Search

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.)

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.

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.)

Objective: We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression., Methods: Baseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. C9orf72 , GRN , and MAPT mutation carriers and noncarriers from the same families were classified by disease severity (asymptomatic, prodromal, and full phenotype) using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed-effect models related NfL to clinical variables., Results: In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL, p = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, p = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers., Conclusions: Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression and is a potential tool to select participants for prevention clinical trials., Trial Registration Information: ClinicalTrials.gov Identifier: NCT02372773 and NCT02365922., Classification of Evidence: This study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

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.