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

Springer Science and Business Media LLC - Tập 16 - Trang 1-14 - 2021
Sofia Bergström1,2, Linn Öijerstedt2,3,4, Julia Remnestål1,2, Jennie Olofsson1,2, Abbe Ullgren2,3, Harro Seelaar5, John C. van Swieten5, Matthis Synofzik6,7, Raquel Sanchez-Valle8, Fermin Moreno9,10, Elizabeth Finger11, Mario Masellis12, Carmela Tartaglia13, Rik Vandenberghe14,15,16, Robert Laforce17, Daniela Galimberti18,19, Barbara Borroni20, Chris R. Butler21,22, Alexander Gerhard23,24, Simon Ducharme25,26, Jonathan D. Rohrer27, Anna Månberg1,2, Caroline Graff2,3,4, Peter Nilsson1,2
1Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Stockholm, Sweden
2Swedish FTD Initiative, Stockholm, Sweden
3Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Unit of Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden
4Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden
5Department of Neurology, Erasmus Medical Centre, Rotterdam, Netherlands
6Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany
7Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
8Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut d’Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona, Barcelona, Spain
9Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Spain
10Neuroscience Area, Biodonostia Health Research Institute, San Sebastian, Spain
11Department of Clinical Neurological Sciences, University of Western Ontario, London, Canada
12Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Canada
13Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada
14Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium
15Neurology Service, University Hospitals Leuven, Leuven, Belgium
16Leuven Brain Institute, KU Leuven, Leuven, Belgium
17Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine, Université Laval, QC, Canada
18Fondazione IRCCS Ospedale Policlinico, Milan, Italy
19University of Milan, Centro Dino Ferrari, Milan, Italy.
20Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
21Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK
22Department of Brain Sciences, Imperial College London, London, UK
23Division of Neuroscience and Experimental Psychology, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK
24Departments of Geriatric Medicine and Nuclear Medicine, University of Duisburg- Essen, Duisburg, Germany
25Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, Canada
26McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada
27Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK

Tóm tắt

A 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. A 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. When 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). In 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.

Tài liệu tham khảo

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