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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, Alzheimer's Disease Related Dementias (ADRD), Basic Behavioral and Social Science, Alzheimer's Disease, Behavioral and Social Science, Neurosciences, Brain Disorders, Dementia, Acquired Cognitive Impairment, Mental Health, Aging, Frontotemporal Dementia (FTD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Clinical Research, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Mental health, Neurological, 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. 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

3. 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

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

Author

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

Published
2024
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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. Give me a knee radiograph, I will tell you where the knee joint area is: a deep convolutional neural network adventure

Author

Yan, Shi, Ramazanian, Taghi, Sagheb, Elham, Kremers, Walter K., Chaudhary, Vipin, Taunton, Michael, Kremers, Hilal Maradit, and Tafti, Ahmad P.

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Artificial Intelligence, Computer Science - Computer Vision and Pattern Recognition
Abstract

Knee pain is undoubtedly the most common musculoskeletal symptom that impairs quality of life, confines mobility and functionality across all ages. Knee pain is clinically evaluated by routine radiographs, where the widespread adoption of radiographic images and their availability at low cost, make them the principle component in the assessment of knee pain and knee pathologies, such as arthritis, trauma, and sport injuries. However, interpretation of the knee radiographs is still highly subjective, and overlapping structures within the radiographs and the large volume of images needing to be analyzed on a daily basis, make interpretation challenging for both naive and experienced practitioners. There is thus a need to implement an artificial intelligence strategy to objectively and automatically interpret knee radiographs, facilitating triage of abnormal radiographs in a timely fashion. The current work proposes an accurate and effective pipeline for autonomous detection, localization, and classification of knee joint area in plain radiographs combining the You Only Look Once (YOLO v3) deep convolutional neural network with a large and fully-annotated knee radiographs dataset. The present work is expected to stimulate more interest from the deep learning computer vision community to this pragmatic and clinical application., Comment: 13 Pages, 4 Figures

Published
2022

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

Author

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

Published
2024
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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. A general, simple, robust method to account for measurement error when analyzing data with an internal validation subsample

Author

Kremers, Walter K

Subjects
Statistics - Methodology, Statistics - Applications
Abstract

Background: Measurement errors in terms of quantification or classification frequently occur in epidemiologic data and can strongly impact inference. Measurement errors may occur when ascertaining, recording or extracting data. Although the effects of measurement errors can be severe and are well described, simple straight forward general analytic solutions are not readily available for statistical analysis and measurement error is frequently not acknowledged or accounted for. Generally, to account for measurement error requires some data where we can observe the variables once with and once without error, to establish the relationship between the two. Methods: Here we describe a general method accounting for measurement error in outcome and/or predictor variables for the parametric regression setting when there is a validation subsample where variables are measured once with and once without error. The method does not describe and thus does not depend on the particular relation between the variables measured with and without error, and is generally robust to the type of measurement error, for example nondifferential, differential or Berkson errors. Results: Simulation studies show how the method reduces bias compared to models based upon variables measured with error alone and reduces variances compared to models based upon the variables measured without error in the validation subsample alone. Conclusion: The proposed estimator has favorable properties in terms of bias and variance, is easily derived empirically, and is robust to different types of measurement error. This method should be a valuable tool in the analysis of data with measurement error.

Published
2021

12. 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

13. 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

14. The Effect of Implant Density on Adolescent Idiopathic Scoliosis Fusion: Results of the Minimize Implants Maximize Outcomes Randomized Clinical Trial

Author

Larson, A. Noelle, Polly, David W., Sponseller, Paul D., Kelly, Michael P., Richards, B. Stephens, Garg, Sumeet, Parent, Stefan, Shah, Suken A., Weinstein, Stuart L., Crawford, Charles H., III, Sanders, James O., Blakemore, Laurel C., Oetgen, Matthew E., Fletcher, Nicholas D., Kremers, Walter K., Marks, Michelle C., Brearley, Ann M., Aubin, Carl-Eric, Sucato, Daniel J., Labelle, Hubert, Erickson, Mark A., Larson, A. Noelle, Polly, David W., Sponseller, Paul D., Kelly, Michael P., Richards, B. Stephens, Garg, Sumeet, Parent, Stefan, Shah, Suken A., Weinstein, Stuart L., Crawford, Charles H., Sanders, James O., Blakemore, Laurel C., Oetgen, Matthew E., Fletcher, Nicholas D., Marks, Michelle C., Aubin, Carl-Eric, Sucato, Daniel J., Labelle, Hubert, Erickson, Mark A., Glassman, Stephen D., Lenke, Lawrence G., McIntosh, Amy L., Carreon, Leah Y., Dolan, Lori A., Nuckley, David J., Luhmann, Scott, Karol, Lori, Rathjen, Karl, Johnston, Charles, Mac-Thiong, Jean-Marc, and Ramo, Brandon

Published
2024
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15. Studying the natural history of frontotemporal lobar degeneration (FTLD): The ARTFL LEFFTDS longitudinal FTLD (ALLFTD) protocol

Author

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

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

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

Author

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

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

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

Published
2020

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

Author

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

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

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

Published
2020

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

Author

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

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

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

Published
2020

20. 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

21. 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

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

Author

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

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

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

Published
2020

23. 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

24. 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

25. 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

26. 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

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

Author

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

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

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

Published
2019

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

Author

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

Subjects
Clinical Sciences, Neurosciences, Geriatrics
Published
2019

30. Rates of lobar atrophy in asymptomatic MAPT mutation carriers.

Author

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

Subjects
LEFFTDS Consortium, Asymptomatic, Frontotemporal dementia, Longitudinal, MAPT, Magnetic resonance image, Prevention, Brain Disorders, Acquired Cognitive Impairment, Dementia, Neurodegenerative, Neurosciences, Rare Diseases
Abstract

IntroductionThe aim of this study was to investigate the rates of lobar atrophy in the asymptomatic microtubule-associated protein tau (MAPT) mutation carriers.MethodsMAPT mutation carriers (n = 14; 10 asymptomatic, 4 converters from asymptomatic to symptomatic) and noncarriers (n = 13) underwent structural magnetic resonance imaging and were followed annually with a median of 9.2 years. Longitudinal changes in lobar atrophy were analyzed using the tensor-based morphometry with symmetric normalization algorithm.ResultsThe rate of temporal lobe atrophy in asymptomatic MAPT mutation carriers was faster than that in noncarriers. Although the greatest rate of atrophy was observed in the temporal lobe in converters, they also had increased atrophy rates in the frontal and parietal lobes compared to noncarriers.DiscussionAccelerated decline in temporal lobe volume occurs in asymptomatic MAPT mutation carriers followed by the frontal and parietal lobe in those who have become symptomatic. The findings have implications for monitoring the progression of neurodegeneration during clinical trials in asymptomatic MAPT mutation carriers.

Published
2019

32. Artificial Intelligence–Enabled Electrocardiogram for Atrial Fibrillation Identifies Cognitive Decline Risk and Cerebral Infarcts

Author

Weil, Erika L., Noseworthy, Peter A., Lopez, Camden L., Rabinstein, Alejandro A., Friedman, Paul A., Attia, Zachi I., Yao, Xiaoxi, Siontis, Konstantinos C., Kremers, Walter K., Christopoulos, Georgios, Mielke, Michelle M., Vemuri, Prashanthi, Jack, Clifford R., Jr., Gersh, Bernard J., Machulda, Mary M., Knopman, David S., Petersen, Ronald C., and Graff-Radford, Jonathan

Published
2022
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33. 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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34. Clinicoradiological and neuropathological evaluation of primary progressive aphasia.

Author

Shir, Dror, Corriveau-Lecavalier, Nick, Bermudez Noguera, Camilo, Barnard, Leland, Nha Trang Thu Pham, Botha, Hugo, Duffy, Joseph R., Clark, Heather M., Utianski, Rene L., Knopman, David S., Petersen, Ronald C., Boeve, Bradley F., Murray, Melissa E., Nguyen, Aivi T., Reichard, R. Ross, Dickson, Dennis W., Day, Gregory S., Kremers, Walter K., Graff-Radford, Neill R., and Jones, David T.

Subjects
ALZHEIMER'S disease, LEWY body dementia, PROGRESSIVE supranuclear palsy, RAPID eye movement sleep, FRONTOTEMPORAL lobar degeneration, MOTOR cortex
Published
2024
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39. Mild Behavioral Impairment in a Population-based Study of Cognitive Aging (P2-9.005)

Author

Vassilaki, Maria, primary, Syrjanen, Jeremy, additional, Krell-Roesch, Janina, additional, Graff-Radford, Jonathan, additional, Vemuri, Prashanthi, additional, Fields, Julie, additional, Kremers, Walter, additional, Jack, Clifford, additional, Knopman, David, additional, Lyketsos, Constantine, additional, Petersen, Ronald, additional, and Geda, Yonas, additional

Published
2024
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41. Interrater Reliability of the Multidomain Impairment Rating (MIR) Scale in Frontotemporal Lobar Degeneration: Data from the ALLFTD Consortium (P3-9.005)

Author

Miyagawa, Toji, primary, Merrilees, Jennifer, additional, Syrjanen, Jeremy, additional, Brushaber, Danielle, additional, Kremers, Walter, additional, Fields, Julie, additional, Forsberg, Leah, additional, Heuer, Hilary, additional, Huey, Edward, additional, Knopman, David, additional, Kornak, John, additional, Boxer, Adam, additional, Rosen, Howard, additional, and Boeve, Bradley, additional

Published
2024
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42. 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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43. Continuous Associations Between Remote Self-Administered Cognitive Measures and Imaging Biomarkers of Alzheimer’s Disease

Author

Boots, Elizabeth A., primary, Frank, Ryan D., additional, Fan, Winnie Z., additional, Christianson, Teresa J., additional, Kremers, Walter K., additional, Stricker, John L., additional, Machulda, Mary M., additional, Fields, Julie A., additional, Hassenstab, Jason, additional, Graff-Radford, Jonathan, additional, Vemuri, Prashanthi, additional, Jack, Clifford R., additional, Knopman, David S., additional, Petersen, Ronald C., additional, and Stricker, Nikki H., additional

Published
2024
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44. DeepTKAClassifier: Brand Classification of Total Knee Arthroplasty Implants Using Explainable Deep Convolutional Neural Networks

Author

Yan, Shi, Ramazanian, Taghi, Sagheb, Elham, Fu, Sunyang, Sohn, Sunghwan, Lewallen, David G., Liu, Hongfang, Kremers, Walter K., Chaudhary, Vipin, Taunton, Michael, Kremers, Hilal Maradit, Tafti, Ahmad P., Goos, Gerhard, Founding Editor, Hartmanis, Juris, Founding Editor, Bertino, Elisa, Editorial Board Member, Gao, Wen, Editorial Board Member, Steffen, Bernhard, Editorial Board Member, Woeginger, Gerhard, Editorial Board Member, Yung, Moti, Editorial Board Member, Bebis, George, editor, Yin, Zhaozheng, editor, Kim, Edward, editor, Bender, Jan, editor, Subr, Kartic, editor, Kwon, Bum Chul, editor, Zhao, Jian, editor, Kalkofen, Denis, editor, and Baciu, George, editor

Published
2020
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47. The value of multimodal imaging with 123I-FP-CIT SPECT in differential diagnosis of dementia with Lewy bodies and Alzheimer's disease dementia

Author

Miyagawa, Toji, Przybelski, Scott A., Maltais, Daniela, Min, Hoon-Ki, Jordan, Lennon, Lesnick, Timothy G., Chen, Qin, Graff-Radford, Jonathan, Jones, David, Savica, Rodolfo, Knopman, David, Petersen, Ronald, Kremers, Walter K., Forsberg, Leah K., Fields, Julie A., Ferman, Tanis J., Allen, Laura, Parisi, Joseph, Reichard, R. Ross, Murray, Melissa, Dickson, Dennis, Boeve, Bradley F., Kantarci, Kejal, and Lowe, Val J.

Published
2021
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