Thomas K Karikari1, Andreja Emeršič2, Agathe Vrillon3,4, Juan Lantero-Rodriguez1, Nicholas J Ashton1,5,6,7, Milica Gregorič Kramberger2,8, Julien Dumurgier3, Claire Hourregue3, Saša Čučnik2,9,10, Gunnar Brinkmalm1, Uroš Rot2,8, Henrik Zetterberg1,11,12,13, Claire Paquet3,4, Kaj Blennow1,11. 1. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 2. Department of Neurology, University Medical Centre Ljubljana, Ljubljana, Slovenia. 3. Université de Paris, Cognitive Neurology Center, GHU Nord APHP Hospital Lariboisière Fernand Widal, Paris, France. 4. Université de Paris, Inserm UMR S11-44 Therapeutic Optimization in Neuropsychopharmacology, Paris, France. 5. Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden. 6. King's College London, Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, UK. 7. NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation, London, UK. 8. Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. 9. Department of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia. 10. Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia. 11. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. 12. Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK. 13. UK Dementia Research Institute at UCL, London, UK.
Abstract
INTRODUCTION: Phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) is an established Alzheimer's disease (AD) biomarker. Novel immunoassays targeting N-terminal and mid-region p-tau181 and p-tau217 fragments are available, but head-to-head comparison in clinical settings is lacking. METHODS: N-terminal-directed p-tau217 (N-p-tau217), N-terminal-directed p-tau181 (N-p-tau181), and standard mid-region p-tau181 (Mid-p-tau181) biomarkers in CSF were evaluated in three cohorts (n = 503) to assess diagnostic performance, concordance, and associations with amyloid beta (Aβ). RESULTS: CSF N-p-tau217 and N-p-tau181 had better concordance (88.2%) than either with Mid-p-tau181 (79.7%-82.7%). N-p-tau217 and N-p-tau181 were significantly increased in early mild cognitive impairment (MCI)-AD (A+T-N-) without changes in Mid-p-tau181 until AD-dementia. N-p-tau217 and N-p-tau181 identified Aβ pathophysiology (area under the curve [AUC] = 94.8%-97.1%) and distinguished MCI-AD from non-AD MCI (AUC = 82.6%-90.5%) signficantly better than Mid-p-tau181 (AUC = 91.2% and 70.6%, respectively). P-tau biomarkers equally differentiated AD from non-AD dementia (AUC = 99.1%-99.8%). DISCUSSION: N-p-tau217 and N-p-tau181 could improve diagnostic accuracy in prodromal-AD and clinical trial recruitment as both identify Aβ pathophysiology and differentiate early MCI-AD better than Mid-p-tau181.
INTRODUCTION: Phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) is an established Alzheimer's disease (AD) biomarker. Novel immunoassays targeting N-terminal and mid-region p-tau181 and p-tau217 fragments are available, but head-to-head comparison in clinical settings is lacking. METHODS:N-terminal-directed p-tau217 (N-p-tau217), N-terminal-directed p-tau181 (N-p-tau181), and standard mid-region p-tau181 (Mid-p-tau181) biomarkers in CSF were evaluated in three cohorts (n = 503) to assess diagnostic performance, concordance, and associations with amyloid beta (Aβ). RESULTS: CSF N-p-tau217 and N-p-tau181 had better concordance (88.2%) than either with Mid-p-tau181 (79.7%-82.7%). N-p-tau217 and N-p-tau181 were significantly increased in early mild cognitive impairment (MCI)-AD (A+T-N-) without changes in Mid-p-tau181 until AD-dementia. N-p-tau217 and N-p-tau181 identified Aβ pathophysiology (area under the curve [AUC] = 94.8%-97.1%) and distinguished MCI-AD from non-AD MCI (AUC = 82.6%-90.5%) signficantly better than Mid-p-tau181 (AUC = 91.2% and 70.6%, respectively). P-tau biomarkers equally differentiated AD from non-AD dementia (AUC = 99.1%-99.8%). DISCUSSION: N-p-tau217 and N-p-tau181 could improve diagnostic accuracy in prodromal-AD and clinical trial recruitment as both identify Aβ pathophysiology and differentiate early MCI-AD better than Mid-p-tau181.
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