Hlin Kvartsberg1, Flora H Duits2, Martin Ingelsson3, Niels Andreasen4, Annika Öhrfelt1, Kerstin Andersson1, Gunnar Brinkmalm1, Lars Lannfelt3, Lennart Minthon5, Oskar Hansson5, Ulf Andreasson1, Charlotte E Teunissen6, Philip Scheltens2, Wiesje M Van der Flier7, Henrik Zetterberg8, Erik Portelius1, Kaj Blennow9. 1. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. 2. Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. 3. Department of Public Health and Geriatrics, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden. 4. Department of NVS, Karolinska Institute, Center for Alzheimer Research, Stockholm, Sweden. 5. Department of Clinical Sciences Malmö, Memory Clinic, Clinical Memory Research Unit, Lund University, Malmö, Sweden. 6. Department of Clinical Chemistry, Neurochemistry Laboratory and Biobank, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. 7. Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands; Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands. 8. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. 9. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. Electronic address: kaj.blennow@neuro.gu.se.
Abstract
INTRODUCTION: Synaptic dysfunction is an early event in Alzheimer's disease (AD) pathogenesis and directly related to cognitive impairment. Consequently, synaptic biomarkers may be valuable tools for both early diagnosis and disease stage. Neurogranin (Ng) is a postsynaptic protein involved in memory consolidation. METHODS: We developed three monoclonal anti-Ng antibodies. Mass spectrometry and a novel enzyme-linked immunosorbent assay were used to analyze cerebrospinal fluid (CSF) Ng in three independent clinical cohorts including patients with AD dementia (n = 100 in total), mild cognitive impairment patients (MCI), (n = 40) and controls (n = 80 in total). RESULTS: We show in three independent clinical cohorts a marked increase in CSF Ng levels in AD dementia (P < .001 in all studies). In addition, high CSF Ng levels at the MCI stage predicted progression to dementia due to AD with a hazard ratio of 12.8 (95% confidence interval 1.6-103.0, P = .02). In amyloid-positive MCI patients, high CSF Ng correlated with a more rapid change in cognition during clinical follow-up (P = .03). DISCUSSION: These results suggest that CSF Ng is a novel AD biomarker that may be used to monitor synaptic degeneration, and correlates with the rate of cognitive decline in prodromal AD.
INTRODUCTION: Synaptic dysfunction is an early event in Alzheimer's disease (AD) pathogenesis and directly related to cognitive impairment. Consequently, synaptic biomarkers may be valuable tools for both early diagnosis and disease stage. Neurogranin (Ng) is a postsynaptic protein involved in memory consolidation. METHODS: We developed three monoclonal anti-Ng antibodies. Mass spectrometry and a novel enzyme-linked immunosorbent assay were used to analyze cerebrospinal fluid (CSF) Ng in three independent clinical cohorts including patients with AD dementia (n = 100 in total), mild cognitive impairmentpatients (MCI), (n = 40) and controls (n = 80 in total). RESULTS: We show in three independent clinical cohorts a marked increase in CSF Ng levels in AD dementia (P < .001 in all studies). In addition, high CSF Ng levels at the MCI stage predicted progression to dementia due to AD with a hazard ratio of 12.8 (95% confidence interval 1.6-103.0, P = .02). In amyloid-positive MCI patients, high CSF Ng correlated with a more rapid change in cognition during clinical follow-up (P = .03). DISCUSSION: These results suggest that CSF Ng is a novel AD biomarker that may be used to monitor synaptic degeneration, and correlates with the rate of cognitive decline in prodromal AD.
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