber, Danielle, additional, Considine, Ciaran, additional, Day, Gregory, additional, Dickerson, Bradford, additional, Domoto-Reilly, Kimiko, additional, Faber, Kelley, additional, Galasko, Douglas, additional, Geschwind, Daniel, additional, Ghoshal, Nupur, additional, Graff-Radford, Neill, additional, Hales, Chadwick, additional, Honig, Lawrence, additional, Hsiung, Ging-Yuek, additional, Huey, Edward, additional, Kornak, John, additional, Kremers, Walter, additional, Lapid, Maria, additional, Lee, Suzee, additional, Litvan, Irene, additional, McMillan, Corey, additional, Mendez, Mario, additional, Miyagawa, Toji, additional, Pantelyat, Alexander, additional, Pascual, Belen, additional, Paulson, Henry, additional, Petrucelli, Leonard, additional, Pressman, Peter, additional, Ramos, Eliana, additional, Rascovsky, Katya, additional, Roberson, Erik, additional, Savica, Rodolfo, additional, Snyder, Allison, additional, Sullivan, A. Campbell, additional, Tartaglia, Carmela, additional, Vandebergh, Marijne, additional, Boeve, Bradley, additional, Rosen, Howie, additional, Rojas, Julio, additional, Boxer, Adam, additional, and Casaletto, Kaitlin, additional

Published
2024
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29. Cerebrospinal fluid soluble insulin receptor levels in Alzheimer's disease.

Author

Thomas, Peter, Leclerc, Manon, Evitts, Kira, Brown, Caitlin, Miller, Wyatt, Hanson, Angela J., Banks, William A., Gibbons, Laura, Domoto‐Reilly, Kimiko, Jayadev, Suman, Li, Ge, Peskind, Elaine, Young, Jessica E., Calon, Frederic, and Rhea, Elizabeth M.

Subjects
ALZHEIMER'S disease, INSULIN receptors, CEREBROSPINAL fluid, AMYLOID beta-protein precursor, TUMOR necrosis factors
Abstract

INTRODUCTION: Brain insulin resistance and deficiency is a consistent feature of Alzheimer's disease (AD). Insulin resistance can be mediated by the surface expression of the insulin receptor (IR). Cleavage of the IR generates the soluble IR (sIR). METHODS: We measured the levels of sIR present in cerebrospinal fluid (CSF) from individuals along the AD diagnostic spectrum from two cohorts: Seattle (n = 58) and the Consortium for the Early Identification of Alzheimer's Disease‐Quebec (CIMA‐Q; n = 61). We further investigated the brain cellular contribution for sIR using human cell lines. RESULTS: CSF sIR levels were not statistically different in AD. CSF sIR and amyloid beta (Aβ)42 and Aβ40 levels significantly correlated as well as CSF sIR and cognition in the CIMA‐Q cohort. Human neurons expressing the amyloid precursor protein "Swedish" mutation generated significantly greater sIR and human astrocytes were also able to release sIR in response to both an inflammatory and insulin stimulus. DISCUSSION: These data support further investigation into the generation and role of sIR in AD. Highlights: Cerebrospinal fluid (CSF) soluble insulin receptor (sIR) levels positively correlate with amyloid beta (Aβ)42 and Aβ40.CSF sIR levels negatively correlate with cognitive performance (Montreal Cognitive Assessment score).CSF sIR levels in humans remain similar across Alzheimer's disease diagnostic groups.Neurons derived from humans with the "Swedish" mutation in which Aβ42 is increased generate increased levels of sIR.Human astrocytes can also produce sIR and generation is stimulated by tumor necrosis factor α and insulin. [ABSTRACT FROM AUTHOR]

Published
2024
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30. Dementias

Author

Domoto-Reilly, Kimiko, Flanagan, Margaret E., Grabowski, Thomas J., Jr., and Rosenberg, Roger N., editor

Published
2019
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31. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study

Author

Heller, Carolin, Convery, Rhian S, Woollacott, Ione OC, Shafei, Rachelle M, Graff-Radford, Jonathan, Jones, David T, Dheel, Christina M, Savica, Rodolfo, Lapid, Maria I, Baker, Matt, Fields, Julie A, Gavrilova, Ralitza, Domoto-Reilly, Kimiko, Poos, Jackie M, Van der Ende, Emma L, Panman, Jessica L, Donker Kaat, Laura, Seelaar, Harro, Richardson, Anna, Frisoni, Giovanni, Mega, Anna, Fostinelli, Silvia, Chiang, Huei-Hsin, Alberici, Antonella, Arighi, Andrea, Fenoglio, Chiara, Heuer, Hilary, Miller, Bruce, Karydas, Anna, Fong, Jamie, João Leitão, Maria, Santiago, Beatriz, Duro, Diana, Ferreira, Carlos, Gabilondo, Alazne, De Arriba, Maria, Tainta, Mikel, Zulaica, Miren, Ferreira, Catarina, Semler, Elisa, Ludolph, Albert, Landwehrmeyer, Bernhard, Volk, Alexander E, Miltenberger, Gabriel, Verdelho, Ana, Afonso, Sónia, Tartaglia, Maria Carmela, Freedman, Morris, Rogaeva, Ekaterina, Ferrari, Camilla, Piaceri, Irene, Bessi, Valentina, Lombardi, Gemma, St-Onge, Frédéric, Doré, Marie-Claire, Bruffaerts, Rose, Vandenbulcke, Mathieu, Van den Stock, Jan, Mesulam, M Marsel, Bigio, Eileen, Koros, Christos, Papatriantafyllou, John, Kroupis, Christos, Stefanis, Leonidas, Shoesmith, Christien, Robertson, Erik, Coppola, Giovanni, Da Silva Ramos, Eliana Marisa, Geschwind, Daniel, 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, Jr, 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, Guerreiro, Rita, Bras, Jose, and Rohrer, Jonathan D

Published
2020
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33. 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., and Rosen, Howard J.

Published
2019
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34. Use of the CDR® plus NACC FTLD in mild FTLD: Data from the ARTFL/LEFFTDS consortium

Author

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

Published
2019
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35. 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., and Rosen, Howard J.

Published
2019
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36. Adipocyte-Derived Small Extracellular Vesicles from Patients with Alzheimer Disease Carry miRNAs Predicted to Target the CREB Signaling Pathway in Neurons

Author

Batabyal, Rachael A., primary, Bansal, Ankush, additional, Cechinel, Laura Reck, additional, Authelet, Kayla, additional, Goldberg, Madeleine, additional, Nadler, Evan, additional, Keene, C. Dirk, additional, Jayadev, Suman, additional, Domoto-Reilly, Kimiko, additional, Li, Gail, additional, Peskind, Elaine, additional, Hashimoto-Torii, Kazue, additional, Buchwald, Dedra, additional, and Freishtat, Robert J., additional

Published
2023
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37. Interrater reliability of the new criteria for behavioral variant frontotemporal dementia

Author

LaMarre, Amanda K, Rascovsky, Katya, Bostrom, Alan, Toofanian, Parnian, Wilkins, Sarah, Sha, Sharon J, Perry, David C, Miller, Zachary A, Naasan, Georges, Laforce, Robert Jr, Hagen, Jayne, Takada, Leonel T, Tartaglia, Maria Carmela, Kang, Gail, Galasko, Douglas, Salmon, David P, Farias, Sarah Tomaszewski, Kaur, Berneet, Olichney, John M, Quitania Park, Lovingly, Mendez, Mario F, Tsai, Po-Heng, Teng, Edmond, Dickerson, Bradford Clark, Domoto-Reilly, Kimiko, McGinnis, Scott, Miller, Bruce L, and Kramer, Joel H

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Brain Disorders, Rare Diseases, Alzheimer's Disease, Behavioral and Social Science, Frontotemporal Dementia (FTD), Alzheimer's Disease Related Dementias (ADRD), Dementia, Aphasia, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Acquired Cognitive Impairment, Mental Health, Neurological, Aged, Aged, 80 and over, Female, Frontotemporal Dementia, Humans, Male, Middle Aged, Neuropsychological Tests, Observer Variation, Physicians, Psychology, Single-Blind Method, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo evaluate the interrater reliability of the new International Behavioural Variant FTD Criteria Consortium (FTDC) criteria for behavioral variant frontotemporal dementia (bvFTD).MethodsTwenty standardized clinical case modules were developed for patients with a range of neurodegenerative diagnoses, including bvFTD, primary progressive aphasia (nonfluent, semantic, and logopenic variant), Alzheimer disease, and Lewy body dementia. Eighteen blinded raters reviewed the modules and 1) rated the presence or absence of core diagnostic features for the FTDC criteria, and 2) provided an overall diagnostic rating. Interrater reliability was determined by κ statistics for multiple raters with categorical ratings.ResultsThe mean κ value for diagnostic agreement was 0.81 for possible bvFTD and 0.82 for probable bvFTD ("almost perfect agreement"). Interrater reliability for 4 of the 6 core features had "substantial" agreement (behavioral disinhibition, perseverative/compulsive, sympathy/empathy, hyperorality; κ = 0.61-0.80), whereas 2 had "moderate" agreement (apathy/inertia, neuropsychological; κ = 0.41-0.6). Clinician years of experience did not significantly influence rater accuracy.ConclusionsThe FTDC criteria show promise for improving the diagnostic accuracy and reliability of clinicians and researchers. As disease-altering therapies are developed, accurate differential diagnosis between bvFTD and other neurodegenerative diseases will become increasingly important.

Published
2013

40. Multisite ALLFTD study modeling progressive empathy loss from the earliest stages of behavioral variant frontotemporal dementia.

Author

Toller, Gianina, Cobigo, Yann, Callahan, Patrick, Appleby, Brian S., Brushaber, Danielle, Domoto‐Reilly, Kimiko, Forsberg, Leah K., Ghoshal, Nupur, Graff‐Radford, Jonathan, Graff‐Radford, Neil R., Grossman, Murray, Heuer, Hilary W., Kornak, John, Kremers, Walter, Lapid, Maria I., Leger, Gabriel, Litvan, Irene, Mackenzie, Ian R., Pascual, Maria B., and Ramos, Eliana M.

Abstract

Introduction: Empathy relies on fronto‐cingular and temporal networks that are selectively vulnerable in behavioral variant frontotemporal dementia (bvFTD). This study modeled when in the disease process empathy changes begin, and how they progress. Methods: Four hundred thirty‐one individuals with asymptomatic genetic FTD (n = 114), genetic and sporadic bvFTD (n = 317), and 163 asymptomatic non‐carrier controls were enrolled. In sub‐samples, we investigated empathy measured by the informant‐based Interpersonal Reactivity Index (IRI) at each disease stage and over time (n = 91), and its correspondence to underlying atrophy (n = 51). Results: Empathic concern (estimate = 4.38, 95% confidence interval [CI] = 2.79, 5.97; p < 0.001) and perspective taking (estimate = 5.64, 95% CI = 3.81, 7.48; p < 0.001) scores declined between the asymptomatic and very mild symptomatic stages regardless of pathogenic variant status. More rapid loss of empathy corresponded with subcortical atrophy. Discussion: Loss of empathy is an early and progressive symptom of bvFTD that is measurable by IRI informant ratings and can be used to monitor behavior in neuropsychiatry practice and treatment trials. [ABSTRACT FROM AUTHOR]

Published
2023
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42. Temporal order of clinical and biomarker changes in familial frontotemporal dementia

Author

Frontotemporal Dementia Prevention Initiative (FPI) Investigators, ALLFTD Investigators, GENFI investigators, 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., Maruta, Carolina, Simões do Couto, Frederico, Almeida, Maria Rosario, and Veritati - Repositório Institucional da Universidade Católica Portuguesa

Abstract

Unlike familial Alzheimer’s disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations using model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. f-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects.

Published
2022

43. WITHDRAWN: 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., and Rosen, Howard J.

Published
2023
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46. Fluid and Tissue Biomarkers of Lewy Body Dementia: Report of an LBDA Symposium

Author

Scott, Gregory D., primary, Arnold, Moriah R., additional, Beach, Thomas G., additional, Gibbons, Christopher H., additional, Kanthasamy, Anumantha G., additional, Lebovitz, Russell M., additional, Lemstra, Afina W., additional, Shaw, Leslie M., additional, Teunissen, Charlotte E., additional, Zetterberg, Henrik, additional, Taylor, Angela S., additional, Graham, Todd C., additional, Boeve, Bradley F., additional, Gomperts, Stephen N., additional, Graff-Radford, Neill R., additional, Moussa, Charbel, additional, Poston, Kathleen L., additional, Rosenthal, Liana S., additional, Sabbagh, Marwan N., additional, Walsh, Ryan R., additional, Weber, Miriam T., additional, Armstrong, Melissa J., additional, Bang, Jee A., additional, Bozoki, Andrea C., additional, Domoto-Reilly, Kimiko, additional, Duda, John E., additional, Fleisher, Jori E., additional, Galasko, Douglas R., additional, Galvin, James E., additional, Goldman, Jennifer G., additional, Holden, Samantha K., additional, Honig, Lawrence S., additional, Huddleston, Daniel E., additional, Leverenz, James B., additional, Litvan, Irene, additional, Manning, Carol A., additional, Marder, Karen S., additional, Pantelyat, Alexander Y., additional, Pelak, Victoria S., additional, Scharre, Douglas W., additional, Sha, Sharon J., additional, Shill, Holly A., additional, Mari, Zoltan, additional, Quinn, Joseph F., additional, and Irwin, David J., additional

Published
2022
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47. Clinical value of CSF tau, p‐tau181, neurogranin and neurofilaments in familial frontotemporal lobar degeneration

Author

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

Published
2021
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48. Diagnostic value of plasma P‐tau217 in frontotemporal dementia spectrum disorders

Author

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

Published
2021
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50. Fluid and Tissue Biomarkers of Lewy Body Dementia: Report of an LBDA Symposium

Author

Scott, Gregory D., primary, Arnold, Moriah R., additional, Beach, Thomas G., additional, Gibbons, Christopher H., additional, Kanthasamy, Anumantha G., additional, Lebovitz, Russell M., additional, Lemstra, Afina W., additional, Shaw, Leslie M., additional, Teunissen, Charlotte E., additional, Zetterberg, Henrik, additional, Taylor, Angela S., additional, Graham, Todd C., additional, Boeve, Bradley F., additional, Gomperts, Stephen N., additional, Graff-Radford, Neill R., additional, Moussa, Charbel E.-H., additional, Poston, Kathleen L., additional, Rosenthal, Liana S., additional, Sabbagh, Marwan N., additional, Walsh, Ryan R., additional, Weber, Miriam T., additional, Armstrong, Melissa J., additional, Bang, Jee A., additional, Bozoki, Andrea C., additional, Domoto-Reilly, Kimiko, additional, Duda, John E., additional, Fleisher, Jori E., additional, Galasko, Douglas R., additional, Galvin, James E., additional, Goldman, Jennifer G., additional, Holden, Samantha K., additional, Honig, Lawrence S., additional, Huddleston, Daniel E., additional, Leverenz, James B., additional, Litvan, Irene, additional, Manning, Carol A., additional, Marder, Karen S., additional, Pantelyat, Alexander Y., additional, Pelak, Victoria S., additional, Scharre, Douglas W., additional, Sha, Sharon J., additional, Shill, Holly A., additional, Zoltan, Mari, additional, Quinn, Joseph F., additional, and Irwin, David J., additional

Published
2021
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