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Original Investigation |

Neurogranin as a Cerebrospinal Fluid Biomarker for Synaptic Loss in Symptomatic Alzheimer Disease

Maartje I. Kester, MD, PhD1; Charlotte E. Teunissen, PhD2; Daniel L. Crimmins, PhD3; Elizabeth M. Herries, BA3; Jack. H. Ladenson, PhD3; Philip Scheltens, MD, PhD1; Wiesje M. van der Flier, PhD1,4; John C. Morris, MD5,6,7; David M. Holtzman, MD5,6,7; Anne M. Fagan, PhD5,6,7
[+] Author Affiliations
1Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands
2Department of Clinical Chemistry, VU University Medical Center, Amsterdam, the Netherlands
3Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri
4Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands
5The Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St Louis, Missouri
6Department of Neurology, Washington University School of Medicine, St Louis, Missouri
7Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri
JAMA Neurol. 2015;72(11):1275-1280. doi:10.1001/jamaneurol.2015.1867.
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Importance  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).

Design, Setting, and Participants  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.

Main Outcome and Measure  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 and Relevance  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.

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Figure 1.
Kaplan-Meier Curve for Progression From Mild Cognitive Impairment (MCI) to Alzheimer Disease (AD), Stratified by Tertiles of Neurogranin Levels

Neurogranin levels were evaluated at the lowest tertile (<1666 pg/mL), the middle tertile (1666-2734 pg/mL), and the highest tertile (>2734 pg/mL). The lowest tertile was used as reference.

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Figure 2.
Annual Change in Neurogranin (NGRN) Levels

The annual change in NGRN levels obtained from samples of cerebrospinal fluid were assessed using age- and sex-adjusted linear mixed models. The NGRN level was the dependent variable, and clinical diagnosis (treated as a categorical variable), time (ie, the interval between lumbar punctures in years; treated as a continuous variable), and the interaction between diagnosis and time were the independent variables. The reported β represents the estimated change in NGRN levels per year, and the error bars represent the 95% CIs of the reported effects.

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