A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study

Molecular Neurodegeneration

Raquel Sanchez-Valle¹  Barbara Borroni²  Robert Laforce³  Fermin Moreno⁴  Elizabeth Finger⁵  Jonathan D. Rohrer⁶  Matthis Synofzik⁷  Harro Seelaar⁸  John C. van Swieten⁸  Simon Ducharme⁹  Peter Nilsson^1,10  Julia Remnestål^1,10  Sofia Bergström^1,10  Anna Månberg^1,10  Jennie Olofsson^1,10  Alexander Gerhard^1,11  Daniela Galimberti^1,12  Rik Vandenberghe^1,13  Chris R. Butler^1,14  Mario Masellis^1,15  Abbe Ullgren^1,16  Linn Öijerstedt^1,17  Caroline Graff^1,17  Carmela Tartaglia^1,18 

[1] 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;Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy;Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine, Université Laval, QC, Canada;Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Gipuzkoa, Spain;Neuroscience Area, Biodonostia Health Research Institute, San Sebastian, Gipuzkoa, Spain;Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada;Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK;Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany;Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany;Department of Neurology, Erasmus Medical Centre, Rotterdam, Netherlands;Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, Québec, Canada;McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada;Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Stockholm, Sweden;Swedish FTD Initiative, Stockholm, Sweden;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, Duisburg, Germany;Fondazione IRCCS Ospedale Policlinico, Milan, Italy;University of Milan, Centro Dino Ferrari, Milan, Italy;Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium;Neurology Service, University Hospitals Leuven, Leuven, Belgium;Leuven Brain Institute, KU Leuven, Leuven, Belgium;Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK;Department of Brain Sciences, Imperial College London, London, UK;Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Canada;Swedish FTD Initiative, Stockholm, Sweden;Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Unit of Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden;Swedish FTD Initiative, Stockholm, Sweden;Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Unit of Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden;Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden;Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada;

关键词: Cerebrospinal fluid;    Neurofilament medium polypeptide (NEFM);    Neuronal pentraxin 2 (NPTX2);    Neurosecretory protein VGF (VGF);    Aquaporin 4 (AQP4);    LASSO;    Random forest;    Suspension bead array;   

DOI  :  10.1186/s13024-021-00499-4

来源: Springer

【 摘 要 】

BackgroundA detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers.MethodsA multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest.ResultsWhen comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN).ConclusionIn conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD.

【 授权许可】

CC BY