Johan Gobom1,2, Lucilla Parnetti3, Pedro Rosa-Neto4,5, Martin Vyhnalek6,7,8, Serge Gauthier4,5, Samuela Cataldi3, Ondrej Lerch6,7,8, Jan Laczo6,7,8, Katerina Cechova6,7,8, Marcus Clarin1,2, Andrea L Benet1,9, Tharick A Pascoal9, Neserine Rahmouni9, Manu Vandijck10, Else Huyck10, Nathalie Le Bastard10, Jenna Stevenson9, Mira Chamoun9, Daniel Alcolea11,12, Alberto Lleó11,12, Ulf Andreasson1,2, Marcel M Verbeek13,14, Giovanni Bellomo3, Roberta Rinaldi3, Nicholas J Ashton1,15,16,17, Henrik Zetterberg1,2,18,19, Katerina Sheardova6,20, Jakub Hort6,7,20, Kaj Blennow1,2. 1. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 2. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. 3. Laboratory of Clinical Neurochemistry, Section of Neurology, University of Perugia, Perugia, Italy. 4. Department of Neurology and Neurosurgery, McGill University Research Centre for Studies in Aging, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada. 5. Montreal Neurological Institute, Montreal, QC, Canada. 6. Department of Neurology, Second Medical Faculty, Charles University, Prague, Czech Republic. 7. Motol University Hospital, Prague, Czech Republic. 8. International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic. 9. Translational Neuroimaging Laboratory, McGill Centre for Studies in Aging, McGill University, Montreal, QC, Canada. 10. Fujirebio Europe N.V., Ghent, Belgium. 11. Department of Neurology, Memory Unit, Hospital de la Santa Creu i Sant Pau- Biomedical Research Institute Sant Pau-Universitat Autònoma de Barcelona, Barcelona, Spain. 12. Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. 13. Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. 14. Department of Neurology, Radboud Alzheimer Centre, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands. 15. Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden. 16. King's College London, Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, UK. 17. NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation, London, UK. 18. Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK. 19. UK Dementia Research Institute at UCL, London, UK. 20. First Department of Neurology, Faculty of Medicine, Masaryk University and St. Anne's University Hospital, Brno, Czech Republic.
Abstract
OBJECTIVES: The core cerebrospinal fluid (CSF) biomarkers; total tau (tTau), phospho-tau (pTau), amyloid β 1-42 (Aβ 1-42), and the Aβ 1-42/Aβ 1-40 ratio have transformed Alzheimer's disease (AD) research and are today increasingly used in clinical routine laboratories as diagnostic tools. Fully automated immunoassay instruments with ready-to-use assay kits and calibrators has simplified their analysis and improved reproducibility of measurements. We evaluated the analytical performance of the fully automated immunoassay instrument LUMIPULSE G (Fujirebio) for measurement of the four core AD CSF biomarkers and determined cutpoints for AD diagnosis. METHODS: Comparison of the LUMIPULSE G assays was performed with the established INNOTEST ELISAs (Fujirebio) for hTau Ag, pTau 181, β-amyloid 1-42, and with V-PLEX Plus Aβ Peptide Panel 1 (6E10) (Meso Scale Discovery) for Aβ 1-42/Aβ 1-40, as well as with a LC-MS reference method for Aβ 1-42. Intra- and inter-laboratory reproducibility was evaluated for all assays. Clinical cutpoints for Aβ 1-42, tTau, and pTau was determined by analysis of three cohorts of clinically diagnosed patients, comprising 651 CSF samples. For the Aβ 1-42/Aβ 1-40 ratio, the cutpoint was determined by mixture model analysis of 2,782 CSF samples. RESULTS: The LUMIPULSE G assays showed strong correlation to all other immunoassays (r>0.93 for all assays). The repeatability (intra-laboratory) CVs ranged between 2.0 and 5.6%, with the highest variation observed for β-amyloid 1-40. The reproducibility (inter-laboratory) CVs ranged between 2.1 and 6.5%, with the highest variation observed for β-amyloid 1-42. The clinical cutpoints for AD were determined to be 409 ng/L for total tau, 50.2 ng/L for pTau 181, 526 ng/L for β-amyloid 1-42, and 0.072 for the Aβ 1-42/Aβ 1-40 ratio. CONCLUSIONS: Our results suggest that the LUMIPULSE G assays for the CSF AD biomarkers are fit for purpose in clinical laboratory practice. Further, they corroborate earlier presented reference limits for the biomarkers.
OBJECTIVES: The core cerebrospinal fluid (CSF) biomarkers; total tau (tTau), phospho-tau (pTau), amyloid β 1-42 (Aβ 1-42), and the Aβ 1-42/Aβ 1-40 ratio have transformed Alzheimer's disease (AD) research and are today increasingly used in clinical routine laboratories as diagnostic tools. Fully automated immunoassay instruments with ready-to-use assay kits and calibrators has simplified their analysis and improved reproducibility of measurements. We evaluated the analytical performance of the fully automated immunoassay instrument LUMIPULSE G (Fujirebio) for measurement of the four core AD CSF biomarkers and determined cutpoints for AD diagnosis. METHODS: Comparison of the LUMIPULSE G assays was performed with the established INNOTEST ELISAs (Fujirebio) for hTau Ag, pTau 181, β-amyloid 1-42, and with V-PLEX Plus Aβ Peptide Panel 1 (6E10) (Meso Scale Discovery) for Aβ 1-42/Aβ 1-40, as well as with a LC-MS reference method for Aβ 1-42. Intra- and inter-laboratory reproducibility was evaluated for all assays. Clinical cutpoints for Aβ 1-42, tTau, and pTau was determined by analysis of three cohorts of clinically diagnosed patients, comprising 651 CSF samples. For the Aβ 1-42/Aβ 1-40 ratio, the cutpoint was determined by mixture model analysis of 2,782 CSF samples. RESULTS: The LUMIPULSE G assays showed strong correlation to all other immunoassays (r>0.93 for all assays). The repeatability (intra-laboratory) CVs ranged between 2.0 and 5.6%, with the highest variation observed for β-amyloid 1-40. The reproducibility (inter-laboratory) CVs ranged between 2.1 and 6.5%, with the highest variation observed for β-amyloid 1-42. The clinical cutpoints for AD were determined to be 409 ng/L for total tau, 50.2 ng/L for pTau 181, 526 ng/L for β-amyloid 1-42, and 0.072 for the Aβ 1-42/Aβ 1-40 ratio. CONCLUSIONS: Our results suggest that the LUMIPULSE G assays for the CSF AD biomarkers are fit for purpose in clinical laboratory practice. Further, they corroborate earlier presented reference limits for the biomarkers.
Authors: Oliver J Ziff; Nicholas J Ashton; Puja R Mehta; Rachel Brown; Dilan Athauda; Judith Heaney; Amanda J Heslegrave; Andrea Lessa Benedet; Kaj Blennow; Anna M Checkley; Catherine F Houlihan; Serge Gauthier; Pedro Rosa-Neto; Nick C Fox; Jonathan M Schott; Henrik Zetterberg; Laura A Benjamin; Ross W Paterson Journal: J Neurochem Date: 2022-03-02 Impact factor: 5.546