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Original Investigation |

Diagnostic and Prognostic Utility of the Synaptic Marker Neurogranin in Alzheimer Disease

Rawan Tarawneh, MD1,2,3,4; Gina D’Angelo, PhD3,5; Dan Crimmins, PhD6; Elizabeth Herries, BA6; Terry Griest, BS6; Anne M. Fagan, PhD1,2,3; Gregory J. Zipfel, MD2,7; Jack H. Ladenson, PhD6; John C. Morris, MD1,2,3,6; David M. Holtzman, MD1,2,3,8
[+] Author Affiliations
1Department of Neurology, Washington University School of Medicine, St Louis, Missouri
2Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri
3Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, Missouri
4Cleveland Clinic Lou Ruvo Center for Brain Health, Department of Neurology, Neurological Institute, Cleveland Clinic, Cleveland, Ohio
5Division of Biostatistics, Washington University School of Medicine, St Louis, Missouri
6Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri
7Department of Neurosurgery, Washington University School of Medicine, St Louis, Missouri
8Department of Developmental Biology, Washington University School of Medicine, St Louis, Missouri
JAMA Neurol. 2016;73(5):561-571. doi:10.1001/jamaneurol.2016.0086.
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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.

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Figure 1.
Scatterplots of Cerebrospinal Fluid (CSF) Biomarker Levels by Clinical Diagnosis and Clinical Dementia Rating (CDR) Scores

A, Mean CSF neurogranin levels were higher in those with CDR scores of 0.5 and those with CDR scores of 1 or higher compared with those with CDR scores of 0 (P < .001) or non-Alzheimer disease (AD) dementias (P < .001). B, Mean CSF neurogranin levels were higher in those with CDR scores of 0.5 and those with CDR scores of 1 or higher compared with those with negative Pittsburgh Compound B (PiB) test results and CDR scores of 0 (P < .001). C, Mean (SE) CSF VILIP-1 levels were higher in those with CDR scores of 0.5 (503 [20] pg/mL, n = 70) and those with CDR scores of 1 or higher (545 [33] pg/mL, n = 25) compared with those with CDR scores of 0 (397 [10] pg/mL, n = 207) (P < .001) and those with non-AD dementias (323 [40] pg/mL, n = 19) (P < .001). D, Mean (SE) CSF tau levels were higher in those with CDR scores of 0.5 (573 [34] pg/mL, n = 67) and those with CDR scores of 1 or higher (680 [57] pg/mL, n = 25) compared with those with CDR scores of 0 (296 [11] pg/mL, n = 197) (P < .001) and non-AD dementias (319 [48] pg/mL, n = 19) (P < .001). One-way analysis of variance with Welch correction for unequal variances and the Tukey post hoc test were used for all group comparisons. Similar results were obtained when Bonferroni corrections were used for all group comparisons. E and F, Receiver operating characteristic curves for the diagnostic utility of CSF biomarkers in differentiating AD from controls by clinical diagnosis and PiB status. Figure panels C and D are reproduced from Tarawneh et al21 with permission from John Wiley & Sons, Inc.

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Figure 2.
Correlations Between Cerebrospinal Fluid (CSF) Neurogranin Levels and CSF, Magnetic Resonance Imaging, or Amyloid Markers

The CSF neurogranin levels correlated with CSF VILIP-1 (r = 0.82, P < .001) (A) and CSF tau levels (r = 0.78, P < .001) (B) in the combined cohort of patients with Alzheimer disease (AD) and controls. The CSF neurogranin levels negatively correlated with normalized whole-brain volume (nWBV) (unadjusted r = −0.38, P = .02; adjusted r = −0.38, P = .02) (C) and hippocampal volumes (unadjusted r = −0.34, P = .04; adjusted r = −0.36, P = .03) in patients with AD (n = 38) (D). Unadjusted linear regression lines are shown. The CSF neurogranin levels correlated with mean cortical binding potential (MCBP) on positron emission tomography with Pittsburgh Compound B (PiB) in the combined (patients with AD and controls) cohort (E) and cognitively normal controls who are PiB–positive (preclinical AD; ie, MCBP ≥0.18, n = 36) (F).

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Figure 3.
Baseline Cerebrospinal Fluid (CSF) Biomarker Levels as Predictors of Conversion From Clinical Dementia Rating (CDR) of 0 to 0.5 or Greater

Kaplan-Meier estimates of the rates of conversion from CDR scores of 0 to 0.5 or greater over time as a function of CSF biomarker measures are shown. The CSF biomarkers or ratios were analyzed as categorical variables (dichotomized at the 85th percentile value), and analyses were adjusted for age, sex, educational level, and APOE ε4 genotype. The adjusted hazard ratios for the CSF biomarkers or ratios (dichotomized at the 85th percentile value) as predictors of future cognitive decline in cognitively normal individuals were 2.78 for neurogranin (95% CI, 1.13-5.99; P = .02), 3.74 for VILIP-1 (95% CI, 1.98-9.57; P = .002), 2.57 for tau (95% CI, 1.31-6.97; P = .03), 1.72 for p-tau181 (95% CI, 0.97-5.38; P = .06), 11.00 for neurogranin/amyloid-β (Aβ42) (95% CI, 4.41-27.39; P < .001), 13.00 for VILIP-1/Aβ42 (95% CI, 4.38-30.90; P < .001), 9.82 for tau/Aβ42 (95% CI, 3.11-21.28; P < .001), and 7.83 for p-tau181/Aβ42 (95% CI, 2.65-16.34; P < .001). The Kaplan-Meier curves for p-tau181 and p-tau181/Aβ42 are not shown in the figure. Figure panels C through F are from Tarawneh et al21 with permission from John Wiley & Sons, Inc.

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Figure 4.
Rates of Cognitive Decline as a Function of Cerebrospinal Fluid (CSF) Neurogranin and Neurogranin/Amyloid-β 42 (Aβ42) Terciles in Alzheimer Disease (AD)

Mixed linear models were used to estimate rates of decline in Clinical Dementia Rating sum of boxes (CDR-SB) (A and B), global composite (C and D), and episodic memory (E and F) scores over time in the symptomatic AD cohort as a function of CSF neurogranin and neurogranin/Aβ42 levels. The slope and intercept for each of the 3 terciles of CSF neurogranin and CSF neurogranin/Aβ42 are plotted. Adjusted rates of cognitive decline in the upper, middle, and lower terciles of neurogranin values were 1.40, 1.21, and 0.58 boxes per year, respectively, for CDR-SB; −0.37, −0.28, and −0.11 points per year, respectively, for global composite scores; and −0.49, −0.22, and −0.06 points per year, respectively, in episodic memory scores. Adjusted rates of cognitive decline in the upper, middle, and lower terciles of neurogranin/Aβ42 values were 1.39, 1.18, and 0.61 boxes per year, respectively, in CDR-SB; −0.44, −0.19, and −0.11 points per year, respectively, in global composite scores; and −0.47, −0.33, and −0.02 points per year, respectively, in episodic memory scores. LP indicates lumbar puncture.

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