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      Neurofilament light chain: a biomarker for genetic frontotemporal dementia

      research-article
      1 , 1 , 1 , 2 , 3 , 4 , 5 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 1 , 20 , 21 , 2 , 3 , 4 , 4 , 22 , 23 , 22 , 24 , 23 ,   23 , 24 , 24 , 23 , 7 , 8 , 8 , 25 , 26 , 27 , 27 , 23 , 28 , 1 , 29 ,
      Annals of Clinical and Translational Neurology
      John Wiley and Sons Inc.

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          Abstract

          Objective

          To evaluate cerebrospinal fluid ( CSF) and serum neurofilament light chain (NfL) levels in genetic frontotemporal dementia ( FTD) as a potential biomarker in the presymptomatic stage and during the conversion into the symptomatic stage. Additionally, to correlate NfL levels to clinical and neuroimaging parameters.

          Methods

          In this multicenter case–control study, we investigated CSF NfL in 174 subjects (48 controls, 40 presymptomatic carriers and 86 patients with microtubule‐associated protein tau ( MAPT ), progranulin ( GRN ), and chromosome 9 open reading frame 72 ( C9orf72) mutations), and serum NfL in 118 subjects (39 controls, 44 presymptomatic carriers, 35 patients). In 55 subjects both CSF and serum was determined. In two subjects CSF was available before and after symptom onset (converters). Additionally, NfL levels were correlated with clinical parameters, survival, and regional brain atrophy.

          Results

          CSF NfL levels in patients (median 6762 pg/mL, interquartile range 3186–9309 pg/mL) were strongly elevated compared with presymptomatic carriers (804 pg/mL, 627–1173 pg/mL, P < 0.001), resulting in a good diagnostic performance to discriminate both groups. Serum NfL correlated highly with CSF NfL ( r s = 0.87, P < 0.001) and was similarly elevated in patients. Longitudinal samples in the converters showed a three‐ to fourfold increase in CSF NfL after disease onset. Additionally, NfL levels in patients correlated with disease severity, brain atrophy, annualized brain atrophy rate and survival.

          Interpretation

          NfL in both serum and CSF has the potential to serve as a biomarker for clinical disease onset and has a prognostic value in genetic FTD.

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          Most cited references42

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                Author and article information

                Journal
                Ann Clin Transl Neurol
                Ann Clin Transl Neurol
                10.1002/(ISSN)2328-9503
                ACN3
                Annals of Clinical and Translational Neurology
                John Wiley and Sons Inc. (Hoboken )
                2328-9503
                01 July 2016
                August 2016
                : 3
                : 8 ( doiID: 10.1111/acn3.2016.3.issue-8 )
                : 623-636
                Affiliations
                [ 1 ] Alzheimer Center Rotterdam and Department of NeurologyErasmus Medical Center PO Box 2040, 3000 CA RotterdamThe Netherlands
                [ 2 ] Alzheimer's Disease and Other Cognitive Disorders Unit Department of NeurologyHospital Clínic Institut d'Investigació Biomèdica August Pi i Sunyer Villarroel, 170 Barcelona 08036Spain
                [ 3 ] Division of Neurogeriatrics Department NVS, Karolinska InstitutetCenter for Alzheimer Research Huddinge 141 57Sweden
                [ 4 ] Department of Geriatric MedicineKarolinska University Hospital‐ Huddinge Stockholm 141 86Sweden
                [ 5 ] Molecular Markers LaboratoryIRCCS Centro San Giovanni di Dio Fatebenefratelli via Pilastroni 4 Brescia 25125Italy
                [ 6 ] Alzheimer Center and Department of NeurologyNeuroscience Campus Amsterdam VU University Medical Center PO Box 7057, 1007 MB AmsterdamThe Netherlands
                [ 7 ] Neurology Unit Department of Clinical and Experimental SciencesCentre for Neurodegenerative Diseases University of Brescia BresciaItaly
                [ 8 ]University of Milan Fondazione Ca’ Granda IRCSS Ospedale Policlinico MilanItaly
                [ 9 ] Département des Sciences NeurologiquesClinique Interdisciplinaire de Mémoire (CIME) CHU de Québec Université Laval QuébecCanada
                [ 10 ] Division of Neurology Department of MedicineSunnybrook Health Sciences Centre University of Toronto TorontoCanada
                [ 11 ] Hurvitz Brain Sciences Research ProgramSunnybrook Research Institute TorontoCanada
                [ 12 ] NeurologyUniversity Hospitals Leuven Herestraat 49 LeuvenBelgium
                [ 13 ] Laboratory for Cognitive NeurologyDepartment of Neurosciences KU Leuven LeuvenBelgium
                [ 14 ]Institut du Cerveau et de la Moelle épinière (ICM) Inserm U1127 CNRS UMR 7225 Sorbonne Universités Université Pierre et Marie Curie Univ Paris 06 UPMC‐P6 UMR S 1127 ‐ Hôpital Pitié‐Salpêtrière ParisFrance
                [ 15 ] Centre de Référence des Démences RaresAP‐HP Hôpital de la Pitié‐Salpêtrière ParisFrance
                [ 16 ] Département des maladies du système nerveuxAP‐HP Hôpital de la Pitié‐Salpêtrière ParisFrance
                [ 17 ] Department of NeurologyUlm University UlmGermany
                [ 18 ] German FTLD consortiumDepartment of Neurology University of Ulm UlmGermany
                [ 19 ] Department of Clinical GeneticsErasmus Medical Center PO Box 2040, 3000 CA RotterdamThe Netherlands
                [ 20 ] Institute of PsychologyLeiden University LeidenThe Netherlands
                [ 21 ] Department of RadiologyLeiden University Medical Center LeidenThe Netherlands
                [ 22 ] Division of clinical geriatrics Deptartment NVS Karolinska InstitutetCenter for Alzheimer Research Huddinge 141 57Sweden
                [ 23 ] Dementia Research Centre Department of Neurodegenerative DisesaseInstitute of Neurology University College London WC1N 3BG LondonUnited Kingdom
                [ 24 ] Translational Imaging GroupCentre for Medical Image Computing University College London NW1 2HE LondonUnited Kingdom
                [ 25 ] Laboratoire de BiochimieAP‐HP Hopital Pitié‐Salpétrière ParisFrance
                [ 26 ]Tanz Center for Research in Neurodegenerative Diseases University of Toronoto ToronotoCanada
                [ 27 ] Neurology Departments of Medicine Biomedicine and Clinical ResearchUniversity Hospital Basel BaselSwitzerland
                [ 28 ] Neurochemistry Lab and Biobank Department of Clinical Chemistry Neuroscience CampusVU University Medical Center PO Box 7057, 1007 MB AmsterdamThe Netherlands
                [ 29 ] Department of Clinical GeneticsVU University Medical Center PO Box 7057, 1007 MB AmsterdamThe Netherlands
                Author notes
                [*] [* ] Correspondence

                John C. van Swieten, Department of Neurology, Erasmus Medical Center Rotterdam, Room Hs 611, PO Box 2040, 3000 CA, Rotterdam, the Netherlands. Tel: +31 10 703 32 74; Fax: +31 10 704 47 27; E‐mail: j.c.vanswieten@ 123456erasmusmc.nl

                Article
                ACN3325
                10.1002/acn3.325
                4999594
                27606344
                2542fedd-7591-420c-8916-6f834b9a21b6
                © 2016 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 29 March 2016
                : 23 May 2016
                : 25 May 2016
                Page count
                Pages: 14
                Funding
                Funded by: Deltaplan Dementie
                Award ID: AC14/00013
                Award ID: 20143810
                Funded by: Karolinska Institutet Doctoral Funding
                Funded by: Swedish Medical Research Council
                Funded by: Swedish Brain Power
                Funded by: Swedish Brain Foundation
                Funded by: Old Servants Foundation
                Funded by: Gun and Bertil Stohne's Foundation
                Funded by: King Gustaf V and Queen Victoria's Foundation of Freemasons
                Funded by: Italian Ministry of Health
                Funded by: Agency for Innovation by Science and Technology
                Award ID: 135043
                Funded by: Canadian Institutes of Health Research
                Award ID: AC14/00013
                Award ID: 20143810
                Award ID: 135043
                Funded by: UK Medical Research Council
                Award ID: AC14/00013
                Award ID: 20143810
                Award ID: 135043
                Funded by: BMBF
                Funded by: JPND
                Funded by: Alzheimer's Research UK
                Funded by: Brain Research Trust
                Funded by: Wolfson Foundation
                Award ID: AC14/00013
                Award ID: 20143810
                Award ID: 135043
                Funded by: Italian Ministry of Health
                Funded by: National Institute of Health Carlos III (ISCIII)
                Award ID: AC14/00013
                Funded by: Fundació Marató de TV3
                Award ID: 20143810
                Funded by: Swedish Alzheimer Foundation
                Funded by: Regional Agreement on Medical Training and Clinical Research (ALF) between Stockholm County Council and Karolinska Institutet
                Funded by: Strategic Research Program in Neuroscience at Karolinska Institutet
                Award ID: 135043
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                acn3325
                August 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:26.08.2016

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