Claire Bridel1, Wessel N van Wieringen2,3, Henrik Zetterberg4,5,6,7, Betty M Tijms8, Charlotte E Teunissen1, José C Alvarez-Cermeño9, Ulf Andreasson4, Markus Axelsson5, David C Bäckström10, Ales Bartos11,12, Maria Bjerke13, Kaj Blennow4,5, Adam Boxer14, Lou Brundin15,16, Joachim Burman17, Tove Christensen18, Lenká Fialová19,20, Lars Forsgren10, Jette L Frederiksen21, Magnus Gisslén22, Elizabeth Gray23, Martin Gunnarsson24, Sara Hall25,26, Oskar Hansson25,26, Megan K Herbert27,28, Joel Jakobsson5, Jan Jessen-Krut22, Shorena Janelidze25,26, Gudmundur Johannsson27,28, Michael Jonsson5, Ludwig Kappos29, Mohsen Khademi15,16, Michael Khalil30, Jens Kuhle29, Mikael Landén5, Ville Leinonen31,32, Giancarlo Logroscino33, Ching-Hua Lu34,35, Jan Lycke5, Nadia K Magdalinou36, Andrea Malaspina34,37,38,39, Niklas Mattsson25,26, Lieke H Meeter40,41, Sanjay R Mehta42, Signe Modvig43, Tomas Olsson15,16, Ross W Paterson44, Josué Pérez-Santiago45, Fredrik Piehl15,16, Yolande A L Pijnenburg8, Okko T Pyykkö31,32, Oskar Ragnarsson24, Julio C Rojas14, Jeppe Romme Christensen21, Linda Sandberg10, Carole S Scherling46, Jonathan M Schott44, Finn T Sellebjerg21, Isabella L Simone47,48, Tobias Skillbäck5, Morten Stilund18, Peter Sundström10, Anders Svenningsson49, Rosanna Tortelli33,50, Carla Tortorella47, Alessandro Trentini51, Maria Troiano47, Martin R Turner23, John C van Swieten40, Mattias Vågberg10, Marcel M Verbeek52,53, Luisa M Villar54, Pieter Jelle Visser8,55, Anders Wallin5, Andreas Weiss56, Carsten Wikkelsø5, Edward J Wild57. 1. Neurochemistry Laboratory, Department of Clinical Chemistry, VU University Medical Centre, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands. 2. Department of Epidemiology and Biostatistics, VU University Medical Centre, Amsterdam, the Netherlands. 3. Department of Mathematics, VU University, Amsterdam, the Netherlands. 4. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. 5. Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. 6. Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, United Kingdom. 7. Dementia Research Institute at UCL, London, United Kingdom. 8. Department of Neurology and Alzheimer Centre, VU University Medical Centre, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands. 9. Multiple Sclerosis Unit, Ramon y Cajal University Hospital, Madrid, Spain. 10. Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden. 11. Third Faculty of Medicine, Department of Neurology, Charles University and General University Hospital, Prague, Czech Republic. 12. National Institute of Mental Health, Klecany, Czech Republic. 13. Department of Biomedical Sciences, Reference Centre for Biological Markers of Dementia (BIODEM), Institute Born Bunge, University of Antwerp, Antwerp, Belgium. 14. Memory and Aging Center, Department of Neurology, University of California, San Francisco. 15. Neuroimmunology Unit, Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden. 16. Department of Neurology, Karolinska University Hospital Stockholm, Sweden. 17. Department of Neuroscience, Uppsala University, Uppsala, Sweden. 18. Department of Biomedicine, Aarhus University, Aarhus, Denmark. 19. First Faculty of Medicine, Institute of Medical Biochemistry, Prague, Czech Republic. 20. Laboratory Diagnostics, Charles University and General University Hospital, Prague, Czech Republic. 21. Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. 22. Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 23. Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom. 24. Department of Neurology, Faculty of Medicine and Health, Orebro University Hospital, Orebro, Sweden. 25. Clinical Memory Research Unit, Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden. 26. Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden. 27. Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg. 28. Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden. 29. Department of Medicine, University Hospital and University of Basel, Basel, Switzerland. 30. Department of Neurology, Medical University of Graz, Graz, Austria. 31. Institute of Clinical Medicine, Neurosurgery, University of Eastern Finland, Kuopio. 32. Department of Neurosurgery, Kuopio University Hospital, Kuopio, Finland. 33. Unit of Neurodegenerative Diseases, Department of Clinical Research in Neurology, University of Bari, Bari, Italy. 34. North-East London and Essex MND Care Centre, Neuroscience and Trauma Centre, Blizard, United Kingdom. 35. Department of Neurology, China Medical University Hospital, Taichung City, Taiwan. 36. Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, Queen Square, London, United Kingdom. 37. Institute of Cell and Molecular Medicine, Barts, United Kingdom. 38. London School of Medicine and Dentistry, Barts, United Kingdom. 39. Barts Health NHS Trust, Barts, United Kingdom. 40. Alzheimer Centre and Department of Neurology, Erasmus Medical Centre, Rotterdam, the Netherlands. 41. Department of Clinical Genetics, VU University Medical Centre, Amsterdam, the Netherlands. 42. Division of Infectious Diseases, University of California, San Diego. 43. Department of Clinical Immunology, Copenhagen University Hospital, Righospitalet, Copenhagen, Denmark. 44. Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, United Kingdom. 45. Puerto Rico OMICS Centre, University of Puerto Rico Comprehensive Cancer Centre, San Juan. 46. Department of Psychological Science and Neuroscience Program, Belmont University, Nashville, Tennessee. 47. Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy. 48. San Camillo Forlanini Hospital, Rome, Italy. 49. Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden. 50. Pia Fondazione Cardinale G. Panico, Tricase, Lecce, Italy. 51. Department of Biomedical and Specialist Surgical Sciences, University of Ferrara, Ferrara, Italy. 52. Radboud University Medical Centre, Donders Institute for Brain, Cognition, and Behaviour, Department of Neurology, Nijmegen, the Netherlands. 53. Department of Laboratory Medicine, Radboud Alzheimer Centre, Nijmegen, the Netherlands. 54. Immunology Department, Ramon y Cajal University Hospital, Madrid, Spain. 55. Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht University, Maastricht, the Netherlands. 56. Evotec AG, Manfred Eigen Campus, Hamburg, Germany. 57. UCL Institute of Neurology, Queen Square, London, United Kingdom.
Abstract
IMPORTANCE: Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date. OBJECTIVES: To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions. DATA SOURCES: PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC. STUDY SELECTION: Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex. DATA EXTRACTION AND SYNTHESIS: Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept. MAIN OUTCOME AND MEASURE: The cNfL levels adjusted for age and sex across diagnoses. RESULTS: Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes. CONCLUSIONS AND RELEVANCE: These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
IMPORTANCE: Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date. OBJECTIVES: To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions. DATA SOURCES: PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC. STUDY SELECTION: Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex. DATA EXTRACTION AND SYNTHESIS: Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept. MAIN OUTCOME AND MEASURE: The cNfL levels adjusted for age and sex across diagnoses. RESULTS: Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes. CONCLUSIONS AND RELEVANCE: These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
Authors: Yakeel T Quiroz; Henrik Zetterberg; Eric M Reiman; Yinghua Chen; Yi Su; Joshua T Fox-Fuller; Gloria Garcia; Andres Villegas; Diego Sepulveda-Falla; Marina Villada; Joseph F Arboleda-Velasquez; Edmarie Guzmán-Vélez; Clara Vila-Castelar; Brian A Gordon; Stephanie A Schultz; Hillary D Protas; Valentina Ghisays; Margarita Giraldo; Victoria Tirado; Ana Baena; Claudia Munoz; Silvia Rios-Romenets; Pierre N Tariot; Kaj Blennow; Francisco Lopera Journal: Lancet Neurol Date: 2020-05-26 Impact factor: 44.182
Authors: Leslie M Shaw; Magdalena Korecka; Michal Figurski; Jon Toledo; David Irwin; Ju Hee Kang; John Q Trojanowski Journal: J Appl Lab Med Date: 2020-01-01
Authors: Andrew J Aschenbrenner; Brian A Gordon; Anne M Fagan; Suzanne E Schindler; David A Balota; John C Morris; Jason J Hassenstab Journal: J Alzheimers Dis Date: 2020 Impact factor: 4.472