Abstract
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. 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. 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. 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.
Highlights
Leveraging the longitudinal multicenter Genetic frontotemporal dementia (FTD) Initiative (GENFI) cohort, we here demonstrate a cascade of biomarker changes in presymptomatic genetic FTD, where the neurofilament light (NfL) increase in blood precedes the hypothetical clinical onset by 15 years, here concurring with the onset of global brain atrophy, followed by a phosphorylated neurofilament heavy (pNfH) increase starting close to clinical onset
We demonstrate that neurofilament levels allow demarcating the conversion stage, for which the onset is marked by increased levels and intra-individual change rates of NfL, and its completion with transition to the symptomatic stage by increased pNfH levels
Our study suggests an association of the onset of the NfL increase to the conversion stage, given that both NfL levels and NfL increase rates were increased in presymptomatic carriers converting to symptomatic disease, but not in carriers remaining presymptomatic during longitudinal follow-up
Summary
From the 1Division Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany; 2Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; 3Department of Neurology, Erasmus Medical Centre, Rotterdam, Netherlands; 4Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy; 5Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi I Sunyer, University of Barcelona, Barcelona, Spain; 6Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Spain; 7Neuroscience Area, Biodonostia Health Research Institute, San Sebastian, Spain; 8Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine, Université Laval, Quebec City, Canada; 9Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institute, Solna, Sweden; 10Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden; 11Fondazione IRCCS Ospedale Policlinico, Milan, Italy; 12University of Milan, Centro Dino Ferrari, Milan, Italy; 13Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; 14Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Canada; 15Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada; 16Department of Clinical Neurological Sciences, University of Western Ontario, London, Canada; 17Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium; 18Neurology Service, University Hospitals Leuven, Leuven, Belgium; 19Leuven Brain Institute, KU Leuven, Leuven, Belgium; 20Faculty of Medicine, University of Lisbon, Lisbon, Portugal; 21Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; 22University Hospital of Coimbra (HUC), Neurology Service, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; 23Center for Neuroscience
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