title: Neurogranin as a Cerebrospinal Fluid Biomarker for Synaptic Loss in Symptomatic Alzheimer Disease.
abstract: OBJECTIVE
  Neurogranin (NGRN) seems to be a promising novel cerebrospinal fluid (CSF) biomarker for synaptic loss; however, clinical, and especially longitudinal, data are sparse.
  
  
  OBJECTIVE
  To examine the utility of NGRN, with repeated CSF sampling, for diagnosis, prognosis, and monitoring of Alzheimer disease (AD).
  
  
  METHODS
  Longitudinal study of consecutive patients who underwent 2 lumbar punctures between the beginning of 1995 and the end of 2010 within the memory clinic-based Amsterdam Dementia Cohort. The study included 163 patients: 37 cognitively normal participants (mean [SE] age, 64 [2] years; 38% female; and mean [SE] Mini-Mental State Examination [MMSE] score, 28 [0.3]), 61 patients with mild cognitive impairment (MCI) (mean [SE] age, 68 [1] years; 38% female; and mean [SE] MMSE score, 27 [0.3]), and 65 patients with AD (mean [SE] age, 65 [1] years; 45% female; and mean [SE] MMSE score, 22 [0.7]). The mean (SE) interval between lumbar punctures was 2.0 (0.1) years, and the mean (SE) duration of cognitive follow-up was 3.8 (0.2) years. Measurements of CSF NGRN levels were obtained in January and February 2014.
  
  
  METHODS
  Levels of NGRN in CSF samples.
  
  
  RESULTS
  Baseline CSF levels of NGRN in patients with AD (median level, 2381 pg/mL [interquartile range, 1651-3416 pg/mL]) were higher than in cognitively normal participants (median level, 1712 pg/mL [interquartile range, 1206-2724 pg/mL]) (P = .04). Baseline NGRN levels were highly correlated with total tau and tau phosphorylated at threonine 181 in all patient groups (all P < .001), but not with Aβ42. Baseline CSF levels of NGRN were also higher in patients with MCI who progressed to AD (median level, 2842 pg/mL [interquartile range, 1882-3950 pg/mL]) compared with those with stable MCI (median level, 1752 pg/mL [interquartile range, 1024-2438 pg/mL]) (P = .004), and they were predictive of progression from MCI to AD (hazard ratio, 1.8 [95% CI, 1.1-2.9]; stratified by tertiles). Linear mixed-model analyses demonstrated that within-person levels of NGRN increased over time in cognitively normal participants (mean [SE] level, 90 [45] pg/mL per year; P < .05) but not in patients with MCI or AD.
  
  
  CONCLUSIONS
  Neurogranin is a promising biomarker for AD because levels were elevated in patients with AD compared with cognitively normal participants and predicted progression from MCI to AD. Within-person levels of NGRN increased in cognitively normal participants but not in patients with later stage MCI or AD, which suggests that NGRN may reflect presymptomatic synaptic dysfunction or loss.
authors.affiliation: Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Maartje I
authors.initials: MI
authors.lastname: Kester
authors.affiliation: Department of Clinical Chemistry, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Teunissen
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Crimmins
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Herries
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Jack H
authors.initials: JH
authors.lastname: Ladenson
authors.affiliation: Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Philip
authors.initials: P
authors.lastname: Scheltens
authors.affiliation: Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands4Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Wiesje M
authors.initials: WM
authors.lastname: van der Flier
authors.affiliation: The Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, Missouri6Department of Neurology, Washington University School of Medicine, St Louis, Missouri7Hope Center for Neurological Disorders, Washington Universit.
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.affiliation: The Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, Missouri6Department of Neurology, Washington University School of Medicine, St Louis, Missouri7Hope Center for Neurological Disorders, Washington Universit.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.affiliation: The Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, Missouri6Department of Neurology, Washington University School of Medicine, St Louis, Missouri7Hope Center for Neurological Disorders, Washington Universit.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D051579:Neurogranin / Q000134:cerebrospinal fluid*; D013569:Synapses / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D051579:Neurogranin