BACKGROUND: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. METHODS: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. RESULTS: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. CONCLUSIONS: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.

A and G Pharmaceutical Inc Columbia MD USA

Alzheimer's Disease and Other Cognitive Disorders Unit FRCB IDIBAPS Institut de Neurociències Neurology Service Hospital Clínic de Barcelona Universitat de Barcelona 08036 Barcelona Spain

Autonomous University of Barcelona 08913 Barcelona Spain

Center for Neuroscience and Cell Biology Centre for Innovative Biomedicine and Biotechnology University of Coimbra Coimbra Portugal

Center for Reproductive Medicine and Andrology Martin Luther University Halle Wittenberg Halle Germany

Center of Pediatric Research University of Leipzig Leipzig Germany

Centre de Référence Des Démences Rares Ou Précoces IM2A Département de Neurologie AP HP Hôpital Pitié Salpêtrière Paris France

Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas 28031 Madrid Spain

Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas Madrid Spain

Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Mölndal Sweden

Cognitive Disorders Unit Department of Neurology Donostia University Hospital San Sebastian Gipuzkoa Spain

Department of Biomedical Sciences University of Antwerp Antwerp Belgium

Department of Clinical and Experimental Sciences University of Brescia Brescia Italy

Department of Endocrinology and Metabolism Hiroshima Red Cross Hospital and Atomicbomb Survivors Hospital Hiroshima Japan

Department of Neonatology Tuebingen University Hospital Tuebingen Germany

Department of Nephrology Faculty of Medicine Juntendo University Tokyo Japan

Department of Neurobiology Care Sciences and Society Center for Alzheimer Research Division of Neurogeriatrics BioclinicumKarolinska Institutet Solna Sweden

Department of Neurodegenerative Disease Dementia Research Centre UCL Institute of Neurology Queen Square London WC1N 3BG UK

Department of Neurodegenerative Disease Dementia Research Institute UCL Institute of Neurology Queen Square London UK

Department of Neurodegenerative Diseases Hertie Institute for Clinical Brain Research University of Tübingen Tübingen Germany

Department of Neurological and Psychiatric Sciences University of Florence Viale Morgagni 85 50134 Florence Italy

Department of Neurological and Vision Sciences Neurophysiology Unit ASST SpedaliCivili Brescia Italy

Department of Neurology and Alzheimer Center Erasmus MC Erasmus MC University Medical Center Rotterdam Netherlands

Department of Neurology and Clinical Neurophysiology Trondheim University Hospital Trondheim Norway

Department of Neurology Fundación Jiménez Díaz Madrid Spain

Department of Neurology Hospital das Clinicas University of São Paulo Medical School São Paulo Brazil

Department of Neurology Klinikum Rechts Der Isar Technical University of Munich Munich Germany

Department of Neurology Martin Luther University Halle Wittenberg University Clinic Halle Halle Germany

Department of Neurology Mayo Clinic Jacksonville FL USA

Department of Neurology Mayo Clinic Rochester MN USA

Department of Neurology Otto Von Guericke University Magdeburg Germany

Department of Neurology University of California Los Angeles California USA

Department of Neurology University of Colorado Anschutz Medical Campus Denver CO USA

Department of Neuromedicine and Movement Science Faculty of Medicine and Health Sciences NTNU Trondheim Norway

Department of Neuroscience Mayo Clinic Jacksonville FL USA

Department of Obstetrics and Gynecology Rostock University Medical Center Rostock Germany

Department of Oncology Mayo Clinic Rochester MN USA

Department of Orthopaedics and Rehabilitation Yale University School of Medicine New Haven CT USA

Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology Sahlgrenska Academy at the University of Gothenburg Mölndal Sweden

Department of Psychiatry Hospital in Tauberbischofsheim Tauberbischofsheim Germany

Department of Psychiatry Psychotherapy and Psychosomatic Medicine University Hospital Frankfurt Frankfurt Germany

Department of Psychiatry Psychotherapy and Psychosomatic Medicine University Hospital Würzburg Würzburg Germany

Department of Psychiatry Semel Institute for Neuroscience and Human Behavior University of California Los Angeles California USA

Department of Psychiatry University College Cork Cork Ireland

Department of Research Trondheim University Hospital Trondheim Norway

Department of Urology Martin Luther University Halle Wittenberg Halle Germany

Dept of Biomedical Surgical and Dental Sciences University of Milan Milan Italy

Division Translational Genomics of Neurodegenerative Diseases Hertie Institute for Clinical Brain Research University of Tübingen Tübingen Germany

DZNE German Center for Neurodegenerative Diseases Tübingen Germany

Faculty of Medicine University of Coimbra Coimbra Portugal

German Center of Neurodegenerative Diseases Tübingen Germany

Hong Kong Center for Neurodegenerative Diseases Hong Kong China

Hospital for Children and Adolescents University of Leipzig Leipzig Germany

Institute for Clinical Research National Hospital Organization Kure Medical Center and Chugoku Cancer Center Hiroshima Japan

Institute of Neuroscience and Physiology Sahlgrenska Academy at the University of Gothenburg 43180 Mölndal Sweden

Institute of Rheumatology Na Slupi 4 12850 Prague 2 Prague Czech Republic

Laboratory of Neurobiology Flanders Interuniversity Institute for Biotechnology Katholieke Universiteit Leuven Campus Gasthuisberg 3000 Louvain Belgium

Leipzig Research Center for Civilization Diseases LIFE University of Leipzig Leipzig Germany

MAC Memory Clinic and Molecular Markers Laboratory IRCCS Istituto Centro San Giovanni Di Dio Fatebenefratelli Brescia Italy

Memory Unit Department of Neurology Institut d'Investigacions Biomèdiques Sant Pau Hospital de Sant Pau Universitat Autònoma de Barcelona Barcelona Spain

Molecular Markers Laboratory IRCCS Istituto Centro San Giovanni Di Dio Fatebenefratelli Brescia Italy

Neurodegerative Diseases Center Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan Italy

Neurology Department Centro Hospitalar E Universitário de Coimbra Coimbra Portugal

Neurology Department Hospital Sant Pau Memory Unit Barcelona Spain

Neuroscience Area Biodonostia Health Research Insitute San Sebastian Gipuzkoa Spain

Program in Oncology University of Maryland Greenebaum Comprehensive Cancer Center Baltimore MD USA

Regional Neurogenetic Centre ASPCZ Lamezia Terme Italy

Sorbonne UniversitéInserm U1127 CNRS UMR 7225 Institut du Cerveau Et La Moelle Épinière AP HP Hôpital Pitié Salpêtrière Paris France

UF de Biochimie Des Maladies Neurométaboliques Et Neurodégénératives Service de Biochimie Métabolique AP HP Hôpital Pitié Salpêtrière Paris France

UF de Neurogénétique Moléculaire Et Cellulaire Département de Génétique AP HP Hôpitaux Universitaires La Pitié Salpêtrière Charles Foix Paris France

UK Dementia Research Institute at University College London UCL Queen Square Institute of Neurology University College London London UK

Unit for Hereditary Dementias Theme Inflammation and Aging Karolinska University Hospital Solna Sweden

Unit of Neurology 5 and Neuropathology Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy

University of Pennsylvania Gene Therapy Program Philadelphia USA

VIB Center for Molecular Neurology VIB Antwerp Belgium

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