Carlo Wilke1,2, Selina Reich1,2, John C van Swieten3, Barbara Borroni4, Raquel Sanchez-Valle5, Fermin Moreno6,7, Robert Laforce8, Caroline Graff9,10, Daniela Galimberti11,12, James B Rowe13, Mario Masellis14, Maria C Tartaglia15, Elizabeth Finger16, Rik Vandenberghe17,18,19, Alexandre de Mendonça20, Fabrizio Tagliavini21, Isabel Santana22,23, Simon Ducharme24,25, Chris R Butler26,27, Alexander Gerhard28,29, Johannes Levin30,31,32, Adrian Danek30, Markus Otto33,34, Giovanni Frisoni35, Roberta Ghidoni36, Sandro Sorbi37,38, Martina Bocchetta39, Emily Todd39, Jens Kuhle40, Christian Barro40,41, Jonathan D Rohrer39, Matthis Synofzik1,2. 1. Division Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany. 2. Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. 3. Department of Neurology, Erasmus Medical Centre, Rotterdam, Netherlands. 4. Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. 5. Alzheimer's disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut d'Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona, Barcelona, Spain. 6. Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Spain. 7. Neuroscience Area, Biodonostia Health Research Institute, San Sebastian, Spain. 8. Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine, Université Laval, Quebec City, Canada. 9. Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institute, Solna, Sweden. 10. Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden. 11. Fondazione IRCCS Ospedale Policlinico, Milan, Italy. 12. University of Milan, Centro Dino Ferrari, Milan, Italy. 13. Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. 14. Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Canada. 15. Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada. 16. Department of Clinical Neurological Sciences, University of Western Ontario, London, Canada. 17. Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium. 18. Neurology Service, University Hospitals Leuven, Leuven, Belgium. 19. Leuven Brain Institute, KU Leuven, Leuven, Belgium. 20. Faculty of Medicine, University of Lisbon, Lisbon, Portugal. 21. Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. 22. University Hospital of Coimbra (HUC), Neurology Service, Faculty of Medicine, University of Coimbra, Coimbra, Portugal. 23. Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal. 24. Department of Psychiatry, McGill University Health Centre, McGill University, Montreal, Québec, Canada. 25. McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada. 26. Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK. 27. Department of Brain Sciences, Imperial College London, London, UK. 28. Division of Neuroscience and Experimental Psychology, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK. 29. Departments of Geriatric Medicine and Nuclear Medicine, Essen University Hospital, Essen, Germany. 30. Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany. 31. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. 32. Munich Cluster of Systems Neurology (SyNergy), Munich, Germany. 33. Department of Neurology, University of Ulm, Ulm, Germany. 34. Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany. 35. Instituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy. 36. Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy. 37. Department of Neurofarba, University of Florence, Florence, Italy. 38. IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy. 39. Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK. 40. Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, University of Basel, Basel, Switzerland. 41. Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Abstract
OBJECTIVE: Although the presymptomatic stages of frontotemporal dementia (FTD) provide a unique chance to delay or even prevent neurodegeneration by early intervention, they remain poorly defined. Leveraging a large multicenter cohort of genetic FTD mutation carriers, we provide a biomarker-based stratification and biomarker cascade of the likely most treatment-relevant stage within the presymptomatic phase: the conversion stage. METHODS: We longitudinally assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in the Genetic FTD Initiative (GENFI) cohort (n = 444), using single-molecule array technique. Subjects comprised 91 symptomatic and 179 presymptomatic subjects with mutations in the FTD genes C9orf72, GRN, or MAPT, and 174 mutation-negative within-family controls. RESULTS: In a biomarker cascade, NfL increase preceded the hypothetical clinical onset by 15 years and concurred with brain atrophy onset, whereas pNfH increase started close to clinical onset. The conversion stage was marked by increased NfL, but still normal pNfH levels, while both were increased at the symptomatic stage. Intra-individual change rates were increased for NfL at the conversion stage and for pNfH at the symptomatic stage, highlighting their respective potential as stage-dependent dynamic biomarkers within the biomarker cascade. Increased NfL levels and NfL change rates allowed identification of presymptomatic subjects converting to symptomatic disease and capture of proximity-to-onset. We estimate stage-dependent sample sizes for trials aiming to decrease neurofilament levels or change rates. INTERPRETATION: Blood NfL and pNfH provide dynamic stage-dependent stratification and, potentially, treatment response biomarkers in presymptomatic FTD, allowing demarcation of the conversion stage. The proposed biomarker cascade might pave the way towards a biomarker-based precision medicine approach to genetic FTD. ANN NEUROL 2022;91:33-47.
OBJECTIVE: Although the presymptomatic stages of frontotemporal dementia (FTD) provide a unique chance to delay or even prevent neurodegeneration by early intervention, they remain poorly defined. Leveraging a large multicenter cohort of genetic FTD mutation carriers, we provide a biomarker-based stratification and biomarker cascade of the likely most treatment-relevant stage within the presymptomatic phase: the conversion stage. METHODS: We longitudinally assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in the Genetic FTD Initiative (GENFI) cohort (n = 444), using single-molecule array technique. Subjects comprised 91 symptomatic and 179 presymptomatic subjects with mutations in the FTD genes C9orf72, GRN, or MAPT, and 174 mutation-negative within-family controls. RESULTS: In a biomarker cascade, NfL increase preceded the hypothetical clinical onset by 15 years and concurred with brain atrophy onset, whereas pNfH increase started close to clinical onset. The conversion stage was marked by increased NfL, but still normal pNfH levels, while both were increased at the symptomatic stage. Intra-individual change rates were increased for NfL at the conversion stage and for pNfH at the symptomatic stage, highlighting their respective potential as stage-dependent dynamic biomarkers within the biomarker cascade. Increased NfL levels and NfL change rates allowed identification of presymptomatic subjects converting to symptomatic disease and capture of proximity-to-onset. We estimate stage-dependent sample sizes for trials aiming to decrease neurofilament levels or change rates. INTERPRETATION: Blood NfL and pNfH provide dynamic stage-dependent stratification and, potentially, treatment response biomarkers in presymptomatic FTD, allowing demarcation of the conversion stage. The proposed biomarker cascade might pave the way towards a biomarker-based precision medicine approach to genetic FTD. ANN NEUROL 2022;91:33-47.
Authors: Tania F Gendron; Michael G Heckman; Launia J White; Austin M Veire; Otto Pedraza; Alexander R Burch; Andrea C Bozoki; Bradford C Dickerson; Kimiko Domoto-Reilly; Tatiana Foroud; Leah K Forsberg; Douglas R Galasko; Nupur Ghoshal; Neill R Graff-Radford; Murray Grossman; Hilary W Heuer; Edward D Huey; Ging-Yuek R Hsiung; David J Irwin; Daniel I Kaufer; Gabriel C Leger; Irene Litvan; Joseph C Masdeu; Mario F Mendez; Chiadi U Onyike; Belen Pascual; Aaron Ritter; Erik D Roberson; Julio C Rojas; Maria Carmela Tartaglia; Zbigniew K Wszolek; Howard Rosen; Bradley F Boeve; Adam L Boxer; Leonard Petrucelli Journal: Cell Rep Med Date: 2022-04-19