期刊论文详细信息
Molecular Neurodegeneration
Antibody-free measurement of cerebrospinal fluid tau phosphorylation across the Alzheimer’s disease continuum
Research Article
Shorena Janelidze1  Nina Schultz1  Niklas Mattsson-Carlgren2  Oskar Hansson3  Mathias Sauer4  Juan Lantero-Rodriguez4  Gunnar Brinkmalm4  Laia Montoliu-Gaya4  Johan Gobom5  Kaj Blennow5  Henrik Zetterberg6  Thomas K. Karikari7  Andréa L. Benedet8  Nicholas J. Ashton9  Tharick A. Pascoal1,10  Stijn Servaes1,10  Pedro Rosa-Neto1,10 
[1] Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden;Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden;Department of Neurology, Skåne University Hospital, Lund University, Lund, Sweden;Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden;Memory Clinic, Skåne University Hospital, Lund University, Lund, Sweden;Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden;Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden;Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK;UK Dementia Research Institute at UCL, London, UK;Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China;Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA;Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;Translational Neuroimaging Laboratory, McGill Centre for Studies in Aging, McGill University, Montreal, QC, Canada;Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden;King’s College London, Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, UK;NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation, London, UK;Translational Neuroimaging Laboratory, McGill Centre for Studies in Aging, McGill University, Montreal, QC, Canada;
关键词: Tau;    Phosphorylation;    Alzheimer’s disease;    LC–MS;    Cerebrospinal fluid;   
DOI  :  10.1186/s13024-022-00586-0
 received in 2022-09-10, accepted in 2022-11-25,  发布年份 2022
来源: Springer
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【 摘 要 】

BackgroundAlzheimer’s disease is characterized by an abnormal increase of phosphorylated tau (pTau) species in the CSF. It has been suggested that emergence of different pTau forms may parallel disease progression. Therefore, targeting multiple specific pTau forms may allow for a deeper understanding of disease evolution and underlying pathophysiology. Current immunoassays measure pTau epitopes separately and may capture phosphorylated tau fragments of different length depending on the non-pTau antibody used in the assay sandwich pair, which bias the measurement.MethodsWe developed the first antibody-free mass spectrometric method to simultaneously measure multiple phosphorylated epitopes in CSF tau: pT181, pS199, pS202, pT205, pT217, pT231, and pS396. The method was first evaluated in biochemically defined Alzheimer’s disease and control CSF samples (n = 38). All seven pTau epitopes clearly separated Alzheimer’s disease from non-AD (p < 0.001, AUC = 0.84–0.98). We proceeded with clinical validation of the method in the TRIAD (n = 165) and BioFINDER-2 cohorts (n = 563), consisting of patients across the full Alzheimer’s disease continuum, including also young controls (< 40 years), as well as patients with frontotemporal dementia and other neurodegenerative disorders.ResultsIncreased levels of all phosphorylated epitopes were found in Alzheimer’s disease dementia and Aβ positron emission tomography-positive patients with mild cognitive impairment compared with Aβ-negative controls. For Alzheimer’s disease dementia compared with Aβ-negative controls, the best biomarker performance was observed for pT231 (TRIAD: AUC = 98.73%, fold change = 7.64; BioFINDER-2: AUC = 91.89%, fold change = 10.65), pT217 (TRIAD: AUC = 99.71%, fold change = 6.33; BioFINDER-2: AUC = 98.12%, fold change = 8.83) and pT205 (TRIAD: AUC = 99.07%, fold change = 5.34; BioFINDER-2: AUC = 93.51%, fold change = 3.92). These phospho-epitopes also discriminated between Aβ-positive and Aβ-negative cognitively unimpaired individuals: pT217 (TRIAD: AUC = 83.26, fold change = 2.39; BioFINDER-2: AUC = 91.05%, fold change = 3.29), pT231 (TRIAD: AUC = 86.25, fold change = 3.80; BioFINDER-2: AUC = 78.69%, fold change = 3.65) and pT205 (TRIAD: AUC = 71.58, fold change = 1.51; BioFINDER-2: AUC = 71.11%, fold change = 1.70).ConclusionsWhile an increase was found for all pTau species examined, the highest fold change in Alzheimer’s disease was found for pT231, pT217 and pT205. Simultaneous antibody-free measurement of pTau epitopes by mass spectrometry avoids possible bias caused by differences in antibody affinity for modified or processed forms of tau, provides insights into tau pathophysiology and may facilitate clinical trials on tau-based drug candidates.

【 授权许可】

CC BY   
© The Author(s) 2022

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