title: Diagnostic and Prognostic Utility of the Synaptic Marker Neurogranin in Alzheimer Disease.
abstract: Synaptic loss is an early pathologic substrate of Alzheimer disease (AD). Neurogranin is a postsynaptic neuronal protein that has demonstrated utility as a cerebrospinal fluid (CSF) marker of synaptic loss in AD.
  
  
  
  To investigate the diagnostic and prognostic utility of CSF neurogranin levels in a large, well-characterized cohort of individuals with symptomatic AD and cognitively normal controls.
  
  
  
  A cross-sectional and longitudinal observational study of cognitive decline in patients with symptomatic AD and cognitively normal controls was performed. Participants were individuals with a clinical diagnosis of early symptomatic AD and cognitively normal controls who were enrolled in longitudinal studies of aging and dementia at the Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, from January 21, 2000, through March 21, 2011. Data analysis was performed from November 1, 2013, to March 31, 2015.
  
  
  
  Correlations between baseline CSF biomarker levels and future cognitive decline in patients with symptomatic AD and cognitively normal controls over time.
  
  
  
  A total of 302 individuals (mean [SE] age, 73.1 [0.4] years) were included in this study (95 patients [52 women and 43 men] with AD and 207 controls [125 women and 82 men]). The CSF neurogranin levels differentiated patients with early symptomatic AD from controls with comparable diagnostic utility (mean [SE] area under the receiver operating characteristic curve, 0.71 [0.03]; 95% CI, 0.64-0.77) to the other CSF biomarkers. The CSF neurogranin levels correlated with brain atrophy (normalized whole-brain volumes: adjusted r = -0.38, P = .02; hippocampal volumes: adjusted r = -0.36, P = .03; entorhinal volumes: adjusted r = -0.46, P = .006; and parahippocampal volumes: adjusted r = -0.47, P = .005, n = 38) in AD and with amyloid load (r = 0.39, P = .02, n = 36) in preclinical AD. The CSF neurogranin levels predicted future cognitive impairment (adjusted hazard ratio, 1.89; 95% CI, 1.29-2.78; P = .001 as a continuous measure, and adjusted hazard ratio, 2.78; 95% CI, 1.13-5.99; P = .02 as a categorical measure using the 85th percentile cutoff value) in controls and rates of cognitive decline (Clinical Dementia Rating sum of boxes score: β estimate, 0.29; P = .001; global composite scores: β estimate, -0.11; P = .001; episodic memory scores: β estimate, -0.18; P < .001; and semantic memory scores: β estimate, -0.06; P = .04, n = 57) in patients with symptomatic AD over time, similarly to the CSF proteins VILIP-1, tau, and p-tau181.
  
  
  
  The CSF levels of the synaptic marker neurogranin offer diagnostic and prognostic utility for early symptomatic AD that is comparable to other CSF markers of AD. Importantly, CSF neurogranin complements the collective ability of these markers to predict future cognitive decline in cognitively normal individuals and, therefore, will be a useful addition to the current panel of AD biomarkers.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, Missouri2Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri3Charles F. and Joanne Knight Alzheimer Disease Research Center, Wash.
authors.forename: Rawan
authors.initials: R
authors.lastname: Tarawneh
authors.affiliation: Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, Missouri5Division of Biostatistics, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Gina
authors.initials: G
authors.lastname: D'Angelo
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Dan
authors.initials: D
authors.lastname: Crimmins
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Herries
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Terry
authors.initials: T
authors.lastname: Griest
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, Missouri2Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri3Charles F. and Joanne Knight Alzheimer Disease Research Center, Wash.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
authors.affiliation: Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri7Department of Neurosurgery, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Zipfel
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: Department of Neurology, Washington University School of Medicine, St Louis, Missouri2Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri3Charles F. and Joanne Knight Alzheimer Disease Research Center, Wash.
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, Missouri2Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri3Charles F. and Joanne Knight Alzheimer Disease Research Center, Wash.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000150:complications / Q000175:diagnosis*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D000814:Aniline Compounds / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000235:genetics; D001284:Atrophy / Q000473:pathology; D003072:Cognition Disorders / Q000175:diagnosis / Q000209:etiology; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D006801:Humans; D057187:Independent Living; D008297:Male; D008875:Middle Aged; D051596:Neurocalcin / Q000134:cerebrospinal fluid; D051579:Neurogranin / Q000134:cerebrospinal fluid*; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D049268:Positron-Emission Tomography; D011237:Predictive Value of Tests; D012372:ROC Curve; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D013844:Thiazoles / Q000378:metabolism; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D053327:Apolipoprotein E4; D051596:Neurocalcin; D010446:Peptide Fragments; D013844:Thiazoles; C496688:VSNL1 protein, human; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D051579:Neurogranin