{
  "abstract": "Introduction: Recent proteomic studies have identified both established and novel proteins in genetic frontotemporal lobar degeneration (FTLD). However, it remains unclear at what point in the disease these proteins deviate from normal levels and how their trajectories relate to one another. Defining the temporal sequence of protein abnormalities could not only improve disease staging but also help identify biomarkers most sensitive to early disease activity in pathogenic variant carriers. We aimed to apply discriminative event-based modelling (DEBM) to characterize the progression profiles of proteins identified in a previous cross-sectional proteomic analysis.\n\nMethods: Building on our prior cross-sectional CSF proteomic analysis of genetic FTLD using a proximity extension assay, we selected the top ten significant proteins for each genetic group (C9orf72, GRN, MAPT). We then applied DEBM to characterize temporal dynamics of these proteins separately in each genetic group and evaluated their potential as early disease markers. To validate model performance, each individual was assigned a disease stage according to their position along the estimated disease timeline, based on protein levels and independent of clinical labels. Next, we assessed how well these stages discriminated symptomatic from presymptomatic carriers and non-carriers.\n\nResults: Across all genetic groups, NfL consistently became abnormal before TPM3, although the earliest abnormal proteins differed between groups. In C9orf72, ELAVL4 is the first protein to become abnormal; in GRN SEMA3G and GRN, and in MAPT MMP-10. Estimated individual-level disease stage effectively distinguished symptomatic carriers from presymptomatic carriers and non-carriers, demonstrating high diagnostic accuracy (range AUC 0.74–0.98).\n\nConclusion: Our data-driven findings provide a temporal ordering of multiple CSF proteins, highlighting potential early biomarkers and disease dynamics in different forms of genetic FTLD. In addition, the model’s accurate estimation of disease stages underscores the value of DEBM for patient stratification, offering a promising tool to support clinical trial design.\n\nSupplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13195-026-02159-5.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Neurology and Alzheimer Centre, Erasmus MC University Medical Center, Dr. Molewaterplein 40, Rotterdam, 3015 GD The Netherlands",
    "Biomedical Imaging Group Rotterdam, Department of Radiology & Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, 3015 GD The Netherlands",
    "Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3AR UK",
    "Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Institut d’Investigacións Biomèdiques August Pi I Sunyer, Hospital Clínic, University of Barcelona, Barcelona, 08036 Spain",
    "Département des Sciences Neurologiques, Faculté de Médecine, Clinique Interdisciplinaire de Mémoire, CHU de Québec, Université Laval, QC, G1V 4G2 Canada",
    "Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Bioclinicum, Solna, 171 65 Sweden",
    "Unit for Hereditary Dementias, Theme Inflammation and Aging, Karolinska University Hospital, Solna, 171 76 Sweden",
    "Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, 20122 Italy",
    "Neurodegenerative Diseases Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, 20122 Italy",
    "Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, 3000 Belgium",
    "Neurology Service, University Hospitals Leuven, Leuven, 3000 Belgium",
    "Leuven Brain Institute, KU Leuven, Leuven, 3000 Belgium",
    "Faculty of Medicine, University of Lisbon, Lisbon, 1649-028 Portugal",
    "Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, 20133 Italy",
    "Neurology Service, Faculty of Medicine, University Hospital of Coimbra (HUC), University of Coimbra, Coimbra, 3004-531 Portugal",
    "Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, 3004-504 Portugal",
    "Division of Neuroscience and Experimental Psychology, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK",
    "Departments of Geriatric Medicine and Nuclear Medicine, University of Duisburg, Essen, Germany",
    "Department of Neurology, Ludwig-Maximilians Universität München, 80802 Munich, Germany",
    "German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany",
    "Munich Cluster of Systems Neurology (SyNergy), 81377 Munich, Germany",
    "Department of Neurofarba, University of Florence, Florence, 50139 Italy",
    "IRCCS Fondazione Don Carlo Gnocchi, Florence, 50139 Italy",
    "Department of Neurology, University of Ulm, Ulm, 45 89081 Germany",
    "Lille Neuroscience & Cognition U1172, University of Lille, CHU Lille, Inserm, 59000 France",
    "Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, Québec H4H 1R3 Canada",
    "McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Québec H4H 1R3 Canada",
    "Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, OX3 7JX UK",
    "Department of Brain Sciences, Imperial College London, London, SW7 2AZ UK",
    "Sorbonne Université, Paris Brain Institute – Institut du Cerveau – ICM, Inserm U1127, CNRS UMR 7225, AP-HP - Hôpital Pitié-Salpêtrière, Paris, 75013 France",
    "Centre de référence des démences rares ou précoces, Département de Neurologie, IM2A, AP-HP - Hôpital Pitié-Salpêtrière, Paris, 75013 France",
    "Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière, Paris, 75013 France",
    "Department of Clinical Neurological Sciences, University of Western Ontario, London, ON N6A 3K7 Canada",
    "Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON M5G 1E8 Canada",
    "Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, ON M4N 3M5 Canada",
    "Department of Clinical Neurosciences, Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge, CB2 3EB UK",
    "Division of Translational Genomics of Neurodegenerative Diseases, Hertie- Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, 72076 Tübingen, Germany",
    "Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany",
    "Cognitive Disorders Unit, Department of Neurology, Hospital Universitario Donostia, San Sebastian, 20014 Spain",
    "Neurosciences Area, Group of Neurodegenerative Diseases, Biogipuzkoa Health Research Institute, San Sebastian, 20014 Spain"
  ],
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      "name": "Barbara Borroni"
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  "bibtex": "https://research.draconitic.com/paper/c3v3qddqgx7e7.bib",
  "cited_by": 0,
  "doi": "10.1186/s13195-026-02159-5",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13741760/",
  "id": "c3v3qddqgx7e7",
  "issns": [
    "1758-9193"
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  "landing_url": "https://doi.org/10.1186/s13195-026-02159-5",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
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      "heading",
      "Research"
    ],
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      "2728|Amyotrophic Lateral Sclerosis Research"
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  "openalex": "W7202137757",
  "pdf_url": null,
  "pmcid": "PMC13741760",
  "pmid": "42995587",
  "published": "2026-08-11",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/c3v3qddqgx7e7.ris",
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      "field": "medicine",
      "origin": "openalex:2728|Amyotrophic Lateral Sclerosis Research",
      "subfield": "neurology"
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  ],
  "title": "Data-driven mapping of known and novel fluid biomarker progression profiles in genetic frontotemporal lobar degeneration",
  "title_text": "Data-driven mapping of known and novel fluid biomarker progression profiles in genetic frontotemporal lobar degeneration",
  "type": "peer-reviewed",
  "updated_at": "2026-11-10T12:22:45Z",
  "url": "https://research.draconitic.com/paper/c3v3qddqgx7e7",
  "venue": "Alzheimer's Research & Therapy",
  "versions": []
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