Abstract:
IMPORTANCE: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. OBJECTIVE: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. DESIGN, SETTING, AND PARTICIPANTS: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. MAIN OUTCOMES AND MEASURES:Correlations between baseline CSF biomarker levels and future cognitive decline in patients with symptomatic AD and cognitively normal controls over time. RESULTS: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. CONCLUSIONS AND RELEVANCE: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.
journal_name
JAMA Neuroljournal_title
JAMA neurologyauthors
Tarawneh R,D'Angelo G,Crimmins D,Herries E,Griest T,Fagan AM,Zipfel GJ,Ladenson JH,Morris JC,Holtzman DMdoi
10.1001/jamaneurol.2016.0086subject
Has Abstractpub_date
2016-05-01 00:00:00pages
561-71issue
5eissn
2168-6149issn
2168-6157pii
2506518journal_volume
73pub_type
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