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Temporal order of clinical and biomarker changes in familial frontotemporal dementia

Abstract

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.

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Fig. 1: Raw data points overlaid on model estimated fit.
Fig. 2: Temporal ordering of clinical and biomarker changes in f-FTD.
Fig. 3: Comparison of mutation carriers with controls at three epochs of DA.

Data availability

The datasets analyzed for the current study reflect collaborative efforts of two research consortia: ALLFTD and GENFI. Each consortium provides clinical data access based on established policies for data use: processes for request are available for review at allftd.org/data for ALLFTD data and by emailing genfi@ucl.ac.uk. Certain data elements from both consortia (for example raw MRI images) may be restricted due to the potential for identifiability in the context of the sensitive nature of the genetic data. The deidentified combined dataset will be available for request through the FTD Prevention Initiative in 2023 (https://www.thefpi.org/).

Code availability

Custom R code is available at https://doi.org/10.5281/zenodo.6687486.

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Acknowledgements

Data collection and dissemination of the data presented in this paper were supported by the ALLFTD Consortium (U19: AG063911, funded by the National Institute on Aging and the National Institute of Neurological Diseases and Stroke) and the former ARTFL and LEFFTDS Consortia (ARTFL: U54 NS092089, funded by the National Institute of Neurological Diseases and Stroke and National Center for Advancing Translational Sciences; LEFFTDS: U01 AG045390, funded by the National Institute on Aging and the National Institute of Neurological Diseases and Stroke). The manuscript was reviewed by the ALLFTD Executive Committee for scientific content. The authors acknowledge the invaluable contributions of the study participants and families as well as the assistance of the support staffs at each of the participating sites. This work is also supported by the Association for Frontotemporal Degeneration (including the FTD Biomarkers Initiative), the Bluefield Project to Cure FTD, Larry L. Hillblom Foundation (2018-A-025-FEL (A.M.S.)), the National Institutes of Health (AG038791 (A.L.B.), AG032306 (H.J.R.), AG016976 (W.K.), AG062677 (Ron C. Peterson), AG019724 (B.L.M.), AG058233 (Suzee E. Lee), AG072122 (Walter Kukull), P30 AG062422 (B.L.M.), K12 HD001459 (N.G.), K23AG061253 (A.M.S.), AG062422 (RCP), K24AG045333 (H.J.R.)) and the Rainwater Charitable Foundation. Samples from the National Centralized Repository for Alzheimer Disease and Related Dementias (NCRAD), which receives government support under a cooperative agreement grant (U24 AG021886 (T.F.)) awarded by the National Institute on Aging (NIA), were used in this study. This work was also supported by Medical Research Council UK GENFI grant MR/M023664/1 (J.D.R.), the Bluefield Project, the National Institute for Health Research including awards to Cambridge and UCL Biomedical Research Centres and a JPND GENFI-PROX grant (2019–02248). Several authors of this publication are members of the European Reference Network for Rare Neurologic Diseases, project 739510. J.D.R. and L.L.R. are also supported by the National Institute for Health and Care Research (NIHR) UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre Clinical Research Facility and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. J.D.R. is also supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). M.B. is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517). RC and C.G. are supported by a Frontotemporal Dementia Research Studentships in Memory of David Blechner funded through The National Brain Appeal (RCN 290173). J.B.R. is supported by NIHR Cambridge Biomedical Research Centre (BRC-1215-20014; the views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care), the Wellcome Trust (220258), the Cambridge Centre for Parkinson-plus and the Medical Research Council (SUAG/092 G116768); I.L.B. is supported by ANR-PRTS PREV-DemAls, PHRC PREDICT-PGRN, and several authors of this publication are members of the European Reference Network for Rare Neurological Diseases (project 739510). J.L. is funded by the Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198). R.S.-V. was funded at the Hospital Clinic de Barcelona by Instituto de Salud Carlos III, Spain (grant code PI20/00448 to RSV) and Fundació Marató TV3, Spain (grant code 20143810 to R.S.-V.). M.M. was, in part, funded by the UK Medical Research Council, the Italian Ministry of Health and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, by Canadian Institutes of Health Research operating grants (MOP- 371851 and PJT-175242) and by funding from the Weston Brain Institute. R.L. is supported by the Canadian Institutes of Health Research and the Chaire de Recherche sur les Aphasies Primaires Progressives Fondation Famille Lemaire. C.G. is supported by the Swedish Frontotemporal Dementia Initiative Schörling Foundation, Swedish Research Council, JPND Prefrontals, 2015–02926,2018–02754, Swedish Alzheimer Foundation, Swedish Brain Foundation, Karolinska Institutet Doctoral Funding, KI Strat-Neuro, Swedish Dementia Foundation, and Stockholm County Council ALF/Region Stockholm. J.L. is supported by Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (German Research Foundation, EXC 2145 Synergy 390857198). The Dementia Research Centre is supported by Alzheimer’s Research UK, Alzheimer’s Society, Brain Research UK, and The Wolfson Foundation. This work was supported by the National Institute for Health Research UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre Clinical Research Facility and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK.

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Authors

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Contributions

A.M.S., M.Q. and B. Wendelberger had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. A.M.S., M.Q., B. Wendelberger, H.W.H., L.R., H.J.R., J.D.R. and A.L.B. were responsible for concept development and design. A.M.S., M.Q. and B. Wendelberger conducted statistical analyses. M.Q. and B. Wendelberger developed the custom code for the DPMs. L.P., T.F.G. and C.H. processed the NfL data. Y.C., A. Wolf. and S.Y.M.G. processed the neuroimaging data. A.M.S., M.Q. and B. Wendelberger drafted the manuscript. A.M.S., M.Q., B. Wendelberger, H.W.H., L.R., H.J.R., J.D.R. and A.L.B. critically revised the manuscript. A.L.B. supervised the research. B.F.B., H.J.R., J.D.R. and A.L.B. obtained funding. All authors contributed to acquisition, analysis or interpretation of data or revision of the manuscript.

Corresponding authors

Correspondence to Adam M. Staffaroni or Adam. L. Boxer.

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Competing interests

B.A. 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. B.F.B. 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. H.B. receives research support from the NIH. A.L.B. receives 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. B.C.D. 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. K.D.-R. receives research support from the NIH and serves as an investigator for a clinical trial sponsored by Lawson Health Research Institute. S.D. has participated or is currently participating in clinical trials of anti-dementia drugs sponsored by Biogen, Ionis Pharmaceuticals, Wave Life Sciences and Janssen. He has received speaking honorarium/advisory fees from Eisai, Biogen, Innodem Neurosciences and NeuroCatch and receives salary support from the Fond de Recherche du Québec – Santé. K.F. receives research support from the NIH. J.A.F. receives research support from the NIH. T.F. receives research support from the NIH. L.F. receives research support from the NIH. R.G. receives research support from the NIH. T.F.G. receives research support from the NIH. N.G. 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. J.G. is serving as a consultant to the Novartis Alzheimer’s Prevention Advisory Board. She receives research support from the NIH, Huntington’s Disease Society of America and the New York State Department of Health (RFA 1510130358). J.G.-R. receives research support from the NIH and is on the editorial board of Neurology. N.G.-R. receives royalties from UpToDate and has participated in multicenter therapy studies by sponsored by Biogen, TauRx, AbbVie, Novartis and Lilly. He receives research support from the NIH. M.G. receives grant support from the NIH, Avid and Piramal; participates in clinical trials sponsored by Biogen, TauRx and Alector; serves as a consultant to Bracco and UCB; and serves on the editorial board of Neurology. G.-Y.H. has served as an investigator for clinical trials sponsored by AstraZeneca, Eli Lilly and Roche/Genentech. He receives research support from the Canadian Institutes of Health Research and the Alzheimer Society of British Columbia. E.D.H. receives research support from the NIH. D.I. receives support from the NIH, BrightFocus Foundation and Penn Institute on Aging. D.T.J. receives research support from the NIH and the Minnesota Partnership for Biotechnology and Medical Genomics. K.K. served on the Data Safety Monitoring Board for Takeda Global Research & Development Center and data monitoring boards of Pfizer and Janssen Alzheimer Immunotherapy and received research support from Avid Radiopharmaceuticals, Eli Lilly, the Alzheimer’s Drug Discovery Foundation and the NIH. D. Kerwin has served on an advisory board for AbbVie and as site principal investigator for studies funded by Roche/Genentech, AbbVie, Avid, Novartis, Eisai, Eli Lilly and UCSF. D. Knopman serves on the data and safety monitoring board of the DIAN-TU study; is a site principal investigator for clinical trials sponsored by Biogen, Lilly and the University of Southern California; and is funded by the NIH. 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-cv-00121 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. J. Kramer receives royalties from Pearson. W.K. receives research funding from AstraZeneca, Biogen, Roche, the Department of Defense and the NIH. M.I.L. receives research support from the NIH. J.L. reports speaker fees from Bayer Vital, Biogen and Roche; consulting fees from Axon Neuroscience and Biogen; author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers; non-financial support from AbbVie; and compensation for duty as part-time chief medical officer from MODAG outside the submitted work. I.L. receives research support from the NIH (grants: 2R01AG038791-06A, U01NS100610, U01NS80818, R25NS098999, U19AG063911 -1 and 1R21NS114764-01A1), the Michael J Fox Foundation, the Parkinson Foundation, the Lewy Body Association, CurePSP, Roche, AbbVie, Biogen, Centogene. EIP Pharma, Biohaven Pharmaceuticals, Novartis, Brain Neurotherapy Bio and United Biopharma SRL - UCB. She was a member of the scientific advisory board of Lundbeck and 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. P.L. 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. D.L. receives research support from the NIH. I.R.M. receives research funding from the Canadian Institutes of Health Research, the Alzheimer’s Association US, the NIH and the Weston Brain Institute. M.M. reports grant funding from the Canadian Institutes of Health Research relating to this work and grants from the Canadian Institutes of Health Research, Woman’s Brain Health Initiative, Brain Canada, Ontario Brain Institute, Weston Brain Institute and Washington University outside of this submitted work. M.M. has received personal fees for serving on a scientific advisory committee for Ionis Pharmaceuticals, Alector Pharmaceuticals, Wave Life Sciences and Biogen Canada outside of this submitted work. M.M. has received royalties from Henry Stewart Talks outside of this submitted work. M.M. is a clinical trial site investigator for Roche and Alector Pharmaceuticals outside of this submitted work. S.M. has served as an investigator for clinical trials sponsored by AbbVie, Allon Therapeutics, Biogen, Bristol Myers Squibb, C2N Diagnostics, Eisai, Eli Lilly and Co., Genentech, Janssen Pharmaceuticals, Medivation, Merck, Navidea Biopharmaceuticals, Novartis, Pfizer and TauRx Therapeutics. He receives research support from the NIH. M.F.M. receives research support from the NIH. B.L.M. is Director and Internal Advisor of The Bluefield Project to Cure FTD, Co-Director and Scientific Advisor of the Tau Consortium, Co-Director of the Global Brain Health Institute, Co-Director and medical advisor for The John Douglas French Foundation, scientific advisor for The Larry L. Hillblom Foundation, Scientific Advisor for Association for Frontotemporal Degeneration, Scientific Advisor for National Institute for Health Research Cambridge Biomedical Research Centre and its subunit, the Biomedical Research Unit in Dementia, external advisor to University of Washington ADRC, Stanford University ADRC, Arizona Alzheimer’s Disease Center, Massachusetts Alzheimer Disease Research Center, and scientific advisor to The Buck Institute for Research on Aging. B.L.M. serves as Editor-in-Chief for Neurocase, on the editorial board of ALS/FTD Journal (Taylor & Francis), Section Editor for Frontiers and editor for PLOS Medicine. He receives royalties from Cambridge University Press, Guilford Publications, Johns Hopkins Press, Oxford University Press, Taylor & Francis Group, Elsevier and Up-to-Date. C.U.O. receives research funding from the NIH, Lawton Health Research Institute, National Ataxia Foundation, Alector and Transposon. He is also supported by the Robert and Nancy Hall Brain Research Fund, the Jane Tanger Black Fund for Young-Onset Dementias and a gift from Joseph Trovato. He is a consultant with Alector and Acadia Pharmaceuticals. L.P. receives research support from the NIH. M.Q. is an employee of Berry Consultants, where she serves as a consultant to numerous pharmaceutical and device companies. R.R. receives research funding from the NIH and the Bluefield Project to Cure Frontotemporal Dementia. R.R. is on the scientific advisory board of Arkuda Therapeutics and receives royalties from progranulin-related patent. She is also on the scientific advisory board of the Fondation Alzheimer. E.M.R. receives research support from the NIH. K.P.R. receives research support from the NIH and the National Science Foundation and serves on a medical advisory board for Eli Lilly. K.R. receives research support from the NIH. E.D.R. receives research support from the NIH, the Bluefield Project to Cure Frontotemporal Dementia, the Alzheimer’s Association, the BrightFocus Foundation, Biogen and Alector; has served as a consultant for AGTC and on a data and safety monitoring board for Lilly; and owns intellectual property related to tau. J.D.R. has served on a medical advisory board and had a consultancy agreement with Alector, Arkuda Therapeutics, Wave Life Sciences, Prevail Therapeutics, UCB, AC Immune, Astex Pharmaceuticals, Biogen, Takeda and Eisai. J.C.R. receives research support from the NIH and is a site principal investigator for clinical trials sponsored by Eli Lilly and Eisai. H.J.R. has received research support from Biogen Pharmaceuticals, has consulting agreements with Wave Neuroscience and Ionis Pharmaceuticals and receives research support from the NIH. J.B.R. has research grants unrelated to the current work from AstraZeneca, Janssen, Lilly and GSK via the Dementias Platform UK and has provided consultancy unrelated to the current work to Asceneuron, Astex, Curasen, UCB, SV Health, WAVE and Alzheimer Research UK. R.S.-V. receives personal fees from Wave Pharmaceuticals for attending advisory board meetings; personal fees from Roche Diagnostics, Janssen and Neuraxpharm for educational activities; and research grants to her institution from Biogen and Sage Therapeutics outside the submitted work. R.S. receives support from the NIA, the National Institute of Neurological Disorders and Stroke, the Parkinson’s Disease Foundation and Acadia Pharmaceuticals. A.M.S. received 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. M.C.T. 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. N.T. was employed by the Association for Frontotemporal Degeneration and is now employed by Alector. L.V.V. receives 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. S.W. receives research support from the NIH. B. Wendelberger is an employee of Berry Consultants, where she serves as a consultant to numerous pharmaceutical and device companies. B. Wong receives research support from the NIH. All other authors have no competing interests.

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Extended data

Extended Data Fig. 1 Baseline comparisons between mutation carriers and controls by DA epoch.

Cross-sectional baseline differences between mutation carriers and controls are presented as effect sizes (omega squared). Bolded cells indicate statistical significance (p < 0.05) using two-sided tests without multiple comparison correction. Comparisons in which mutation carriers are more impaired than controls are colored, with darker shades illustrating larger effect sizes. Note that statistical comparisons for the CDR+NACC-FTLD SB should be interpreted with caution given that controls were defined as having a baseline CDR+NACC-FTLD=0 and thus have no variance due to this selection process. Abbreviations: EF: Executive Functioning; NfL: Plasma neurofilament light chain levels; RSMS: Revised Self-Monitoring Scale. CDR+NACC FTLD SB: Clinical Dementia Rating Scale plus National Alzheimer’s Coordinating Center’s Frontotemporal Lobar Degeneration Module Sum of Boxes.

Extended Data Fig. 2 Voxelwise atrophy by estimated disease stage in familial frontotemporal dementia.

Voxelwise maps display brain atrophy as the number of standardized units from controls (W-scores), controlling for head size and scanner. Images are shown in radiological orientation (that is, right is left). Voxelwise results are presented with a greater number of axial slices in Supplementary Figs. 24. Results were generally consistent with the region of interest findings, supporting the validity of the DPM approach. In C9orf72, thalamic atrophy, particularly in the pulvinar, was the primary region of atrophy in the −40 to −10 epoch and continued to be a region of prominent atrophy throughout the disease course. Medial temporal lobe volume loss became prominent in the −10 to −0 epoch. Frontoinsular, medial parietal, and medial temporal atrophy became prominent in the symptomatic phase (see also Supplementary Fig. 2). In GRN, subtle early cerebellar atrophy was observed (−40 to −10), along with atrophy in frontotemporal, subcortical, and insular structures in the −10 to 0 epoch. In the symptomatic stage, atrophy extended into the temporal lobe, frontoparietal regions, and striatum (see also Supplementary Fig. 3). Atrophy in MAPT appeared to begin in the medial temporal lobe and temporal pole (−10 to 0), and symptomatic mutation carriers showed temporal, insular, ventral and medial frontal, and striatal atrophy (see also Supplementary Fig. 4).

Extended Data Fig. 3 Patient-level data contributing to the disease progression models.

For each genetic group, each mutation carrier with longitudinal data is displayed in a single column, organized on the x-axis by their model estimated Disease Age at baseline. Participants’ baseline and last available (Final) observation for each outcome are presented. For the CDR+NACC-FTLD-SB, white cells indicate a score of 0, and increasingly dark red tones denote higher scores (that is, more severe impairments or greater atrophy). Log-transformed plasma NfL concentrations and the mean of all available neuropsychological scores and regional gray matter volume estimates are also presented, with the color scale indicating their scores relative to controls of the same Disease Age. Lastly, the model’s prior estimate of Years Since Onset is displayed. For participants with documented onset, we display the difference between their chronological age and the clinician estimated age of onset. For those participants in whom clinical onset has not yet occurred (or this data was unavailable), we display the difference between their chronological age and the mean age of onset for their mutation.

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Staffaroni, A.M., Quintana, M., Wendelberger, B. et al. Temporal order of clinical and biomarker changes in familial frontotemporal dementia. Nat Med (2022). https://doi.org/10.1038/s41591-022-01942-9

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