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      Neuronal pentraxin 2: a synapse-derived CSF biomarker in genetic frontotemporal dementia

      research-article
      1 , 2 , 2 , 1 , 1 , 3 , 1 , 4 , 1 , 1 , 1 , 5 , 4 , 4 , 4 , 4 , 4 , 4 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 1 , 4 , 2 , 34 , 1 , , Genetic Frontotemporal Dementia Initiative (GENFI)
      Journal of Neurology, Neurosurgery, and Psychiatry
      BMJ Publishing Group

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          Abstract

          Introduction

          Synapse dysfunction is emerging as an early pathological event in frontotemporal dementia (FTD), however biomarkers are lacking. We aimed to investigate the value of cerebrospinal fluid (CSF) neuronal pentraxins (NPTXs), a family of proteins involved in homeostatic synapse plasticity, as novel biomarkers in genetic FTD.

          Methods

          We included 106 presymptomatic and 54 symptomatic carriers of a pathogenic mutation in GRN, C9orf72 or MAPT, and 70 healthy non-carriers participating in the Genetic Frontotemporal dementia Initiative (GENFI), all of whom had at least one CSF sample. We measured CSF concentrations of NPTX2 using an in-house ELISA, and NPTX1 and NPTX receptor (NPTXR) by Western blot. We correlated NPTX2 with corresponding clinical and neuroimaging datasets as well as with CSF neurofilament light chain (NfL) using linear regression analyses.

          Results

          Symptomatic mutation carriers had lower NPTX2 concentrations (median 643 pg/mL, IQR (301–872)) than presymptomatic carriers (1003 pg/mL (624–1358), p<0.001) and non-carriers (990 pg/mL (597–1373), p<0.001) (corrected for age). Similar results were found for NPTX1 and NPTXR. Among mutation carriers, NPTX2 concentration correlated with several clinical disease severity measures, NfL and grey matter volume of the frontal, temporal and parietal lobes, insula and whole brain. NPTX2 predicted subsequent decline in phonemic verbal fluency and Clinical Dementia Rating scale plus FTD modules. In longitudinal CSF samples, available in 13 subjects, NPTX2 decreased around symptom onset and in the symptomatic stage.

          Discussion

          We conclude that NPTX2 is a promising synapse-derived disease progression biomarker in genetic FTD.

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          Most cited references39

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            Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.

            Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, 'possible' behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). 'Probable' behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia 'with definite frontotemporal lobar degeneration' requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer's disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met 'possible' criteria, and 104 (76%) met criteria for 'probable' behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with 'possible' and 'probable' criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.
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              Classification of primary progressive aphasia and its variants

              This article provides a classification of primary progressive aphasia (PPA) and its 3 main variants to improve the uniformity of case reporting and the reliability of research results. Criteria for the 3 variants of PPA--nonfluent/agrammatic, semantic, and logopenic--were developed by an international group of PPA investigators who convened on 3 occasions to operationalize earlier published clinical descriptions for PPA subtypes. Patients are first diagnosed with PPA and are then divided into clinical variants based on specific speech and language features characteristic of each subtype. Classification can then be further specified as "imaging-supported" if the expected pattern of atrophy is found and "with definite pathology" if pathologic or genetic data are available. The working recommendations are presented in lists of features, and suggested assessment tasks are also provided. These recommendations have been widely agreed upon by a large group of experts and should be used to ensure consistency of PPA classification in future studies. Future collaborations will collect prospective data to identify relationships between each of these syndromes and specific biomarkers for a more detailed understanding of clinicopathologic correlations.
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                Author and article information

                Journal
                J Neurol Neurosurg Psychiatry
                J. Neurol. Neurosurg. Psychiatry
                jnnp
                jnnp
                Journal of Neurology, Neurosurgery, and Psychiatry
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0022-3050
                1468-330X
                June 2020
                9 April 2020
                : 91
                : 6
                : 612-621
                Affiliations
                [1 ] departmentDepartment of Neurology and Alzheimer Center , Erasmus University Medical Center , Rotterdam, Netherlands
                [2 ] departmentSolomon H Snyder Department of Neuroscience , Johns Hopkins University School of Medicine , Baltimore, Maryland, United States
                [3 ] departmentDepartment of Radiology , Leiden University Medical Center , Leiden, Netherlands
                [4 ] departmentDementia Research Centre , UCL Queen Square Institute of Neurology , London, United Kingdom
                [5 ] departmentDementia Research Institute, Department of Neurodegenerative Disease , University College London , London, United Kingdom
                [6 ] departmentNeurochemistry Laboratory, Department of Clinical Chemistry , Amsterdam Neuroscience, Amsterdam University Medical Center , Amsterdam, Netherlands
                [7 ] departmentKarolinska Institutet, Dept NVS, Division of Neurogeriatrics , Bioclinicum , Stockholm, Sweden
                [8 ] departmentUnit of Hereditary Dementia, Theme Aging , Karolinska University Hospital-Solna , Stockholm, Sweden
                [9 ] departmentGerman Center for Neurodegenerative Diseases (DZNE) , University of Tübingen , Tübingen, Germany
                [10 ] departmentDepartment of Neurodegenerative Diseases , Hertie Institute for Clinical Brain Research , Tübingen, Germany
                [11 ] departmentDepartment of Neurology , Donostia University Hospital , San Sebastian, Gipuzkoa, Spain
                [12 ] departmentDepartment of Clinical Neurological Sciences , University of Western Ontario , London, Ontario, Canada
                [13 ] departmentAlzheimer's Disease and Other Cognitive Disorders Unit , Hospital Clinic de Barcelona , Barcelona, Spain
                [14 ] departmentLaboratory for Cognitive Neurology, Department of Neurosciences , KU Leuven , Leuven, Belgium
                [15 ] departmentClinique Interdisciplinaire de Mémoire du CHU de Québec, Département des Sciences Neurologiques , Université Laval , Québec, Quebec City, Canada
                [16 ] departmentSunnybrook Health Sciences Centre , Sunnybrook Research Institute, University of Toronto , Toronto, Ontario, Canada
                [17 ] departmentTanz Centre for Research in Neurodegenerative Disease , University of Toronto , Toronto, Ontario, Canada
                [18 ] departmentCambridge University Centre for Frontotemporal Dementia , University of Cambridge , Cambridge, United Kingdom
                [19 ] departmentDepartment of Clinical Neurology , University of Oxford , Oxford, United Kingdom
                [20 ] departmentMontreal Neurological Institute and McGill University Health Centre , McGill University , Montreal, Québec, Canada
                [21 ] departmentDepartment of Nuclear Medicine and Geriatric Medicine , University Hospital Essen , Essen, Germany
                [22 ] departmentDivison of Neuroscience and Experimental Psychology , University of Manchester , Manchester, United Kingdom
                [23 ] departmentNeurologische Klinik und Poliklinik , Ludwig-Maximilians-Universität München , Munich, Germany
                [24 ] departmentGerman Center for Neurodegenerative Diseases , (DZNE) , Munich, Germany
                [25 ] departmentMunich Cluster for Systems Neurology , (SyNergy) , Munich, Germany
                [26 ] departmentAlzheimer Center Amsterdam, Department of Neurology , Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC , Amsterdam, Netherlands
                [27 ] departmentDepartment of Neurology , Universität Ulm , Ulm, Germany
                [28 ] departmentCentre for Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences , University of Brescia , Brescia, Italy
                [29 ] departmentFondazione IRCCS , Istituto Neurologico Carlo Besta , Milan, Italy
                [30 ] departmentFaculty of Medicine , University of Lisbon , Lisbon, Portugal
                [31 ] departmentCenter for Neuroscience and Cell Biology, Faculty of Medicine , University of Coimbra , Coimbra, Portugal
                [32 ] departmentDepartment of Neurological Sciences, Dino Ferrari Center , University of Milan , Milan, Italy
                [33 ] departmentFondazione IRCCS Ca' Granda , Ospedale Maggiore Policlinico , Milan, Italy
                [34 ] departmentDepartment of Neurology , Johns Hopkins University School of Medicine , Baltimore, Maryland, United States
                Author notes
                [Correspondence to ] Dr John C van Swieten, Department of Neurology, Erasmus MC, Rotterdam, Netherlands; j.c.vanswieten@ 123456erasmusmc.nl
                Author information
                http://orcid.org/0000-0003-2570-8796
                http://orcid.org/0000-0001-8843-7247
                http://orcid.org/0000-0002-1120-1858
                http://orcid.org/0000-0002-1934-6162
                http://orcid.org/0000-0002-9477-1812
                http://orcid.org/0000-0003-1814-5024
                http://orcid.org/0000-0003-4461-7427
                http://orcid.org/0000-0001-7216-8679
                http://orcid.org/0000-0002-6647-5944
                http://orcid.org/0000-0001-9340-9814
                http://orcid.org/0000-0001-6278-6844
                Article
                jnnp-2019-322493
                10.1136/jnnp-2019-322493
                7279197
                32273328
                4539034b-44b9-48c2-9c27-c018bb250c97
                © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.

                This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the license is given, and indication of whether changes were made. See:  https://creativecommons.org/licenses/by/4.0/.

                History
                : 22 November 2019
                : 26 February 2020
                : 02 March 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Funded by: FundRef http://dx.doi.org/10.13039/100010661, Horizon 2020 Framework Programme;
                Award ID: 779357
                Funded by: Schorling foundation;
                Funded by: NIHR Rare Disease Translational Research Collaboration;
                Award ID: BRC149/NS/MH
                Funded by: FundRef http://dx.doi.org/10.13039/501100004348, Stockholms Läns Landsting;
                Funded by: Munich Cluster for Systems Neurology;
                Award ID: EXC 2145 SyNergy 390857198
                Funded by: Swedish Demensfonden;
                Funded by: Swedish FTD Initiative;
                Funded by: The Bluefield Project to Cure Frontotemporal Dementia;
                Funded by: FundRef http://dx.doi.org/10.13039/501100010573, Stichting Dioraphte;
                Award ID: 1402 1300
                Funded by: Swedish Alzheimer Foundation;
                Funded by: FundRef http://dx.doi.org/10.13039/100010815, Stiftelsen för Gamla Tjänarinnor;
                Funded by: FundRef http://dx.doi.org/10.13039/501100004359, Vetenskapsrådet;
                Award ID: 2015-02926
                Award ID: 2018-02754
                Award ID: 529-2014-7504
                Funded by: FundRef http://dx.doi.org/10.13039/501100003792, Hjärnfonden;
                Funded by: MRC UK;
                Award ID: MR/M023664/1
                Funded by: FundRef http://dx.doi.org/10.13039/501100003246, Nederlandse Organisatie voor Wetenschappelijk Onderzoek;
                Award ID: 733050103
                Award ID: 733050813
                Funded by: FundRef http://dx.doi.org/10.13039/501100010969, Alzheimer Nederland;
                Award ID: 733050103
                Award ID: 733050813
                Funded by: StratNeuro;
                Funded by: European Joint Programme - Neurodegenerative Disease Research;
                Award ID: 733051024
                Award ID: 733051042
                Funded by: Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie;
                Funded by: Karolinska Institutet Doctoral funding;
                Funded by: Fundacio Marato de TV3;
                Award ID: 20143810
                Funded by: MRC Clinician Scientist Fellowship;
                Award ID: MR/M008525/1
                Funded by: FundRef http://dx.doi.org/10.13039/100004440, Wellcome Trust;
                Award ID: 103838
                Funded by: FundRef http://dx.doi.org/10.13039/501100000320, Alzheimer's Society;
                Award ID: As-PhD-2015-005
                Categories
                Neurodegeneration
                1506
                Original research
                Custom metadata
                unlocked

                Surgery
                Surgery

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