title: Characterization of the postsynaptic protein neurogranin in paired cerebrospinal fluid and plasma samples from Alzheimer's disease patients and healthy controls.
abstract: BACKGROUND
  Synaptic dysfunction and degeneration are central events in Alzheimer's disease (AD) pathophysiology that are thought to occur early in disease progression. Synaptic pathology may be studied by examining protein biomarkers specific for different synaptic elements. We recently showed that the dendritic protein neurogranin (Ng), including the endogenous Ng peptide 48 to 76 (Ng48-76), is markedly increased in cerebrospinal fluid (CSF) in AD and that Ng48-76 is the dominant peptide in human brain tissue. The aim of this study was to characterize Ng in plasma and CSF using mass spectrometry and to investigate the performance of plasma Ng as an AD biomarker.
  
  
  METHODS
  Paired plasma and CSF samples from patients with AD (n = 25) and healthy controls (n = 20) were analyzed in parallel using an immunoassay developed in-house on the Meso Scale Discovery platform and hybrid immunoaffinity-mass spectrometry (HI-MS). A second plasma material from patients with AD (n = 13) and healthy controls (n = 17) was also analyzed with HI-MS. High-resolution mass spectrometry was used for identification of endogenous plasma Ng peptides.
  
  
  RESULTS
  Ng in human plasma is present as several endogenous peptides. Of the 16 endogenous Ng peptides identified, seven were unique for plasma and not detectable in CSF. However, Ng48-76 was not present in plasma. CSF Ng was significantly increased in AD compared with controls (P < 0.0001), whereas the plasma Ng levels were similar between the groups in both studies. Plasma and CSF Ng levels showed no correlation. CSF Ng was stable during storage at -20°C for up to 2 days, and no de novo generation of peptides were detected.
  
  
  CONCLUSIONS
  For the first time, to our knowledge, we have identified several endogenous Ng peptides in human plasma. In agreement with previous studies, we show that CSF Ng is significantly increased in AD as compared with healthy controls. The origin of Ng in plasma and its possible use as a biomarker need to be further investigated. The results suggest that CSF Ng, in particular Ng48-76, might reflect the neurodegenerative processes within the brain, indicating a role for Ng as a potential novel clinical biomarker for synaptic function in AD.
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, House V3/SU Mölndal, SE-431 80 Mölndal, Sweden ; AlzeCure Foundation, Karolinska Institutet Science Park, Hälsovägen 7, SE-141 57 Huddinge, Sweden.
authors.forename: Hlin
authors.initials: H
authors.lastname: Kvartsberg
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, House V3/SU Mölndal, SE-431 80 Mölndal, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Portelius
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, House V3/SU Mölndal, SE-431 80 Mölndal, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Andreasson
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, House V3/SU Mölndal, SE-431 80 Mölndal, Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Brinkmalm
authors.affiliation: Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Hellwig
authors.affiliation: Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Lelental
authors.affiliation: Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kornhuber
authors.affiliation: Department of Clinical Sciences Malmö, Memory Clinic, Clinical Memory Research Unit, Faculty of Medicine, Lund University, Malmö, Klinikgatan 22, SE-222 42 Lund, Sweden.
authors.forename: Oskar
authors.initials: O
authors.lastname: Hansson
authors.affiliation: Department of Clinical Sciences Malmö, Memory Clinic, Clinical Memory Research Unit, Faculty of Medicine, Lund University, Malmö, Klinikgatan 22, SE-222 42 Lund, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Minthon
authors.affiliation: Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Spitzer
authors.affiliation: Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Maler
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, House V3/SU Mölndal, SE-431 80 Mölndal, Sweden ; Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square 588, WC1N 3BG London, UK.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, House V3/SU Mölndal, SE-431 80 Mölndal, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany.
authors.forename: Piotr
authors.initials: P
authors.lastname: Lewczuk