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IntroductionLeisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD).MethodsA total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans.ResultsGreater physical and cognitive activities were each associated with an estimated >55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated >two-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates.DiscussionActive lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.

Background: Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged <65 years. Several challenges to conducting in-person evaluations in FTLD illustrate an urgent need to develop remote, accessible, and low-burden assessment techniques. Studies of unobtrusive monitoring of at-home computer use in older adults with mild cognitive impairment show that declining function is reflected in reduced computer use; however, associations with smartphone use are unknown., Objective: This study aims to characterize daily trajectories in smartphone battery use, a proxy for smartphone use, and examine relationships with clinical indicators of severity in FTLD., Methods: Participants were 231 adults (mean age 52.5, SD 14.9 years; n=94, 40.7% men; n=223, 96.5% non-Hispanic White) enrolled in the Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL study) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS study) Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Mobile App study, including 49 (21.2%) with mild neurobehavioral changes and no functional impairment (ie, prodromal FTLD), 43 (18.6%) with neurobehavioral changes and functional impairment (ie, symptomatic FTLD), and 139 (60.2%) clinically normal adults, of whom 55 (39.6%) harbored heterozygous pathogenic or likely pathogenic variants in an autosomal dominant FTLD gene. Participants completed the Clinical Dementia Rating plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR+NACC FTLD) scale, a neuropsychological battery; the Neuropsychiatric Inventory; and brain magnetic resonance imaging. The ALLFTD Mobile App was installed on participants' smartphones for remote, passive, and continuous monitoring of smartphone use. Battery percentage was collected every 15 minutes over an average of 28 (SD 4.2; range 14-30) days. To determine whether temporal patterns of battery percentage varied as a function of disease severity, linear mixed effects models examined linear, quadratic, and cubic effects of the time of day and their interactions with each measure of disease severity on battery percentage. Models covaried for age, sex, smartphone type, and estimated smartphone age., Results: The CDR+NACC FTLD global score interacted with time on battery percentage such that participants with prodromal or symptomatic FTLD demonstrated less change in battery percentage throughout the day (a proxy for less smartphone use) than clinically normal participants (P<.001 in both cases). Additional models showed that worse performance in all cognitive domains assessed (ie, executive functioning, memory, language, and visuospatial skills), more neuropsychiatric symptoms, and smaller brain volumes also associated with less battery use throughout the day (P<.001 in all cases)., Conclusions: These findings support a proof of concept that passively collected data about smartphone use behaviors associate with clinical impairment in FTLD. This work underscores the need for future studies to develop and validate passive digital markers sensitive to longitudinal clinical decline across neurodegenerative diseases, with potential to enhance real-world monitoring of neurobehavioral change., (©Emily W Paolillo, Kaitlin B Casaletto, Annie L Clark, Jack C Taylor, Hilary W Heuer, Amy B Wise, Sreya Dhanam, Mark Sanderson-Cimino, Rowan Saloner, Joel H Kramer, John Kornak, Walter Kremers, Leah Forsberg, Brian Appleby, Ece Bayram, Andrea Bozoki, Danielle Brushaber, R Ryan Darby, Gregory S Day, Bradford C Dickerson, Kimiko Domoto-Reilly, Fanny Elahi, Julie A Fields, Nupur Ghoshal, Neill Graff-Radford, Matthew G H Hall, Lawrence S Honig, Edward D Huey, Maria I Lapid, Irene Litvan, Ian R Mackenzie, Joseph C Masdeu, Mario F Mendez, Carly Mester, Toji Miyagawa, Georges Naasan, Belen Pascual, Peter Pressman, Eliana Marisa Ramos, Katherine P Rankin, Jessica Rexach, Julio C Rojas, Lawren VandeVrede, Bonnie Wong, Zbigniew K Wszolek, Bradley F Boeve, Howard J Rosen, Adam L Boxer, Adam M Staffaroni, ALLFTD Consortium. Originally published in JMIR Aging (https://aging.jmir.org), 26.06.2024.)

Objective: Solid organ transplant recipients (SOTRs) have an increased risk of skin cancer development, but limited data exist on the development pattern of cutaneous malignancies in non-White SOTRs. The aim of this study was to describe the characteristics and outcomes of non-White patients who developed skin cancer following solid organ transplantation., Methods: We conducted a retrospective chart review of non-White SOTRs at the Mayo Clinic who underwent transplantation between November 1987 and April 2020 and subsequently developed skin cancer., Results: We identified 32 non-White SOTRs who developed skin cancer in the posttransplant period. Among these, 46.9% were Hispanic/Latinx, 25% were American Indian/Alaskan Native, 21.9% were Asian, and 6.3% were Black/African American. Four patients had a history of nonmelanoma skin cancer pretransplant. In regard to skin cancer type, 21 (65.6%) patients developed squamous cell carcinoma, 15 (46.9%) developed basal cell carcinoma, 5 (15.6%) developed melanoma, and 2 (6.3%) developed sebaceous carcinoma. The median time from transplant to first posttransplant skin cancer was 7.8 years., Conclusions: Our study provides further characterization of the development of skin cancer in non-White SOTRs following transplant and identifies a variety of relevant pre- and posttransplant factors. Despite a long follow-up period, the number of patients identified remained low, which is consistent with the literature, indicating a low incidence of skin cancer development in non-White SOTRs. Continued investigation may allow for a more precise identification of risk factors and their degree of significance.

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., (© 2022 the Alzheimer's Association.)

Introduction: Remote 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)., Methods: A 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., Results: It 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., Discussion: These findings suggest that the ALLFTD-mApp study protocol is feasible and acceptable for remote FTD research., Highlights: The 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., Competing Interests: Appleby, BS – receives research support from CDC, NIH, Ionis, Alector, and the CJD Foundation. He has provided consultation to Acadia, Ionis, and Sangamo.Boeve, BF – has served as an investigator for clinical trials sponsored by Alector, Biogen and Transposon. He receives royalties from the publication of a book entitled Behavioral Neurology Of Dementia (Cambridge Medicine, 2009, 2017). He serves on the Scientific Advisory Board of the Tau Consortium. He receives research support from NIH, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program, and the Little Family Foundation.Boxer, AL – receives research support from NIH (U19AG063911, R01AG038791, R01AG073482), the Tau Research Consortium, the Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Corticobasal Degeneration Solutions, the Alzheimer's Drug Discovery Foundation, and the Alzheimer's Association. He has served as a consultant for Aeovian, AGTC, Alector, Arkuda, Arvinas, AviadoBio, Boehringer Ingelheim, Denali, GSK, Life Edit, Humana, Oligomerix, Oscotec, Roche, Transposon, TrueBinding and Wave, and received research support from Biogen, Eisai, and Regeneron. As a co‐inventor of ALLFTD‐mApp tasks, Dr. Boxer has received licensing fees.Brushaber, D – nothing to disclose.Clark, AL – nothing to disclose.Dickerson, BC – Dr Dickerson is a consultant for Acadia, Alector, Arkuda, Biogen, Denali, Eisai, Genentech, Lilly, Merck, Novartis, Takeda, Wave Lifesciences. Dr Dickerson receives royalties from Cambridge University Press, Elsevier, Oxford University Press. Dr Dickerson receives grant funding from the NIA, NINDS, NIMH, and the Bluefield Foundation.Domoto‐Reilly, K – receives research support from NIH, and serves as an investigator for a clinical trial sponsored by Lawson Health Research Institute.Fields, JA – receives research support from NIH.Forsberg, L – receives research support from NIH.Ghoshal, N – has participated or is currently participating in clinical trials of anti‐dementia drugs sponsored by the following companies: Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals, Janssen Immunotherapy, Novartis, Pfizer, Wyeth, SNIFF (The Study of Nasal Insulin to Fight Forgetfulness) study, and A4 (The Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease) trial. She receives research support from Tau Consortium and Association for Frontotemporal Dementia and is funded by the NIH.Gorno‐Tempini, ML – receives research support from NIH. As a co‐inventor of one of the ALLFTD mApp tasks, Dr Gorno‐Tempini's lab receives licensing fees , consistent with UCSF institutional policy.Graff‐Radford, N – receives royalties from UpToDate, has participated in multicenter therapy studies by sponsored by Biogen, TauRx, AbbVie, Novartis, and Lilly. He receives research support from NIH.Grossman, M – receives grant support from NIH, Avid, and Piramal; participates in clinical trials sponsored by Biogen, TauRx, and Alector; serves as a consultant to Bracco and UCB; and serves on the Editorial Board of Neurology.Hall, MGH – nothing to disclose.Heuer, HW – nothing to disclose.Huey, ED – receives research support from NIH.Irwin, D – receives support from NIH, Brightfocus Foundation, and Penn Institute on Aging.Kornak, J – has provided expert witness testimony for Teva Pharmaceuticals in Forest Laboratories Inc. et al. v. Teva Pharmaceuticals USA, Inc., Case Nos. 1:14‐cv‐00121 and 1:14‐cv‐00686 (D. Del. filed Jan. 31, 2014, and May 30, 2014) regarding the drug Memantine; for Apotex/HEC/Ezra in Novartis AG et al. v. Apotex Inc., No. 1:15‐cv‐975 (D. Del. filed Oct. 26, 2015, regarding the drug Fingolimod. He has also given testimony on behalf of Puma Biotechnology in Hsingching Hsu et al, vs. Puma Biotechnology, INC., et al. 2018 regarding the drug Neratinib. He receives research support from the NIH.Kramer, J – receives research support from NIH and royalties from Pearson Inc.Kremers, W—receives research funding from AstraZeneca, Biogen, Roche, DOD, and NIH.Lapid, MI – receives research support from the NIH.Litvan, I – receives research support from the National Institutes of Health grants: 2R01AG038791‐06A, U01NS100610, U01NS80818, R25NS098999; U19 AG063911‐1 and 1R21NS114764‐01A1; the Michael J Fox Foundation, Parkinson Foundation, Lewy Body Association, CurePSP, Roche, Abbvie, Biogen, Centogene. EIP‐Pharma, Biohaven Pharmaceuticals, Novartis, and United Biopharma SRL‐UCB. She is a Scientific advisor for Amydis (Gratis) and Rossy Center for Progressive Supranuclear Palsy University of Toronto. She receives her salary from the University of California San Diego and as Chief Editor of Frontiers in Neurology.Mackenzie, IR – receives research funding from Canadian Institutes of Health Research, Alzheimer's Association US, NIH, Weston Brain Institute.Manoochehri, M – nothing to disclose.Masdeu, JC – is a consultant and received research funding from Eli Lilly, parent co. of Avid Radiopharmaceuticals, manufacturer of 18F‐flortaucipir, receives personal fees from GE Healthcare, grants and personal fees from Eli Lilly, grants from Acadia, Avanir, Biogen, Eisai, Janssen, NIH, Novartis, with no relation to the submitted work.Mendez, MF – receives research support from NIH.Mester, C – nothing to disclose.Nevler, N – receives research funding from the NIH and Department of Defense.Onyike, C – receives research funding from the NIH, Lawton Health Research Institute, National Ataxia Foundation, Alector Inc., and Transposon, Inc. He is also supported by the Robert and Nancy Hall Brain Research Fund, the Jane Tanger Black Fund for Young‐Onset Dementias, and the gift from Joseph Trovato. He is a consultant with Alector, Inc. and Acadia Pharmaceuticals.Pascual, B – receives research support from NIH.Pressman, PS – receives research support from NIH.Rankin, KP – receives research support from NIH and NSF, and serves on a Medical Advisory Board for Eli Lilly.Rao, M – nothing to disclose.Rojas, JC – receives research support from NIH and is a site PI for clinical trials sponsored by Eli‐Lilly and Eisai.Rosen, HJ – has received research support from Biogen Pharmaceuticals, has consulting agreements with Wave Neuroscience and Ionis Pharmaceuticals, and receives research support from NIH.Ratnasiri, B – nothing to disclose.Staffaroni, AM – received research support from the NIA/NIH, Bluefield Project to Cure FTD, and the Larry L. Hillblom Foundation, and has provided consultation to Alector, Lilly/Prevail, Passage Bio, and Takeda. Dr Staffaroni is a co‐inventor of four ALLFTD mApp tasks and receives licensing fees, consistent with UCSF institutional policy.Tartaglia, M – has served as an investigator for clinical trials sponsored by Biogen, Avanex, Green Valley, and Roche / Genentech, Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals, Janssen. She receives research support from Canadian Institutes of Health Research. Author disclosures are available in the supporting information.Taylor, JC – nothing to disclose.Wise, AB – nothing to disclose.Welch, AE – nothing to disclose.Wong, B – receives research support from the NIH., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

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., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: Caregivers of patients with frontotemporal lobar degeneration (FTLD) spectrum disorders experience tremendous burden, which has been associated with the neuropsychiatric and behavioral features of the disorders., Methods: In a sample of 558 participants with FTLD spectrum disorders, we performed multiple-variable regressions to identify the behavioral features that were most strongly associated with caregiver burden, as measured by the Zarit Burden Interview, at each stage of disease., Results: Apathy and disinhibition, as rated by both clinicians and caregivers, as well as clinician-rated psychosis, showed the strongest associations with caregiver burden, a pattern that was consistent when participants were separated cross-sectionally by disease stage. In addition, behavioral features appeared to contribute most to caregiver burden in patients with early dementia., Discussion: Caregivers should be provided with early education on the management of the behavioral features of FTLD spectrum disorders. Interventions targeting apathy, disinhibition, and psychosis may be most useful to reduce caregiver burden., (© 2021 the Alzheimer's Association.)

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 <10% in healthy controls. Finally, the MBCI-FTD criteria were tested on a cohort of individuals with prodromal Alzheimer's disease, and the false positive rate of diagnosis was 11-16%. Future research will need to refine the sensitivity and specificity of these criteria, and incorporate emerging biomarker evidence., (© The Author(s) (2022). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Although executive dysfunction is the characteristic cognitive marker of behavioral variant frontotemporal dementia (bvFTD), episodic memory deficits are relatively common, and may be present even during the prodromal disease phase. In a cohort of mutation carriers with mild behavioral and/or cognitive symptoms consistent with prodromal bvFTD, we aimed to investigate patterns of performance on an abbreviated list learning task, with a particular focus on recognition memory. We further aimed to characterize the cognitive prodromes associated with the three major genetic causes of frontotemporal dementia, as emerging evidence suggests there may be subtle differences in cognitive profiles among carriers of different genetic mutations. Participants included 57 carriers of a pathogenic mutation in microtubule-associated protein tau (MAPT, N = 23), or progranulin (GRN, N = 15), or a or a hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72, N = 19), with mild cognitive and/or behavioral symptoms consistent with prodromal bvFTD. Familial non-carriers were included as controls (N = 143). All participants completed a comprehensive neuropsychological examination, including an abbreviated list learning test assessing episodic memory recall and recognition. MAPT mutation carriers performed worse than non-carriers in terms of list recall, and had difficulty discriminating targets from distractors on the recognition memory task, primarily due to the endorsement of distractors as targets. MAPT mutation carriers also showed nonverbal episodic memory and semantic memory dysfunction (object naming). GRN mutation carriers were variable in performance and overall the most dysexecutive. Slowed psychomotor speed was evident in C9orf72 repeat expansion carriers. Identifying the earliest cognitive indicators of bvFTD is of critical clinical and research importance. List learning may be a sensitive cognitive marker for incipient dementia in MAPT and potentially a subset of GRN carriers. Our results highlight that distinct cognitive profiles may be evident in carriers of the three disease-causing genes during the prodromal disease stage., Competing Interests: Declaration of competing interest M.S. Barker, Ph.D.: Nothing to disclose. M. Manoochehri, B.A.: Nothing to disclose. S.J. Rizer, M.A.: Nothing to disclose. B.S. Appleby, M.D.: Has received research funding from Centers for Disease Control and prevention, National Institutes of Health, Ionis, & Alector. D. Brushaber, B.S.: Nothing to disclose. S.I. Dev, Ph.D.: Nothing to disclose. K.L. Devick, Ph.D.: Nothing to disclose. B.C. Dickerson, M.D.: Research support from National Institutes of Health, Alzheimer's Drug Discovery Foundation, consulting for Acadia, Arkuda, Axovant, Lilly, Biogen, Merck, Novartis, Wave LifeSciences. Editorial duties with payment for Elsevier (Neuroimage: Clinical and Cortex). Royalties from Oxford University Press and Cambridge University Press. J.A. Fields, Ph.D., L.P.: Receives research funding from the National Institutes of Health. T.M. Foroud, Ph.D.: Nothing to disclose. L.K. Forsberg, Ph.D.: Nothing to disclose. D.R. Galasko, M.D.: Paid consultant for Biogen, vTv Pharmaceuticals, Cognition Theraptutics, Fujirebio and Amprion and received payment as a journal Editor from Springer. N. Ghoshal, M.D., Ph.D.: Has participated or is currently participating in clinical trials of anti-dementia drugs sponsored by the following companies: Bristol Myers Squibb, Lilly/Avid Radiopharmaceuticals, Janssen, Novartis, Pfizer, Wyeth, SNIFF (The Study of Nasal Insulin to Fight Forgetfulness) study, and A4 (The Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease) trial. She receives research support from Tau Consortium and Association for Frontotemporal Dementia and is funded by the National Institutes of Health. N.R. Graff-Radford, MBBCh: Takes part in multicenter studies funded by Biogen, AbbVie, and Lilly. M. Grossman, M.D., Ed.D.: Nothing to disclose. H.W. Heuer, Ph.D.: Nothing to disclose. G-Y. Hsiung, M.D.: Has received research support as a clinical trials site investigator from Anavax, Biogen, Eli Lilly and Roche; and has received research funding from the Canadian Institutes of Health Research, Alzheimer Society of Canada, and National Institutes of Health. J. Kornak, Ph.D.: Has provided expert witness testimony for 1) Teva Pharmaceuticals in Forest Laboratories Inc. et al. v. Teva Pharmaceuticals USA, Inc., Case Nos. 1:14-cv-00121 and 1:14-cv-00686 (D. Del. filed Jan. 31, 2014 and May 30, 2014) regarding the drug Memantine; 2) for Apotex/HEC/Ezra in Novartis AG et al. v. Apotex Inc., No. 1:15-cv-975 (D. Del. filed Oct. 26, 2015, regarding the drug Fingolimod; 3) on behalf of Puma Biotechnology in Hsingching Hsu et al. versus Puma Biotechnology, INC., et al., 2018 regarding the drug Neratinib and 4) on behalf of Hikma Pharmaceuticals in Amarin Pharma, Inc versus Hikma Pharmaceuticals in 2019. He receives research support from the National Institutes of Health. I. Litvan, M.D.: Research is supported by the National Institutes of Health grants: 5P50AG005131-33, 2R01AG038791-06A, U01NS090259, U01NS100610, U01NS80818, R25NS098999, P20GM109025; U19 AG063911-1; 1R21NS114764-01A1; Parkinson Study Group, Michael J Fox Foundation, Parkinson Foundation, Lewy Body Association, Parkinson Foundation, Roche, Abbvie, Biogen, EIP-Pharma and Biohaven Pharmaceuticals. She was member of a Lundbeck Advisory Board and Corticobasal Degeneration Solutions. She receives her salary from the University of California San Diego and as Chief Editor of Frontiers in Neurology. I.R. Mackenzie, M.D.: Scientific advisory board member for Prevail Therapeutics. M.F. Mendez, M.D.: Nothing to disclose. B. Pascual, Ph.D. Nothing to disclose. K.P. Rankin, Ph.D.: Funding from the National Institutes of Health, Quest Diagnostics, the Rainwater Charitable Foundation, and the Marcus Foundation. K. Rascovsky, Ph.D.: Nothing to disclose. A.M. Staffaroni, Ph.D.: Receives research funding from the National Institute on Aging-National Institutes of Health and Larry L. Hillblom Foundation. M.C. Tartaglia, M.D.: Nothing to disclose. S. Weintraub, Ph.D.: Nothing to disclose. B. Wong, Ph.D.: Nothing to disclose. B.F. Boeve, M.D.: Has served as an investigator for clinical trials sponsored by GE Healthcareand Axovant. He receives royalties from the publication of a book entitled Behavioral Neurology Of Dementia (Cambridge Medicine, 2009,2017). He serves on the Scientific Advisory Board of the Tau Consortium. He receives research support from National Institutes of Health, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program and the Little Family Foundation. A.L. Boxer, M.D., Ph.D.: Receives research support from National Institutes of Health, the Tau Research Consortium, the Association for Frontotemporal Degeneration and the Bluefield Project to Cure Frontotemporal Dementia. He has served as a consultant for AGTC, Alector, Arkuda, Arvinas, Bioage, Ionis, Lundbeck, Passage BIO, Samumed, Ono, Sangamo, Stealth, Transposon, UCBand Wave, and received research support from Avid, Eisai, Biogen and Roche. H. Rosen, M.D.: has received research support from Biogen Pharmaceuticals, has consulting agreements with Wave Neuroscience and Ionis Pharmaceuticals, and receives research support from National Institutes of Health. J. Goldman, M.S., M.Phil.: Receives research support from National Institutes of Health, Huntington's Disease Society of America, New York State Department of Health (RFA #1510130358). E.D. Huey, M.D.: Nothing to disclose. S. Cosentino, Ph.D.: Nothing to disclose., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: The 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., Methods: Individuals 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., Results: The 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 <.0001)., Conclusion: Lower HRQoL was associated with higher cognitive/behavior impairment and higher caregiver burden. These findings demonstrate the negative impact of FTLD on individuals and caregivers., (© 2020 the Alzheimer's Association.)

Objective: To 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)., Methods: We 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., Results: RSMS 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)., Conclusions: The 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., (© 2020 American Academy of Neurology.)

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: We 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., Methods: The 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., Results: The 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., Discussion: The 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., (© 2020 the Alzheimer's Association.)

Introduction: Identifying 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., Methods: Ninety-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., Results: NIH-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., Discussion: The NIH-EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint., (© 2019 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Introduction: The 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., Methods: We 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., Results: Asymptomatic 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., Discussion: Imaging changes appear to precede clinical changes in familial-frontotemporal lobar degeneration, but specific early clinical and imaging changes vary across individuals., (© 2019 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Introduction: Behavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments., Methods: A total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation., Results: Participants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability., Discussion: f-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other., (© 2020 the Alzheimer's Association.)

Introduction: Some 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., Methods: We 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., Results: Cross-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])., Discussion: Individualized quantification of baseline brain atrophy is a promising predictor of progression in asymptomatic familial frontotemporal lobar degeneration mutation carriers., (© 2019 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Introduction: Behavior/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)., Methods: We 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., Results: The 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., Discussion: The BEHAV and LANG domains enable the CDR® plus NACC FTLD to capture early symptomatology of FTLD., (© 2019 the Alzheimer's Association.)

Introduction: It 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., Methods: The 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., Results: We 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., Discussion: These data and samples, which are available to interested investigators worldwide, will facilitate planning for upcoming disease-modifying therapeutic trials in f-FTLD., (© 2019 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Introduction: Conventional 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., Methods: In 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)., Results: Corrected Z-scores based on nonlinear shape constrained additive models provide improved adjustment for age, sex, and education, as indicated by higher adjusted-R 2 ., Discussion: Nonlinearly 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., (© 2019 Published by Elsevier Inc. on behalf of the Alzheimer's Association.)

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Purpose: The objective of this study was to longitudinally investigate the trajectory of change in 1 H MRS measurements in asymptomatic MAPT mutation carriers who became symptomatic during follow-up, and to determine the time at which the neurochemical alterations accelerated during disease progression., Methods: We identified eight MAPT mutations carriers who transitioned from asymptomatic to symptomatic disease during follow-up. All participants were longitudinally followed with an average of 7.75 years (range 4-11 years) and underwent two or more single voxel 1 H MRS examinations from the posterior cingulate voxel, with a total of 60 examinations. The rate of longitudinal change for each metabolite was estimated using linear mixed models. A flex point model was used to estimate the flex time point of the change in slope., Results: The decrease in the NAA/mI ratio accelerated 2.09 years prior to symptom onset, and continued to decline. A similar trajectory was observed in the presumed glial marker mI/Cr ratio accelerating 1.86 years prior to symptom onset., Conclusions: Our findings support the potential use of longitudinal 1 H MRS for monitoring the neurodegenerative progression in MAPT mutation carriers starting from the asymptomatic stage., (© 2019 The Authors. Journal of Neuroimaging published by Wiley Periodicals, Inc. on behalf of American Society of Neuroimaging.)

Objective: To determine the frontal lobe proton magnetic resonance spectroscopy ( 1 H MRS) abnormalities in asymptomatic and symptomatic carriers of microtubule-associated protein tau ( MAPT ) mutations., Methods: We recruited patients with MAPT mutations from 5 individual families, who underwent single voxel 1 H MRS from the medial frontal lobe at 3T (n = 19) from the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Study at the Mayo Clinic site. Asymptomatic MAPT mutation carriers (n = 9) had Frontotemporal Lobar Degeneration Clinical Dementia Rating Sum of Boxes (FTLD-CDR SOB) score of zero, and symptomatic MAPT mutation carriers (n = 10) had a median FTLD-CDR SOB score of 5. Noncarriers from healthy first-degree relatives of the patients were recruited as controls (n = 25). The demographic aspects and 1 H MRS metabolite ratios were compared by use of the Fisher exact test for sex and linear mixed models to account for within-family correlations. We used Tukey contrasts for pair-wise comparisons., Results: Asymptomatic MAPT mutation carriers had lower neuronal marker N-acetylaspartate (NAA)/creatine (Cr) ( p = 0.001) and lower NAA/myo-inositol (mI) ( p = 0.026) than noncarriers after adjustment for age. Symptomatic MAPT mutation carriers had lower NAA/Cr ( p = 0.01) and NAA/mI ( p = 0.01) and higher mI/Cr ( p = 0.02) compared to noncarriers after adjustment for age. Furthermore, NAA/Cr ( p = 0.006) and NAA/mI ( p < 0.001) ratios decreased, accompanied by an increase in mI/Cr ratio ( p = 0.001), as the ages of carriers approached and passed the age at symptom onset., Conclusion: Frontal lobe neurochemical alterations measured with 1 H MRS precede the symptom onset in MAPT mutation carriers. Frontal lobe 1 H MRS is a potential biomarker for early neurodegenerative processes in MAPT mutation carriers., (© 2019 American Academy of Neurology.)

Introduction: The aim of this study was to investigate the rates of lobar atrophy in the asymptomatic microtubule-associated protein tau ( MAPT ) mutation carriers., Methods: MAPT 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., Results: The 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., Discussion: Accelerated 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.