Cerebrospinal fluid levels of the synaptic protein neurogranin correlates with cognitive decline in prodromal Alzheimer's disease

Hlin Kvartsberg; Flora H Duits; Martin Ingelsson; Niels Andreasen; Annika Öhrfelt; Kerstin Andersson; Gunnar Brinkmalm; Lars Lannfelt; Lennart Minthon; Oskar Hansson; Ulf Andreasson; Charlotte E Teunissen; Philip Scheltens; Wiesje M Van der Flier; Henrik Zetterberg; Erik Portelius; Kaj Blennow

doi:10.1016/j.jalz.2014.10.009

Cerebrospinal fluid levels of the synaptic protein neurogranin correlates with cognitive decline in prodromal Alzheimer's disease

Alzheimers Dement. 2015 Oct;11(10):1180-90. doi: 10.1016/j.jalz.2014.10.009. Epub 2014 Dec 19.

Authors

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

Affiliations

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.

PMID: 25533203
DOI: 10.1016/j.jalz.2014.10.009

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.

Keywords: Alzheimer's disease; ELISA; Mass spectrometry; Mild cognitive impairment; Neurogranin; Prognostic marker.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Alzheimer Disease / complications
Alzheimer Disease / diagnosis*
Alzheimer Disease / physiopathology*
Biomarkers / cerebrospinal fluid*
Case-Control Studies
Cognition Disorders / etiology*
Cognitive Dysfunction / diagnosis
Disease Progression
Enzyme-Linked Immunosorbent Assay
Female
Humans
Male
Mass Spectrometry
Middle Aged
Neurogranin / cerebrospinal fluid*
Prognosis
Time Factors

Substances

Biomarkers
Neurogranin