Rawan Tarawneh1, Gina D'Angelo2, Dan Crimmins3, Elizabeth Herries3, Terry Griest3, Anne M Fagan1, Gregory J Zipfel4, Jack H Ladenson3, John C Morris1, David M Holtzman1. 1. 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. 2. 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. 3. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri. 4. Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri7Department of Neurosurgery, Washington University School of Medicine, St Louis, Missouri.
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.
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.
Authors: M Bobinski; M J de Leon; J Wegiel; S Desanti; A Convit; L A Saint Louis; H Rusinek; H M Wisniewski Journal: Neuroscience Date: 2000 Impact factor: 3.590
Authors: L Mucke; E Masliah; G Q Yu; M Mallory; E M Rockenstein; G Tatsuno; K Hu; D Kholodenko; K Johnson-Wood; L McConlogue Journal: J Neurosci Date: 2000-06-01 Impact factor: 6.167
Authors: John C Morris; Sandra Weintraub; Helena C Chui; Jeffrey Cummings; Charles Decarli; Steven Ferris; Norman L Foster; Douglas Galasko; Neill Graff-Radford; Elaine R Peskind; Duane Beekly; Erin M Ramos; Walter A Kukull Journal: Alzheimer Dis Assoc Disord Date: 2006 Oct-Dec Impact factor: 2.703
Authors: J H Pak; F L Huang; J Li; D Balschun; K G Reymann; C Chiang; H Westphal; K P Huang Journal: Proc Natl Acad Sci U S A Date: 2000-10-10 Impact factor: 11.205
Authors: David S Knopman; Samantha Budd Haeberlein; Maria C Carrillo; James A Hendrix; Geoff Kerchner; Richard Margolin; Paul Maruff; David S Miller; Gary Tong; Maria B Tome; Melissa E Murray; Peter T Nelson; Mary Sano; Niklas Mattsson; David L Sultzer; Thomas J Montine; Clifford R Jack; Hartmuth Kolb; Ronald C Petersen; Prashanthi Vemuri; Megan Zoschg Canniere; Julie A Schneider; Susan M Resnick; Gary Romano; Argonde Corien van Harten; David A Wolk; Lisa J Bain; Eric Siemers Journal: Alzheimers Dement Date: 2018-04 Impact factor: 21.566
Authors: Randall J Bateman; Tammie L Benzinger; Scott Berry; David B Clifford; Cynthia Duggan; Anne M Fagan; Kathleen Fanning; Martin R Farlow; Jason Hassenstab; Eric M McDade; Susan Mills; Katrina Paumier; Melanie Quintana; Stephen P Salloway; Anna Santacruz; Lon S Schneider; Guoqiao Wang; Chengjie Xiong Journal: Alzheimers Dement Date: 2016-08-29 Impact factor: 21.566
Authors: Suzanne E Schindler; Yan Li; Kaitlin W Todd; Elizabeth M Herries; Rachel L Henson; Julia D Gray; Guoqiao Wang; Danielle L Graham; Leslie M Shaw; John Q Trojanowski; Jason J Hassenstab; Tammie L S Benzinger; Carlos Cruchaga; Mathias Jucker; Johannes Levin; Jasmeer P Chhatwal; James M Noble; John M Ringman; Neill R Graff-Radford; David M Holtzman; Jack H Ladenson; John C Morris; Randall J Bateman; Chengjie Xiong; Anne M Fagan Journal: Alzheimers Dement Date: 2019-03-04 Impact factor: 21.566