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Background: Traumatic brain injury (TBI) and repetitive head impacts (RHI) have been linked to increased risk for multiple types of neurodegenerative disease, higher dementia risk, and earlier age of dementia symptom onset, suggesting transdiagnostic implications for later-life brain health. Frontotemporal dementia (FTD) and primary progressive aphasia (PPA) represent a spectrum of clinical phenotypes that are neuropathologically diverse. FTD/PPA diagnoses bring unique challenges due to complex cognitive and behavioral symptoms that disproportionately present as an early-onset dementia (before age 65). We performed a detailed characterization of lifetime head trauma exposure in individuals with FTD and PPA compared to healthy controls to examine frequency of lifetime TBI and RHI and associated clinical implications., Methods: We studied 132 FTD/PPA (age 68.9 ± 8.1, 65% male) and 132 sex-matched healthy controls (HC; age 73.4 ± 7.6). We compared rates of prior TBI and RHI (contact/collision sports) between FTD/PPA and HC (chi-square, logistic regression, analysis of variance). Within FTD/PPA, we evaluated associations with age of symptom onset (analysis of variance). Within behavioral variant FTD, we evaluated associations with cognitive function and neuropsychiatric symptoms (linear regression controlling for age, sex, and years of education)., Results: Years of participation were greater in FTD/PPA than HC for any contact/collision sport (8.5 ± 6.7yrs vs. 5.3 ± 4.5yrs, p = .008) and for American football (6.2yrs ± 4.3yrs vs. 3.1 ± 2.4yrs; p = .003). Within FTD/PPA, there were dose-dependent associations with earlier age of symptom onset for TBI (0 TBI: 62.1 ± 8.1, 1 TBI: 59.9 ± 6.9, 2 + TBI: 57.3 ± 8.4; p = .03) and years of American football (0yrs: 62.2 ± 8.7, 1-4yrs: 59.7 ± 7.0, 5 + yrs: 55.9 ± 6.3; p = .009). Within bvFTD, those who played American football had worse memory (z-score: -2.4 ± 1.2 vs. -1.4 ± 1.6, p = .02, d = 1.1)., Conclusions: Lifetime head trauma may represent a preventable environmental risk factor for FTD/PPA. Dose-dependent exposure to TBI or RHI influences FTD/PPA symptom onset and memory function in bvFTD. Clinico-pathological studies are needed to better understand the neuropathological correlates linking RHI or TBI to FTD/PPA onset and symptoms., (© 2024. The Author(s).)

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.)

GRN mutations cause progranulin haploinsufficiency, which eventually leads to frontotemporal dementia (FTD-GRN). PR006 is an investigational gene therapy delivering the granulin gene (GRN) using an adeno-associated virus serotype 9 (AAV9) vector. In non-clinical studies, PR006 transduced neurons derived from induced pluripotent stem cells of patients with FTD-GRN, resulted in progranulin expression and improvement of lipofuscin, lysosomal and neuroinflammation pathologies in Grn-knockout mice, and was well tolerated except for minimal, asymptomatic dorsal root ganglionopathy in non-human primates. We initiated a first-in-human phase 1/2 open-label trial. Here we report results of a pre-specified interim analysis triggered with the last treated patient of the low-dose cohort (n = 6) reaching the 12-month follow-up timepoint. We also include preliminary data from the mid-dose cohort (n = 7). Primary endpoints were safety, immunogenicity and change in progranulin levels in cerebrospinal fluid (CSF) and blood. Secondary endpoints were Clinical Dementia Rating (CDR) plus National Alzheimer's Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) rating scale and levels of neurofilament light chain (NfL). One-time administration of PR006 into the cisterna magna was generally safe and well tolerated. All patients developed treatment-emergent anti-AAV9 antibodies in the CSF, but none developed anti-progranulin antibodies. CSF pleocytosis was the most common PR006-related adverse event. Twelve serious adverse events occurred, mostly unrelated to PR006. Deep vein thrombosis developed in three patients. There was one death (unrelated) occurring 18 months after treatment. CSF progranulin increased after PR006 treatment in all patients; blood progranulin increased in most patients but only transiently. NfL levels transiently increased after PR006 treatment, likely reflecting dorsal root ganglia toxicity. Progression rates, based on the CDR scale, were within the broad ranges reported for patients with FTD. These data provide preliminary insights into the safety and bioactivity of PR006. Longer follow-up and additional studies are needed to confirm the safety and potential efficacy of PR006. ClinicalTrials.gov identifier: NCT04408625 ., (© 2024. The Author(s).)

Importance: Frontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated for FTLD., Objective: To evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations., Design, Setting, and Participants: In this cohort study conducted from January 10, 2019, to July 31, 2023, controls and participants with FTLD performed smartphone application (app)-based executive functioning tasks and an associative memory task 3 times over 2 weeks. Observational research participants were enrolled through 18 centers of a North American FTLD research consortium (ALLFTD) and were asked to complete the tests remotely using their own smartphones. Of 1163 eligible individuals (enrolled in parent studies), 360 were enrolled in the present study; 364 refused and 439 were excluded. Participants were divided into discovery (n = 258) and validation (n = 102) cohorts. Among 329 participants with data available on disease stage, 195 were asymptomatic or had preclinical FTLD (59.3%), 66 had prodromal FTLD (20.1%), and 68 had symptomatic FTLD (20.7%) with a range of clinical syndromes., Exposure: Participants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests., Main Outcomes and Measures: Internal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy., Results: In the 360 participants (mean [SD] age, 54.0 [15.4] years; 209 [58.1%] women), smartphone tests showed moderate-to-excellent reliability (intraclass correlation coefficients, 0.77-0.95). Validity was supported by association of smartphones tests with disease severity (r range, 0.38-0.59), criterion-standard neuropsychological tests (r range, 0.40-0.66), and brain volume (standardized β range, 0.34-0.50). Smartphone tests accurately differentiated individuals with dementia from controls (area under the curve [AUC], 0.93 [95% CI, 0.90-0.96]) and were more sensitive to early symptoms (AUC, 0.82 [95% CI, 0.76-0.88]) than the Montreal Cognitive Assessment (AUC, 0.68 [95% CI, 0.59-0.78]) (z of comparison, -2.49 [95% CI, -0.19 to -0.02]; P = .01). Reliability and validity findings were highly similar in the discovery and validation cohorts. Preclinical participants who carried pathogenic variants performed significantly worse than noncarrier family controls on 3 app tasks (eg, 2-back β = -0.49 [95% CI, -0.72 to -0.25]; P < .001) but not a composite of traditional neuropsychological measures (β = -0.14 [95% CI, -0.42 to 0.14]; P = .32)., Conclusions and Relevance: The findings of this cohort study suggest that smartphones could offer a feasible, reliable, valid, and scalable solution for remote evaluations of FTLD and may improve early detection. Smartphone assessments should be considered as a complementary approach to traditional in-person trial designs. Future research should validate these results in diverse populations and evaluate the utility of these tests for longitudinal monitoring.

Introduction: C9orf72 expansion is the most common genetic abnormality in behavioral variant frontotemporal dementia (bvFTD) and amyotrophic lateral sclerosis. Although psychiatric prodromes are common in C9orf72 expansion carriers, there are only scattered reported cases of primary psychiatric disorders, such as bipolar disorder, diagnosed at disease onset. Moreover, C9orf72 carrier status is rarely identified in bipolar disorder genetic studies., Case Report: A 51-year-old, right-handed woman with 16 years of education presented for evaluation of long-standing cognitive and behavioral change. She initially displayed symptoms of mania and florid, multimodal psychotic symptoms at age 39. Her bipolar disorder symptoms were initially responsive to medication; however, she later developed executive dysfunction and behavioral symptoms consistent with bvFTD. She became progressively nonverbal, and her limited speech was notable for speech apraxia. At the time of presentation, she demonstrated cortical sensory deficit, ideomotor and oral-buccal apraxia, and unstable gait. Neuroimaging revealed diffuse brain atrophy. Postmortem histopathological evaluation revealed frontotemporal lobar degeneration with TDP-43 inclusions, type B, and genetic study identified C9orf72 expansion. A detailed review of family history found a strong paternal history of bipolar disorder and substance use disorder., Conclusions: We describe a rare case of C9orf72 expansion initially characterized by late-onset bipolar disorder and florid, multimodal psychotic symptoms, followed years later by bvFTD diagnosis. This report emphasizes the importance of completing a neurological examination, obtaining a detailed family history, and pursuing genetic screening to distinguish between primary psychiatric disorder and bvFTD in individuals who meet the criteria for late-onset bipolar disorder., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Diminished basal parasympathetic nervous system activity is a feature of frontotemporal dementia that relates to left frontoinsula dysfunction and empathy impairment. Individuals with a pathogenic expansion of the hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72), the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis, provide a unique opportunity to examine whether parasympathetic activity is disrupted in genetic forms of frontotemporal dementia and to investigate when parasympathetic deficits manifest in the pathophysiological cascade. We measured baseline respiratory sinus arrhythmia, a parasympathetic measure of heart rate variability, over two minutes in a sample of 102 participants that included 19 asymptomatic expansion carriers (C9 + asymp), 14 expansion carriers with mild cognitive impairment (C9 + MCI), 16 symptomatic expansion carriers with frontotemporal dementia (C9 + FTD), and 53 expansion-negative healthy controls (C9 - HC) who also underwent structural magnetic resonance imaging. In follow-up analyses, we compared baseline respiratory sinus arrhythmia in the C9 + FTD group with an independent age-, sex-, and clinical severity-matched group of 26 people with sporadic behavioral variant frontotemporal dementia. The Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating-Sum of Boxes score was used to quantify behavioral symptom severity, and informant ratings on the Interpersonal Reactivity Index provided measures of participants' current emotional (empathic concern) and cognitive (perspective-taking) empathy. Results indicated that the C9 + FTD group had lower baseline respiratory sinus arrhythmia than the C9 + MCI, C9 + asymp, and C9 - HC groups, a deficit that was comparable to that of sporadic behavioral variant frontotemporal dementia. Linear regression analyses indicated that lower baseline respiratory sinus arrhythmia was associated with worse behavioral symptom severity and lower empathic concern and perspective-taking across the C9orf72 expansion carrier clinical spectrum. Whole-brain voxel-based morphometry analyses in participants with C9orf72 pathogenic expansions found that lower baseline respiratory sinus arrhythmia correlated with smaller gray matter volume in the left frontoinsula and bilateral thalamus, key structures that support parasympathetic function, and in the bilateral parietal lobes, occipital lobes, and cerebellum, regions that are also vulnerable in individuals with C9orf72 expansions. This study provides novel evidence that basal parasympathetic functioning is diminished in FTD due to C9orf72 expansions and suggests that baseline respiratory sinus arrhythmia may be a potential non-invasive biomarker that is sensitive to behavioral symptoms in the early stages of disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Tau PET has enabled the visualization of paired helical filaments of 3 or 4 C-terminal repeat tau in Alzheimer disease (AD), but its ability to detect aggregated tau in frontotemporal lobar degeneration (FTLD) spectrum disorders is uncertain. We investigated 2-(2-([ 18 F]fluoro)pyridin-4-yl)-9 H -pyrrolo[2,3-b:4,5c']dipyridine ([ 18 F]PI-2620), a newer tracer with ex vivo evidence for binding to FTLD tau, in a convenience sample of patients with suspected FTLD and AD using a static acquisition protocol and parametric SUV ratio (SUVr) images. Methods: We analyzed [ 18 F]PI-2620 PET data from 65 patients with clinical diagnoses associated with AD or FTLD neuropathology; most (60/65) also had amyloid-β (Aβ) PET. Scans were acquired 30-60 min after injection; SUVr maps (reference, inferior cerebellar cortex) were created for the full acquisition and for 10-min truncated sliding windows (30-40, 35-45,…50-60 min). Age- and sex-adjusted z score maps were computed for each patient, relative to 23 Aβ-negative cognitively healthy controls (HC). Mean SUVr in the globus pallidus, substantia nigra, subthalamic nuclei, dentate nuclei, white matter, and temporal gray matter was extracted for the full and truncated windows. Results: Patients with suspected AD neuropathology (Aβ-positive patients with mild cognitive impairment or AD dementia) showed high-intensity temporoparietal cortex-predominant [ 18 F]PI-2620 binding. At the group level, patients with clinical diagnoses associated with FTLD (progressive supranuclear palsy with Richardson syndrome [PSP Richardson syndrome], corticobasal syndrome, and nonfluent-variant primary progressive aphasia) exhibited higher globus pallidus SUVr than did HCs; pallidal retention was highest in the PSP Richardson syndrome group, in whom SUVr was correlated with symptom severity (ρ = 0.53, P = 0.05). At the individual level, only half of PSP Richardson syndrome, corticobasal syndrome, and nonfluent-variant primary progressive aphasia patients had a pallidal SUVr above that of HCs. Temporal SUVr discriminated AD patients from HCs with high accuracy (area under the receiver operating characteristic curve, 0.94 [95% CI, 0.83-1.00]) for all time windows, whereas discrimination between patients with PSP Richardson syndrome and HCs using pallidal SUVr was fair regardless of time window (area under the receiver operating characteristic curve, 0.77 [95% CI, 0.61-0.92] at 30-40 min vs. 0.81 [95% CI, 0.66-0.96] at 50-60 min; P = 0.67). Conclusion: [ 18 F]PI-2620 SUVr shows an intense and consistent signal in AD but lower-intensity, heterogeneous, and rapidly decreasing binding in patients with suspected FTLD. Further work is needed to delineate the substrate of [ 18 F]PI-2620 binding and the usefulness of [ 18 F]PI2620 SUVr quantification outside the AD continuum., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

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

Frontotemporal lobar degeneration (FTLD) is one of the most common causes of early-onset dementia and presents with early social-emotional-behavioural and/or language changes that can be accompanied by a pyramidal or extrapyramidal motor disorder. About 20-25% of individuals with FTLD are estimated to carry a mutation associated with a specific FTLD pathology. The discovery of these mutations has led to important advances in potentially disease-modifying treatments that aim to slow progression or delay disease onset and has improved understanding of brain functioning. In both mutation carriers and those with sporadic disease, the most common underlying diagnoses are linked to neuronal and glial inclusions containing tau (FTLD-tau) or TDP-43 (FTLD-TDP), although 5-10% of patients may have inclusions containing proteins from the FUS-Ewing sarcoma-TAF15 family (FTLD-FET). Biomarkers definitively identifying specific pathological entities in sporadic disease have been elusive, which has impeded development of disease-modifying treatments. Nevertheless, disease-monitoring biofluid and imaging biomarkers are becoming increasingly sophisticated and are likely to serve as useful measures of treatment response during trials of disease-modifying treatments. Symptomatic trials using novel approaches such as transcranial direct current stimulation are also beginning to show promise., (© 2023. Springer Nature Limited.)

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<0.001), while higher IL-6 was associated with faster functional decline (B=0.12 (0.03, 0.21), p=0.01). TNFα was higher in asymptomatic converters than non-converters (β=0.29 (0.09, 0.48), p=0.004) and improved discriminability compared with plasma NfL alone (ΔR 2 =0.16, p=0.007; NfL: OR=1.4 (1.03, 1.9), p=0.03; TNFα: OR=7.7 (1.7, 31.7), p=0.007)., Conclusions: Systemic proinflammatory protein measurement, particularly TNFα, may improve clinical prognosis in autosomal dominant FTLD pathogenic variant carriers who are not yet exhibiting severe impairment. Integrating TNFα with markers of neuronal dysfunction like NfL could optimise detection of impending symptom conversion in asymptomatic pathogenic variant carriers and may help personalise therapeutic approaches., Competing Interests: Competing interests: JCR and JCM report being site PIs for clinical trials sponsored by Eli Lilly and Eisai. BA (Appleby) receives research support from the Centers for Disease Control and Prevention, the National Institutes of Health (NIH), Ionis, Alector and the CJD Foundation; he has provided consultation to Acadia, Ionis and Sangamo. BCD is a consultant for Acadia, Alector, Arkuda, Biogen, Denali, Eisai, Genentech, Lilly, Merck, Novartis, Takeda and Wave Lifesciences; receives royalties from Cambridge University Press, Elsevier and Oxford University Press; and receives grant funding from the NIA, the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health and the Bluefield Foundation. NG has participated or is currently participating in clinical trials of anti-dementia drugs sponsored by Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals, Janssen Immunotherapy, Novartis, Pfizer, Wyeth, SNIFF (The Study of Nasal Insulin to Fight Forgetfulness) and the A4 (The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease) trial; she receives research support from Tau Consortium and the Association for Frontotemporal Dementia and is funded by the NIH. IL reports funding support from the National Institutes of Health, the Michael J Fox Foundation, Parkinson Foundation, Lewy Body Association, CurePSP, Roche, Abbvie, Biogen, Centogene. EIP-Pharma, Biohaven Pharmaceuticals, Novartis, Brain Neurotherapy Bio and United Biopharma SRL – UCB; she is a Scientific advisor for Amydis 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. AB reports research support from the NIH, 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, Boehringer Ingelheim, Denali, GSK, Life Edit, Humana, Oligomerix, Oscotec, Roche, TrueBinding and Wave and received research support from Biogen, Eisai and Regeneron. BFB has served as an investigator for clinical trials sponsored by EIP Pharma, Alector and Biogen; 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 the NIH, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program and the Little Family Foundation. AS reports research support from the NIA/NIH, the Bluefield Project to Cure FTD and the Larry L. Hillblom Foundation; he has provided consultation to Passage Bio and Takeda. PL is a site primary investigator for clinical trials by Alector, AbbVie and Woolsey; he serves as an advisor for Retrotrope; he receives research and salary support from the NIH-NIA and the Alzheimer’s Association-Part the Cloud partnership. KBC reports research support from NIH. LV reports research support from the Alzheimer’s Association, the American Academy of Neurology, the American Brain Foundation and the NIH and has provided consultation for Retrotope. KPR reports research support from the NIH and the National Science Foundation and serves on a medical advisory board for Eli Lilly. MCT has served as an investigator for clinical trials sponsored by Biogen, Avanex, Green Valley, Roche/Genentech, Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals and Janssen; she receives research support from the Canadian Institutes of Health Research. KD-R. receives research support from the NIH and serves as an investigator for a clinical trial sponsored by Lawson Health Research Institute. J. Kornak has provided expert witness testimony for Teva Pharmaceuticals in Forest Laboratories Inc. et al. v. Teva Pharmaceuticals USA, Inc., case numbers 1:14-cv00121 and 1:14-cv-00686 (D. Del. filed 31 January 2014 and 30 May 2014 regarding the drug Memantine) and for Apotex/HEC/Ezra in Novartis AG et al. v. Apotex Inc., case number 1:15-cv-975 (D. Del. filed 26 October 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. WK reports research funding from AstraZeneca, Biogen, Roche, the Department of Defense and the NIH. LF reports research funding from NIH. HJR reports research support from Biogen Pharmaceuticals, has consulting agreements with Wave Neuroscience and Ionis Pharmaceuticals and receives research support from the NIH. JHK reports research support from NIH and receives royalties from Pearson Inc., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.)

Importance: Plasma phosphorylated tau217 (p-tau217), a biomarker of Alzheimer disease (AD), is of special interest in corticobasal syndrome (CBS) because autopsy studies have revealed AD is the driving neuropathology in up to 40% of cases. This differentiates CBS from other 4-repeat tauopathy (4RT)-associated syndromes, such as progressive supranuclear palsy Richardson syndrome (PSP-RS) and nonfluent primary progressive aphasia (nfvPPA), where underlying frontotemporal lobar degeneration (FTLD) is typically the primary neuropathology., Objective: To validate plasma p-tau217 against positron emission tomography (PET) in 4RT-associated syndromes, especially CBS., Design, Setting, and Participants: This multicohort study with 6, 12, and 24-month follow-up recruited adult participants between January 2011 and September 2020 from 8 tertiary care centers in the 4RT Neuroimaging Initiative (4RTNI). All participants with CBS (n = 113), PSP-RS (n = 121), and nfvPPA (n = 39) were included; other diagnoses were excluded due to rarity (n = 29). Individuals with PET-confirmed AD (n = 54) and PET-negative cognitively normal control individuals (n = 59) were evaluated at University of California San Francisco. Operators were blinded to the cohort., Main Outcome and Measures: Plasma p-tau217, measured by Meso Scale Discovery electrochemiluminescence, was validated against amyloid-β (Aβ) and flortaucipir (FTP) PET. Imaging analyses used voxel-based morphometry and bayesian linear mixed-effects modeling. Clinical biomarker associations were evaluated using longitudinal mixed-effect modeling., Results: Of 386 participants, 199 (52%) were female, and the mean (SD) age was 68 (8) years. Plasma p-tau217 was elevated in patients with CBS with positive Aβ PET results (mean [SD], 0.57 [0.43] pg/mL) or FTP PET (mean [SD], 0.75 [0.30] pg/mL) to concentrations comparable to control individuals with AD (mean [SD], 0.72 [0.37]), whereas PSP-RS and nfvPPA showed no increase relative to control. Within CBS, p-tau217 had excellent diagnostic performance with area under the receiver operating characteristic curve (AUC) for Aβ PET of 0.87 (95% CI, 0.76-0.98; P < .001) and FTP PET of 0.93 (95% CI, 0.83-1.00; P < .001). At baseline, individuals with CBS-AD (n = 12), defined by a PET-validated plasma p-tau217 cutoff 0.25 pg/mL or greater, had increased temporoparietal atrophy at baseline compared to individuals with CBS-FTLD (n = 39), whereas longitudinally, individuals with CBS-FTLD had faster brainstem atrophy rates. Individuals with CBS-FTLD also progressed more rapidly on a modified version of the PSP Rating Scale than those with CBS-AD (mean [SD], 3.5 [0.5] vs 0.8 [0.8] points/year; P = .005)., Conclusions and Relevance: In this cohort study, plasma p-tau217 had excellent diagnostic performance for identifying Aβ or FTP PET positivity within CBS with likely underlying AD pathology. Plasma P-tau217 may be a useful and inexpensive biomarker to select patients for CBS clinical trials.

Hexanucleotide repeat expansion (HRE) within C9orf72 is the most common genetic cause of frontotemporal dementia (FTD). Thalamic atrophy occurs in both sporadic and familial FTD but is thought to distinctly affect HRE carriers. Separately, emerging evidence suggests widespread derepression of transposable elements (TEs) in the brain in several neurodegenerative diseases, including C9orf72 HRE-mediated FTD (C9-FTD). Whether TE activation can be measured in peripheral blood and how the reduction in peripheral C9orf72 expression observed in HRE carriers relates to atrophy and clinical impairment remain unknown. We used FreeSurfer software to assess the effects of C9orf72 HRE and clinical diagnosis ( n = 78 individuals, male and female) on atrophy of thalamic nuclei. We also generated a novel, human, whole-blood RNA-sequencing dataset to determine the relationships among peripheral C9orf72 expression, TE activation, thalamic atrophy, and clinical severity ( n = 114 individuals, male and female). We confirmed global thalamic atrophy and reduced C9orf72 expression in HRE carriers. Moreover, we identified disproportionate atrophy of the right mediodorsal lateral nucleus in HRE carriers and showed that C9orf72 expression associated with clinical severity, independent of thalamic atrophy. Strikingly, we found global peripheral activation of TEs, including the human endogenous LINE-1 element L1HS L1HS levels were associated with atrophy of multiple pulvinar nuclei, a thalamic region implicated in C9-FTD. Integration of peripheral transcriptomic and neuroimaging data from human HRE carriers revealed atrophy of specific thalamic nuclei, demonstrated that C9orf72 levels relate to clinical severity, and identified marked derepression of TEs, including L1HS , which predicted atrophy of FTD-relevant thalamic nuclei. SIGNIFICANCE STATEMENT Pathogenic repeat expansion in C9orf72 is the most frequent genetic cause of FTD and amyotrophic lateral sclerosis (ALS; C9-FTD/ALS). The clinical, neuroimaging, and pathologic features of C9-FTD/ALS are well characterized, whereas the intersections of transcriptomic dysregulation and brain structure remain largely unexplored. Herein, we used a novel radiogenomic approach to examine the relationship between peripheral blood transcriptomics and thalamic atrophy, a neuroimaging feature disproportionately impacted in C9-FTD/ALS. We confirmed reduction of C9orf72 in blood and found broad dysregulation of transposable elements-genetic elements typically repressed in the human genome-in symptomatic C9orf72 expansion carriers, which associated with atrophy of thalamic nuclei relevant to FTD. C9orf72 expression was also associated with clinical severity, suggesting that peripheral C9orf72 levels capture disease-relevant information., (Copyright © 2023 Bonham et al.)

Despite recent advances in fluid biomarker research in Alzheimer's disease (AD), there are no fluid biomarkers or imaging tracers with utility for diagnosis and/or theragnosis available for other tauopathies. Using immunoprecipitation and mass spectrometry, we show that 4 repeat (4R) isoform-specific tau species from microtubule-binding region (MTBR-tau 275 and MTBR-tau 282 ) increase in the brains of corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), frontotemporal lobar degeneration (FTLD)-MAPT and AD but decrease inversely in the cerebrospinal fluid (CSF) of CBD, FTLD-MAPT and AD compared to control and other FTLD-tau (for example, Pick's disease). CSF MTBR-tau measures are reproducible in repeated lumbar punctures and can be used to distinguish CBD from control (receiver operating characteristic area under the curve (AUC) = 0.889) and other FTLD-tau, such as PSP (AUC = 0.886). CSF MTBR-tau 275 and MTBR-tau 282 may represent the first affirmative biomarkers to aid in the diagnosis of primary tauopathies and facilitate clinical trial designs., (© 2022. The Author(s).)

Focal anterior temporal lobe degeneration often preferentially affects the left or right hemisphere. While patients with left-predominant anterior temporal lobe atrophy show severe anomia and verbal semantic deficits and meet criteria for semantic variant primary progressive aphasia and semantic dementia, patients with early right anterior temporal lobe atrophy are more difficult to diagnose as their symptoms are less well understood. Focal right anterior temporal lobe atrophy is associated with prominent emotional and behavioural changes, and patients often meet, or go on to meet, criteria for behavioural variant frontotemporal dementia. Uncertainty around early symptoms and absence of an overarching clinico-anatomical framework continue to hinder proper diagnosis and care of patients with right anterior temporal lobe disease. Here, we examine a large, well-characterized, longitudinal cohort of patients with right anterior temporal lobe-predominant degeneration and propose new criteria and nosology. We identified individuals from our database with a clinical diagnosis of behavioural variant frontotemporal dementia or semantic variant primary progressive aphasia and a structural MRI (n = 478). On the basis of neuroimaging criteria, we defined three patient groups: right anterior temporal lobe-predominant atrophy with relative sparing of the frontal lobes (n = 46), frontal-predominant atrophy with relative sparing of the right anterior temporal lobe (n = 79) and left-predominant anterior temporal lobe-predominant atrophy with relative sparing of the frontal lobes (n = 75). We compared the clinical, neuropsychological, genetic and pathological profiles of these groups. In the right anterior temporal lobe-predominant group, the earliest symptoms were loss of empathy (27%), person-specific semantic impairment (23%) and complex compulsions and rigid thought process (18%). On testing, this group exhibited greater impairments in Emotional Theory of Mind, recognition of famous people (from names and faces) and facial affect naming (despite preserved face perception) than the frontal- and left-predominant anterior temporal lobe-predominant groups. The clinical symptoms in the first 3 years of the disease alone were highly sensitive (81%) and specific (84%) differentiating right anterior temporal lobe-predominant from frontal-predominant groups. Frontotemporal lobar degeneration-transactive response DNA binding protein (84%) was the most common pathology of the right anterior temporal lobe-predominant group. Right anterior temporal lobe-predominant degeneration is characterized by early loss of empathy and person-specific knowledge, deficits that are caused by progressive decline in semantic memory for concepts of socioemotional relevance. Guided by our results, we outline new diagnostic criteria and propose the name, 'semantic behavioural variant frontotemporal dementia', which highlights the underlying cognitive mechanism and the predominant symptomatology. These diagnostic criteria will facilitate early identification and care of patients with early, focal right anterior temporal lobe degeneration as well as in vivo prediction of frontotemporal lobar degeneration-transactive response DNA binding protein pathology., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.)

Background and Objectives: Familial frontotemporal lobar degeneration (f-FTLD) is a phenotypically heterogeneous spectrum of neurodegenerative disorders most often caused by variants within chromosome 9 open reading frame 72 ( C9orf72 ), microtubule-associated protein tau ( MAPT ), or granulin ( GRN ). The phenotypic association with each of these genes is incompletely understood. We hypothesized that the frequency of specific clinical features would correspond with different genes., Methods: We screened the Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS)/ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium for symptomatic carriers of pathogenic variants in C9orf72 , MAPT , or GRN . We assessed for clinical differences among these 3 groups based on data recorded as part of a detailed neurologic examination, the Progressive Supranuclear Palsy Rating Scale, Progressive Supranuclear Palsy-Quality of Life Rating Scale, Unified Parkinson's Disease Rating Scale Part III (motor items), and the Amyotrophic Lateral Sclerosis Functional Rating Scale, revised version. Data were analyzed using Kruskal-Wallis and Wilcoxon rank-sum tests and Fisher exact test., Results: We identified 184 symptomatic participants who had a single pathogenic variant in C9orf72 (n = 88), MAPT (n = 53), or GRN (n = 43). Motor symptom age at onset was earliest in the MAPT participants followed by C9orf72 , whereas the GRN pathogenic variant carriers developed symptoms later. C9orf72 participants more often had fasciculations, muscle atrophy, and weakness, whereas parkinsonism was less frequent. Vertical oculomotor abnormalities were more common in the MAPT cohort, whereas apraxia and focal limb dystonia occurred more often in participants with GRN variants., Discussion: We present a large comparative study of motor features in C9orf72 , MAPT , and GRN pathogenic variant carriers with symptomatic f-FTLD. Our findings demonstrate characteristic phenotypic differences corresponding with specific gene variants that increase our understanding of the genotype-phenotype relationship in this complex spectrum of neurodegenerative disorders., Trial Registration Information: NCT02365922, NCT02372773, and NCT04363684., (© 2022 American Academy of Neurology.)

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.)

Background and Objectives: Changes in social behavior are common symptoms of frontotemporal lobar degeneration (FTLD) and Alzheimer disease syndromes. For early identification of individual patients and differential diagnosis, sensitive clinical measures are required that are able to assess patterns of behaviors and detect syndromic differences in both asymptomatic and symptomatic stages. We investigated whether the examiner-based Social Behavior Observer Checklist (SBOCL) is sensitive to early behavior changes and reflects disease severity within and between neurodegenerative syndromes., Methods: Asymptomatic individuals and patients with neurodegenerative disease were selected from the multisite ALLFTD cohort study. In a sample of participants with at least 1 time point of SBOCL data, we investigated whether the Disorganized, Reactive, and Insensitive subscales of the SBOCL change as a function of disease stage within and between these syndromes. In a longitudinal subsample with both SBOCL and neuroimaging data, we examined whether change over time on each subscale corresponds to progressive gray matter atrophy., Results: A total of 1,082 FTLD pathogenic variant carriers and noncarriers were enrolled (282 asymptomatic, 341 behavioral variant frontotemporal dementia, 114 semantic and 95 nonfluent variant primary progressive aphasia, 137 progressive supranuclear palsy, and 113 Alzheimer disease syndrome). The Disorganized score increased between asymptomatic to very mild ( p = 0.016, estimate = -1.10, 95% CI = -1.99 to -0.22), very mild to mild ( p = 0.013, estimate = -1.17, 95% CI = -2.08 to -0.26), and mild to moderate/severe ( p < 0.001, estimate = -2.00, 95% CI = -2.55 to -1.45) disease stages in behavioral variant frontotemporal dementia regardless of pathogenic variant status. Asymptomatic GRN pathogenic gene variant carriers showed more reactive behaviors (preoccupation with time: p = 0.001, estimate = 1.11, 95% CI = 1.06 to 1.16; self-consciousness: p = 0.003, estimate = 1.77, 95% CI = 1.52 to 2.01) than asymptomatic noncarriers (estimate = 1.01, 95% CI = 0.98 to 1.03; estimate = 1.31, 95% CI = 1.20 to 1.41). The Insensitive score increased to a clinically abnormal level in advanced stages of behavioral variant frontotemporal dementia ( p = 0.003, estimate = -0.73, 95% CI = -1.18 to -0.29). Higher scores on each subscale corresponded with higher caregiver burden ( p < 0.001). Greater change over time corresponded to greater fronto-subcortical atrophy in the semantic-appraisal and fronto-parietal intrinsically connected networks., Discussion: The SBOCL is sensitive to early symptoms and reflects disease severity, with some evidence for progression across asymptomatic and symptomatic stages of FTLD syndromes; thus, it may hold promise for early measurement and monitoring of behavioral symptoms in clinical practice and treatment trials., Classification of Evidence: This study provides Class II evidence that the SBOCL is sensitive to early behavioral changes in FTLD pathogenic variants and early symptomatic individuals in a highly educated patient cohort., (© 2022 American Academy of Neurology.)

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.)

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., Competing Interests: A.C.B. is site PI for the Alector INFRONT-3 trial. A.L.B. receives research support from NIH (R01AG038791, R01AG073482, and U24AG057437), Rainwater Charitable Foundation, Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Alzheimer’s Drug Discovery Foundation, and the Alzheimer’s Association. He has served as a consultant for Alector, AGTC, Arkuda, Arvinas, AZTherapies, GSK, Oligomerix, Ono, Roche, Samumed, Stealth, Third Rock, Transposon, TrueBinding, and Wave and received research support from Biogen, Eisai, and Regeneron. B.F.B. has served as an investigator for clinical trials sponsored by Biogen, Alector, and EIP Pharma. He receives royalties from a published book entitled Behavioral Neurology of Dementia (Cambridge Medicine, 2009, 2017), serves on the Tau Consortium Scientific Advisory Board, and receives research support from the NIH. B.C.D. consults for Acadia, Arkuda, Axovant, Lilly, Biogen, Merck, Novartis, and Wave LifeSciences; has Elsevier editorial duties with payment (Neuroimage: Clinical and Cortex); and receives royalties from Oxford University Press and Cambridge University Press. K.D.-R. has research funding from Biogen and Lawson Health Research Institute and receives consultant fees from Biogen and educational fees from MedBridge. D.R.G. consults for Biogen, Fujirebio, and Amprion and is on the DSMB for Cognition Therapeutics. M.G. is participating in treatment trials sponsored by Alector, Prevail, and Passage Bio and is a consultant to Takeda, Passage Bio, and Biogen. N.G. has or is participating in clinical trials of anti-dementia drugs sponsored by Bristol Myers Squibb, Lilly/Avid Radiopharmaceuticals, Janssen, Novartis, Pfizer, and Wyeth. N.R.G.-R. has taken part in multicenter studies funded by Biogen, AbbVie, and Lilly. G.-Y.R.H. has received research support from Anavax, Biogen, and Roche. I.L. received support from Roche, Abbvie, Biogen, EIP-Pharma, and Biohaven Pharmaceuticals; was member of a Lundbeck Advisory Board; and receives salary from the University of California, San Diego and as Chief Editor of Frontiers in Neurology. J.C.M. participates on a speaker forum for Biogen and receives research support from Biogen, Eisai, Eli Lilly, Green Valley, and Novartis. C.U.O. is a consultant with Alector and Acadia and receives research funding from Alector. L.P. is a consultant for Expansion Therapeutics. E.D.R. receives funding from NIH, Alzheimer’s Drug Discovery Foundation, Bluefield Project, and Alector; consults for Biogen, AVROBIO, and AGTC; and owns intellectual property related to tau. J.C.R. is a site PI for Eli Lilly and Eisai clinical trials and receives research support from NIH K23AG059888. M.C.T. participates in clinical trials with Biogen, Avanex, UCB, and Janssen. Z.K.W. is supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, Mayo Clinic in Florida Focused Research Team Program, the gifts from The Sol Goldman Charitable Trust, the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson’s Research Foundation. He serves as PI or co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301); Neuraly, Inc. (NLY01-PD-1); and Vigil Neuroscience, Inc. (VGL101–01.001) grants. He serves as co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for Vigil Neuroscience, Inc. All other authors report no competing interests., (© 2022 The Author(s).)

Frontotemporal dementia comprises a group of clinical syndromes that are characterised by progressive changes in behaviour, executive function, or language. The term frontotemporal lobar degeneration encompasses the neurodegenerative diseases that give rise to these clinical syndromes and involve proteinopathies associated with frontotemporal network dysfunction. Improvements in clinical, genetic, and molecular characterisation have provided new insights into frontotemporal dementia and frontotemporal lobar degeneration, with a much broader range of signs and symptoms at presentation than has been previously considered. Accurate and early diagnosis of frontotemporal dementia is now a possibility due to development of neuropsychological measures with a special focus on social cognition. Advances in plasma and CSF biomarkers, and innovations in structural and functional imaging, will prove useful for future clinical trials in people with frontotemporal dementia., Competing Interests: Declaration of interests BFB has served as an investigator for clinical trials sponsored by Alector, Biogen, and EIP Pharma; serves on the scientific advisory board for the Tau Consortium; and receives funding from the US National Institutes of Health (NIH), the Mangurian Foundation, and the Little Family Foundation. ALB receives research support from the NIH, the Rainwater Charitable Foundation, the Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, the Alzheimer's Drug Discovery Foundation, and the Alzheimer's Association; has served as a consultant for Alector, Applied Genetic Technologies Corporation, Arkuda, Arvinas, AZTherapies, GlaxoSmithKline, Oligomerix, Ono, Regeneron, Roche, Samumed, Stealth, Third Rock, Transposon, TrueBinding, and Wave; and has received research support from Biogen, Eisai, and Regeneron. FK receives funding from the Australian National Health and Medical Research Council. YP receives funding from the Dioraphte Foundation, Health Holland, and ZonMW. JDR has served on the medical advisory board for Alector, Wave Life Sciences, Arkuda Therapeutics, and Prevail Therapeutics; receives funding from the UK Medical Research Council, UK National Institute for Health Research, Association for Frontotemporal Degeneration, Alzheimer's Association, and the Bluefield Project., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Early detection of neurodegeneration, and prediction of when neurodegenerative diseases will lead to symptoms, are critical for developing and initiating disease modifying treatments for these disorders. While each neurodegenerative disease has a typical pattern of early changes in the brain, these disorders are heterogeneous, and early manifestations can vary greatly across people. Methods for detecting emerging neurodegeneration in any part of the brain are therefore needed. Prior publications have described the use of Bayesian linear mixed-effects (BLME) modeling for characterizing the trajectory of change across the brain in healthy controls and patients with neurodegenerative disease. Here, we use an extension of such a model to detect emerging neurodegeneration in cognitively healthy individuals at risk for dementia. We use BLME to quantify individualized rates of volume loss across the cerebral cortex from the first two MRIs in each person and then extend the BLME model to predict future values for each voxel. We then compare observed values at subsequent time points with the values that were expected from the initial rates of change and identify voxels that are lower than the expected values, indicating accelerated volume loss and neurodegeneration. We apply the model to longitudinal imaging data from cognitively normal participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI), some of whom subsequently developed dementia, and two cognitively normal cases who developed pathology-proven frontotemporal lobar degeneration (FTLD). These analyses identified regions of accelerated volume loss prior to or accompanying the earliest symptoms, and expanding across the brain over time, in all cases. The changes were detected in regions that are typical for the likely diseases affecting each patient, including medial temporal regions in patients at risk for Alzheimer's disease, and insular, frontal, and/or anterior/inferior temporal regions in patients with likely or proven FTLD. In the cases where detailed histories were available, the first regions identified were consistent with early symptoms. Furthermore, survival analysis in the ADNI cases demonstrated that the rate of spread of accelerated volume loss across the brain was a statistically significant predictor of time to conversion to dementia. This method for detection of neurodegeneration is a potentially promising approach for identifying early changes due to a variety of diseases, without prior assumptions about what regions are most likely to be affected first in an individual., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Importance: Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations., Objective: To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency., Design, Setting, and Participants: In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021., Interventions: Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days., Main Outcomes and Measures: Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau])., Results: A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN variations were randomized and completed treatment. FRM-0334 was safe and well tolerated but did not affect plasma progranulin (4.3 pg/mL per day change after treatment; 95% CI, -10.1 to 18.8 pg/mL; P = .56), cerebrospinal fluid progranulin (0.42 pg/mL per day; 95% CI, -0.12 to 0.95 pg/mL; P = .13), or exploratory pharmacodynamic measures. Plasma FRM-0334 exposure did not increase proportionally with dose. Brain FDG-PET data were available in 26 of 27 randomized participants. In a cross-sectional analysis of 26 individuals, bifrontal cortical FDG hypometabolism was associated with worse Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration sum of boxes score (b = -3.6 × 10-2 standardized uptake value ratio [SUVR] units/CDR units; 95% CI, -4.9 × 10-2 to -2.2 × 10-2; P < .001), high cerebrospinal fluid NfL (b = -9.2 × 10-5 SUVR units/pg NfL/mL; 95% CI, -1.3 × 10-4 to -5.6 × 10-5; P < .001), and high CSF t-tau (-7.2 × 10-4 SUVR units/pg t-tau/mL; 95% CI, -1.4 × 10-3 to -9.5 × 10-5; P = .03)., Conclusions and Relevance: In this randomized clinical trial, the current formulation of FRM-0334 did not elevate PRGN levels, which could reflect a lack of efficacy at attained exposures, low bioavailability, or some combination of the 2 factors. Bifrontal FDG-PET is a sensitive measure of symptomatic GRN haploinsufficiency. International multicenter clinical trials of FTD-GRN are feasible., Trial Registration: ClinicalTrials.gov Identifier: NCT02149160.

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.)

Around one-third of frontotemporal dementia (FTD) is autosomal dominant with the major genetic causes being mutations in MAPT, GRN and C9orf72. Studying familial forms of FTD can provide a window into the earliest stages of the illness, many years before symptoms start. Large cohort studies have been set up in recent years to better understand this presymptomatic phase, including the Genetic FTD Initiative (GENFI) and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (ARTFL/LEFFTDS) studies. Whilst these studies have focused on the investigation of a variety of aspects of genetic FTD, from understanding the molecular pathogenesis to developing biomarkers, they also have a common goal: finding a way to prevent FTD. Researchers from these cohort studies have therefore come together to form the FTD Prevention Initiative (FPI), which has the overarching aim of promoting clinical trials of new therapies to prevent FTD through creating an international database of participants eligible for trials and uniform standards for conducting such trials. This chapter outlines the work of the FPI so far and its future goals over the next few years.

Objective: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach., Methods: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers' clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson's disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype., Results: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers., Interpretation: A subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

While behavioral variant frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA) remain unrelenting and universally fatal conditions, there is a framework for supportive treatment in patients diagnosed with these frontotemporal dementia (FTD) syndromes and the larger spectrum of clinical syndromes associated with frontotemporal lobar degeneration (FTLD) pathology on autopsy. A managing physician has an important role in weighing therapeutic options, organizing caregiver support, and framing long-term expectations for patients and caregivers. Additionally, a dedicated neurologist may assist patients and caregivers in navigating a growing range of FTD research, including exciting opportunities in clinical therapeutic trials. This chapter will review current therapeutic options for patients with bvFTD and PPA and detail the landscape of potential new disease-modifying therapies targeting the pathophysiology or FTLD.

Objective: To develop a patient/care-giver reported scale capable of easily and reliably assessing functional disability in 4 repeat tauopathies (4RTs)., Background: 4R tauopathies including progressive supranuclear palsy, corticobasal degeneration and a subset of frontotemporal dementias manifest a range of overlapping clinical phenotypes. No available rating scale is capable of evaluating the functional impact of these complex disorders., Methods: A multi-staged modified Delphi process was used to propose, evaluate and rank potential scale items providing content validity ratios. Staged cognitive pretesting involving input from examiners, patients and caregivers was followed by validation testing in patients participating in the 4R Tauopathy Neuroimaging Initiative or the PROgressive Supranuclear Palsy CorTico-Basal Syndrome MSA Longitudinal Study. Clinimetric properties were examined using classical test theory and item response methods, assessing data quality, reliability, construct validity, convergent validity and known-group validity., Results: The resultant Cortical Basal ganglia Functional Scale (CBFS) included questions on Motor Experiences in Daily Living (14 items) and Non-Motor Experiences of Daily Living (17 items). Reliability was acceptable for internal consistency, test-retest stability, item discrimination, item-scaling thresholds and item-fit. Examination of construct validity revealed a parsimonious two-factor solution, and concurrent validity demonstrated significant correlations between the CBFS and other measures of disease severity and functional impairment. The CBFS significantly discriminated between all diagnostic groups and controls (all AUCs>90). The CBFS scores demonstrated sensitivity to change over a 12 month follow-up in patients with probable 4RTs., Conclusions: The CBFS is a patient/care-giver reported outcome measure with excellent clinimetric properties that captures disability correlated with motor, cognitive and psychiatric impairments., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Importance: Several clinical trials are planned for familial forms of frontotemporal lobar degeneration (f-FTLD). Precise modeling of brain atrophy in f-FTLD could improve the power to detect a treatment effect., Objective: To characterize regions and rates of atrophy in the 3 primary f-FTLD genetic groups (MAPT, GRN, and C9orf72) across all disease stages from asymptomatic to dementia., Design, Setting, and Participants: This investigation was a case-control study of participants enrolled in the Advancing Research and Treatment for Frontotemporal Lobar Degeneration or Longitudinal Evaluation of Familial Frontotemporal Dementia studies. The study took place at 18 North American academic medical centers between January 2009 and September 2018. Participants with f-FTLD (n = 100) with a known pathogenic variant (MAPT [n = 28], GRN [n = 33], or C9orf72 [n = 39]) were grouped according to disease stage (ie, Clinical Dementia Rating [CDR] plus National Alzheimer's Coordinating Center [NACC] FTLD module). Included were participants with at least 2 structural magnetic resonance images at presymptomatic (CDR + NACC FTLD = 0 [n = 57]), mild or questionable (CDR + NACC FTLD = 0.5 [n = 15]), or symptomatic (CDR + NACC FTLD = ≥1 [n = 28]) disease stages. The control group included family members of known pathogenic variant carriers who did not carry the pathogenic variant (n = 60)., Main Outcomes and Measures: This study fitted bayesian linear mixed-effects models in each voxel of the brain to quantify the rate of atrophy in each of the 3 genes, at each of the 3 disease stages, compared with controls. The study also analyzed rates of clinical decline in each of these groups, as measured by the CDR + NACC FTLD box score., Results: The sample included 100 participants with f-FTLD with a known pathogenic variant (mean [SD] age, 50.48 [13.78] years; 53 [53%] female) and 60 family members of known pathogenic variant carriers who did not carry the pathogenic variant (mean [SD] age, 47.51 [12.43] years; 36 [60%] female). MAPT and GRN pathogenic variants were associated with increased rates of volume loss compared with controls at all stages of disease. In MAPT pathogenic variant carriers, statistically significant regions of accelerated volume loss compared with controls were identified in temporal regions bilaterally in the presymptomatic stage, with global spread in the symptomatic stage. For example, mean [SD] rates of atrophy in the left temporal were -231 [47] mm3 per year during the presymptomatic stage, -381 [208] mm3 per year during the mild stage, and -1485 [1025] mm3 per year during the symptomatic stage (P < .05). GRN pathogenic variant carriers generally had minimal increases in atrophy rates between the presymptomatic and mild stages, with rapid increases in atrophy rates in the symptomatic stages. For example, in the right frontal lobes, annualized volume loss was -267 [81] mm3 per year in the presymptomatic stage and -182 [90] mm3 per year in the mild stage, but -1169 [555] mm3 per year in the symptomatic stage. Compared with the other groups, C9orf72 expansion carriers showed minimal increases in rate of volume loss with disease progression. For example, the mean (SD) annualized rates of atrophy in the right frontal lobe in C9orf72 expansion carriers was -272 (118) mm3 per year in presymptomatic stages, -310 (189) mm3 per year in mildly symptomatic stages, and -251 (145) mm3 per year in symptomatic stages., Conclusions and Relevance: These findings are relevant to clinical trial planning and suggest that the mechanism by which C9orf72 pathogenic variants lead to symptoms may be fundamentally different from the mechanisms associated with other pathogenic variants.

Objective: To compare the sensitivity of structural MRI and 18 F-fludeoxyglucose PET ( 18 FDG-PET) to detect longitudinal changes in frontotemporal dementia (FTD)., Methods: Thirty patients with behavioral variant FTD (bvFTD), 7 with nonfluent/agrammatic variant primary progressive aphasia (nfvPPA), 16 with semantic variant primary progressive aphasia (svPPA), and 43 cognitively normal controls underwent 2-4 MRI and 18 FDG-PET scans (total scans/visit = 270) as part of the Frontotemporal Lobar Degeneration Neuroimaging Initiative study. Linear mixed-effects models were carried out voxel-wise and in regions of interest to identify areas showing decreased volume or metabolism over time in patients as compared to controls., Results: At baseline, patients with bvFTD showed bilateral temporal, dorsolateral, and medial prefrontal atrophy/hypometabolism that extended with time into adjacent structures and parietal lobe. In nfvPPA, baseline atrophy/hypometabolism in supplementary motor cortex extended with time into left greater than right precentral, dorsolateral, and dorsomedial prefrontal cortex. In svPPA, baseline atrophy/hypometabolism encompassed the anterior temporal and medial prefrontal cortex and longitudinal changes were found in temporal, orbitofrontal, and lateral parietal cortex. Across syndromes, there was substantial overlap in the brain regions showing volume and metabolism loss. Even though the pattern of metabolic decline was more extensive, metabolic changes were also more variable and sample size estimates were similar or higher for 18 FDG-PET compared to MRI., Conclusion: Our findings demonstrated the sensitivity of 18 FDG-PET and structural MRI for tracking disease progression in FTD. Both modalities showed highly overlapping patterns of longitudinal change and comparable sample size estimates to detect longitudinal changes in future clinical trials., (© 2020 American Academy of Neurology.)

Tauopathies are a group of over 20 clinicopathological neurodegenerative diseases including Alzheimer's disease (AD), the most common type of dementia, progressive supranuclear palsy, Pick's disease, corticobasal degeneration, among others. Tauopathies are defined by neurodegeneration and the presence of tau aggregates in affected brains regions. Interestingly, regional tau aggregation burden correlates with clinical phenotype and predicts cognitive status. Autosomal dominant mutations in the MAPT gene lead to tau deposition and clinical FTD syndromes with cognitive, behavioral, and motor impairment. Polymorphisms in or around the MAPT gene have also been strongly linked to other proteinopathies including synucleinopathies. Taken together these findings suggests that tau plays a critical role in neurodegeneration and proteinopathies, supporting the idea that tau targeted approaches can be disease-modifying and lead to clinically meaningful benefits in slowing or reversing disease progression. Increasingly, human clinical trials are testing this hypothesis. This article reviews tau-targeted therapies tested in clinical trials as well as agents currently in active development based on publicly disclosed information. We describe the therapeutic approaches of these trials based on the potential pathogenic mechanism they target., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Globular glial tauopathy (GGT) is a rare 4-repeat tauopathy characterized by the accumulation of tau globular inclusions in astrocytes and oligodendrocytes. Several clinical phenotypes have been associated with GGT, making the prediction of this rare pathological entity difficult. We report the case of a patient with eye-movement abnormalities and gait instability, reminiscent of progressive supranuclear palsy-Richardson's syndrome (PSP-RS), who later developed upper motor neuron symptoms suggestive of primary lateral sclerosis (PLS). Neuropathological assessment revealed GGT type III pathology. A theoretical framework is proposed to help clinicians predict GGT in subjects with coexistent features of PSP-RS and PLS.

Importance: Individuals with tuberous sclerosis complex can develop a progressive neuropsychiatric syndrome known as tuberous sclerosis-associated neuropsychiatric disorders. Tuberous sclerosis-associated neuropsychiatric disorders symptoms overlap with clinical criteria for frontotemporal dementia, yet the association between the 2 has not been explored., Objective: To investigate the potential association between tuberous sclerosis-associated neuropsychiatric disorders and frontotemporal dementia., Design, Setting, and Participants: Case-control study that enrolled patients with tuberous sclerosis complex with normal IQs in an observational clinical study at the University of California, San Francisco, from 2017 to 2019 where they underwent a comprehensive clinical evaluation including neuropsychologic testing, cerebral spinal fluid biomarker profiling, and structural neuroimaging. The study included adults who fulfilled the clinical criteria for tuberous sclerosis complex and had normal IQs, had frontotemporal dementia, or were healthy control individuals., Main Outcomes and Measures: Tuberous sclerosis-associated neuropsychiatric disorders checklist severity score, neuropsychologic test scores, cerebral spinal fluid concentrations of phosphorylated tau181, total tau, amyloid-β 42, and neurofilament light chain. Amyloid and tau positron emission tomography scans were obtained in a subset of patients., Results: Eighteen patients with tuberous sclerosis complex (mean [SD] age, 48 years [9.54]; 13 women [72%]), 16 with frontotemporal dementia (60 [6.93] years; 7 women [44%]) and 18 healthy control individuals (63 [3.85] years; 9 women [50%]) were included. The tuberous sclerosis-associated neuropsychiatric disorders checklist and neuropsychological test results were not significantly different when the tuberous sclerosis complex and frontotemporal dementia cohorts were compared. The tuberous sclerosis complex cohort exhibited elevated cerebral spinal fluid phosphorylated tau181 and neurofilament light chain with a mean of 32 pg/mL and 2300 pg/mL, respectively, when compared to healthy control individuals. All 3 patients with tuberous sclerosis complex who underwent fluorine 1B-labeled flortaucipir tau positron emission tomographic neuroimaging showed punctate foci of elevated [18F]flortaucipir binding in the frontal and temporal regions., Conclusions and Relevance: Adults with tuberous sclerosis complex showed phenotypic overlap with frontotemporal dementia. The results support a possible clinical continuum between tuberous sclerosis-associated neuropsychiatric disorders and frontotemporal dementia and highlights a potential pathophysiological link between neurodevelopmental and neurodegenerative processes. Quantitative neuropsychological testing and the tuberous sclerosis-associated neuropsychiatric disorders checklist, potentially supplemented by cerebral spinal fluid and imaging biomarkers, could be used to screen and prognosticate for risk of a neurodegenerative process in adult patients with tuberous sclerosis complex.

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72., Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried., Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0·45 between individual and parental age at onset, r=0·63 between individual and mean family age at onset, r=0·58 between individual and parental age at death, and r=0·69 between individual and mean family age at death) than in either the C9orf72 group (r=0·32 individual and parental age at onset, r=0·36 individual and mean family age at onset, r=0·38 individual and parental age at death, and r=0·40 individual and mean family age at death) or the GRN group (r=0·22 individual and parental age at onset, r=0·18 individual and mean family age at onset, r=0·22 individual and parental age at death, and r=0·32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35-62, for age at onset; 61%, 47-73, for age at death), and even more by family membership (66%, 56-75, for age at onset; 74%, 65-82, for age at death). In the GRN group, only 2% (0-10) of the variability of age at onset and 9% (3-21) of that of age of death was explained by the specific mutation, whereas 14% (9-22) of the variability of age at onset and 20% (12-30) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11-26) of the variability of age at onset and 19% (12-29) of that of age at death., Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates., Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Common neurodegenerative diseases feature progressive accumulation of disease-specific protein aggregates in selectively vulnerable brain regions. Increasing experimental evidence suggests that misfolded disease proteins exhibit prion-like properties, including the ability to seed corruptive templating and self-propagation along axons. Direct evidence for transneuronal spread in patients, however, remains limited. To test predictions made by the transneuronal spread hypothesis in human tissues, we asked whether tau deposition within axons of the corticospinal and corticopontine pathways can be predicted based on clinical syndromes and cortical atrophy patterns seen in frontotemporal lobar degeneration (FTLD). Sixteen patients with Pick's disease, 21 with corticobasal degeneration, and 3 with FTLD-MAPT were included, spanning a range of clinical syndromes across the frontotemporal dementia (FTD) spectrum. Cortical involvement was measured using a neurodegeneration score, a tau score, and a composite score based on semiquantitative ratings and complemented by an MRI-based cortical atrophy W-map based on antemortem imaging. Midbrain cerebral peduncle and pontine base descending fibers were divided into three subregions, representing prefrontopontine, corticospinal, and parieto-temporo-occipital fiber pathways. Tau area fraction was calculated in each subregion and related to clinical syndrome and cortical measures. Within each clinical syndrome, there were predicted relationships between cortical atrophy patterns and axonal tau deposition in midbrain cerebral peduncle and pontine base. Between syndromes, contrasting and predictable patterns of brainstem axonal tau deposition emerged, with, for example, greater tau in prefrontopontine fibers in behavioral variant FTD and in corticospinal fibers in corticobasal syndrome. Finally, semiquantitative and quantitative cortical degeneration scores predicted brainstem axonal tau deposition based on anatomical principles. Taken together, these findings provide important human evidence in support of axonal tau spreading in patients with specific forms of tau-related neurodegeneration.

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 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., Methods: We screened the major dementia-associated genes in 302 sporadic and 390 familial (symptomatic or at-risk) participants enrolled in these studies., Results: Among 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., Discussion: Our study reports the genetic characterization of a large FTD series and supports an unbiased sequencing screen, irrespective of clinical presentation or family history., (© 2020 the Alzheimer's Association.)

Introduction: Familial frontotemporal lobar degeneration (f-FTLD) due to autosomal dominant mutations is an important entity for developing treatments for FTLD. The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) longitudinal studies were designed to describe the natural history of f-FTLD., Methods: We summarized recent publications from the ARTFL and LEFFTDS studies, along with other recent publications describing the natural history of f-FTLD., Results: Published and emerging studies are producing data on all phases of f-FTLD, including the asymptomatic and symptomatic phases of disease, as well as the transitional phase when symptoms are just beginning to develop. These data indicate that rates of change increase along with disease severity, which is consistent with commonly cited models of neurodegeneration, and that measurement of biomarkers may predict onset of symptoms., Discussion: Data from large multisite studies are producing important data on the natural history of f-FTLD that will be critical for planning intervention trials., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of 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.)

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: Semantic dementia (SD) is a neurodegenerative disorder characterised by progressive language problems falling within the clinicopathological spectrum of frontotemporal lobar degeneration (FTLD). The development of disease-modifying agents may be facilitated by the relative clinical and pathological homogeneity of SD, but we need robust monitoring biomarkers to measure their efficacy. In different FTLD subtypes, neurofilament light chain (NfL) is a promising marker, therefore we investigated the utility of cerebrospinal fluid (CSF) NfL in SD., Methods: This large retrospective multicentre study compared cross-sectional CSF NfL levels of 162 patients with SD with 65 controls. CSF NfL levels of patients were correlated with clinical parameters (including survival), neuropsychological test scores and regional grey matter atrophy (including longitudinal data in a subset)., Results: CSF NfL levels were significantly higher in patients with SD (median: 2326 pg/mL, IQR: 1628-3593) than in controls (577 (446-766), p<0.001). Higher CSF NfL levels were moderately associated with naming impairment as measured by the Boston Naming Test ( r s =-0.32, p=0.002) and with smaller grey matter volume of the parahippocampal gyri ( r s =-0.31, p=0.004). However, cross-sectional CSF NfL levels were not associated with progression of grey matter atrophy and did not predict survival., Conclusion: CSF NfL is a promising biomarker in the diagnostic process of SD, although it has limited cross-sectional monitoring or prognostic abilities., Competing Interests: Competing interests: The authors report no conflicts of interest relevant to this study. LHHM is supported by Alzheimer Nederland (grant number WE.09 2014 04). ALB and JCR are supported by the NIH (U54NS092089, R01AG031278, R01AG038791, R01AG032306, R01AG022983) and the Association for Frontotemporal Degeneration. ALB, JCR and LDK are supported by the Bluefield Project to Cure Frontotemporal Dementia. The Dementia Research Centre is supported by Alzheimer’s Research UK, Brain Research Trust and The Wolfson Foundation. This work was supported by the NIHR Queen Square Dementia Biomedical Research Unit, the NIHR UCL/H Biomedical Research Centre and the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility as well as an Alzheimer’s Society grant (AS-PG-16-007). JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). IOCW is supported by an MRC Clinical Research Training Fellowship (MR/M018288/1). AS is supported by the Swedish Society for Medical Research. CET is supported by ZonMW Memorabel Program (grant number 733050206). JCvS is supported by the Dioraphte Foundation., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

The frontotemporal dementia (FTD) spectrum is a heterogeneous group of neurodegenerative syndromes with overlapping clinical, molecular and pathological features, all of which challenge the design of clinical trials in these conditions. To date, no pharmacological interventions have been proven effective in significantly modifying the course of these disorders. This study critically reviews the construct and methodology of previously published randomised controlled trials (RCTs) in FTD spectrum disorders in order to identify limitations and potential reasons for negative results. Moreover, recommendations based on the identified gaps are elaborated in order to guide future clinical trial design. A systematic literature review was carried out and presented in conformity with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. A total of 23 RCTs in cohorts with diagnoses of behavioural and language variants of FTD, corticobasal syndrome and progressive supranuclear palsy syndrome were identified out of the 943 citations retrieved and were included in the qualitative review. Most studies identified were early-phase clinical trials that were small in size, short in duration and frequently underpowered. Diagnoses of populations enrolled in clinical trials were based on clinical presentation and rarely included precision-medicine tools, such as genetic and molecular testing. Uniformity and standardisation of research outcomes in the FTD spectrum are essential. Several elements should be carefully considered and planned in future clinical trials. We anticipate that precision-medicine approaches will be crucial to adequately address heterogeneity in the FTD spectrum research., Competing Interests: Competing interests: PD and QDN have nothing to disclose. SEB and MM are supported by the Department of Medicine (Sunnybrook Health Sciences Centre and the University of Toronto), the Sunnybrook Foundation, the Hurvitz Brain Sciences Research Program and the Sunnybrook Research Institute. MM also receives support as co-lead of the Ontario Neurodegenerative Disease Research Initiative funded by the Ontario Brain Institute. SEB also receives support as the executive director of the Toronto Dementia Research Alliance. SEB does contract research for Eli Lilly, Biogen, GE Healthcare, Genentech, Novartis, Optina and Roche; received peer-reviewed funding from CIHR, CPSR, Brain Canada, ADDF, NIA, NIH, Leducq Foundation, OBI and Weston Brain Institute; and received speaker fees from Novartis and Eli Lilly. MM receives peer-reviewed research support from the Canadian Institutes of Health Research, Weston Brain Institute, Washington University, Parkinson Society Canada, Alzheimer’s Drug Discovery Foundation, Brain Canada, Canadian Consortium on Neurodegeneration in Aging and Ontario Brain Institute. MM has also served as an advisor to Bioscape Medical Imaging CRO, Novartis, Ionis Pharmaceuticals, Arkuda Therapeutics and UCB; received honoraria from Novartis; received royalties from Henry Stewart Talks; received an investigator-initiated research grant from Teva; and received contract research support from Roche, Novartis and Axovant. NH is supported by the Canadian Consortium on Neurodegeneration in Aging and peer-reviewed grants from the Alzheimer Society of Canada (grant 15-17), Alzheimer’s Drug Discovery Foundation (grant 20140503), Canadian Institutes of Health Research, National Institute on Aging of the National Institutes of Health (grant R01AG046543), and the Heart and Stroke Foundation (grant NA 7220), in addition to research contracts funded by Roche, Axovant and Lundbeck Canada. NH received consultation fees from Astellas, Lilly, Merck, Pfizer and Mediti. AEL has served as an advisor for AbbVie, Acorda, Biogen, Bristol-Myers Squibb, Janssen, Sun Pharma, Kallyope, Merck, Paladin and Corticobasal Degeneration Solutions; received honoraria from Sun Pharma, Medichem, Medtronic, AbbVie and Sunovion; received grants from Brain Canada, Canadian Institutes of Health Research, Corticobasal Degeneration Solutions, Edmond J Safra Philanthropic Foundation, Michael J Fox Foundation, the Ontario Brain Institute, National Parkinson Foundation, Parkinson Society Canada and W Garfield Weston Foundation; received publishing royalties from Elsevier, Saunders, Wiley-Blackwell, Johns Hopkins Press and Cambridge University Press. HHF receives peer-reviewed grant funding support from the Canadian Consortium on Neurodegeneration in Aging (CIHR 137794), National Institute on Aging (U19AG010483) (2UF1Ago32438-07), CIHR and Weston Brain Institute (Grant # 363926), and Brain Canada (IMPACT AD study), and other grant funding from Toyama Pharmaceutical, Biohaven Pharmaceuticals and Probiodrug. He has either current or past service agreements through UC San Diego with Banner Health, Roche Genentech, Arkuda Therapeutics, Samus, Samumed, Eisai, Merck and TauRx, and has received travel expenses from Axon Neurosciences, Alion Pharmaceuticals and Probiodrug. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Frontotemporal dementia refers to a group of progressive neurodegenerative syndromes usually caused by the accumulation of pathological tau or TDP-43 proteins. The effects of these proteins in the brain are complex, and each can present with several different clinical syndromes. Clinical efficacy trials of drugs targeting these proteins must use endpoints that are meaningful to all participants despite the variability in symptoms across patients. There are many candidate clinical measures, including neuropsychological scores and functional measures. Brain imaging is another potentially attractive outcome that can be precisely quantified and provides evidence of disease modification. Most imaging studies in frontotemporal dementia have been cross-sectional, and few have compared longitudinal changes in cortical volume with changes in other measures such as perfusion and white matter integrity. The current study characterized longitudinal changes in 161 patients with three frontotemporal dementia syndromes: behavioural variant frontotemporal dementia (n = 77) and the semantic (n = 45) and non-fluent (n = 39) variants of primary progressive aphasia. Visits included comprehensive neuropsychological and functional assessment, structural MRI (3 T), diffusion tensor imaging, and arterial spin labelled perfusion imaging. The goal was to identify measures that are appropriate as clinical trial outcomes for each group, as well as those that might be appropriate for trials that would include more than one of these groups. Linear mixed effects models were used to estimate changes in each measure, and to examine the correlation between imaging and clinical changes. Sample sizes were estimated based on the observed effects for theoretical clinical trials using bootstrapping techniques to provide 95% confidence intervals for these estimates. Declines in functional and neuropsychological measures, as well as frontal and temporal cortical volumes and white matter microstructure were detected in all groups. Imaging changes were statistically significantly correlated with, and explained a substantial portion of variance in, the change in most clinical measures. Perfusion and diffusion tensor imaging accounted for variation in clinical decline beyond volume alone. Sample size estimates for atrophy and diffusion imaging were comparable to clinical measures. Corpus callosal fractional anisotropy led to the lowest sample size estimates for all three syndromes. These findings provide further guidance on selection of trial endpoints for studies in frontotemporal dementia and support the use of neuroimaging, particularly structural and diffusion weighted imaging, as biomarkers. Diffusion and perfusion imaging appear to offer additional utility for explaining clinical change beyond the variance explained by volume alone, arguing for considering multimodal imaging in treatment trials.

Background: The tau positron emission tomography (PET) ligand 18 F-flortaucipir binds to paired helical filaments of tau in aging and Alzheimer's disease (AD), but its utility in detecting tau aggregates in frontotemporal dementia (FTD) is uncertain., Methods: We performed 18 F-flortaucipir imaging in patients with the FTD syndromes (n = 45): nonfluent variant primary progressive aphasia (nfvPPA) (n = 11), corticobasal syndrome (CBS) (n = 10), behavioral variant frontotemporal dementia (bvFTD) (n = 10), semantic variant primary progressive aphasia (svPPA) (n = 2) and FTD associated pathogenic genetic mutations microtubule-associated protein tau (MAPT) (n = 6), chromosome 9 open reading frame 72 (C9ORF72) (n = 5), and progranulin (GRN) (n = 1). All patients underwent MRI and β-amyloid biomarker testing via 11 C-PiB or cerebrospinal fluid. 18 F-flortaucipir uptake in patients was compared to 53 β-amyloid negative normal controls using voxelwise and pre-specified region of interest approaches., Results: On qualitative assessment, patients with nfvPPA showed elevated 18 F-flortacupir binding in the left greater than right inferior frontal gyrus. Patients with CBS showed elevated binding in frontal white matter, with higher cortical gray matter uptake in a subset of β-amyloid-positive patients. Five of ten patients with sporadic bvFTD demonstrated increased frontotemporal binding. MAPT mutation carriers had elevated 18 F-flortaucipir retention primarily, but not exclusively, in mutations with Alzheimer's-like neurofibrillary tangles. However, tracer retention was also seen in patients with svPPA, and the mutations C9ORF72, GRN predicted to have TDP-43 pathology. Quantitative region-of-interest differences between patients and controls were seen only in inferior frontal gyrus in nfvPPA and left insula and bilateral temporal poles in MAPT carriers. No significant regional differences were found in CBS or sporadic bvFTD. Two patients underwent postmortem neuropathological examination. A patient with C9ORF72, TDP-43-type B pathology, and incidental co-pathology of scattered neurofibrillary tangles in the middle frontal, inferior temporal gyrus showed corresponding mild 18 F-flortaucipir retention without additional uptake matching the widespread TDP-43 type B pathology. A patient with sporadic bvFTD demonstrated punctate inferior temporal and hippocampus tracer retention, corresponding to the area of severe argyrophilic grain disease pathology., Conclusions: 18 F-flortaucipir in patients with FTD and predicted tauopathy or TDP-43 pathology demonstrated limited sensitivity and specificity. Further postmortem pathological confirmation and development of FTD tau-specific ligands are needed.

Mutations in progranulin (GRN) cause heterogeneous clinical syndromes, including behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), corticobasal syndrome (CBS) and Alzheimer-type dementia (AD-type dementia). Human studies have shown that presymptomatic GRN carriers feature reduced connectivity in the salience network, a system targeted in bvFTD. Mice with homozygous deletion of GRN, in contrast, show thalamo-cortical hypersynchrony due to aberrant pruning of inhibitory synapses onto thalamo-cortical projection neurons. No studies have systematically explored the intrinsic connectivity networks (ICNs) targeted by the four GRN-associated clinical syndromes, or have forged clear links between human and mouse model findings. We compared 17 preclinical GRN carriers (14 "presymptomatic" clinically normal and three "prodromal" with mild cognitive symptoms) to healthy controls to assess for differences in cognitive testing and gray matter volume. Using task-free fMRI, we assessed connectivity in the salience network, a non-fluent variant primary progressive aphasia network (nfvPPA), the perirolandic network (CBS), and the default mode network (AD-type dementia). GRN carriers and controls showed similar performance on cognitive testing. Although carriers showed little evidence of brain atrophy, markedly enhanced connectivity emerged in all four networks, and thalamo-cortical hyperconnectivity stood out as a unifying feature. Voxelwise assessment of whole brain degree centrality, an unbiased graph theoretical connectivity metric, confirmed thalamic hyperconnectivity. These results show that human GRN disease and the prevailing GRN mouse model share a thalamo-cortical network hypersynchrony phenotype. Longitudinal studies will determine whether this network physiology represents a compensatory response as carriers approach symptom onset, or an early and sustained preclinical manifestation of lifelong progranulin haploinsufficiency., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Accurately predicting the underlying neuropathological diagnosis in patients with behavioural variant frontotemporal dementia (bvFTD) poses a daunting challenge for clinicians but will be critical for the success of disease-modifying therapies. We sought to improve pathological prediction by exploring clinicopathological correlations in a large bvFTD cohort. Among 438 patients in whom bvFTD was either the top or an alternative possible clinical diagnosis, 117 had available autopsy data, including 98 with a primary pathological diagnosis of frontotemporal lobar degeneration (FTLD), 15 with Alzheimer's disease, and four with amyotrophic lateral sclerosis who lacked neurodegenerative disease-related pathology outside of the motor system. Patients with FTLD were distributed between FTLD-tau (34 patients: 10 corticobasal degeneration, nine progressive supranuclear palsy, eight Pick's disease, three frontotemporal dementia with parkinsonism associated with chromosome 17, three unclassifiable tauopathy, and one argyrophilic grain disease); FTLD-TDP (55 patients: nine type A including one with motor neuron disease, 27 type B including 21 with motor neuron disease, eight type C with right temporal lobe presentations, and 11 unclassifiable including eight with motor neuron disease), FTLD-FUS (eight patients), and one patient with FTLD-ubiquitin proteasome system positive inclusions (FTLD-UPS) that stained negatively for tau, TDP-43, and FUS. Alzheimer's disease was uncommon (6%) among patients whose only top diagnosis during follow-up was bvFTD. Seventy-nine per cent of FTLD-tau, 86% of FTLD-TDP, and 88% of FTLD-FUS met at least 'possible' bvFTD diagnostic criteria at first presentation. The frequency of the six core bvFTD diagnostic features was similar in FTLD-tau and FTLD-TDP, suggesting that these features alone cannot be used to separate patients by major molecular class. Voxel-based morphometry revealed that nearly all pathological subgroups and even individual patients share atrophy in anterior cingulate, frontoinsula, striatum, and amygdala, indicating that degeneration of these regions is intimately linked to the behavioural syndrome produced by these diverse aetiologies. In addition to these unifying features, symptom profiles also differed among pathological subtypes, suggesting distinct anatomical vulnerabilities and informing a clinician's prediction of pathological diagnosis. Data-driven classification into one of the 10 most common pathological diagnoses was most accurate (up to 60.2%) when using a combination of known predictive factors (genetic mutations, motor features, or striking atrophy patterns) and the results of a discriminant function analysis that incorporated clinical, neuroimaging, and neuropsychological data., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Degradation of white matter microstructure has been demonstrated in frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). In preparation for clinical trials, ongoing studies are investigating the utility of longitudinal brain imaging for quantification of disease progression. To date only one study has examined sample size calculations based on longitudinal changes in white matter integrity in FTLD., Objective: To quantify longitudinal changes in white matter microstructural integrity in the three canonical subtypes of frontotemporal dementia (FTD) and AD using diffusion tensor imaging (DTI)., Methods: 60 patients with clinical diagnoses of FTD, including 27 with behavioral variant frontotemporal dementia (bvFTD), 14 with non-fluent variant primary progressive aphasia (nfvPPA), and 19 with semantic variant PPA (svPPA), as well as 19 patients with AD and 69 healthy controls were studied. We used a voxel-wise approach to calculate annual rate of change in fractional anisotropy (FA) and mean diffusivity (MD) in each group using two time points approximately one year apart. Mean rates of change in FA and MD in 48 atlas-based regions-of-interest, as well as global measures of cognitive function were used to calculate sample sizes for clinical trials (80% power, alpha of 5%)., Results: All FTD groups showed statistically significant baseline and longitudinal white matter degeneration, with predominant involvement of frontal tracts in the bvFTD group, frontal and temporal tracts in the PPA groups and posterior tracts in the AD group. Longitudinal change in MD yielded a larger number of regions with sample sizes below 100 participants per therapeutic arm in comparison with FA. SvPPA had the smallest sample size based on change in MD in the fornix (n = 41 participants per study arm to detect a 40% effect of drug), and nfvPPA and AD had their smallest sample sizes based on rate of change in MD within the left superior longitudinal fasciculus (n = 49 for nfvPPA, and n = 23 for AD). BvFTD generally showed the largest sample size estimates (minimum n = 140 based on MD in the corpus callosum). The corpus callosum appeared to be the best region for a potential study that would include all FTD subtypes. Change in global measure of functional status (CDR box score) yielded the smallest sample size for bvFTD (n = 71), but clinical measures were inferior to white matter change for the other groups., Conclusions: All three of the canonical subtypes of FTD are associated with significant change in white matter integrity over one year. These changes are consistent enough that drug effects in future clinical trials could be detected with relatively small numbers of participants. While there are some differences in regions of change across groups, the genu of the corpus callosum is a region that could be used to track progression in studies that include all subtypes.

Corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and a subset of frontotemporal dementia (FTD) are neurodegenerative disorders characterized by tau inclusions in neurons and glia (tauopathies). Although clinical, pathological and genetic evidence suggests overlapping pathobiology between CBD, PSP, and FTD, the relationship between these disorders is still not well understood. Using summary statistics (odds ratios and p values) from large genome-wide association studies (total n = 14,286 cases and controls) and recently established genetic methods, we investigated the genetic overlap between CBD and PSP and CBD and FTD. We found up to 800-fold enrichment of genetic risk in CBD across different levels of significance for PSP or FTD. In addition to NSF (tagging the MAPT H1 haplotype), we observed that SNPs in or near MOBP, CXCR4, EGFR, and GLDC showed significant genetic overlap between CBD and PSP, whereas only SNPs tagging the MAPT haplotype overlapped between CBD and FTD. The risk alleles of the shared SNPs were associated with expression changes in cis-genes. Evaluating transcriptome levels across adult human brains, we found a unique neuroanatomic gene expression signature for each of the five overlapping gene loci (omnibus ANOVA p < 2.0 × 10 -16 ). Functionally, we found that these shared risk genes were associated with protein interaction and gene co-expression networks and showed enrichment for several neurodevelopmental pathways. Our findings suggest: (1) novel genetic overlap between CBD and PSP beyond the MAPT locus; (2) strong ties between CBD and FTD through the MAPT clade, and (3) unique combinations of overlapping genes that may, in part, influence selective regional or neuronal vulnerability observed in specific tauopathies.

Objective: To assess the efficacy of [ 18 F]AV1451 PET in visualizing tau pathology in vivo in a patient with frontotemporal dementia (FTD) associated with the V337M microtubule-associated protein tau ( MAPT) mutation., Methods: MAPT mutations are associated with the deposition of hyperphosphorylated tau protein in neurons and glia. The PET tracer [ 18 F]AV1451 binds with high affinity to paired helical filaments tau that comprises neurofibrillary tangles in Alzheimer disease (AD), while postmortem studies suggest lower or absent binding to the tau filaments of the majority of non-AD tauopathies. We describe clinical, structural MRI, and [ 18 F]AV1451 PET findings in a V337M MAPT mutation carrier affected by FTD and pathologic findings in his affected mother and in an unrelated V337M MAPT carrier also affected with FTD. The biochemical similarity between paired helical filament tau in AD and MAPT V337M predicts that the tau pathology associated with this mutation constitutes a compelling target for [ 18 F]AV1451 imaging., Results: We found a strong association between topography and degree of [ 18 F]AV1451 tracer retention in the proband and distribution of tau pathology in the brain of the proband's mother and the unrelated V337M mutation carrier. We also found a significant correlation between the degree of regional MRI brain atrophy and the extent of [ 18 F]AV1451 binding in the proband and a strong association between the proband's clinical presentation and the extent of regional brain atrophy and tau accumulation as assessed by structural brain MRI and [ 18 F]AV1451PET., Conclusion: Our study supports the usefulness of [ 18 F]AV1451 to characterize tau pathology in at least a subset of pathogenic MAPT mutations., (© 2017 American Academy of Neurology.)