NEW
Via: https://www.medrxiv.org
Background and Objectives: Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods: This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results: Variant carriers (n=147) and familial non-carriers (n=113) did not differ in age (mean±SD, 25.9±3.2 years), sex (53% female), or number of visits (2.1±1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years (b=-982.8mm3, SE=317.0, p=0.0046, f2=0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines (b=64.4mm3, SE=29.9, p=0.035, f2=0.07). For MAPT and GRN, there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion: C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.
### Competing Interest Statement
J.D.R. has received consulting fees from UCB, AC Immune, Astex Pharmaceuticals, Biogen, Takeda, and Eisai and serves on advisory boards for Alector, Arkuda Therapeutics, Wave Life Sciences, and Prevail Therapeutics. R.S.-V. has received consulting fees from Wave Pharmaceuticals, Ionis-Biogen, Roche Diagnostics, and Janssen, and serves on Data Safety Monitoring Boards for Wave Pharmaceuticals and Ionis-Biogen. B.B. has received consulting fees from Alector and Wave Pharmaceuticals and has a pending patent on noninvasive brain stimulation. M.M. has received royalties from Henry Stewart Talks Ltd., consulting fees from Arkuda Therapeutics, Ionis, Alector, Biogen, and Wave Life Sciences, and honoraria and travel support from Alector and Arkuda Therapeutics. M.C.T. has received consulting fees from Roche. C.G. has received consulting fees and travel reimbursement related to academic activities. J.R. has received consulting fees from Asceneuron, Biogen, UCB, SV Health, and Astex; has provided expert testimony; and holds advisory roles in academic and nonprofit organizations. R.V. has received consulting fees from CyTox and serves on a Data Safety Monitoring Board for AC Immune. I. Santana has received consulting fees and honoraria from Biogen and Roche and serves on a Data Safety Monitoring Board for Novo Nordisk. S.D. has received consulting fees from Innodem Neurosciences and personal fees from Sunovion and Eisai. J.L. has received consulting fees from Bayer Vital, Roche, and Biogen; advisory roles with Axon Neurosciences; compensation as part-time CMO of Modag; and publishing-related fees. E.S. has served on the advisory board of Novartis, EISAI, Lilly, Bioarctic and Roche, served as a consult for Novo Nordisk, EISAI, Roche, BioArctic and Lilly, received research funding from Eli Lilly, and Roche and received honoraria from lectures from Lundbeck, BioArctic, Lilly, TEVA, Novo Nordisk and Roche and travel support from Eli Lilly. M.O. has received consulting fees from Biogen, Axon, and Roche and serves on an advisory board for Axon. I.L.B. has received consulting fees from Alector and Prevail Therapeutics and serves on a Data Safety Monitoring Board. K.K. has served on Data Safety Monitoring Boards for Takeda, Pfizer, and Janssen and received research support from Avid Radiopharmaceuticals, Eli Lilly, the Alzheimer's Drug Discovery Foundation, and the NIH. B.F.B. has participated in clinical trials sponsored by Alector, Biogen, Transposon, and Cognition Therapeutics and serves on the Scientific Advisory Board of the Tau Consortium. A.L.B. has served as a consultant for Aeovian, AGTC, Alector, Arkuda Therapeutics, Arvinas, Boehringer Ingelheim, Denali Therapeutics, GSK, Life Edit, Humana, Oligomerix, Oscotec, Roche, TrueBinding, Wave Life Sciences, and Merck, and has received research support from Biogen, Eisai, and Regeneron. H.J.R. has received research support from Biogen and consulting fees from Wave Neuroscience, Ionis Pharmaceuticals, Eisai, and Genentech. E.C.F. has received honoraria for the American Academy of Neurology (AAN) Annual Meeting, including speaker and course director honoraria; serves on the Data Safety Monitoring Board for the Lithium trial (PI: E. Huey; funded by the Alzheimer's Drug Discovery Foundation); and is a member of the scientific advisory boards for Vigil Neuroscience and Denali Therapeutics, and an advisory panel member for Biogen. M. Synofzik has received consulting fees from Janssen, Ionis, and Orphazyme and travel support from the Movement Disorder Society. Additional disclosures include consultancy roles (e.g., A.M.S. for Alector, Lilly, Passage Bio, and Takeda) and advisory board participation (e.g., R.R. for Arkuda Therapeutics and Foundation Alzheimer). All other authors not already listed have no disclosures to report.
### Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
Ethics committees of each individual site and institution gave ethical approval for this work. The datasets used in this study were de-identified prior to use.
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
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Yes
Data requests can be made by an FPI-affiliated investigator to the coordinating centre. Preprocessing and analytical scripts can be shared upon request.
This study was supported by Canadian Institutes of Health Research (CIHR) grants #470797 and #452843, held by E.F., who also holds funding from CIHR grant #327387. I.So is supported by a CIHR Canada Graduate Scholarship-Doctoral #193336 and Parkwood Institute Research Cross-Theme Collaboration Studentship (funded by the St. Josephs Health Care Foundation). J.C.V.S., L.C.J. and H.S. are supported by the Dioraphte Foundation grant 09-02-03-00, Association for Frontotemporal Dementias Research Grant 2009, Netherlands Organization for Scientific Research grant HCMI 056-13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), ZonMw Onderzoeksprogramma Dementie (YOD-INCLUDED, project number 10510032120002), EU Joint Programme-Neurodegenerative Disease Research GENFI-PROX, Alzheimer Nederland, and the Bluefield Project. R.S.-V. is supported by Alzheimers Research UK Clinical Research Training Fellowship (ARUK-CRF2017B-2) and has received funding from Fundació Marató de TV3 (Spain; grant no. 20143810) and Instituto de Salud Carlos III (PI20/00448). RL is supported by the Canadian Institutes of Health Research and the Chaire de Recherche sur les Aphasies Primaires Progressives Fondation Famille Lemaire. C.G. has received funding from multiple sources including the EU Joint Programme-Neurodegenerative Disease Research, Vetenskapsrådet, the Swedish FTD Initiative-Schörling Foundation, Alzheimer Foundation, Brain Foundation, Dementia Foundation, and Region Stockholm ALF-project, and is additionally supported by Karolinska Institutet Doctoral Funding and KI Strat-Neuro. R.V. has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia. J.L. is supported by the Deutsche Forschungsgemeinschaft under Germanys Excellence Strategy (EXC 2145 SyNergy-ID 390857198). M.O. has received funding from Germanys Federal Ministry of Education and Research (BMBF). S.D. receives salary support from the Fonds de Recherche du Québec - Santé and funding from the Canada First Research Excellence Fund (Healthy Brains, Healthy Lives initiative). M.M. has received funding from the UK Medical Research Council, the Italian Ministry of Health, the Canadian Institutes of Health Research, and the Weston Brain Institute. J.B.R. is supported by the Wellcome Trust, the Medical Research Council, and the NIHR Cambridge Biomedical Research Centre. F.M. is supported by the Tau Consortium and the Carlos III Health Institute (PI19/01637). J.D.R. is supported by the Bluefield Project and NIHR University College London Hospitals Biomedical Research Centre. Additional support from the EU Joint Programme-Neurodegenerative Disease Research GENFI-PROX grant was received by J.D.R., M.O., B.B., C.G., J.C.V.S., and M.S. Several authors (J.C.V.S., M.S., R.V., A.d.M., M.O., and J.D.R.) are members of the European Reference Network for Rare Neurological Diseases (ERN-RND; Project ID No. 739510). E.S. is funded by the following: Wihuri Foundation, Sigrid Juselius Foundation, The State Research Funding, The Research Council of Finland (grant no. 360451), and Jane and Aatos Erkko Foundation. P.K. has received funding for his work from the EU horizon 2020 project. M.L.S. has been supported by the eHealthSax Initiative of the Sächsische Aufbaubank (SAB; project TelDem), and European Union (EFRE InfraProNet, 100757914, NeuroTrace). Accordingly, the work is supported with tax revenue based on the budget approved by the Saxon state parliament. I.I-G is supported by the Institute of Health Carlos III (ISCIII), Spain (PI21/00791 and PI24/00598) jointly funded by Fondo Europeo de Desarrollo Regional, Unión Europea, Una manera de hacer Europa. I.I-G is a senior Atlantic Fellow for Equity in Brain Health at the Global Brain Health Institute (GBHI) and receives funding from the Alzheimers Association (AACSF-21-850193), and the Alzheimer Society (GBHI ALZ UK-21-72097). I.I-G was also supported by the Juan Rodés Contract (JR20/0018) from the Carlos III National Institute of Health of Spain, partly funded by the European Social Fund. J.K. has received funding from the State Research Funding, Päivikki and Sakari Sohlberg Foundation, and Wihuri foundation. T.L. has received funding from The Bluefield Project. The following authors report research support from the NIH: K.F., T.F., L.F., T.G., L.P., E.M.R., K.P.R., K.R., S.W., B.W., L.K.F., B.F.B., K.K., A.L.B., H.J.R., and S.E.L. In addition, K.F. received funding from National Centralized Repository for Alzheimers Disease (U24 AG021886). A.L.B. received funding from the Tau Research Consortium, the Association for Frontotemporal Degeneration, the Bluefield Project to Cure Frontotemporal Dementia, Corticobasal Degeneration Solutions, the Alzheimers Drug Discovery Foundation, and the Alzheimers Association. H.J.R. received research support from the State of California. S.E.L is supported by NIH-NIA R01 AG058233, NIH-NIA R01AG071756, and the Tau Consortium Bluefield Project to Cure FTD.