Levels of neurogranin in cerebrospinal fluid (CSF) are useful as a biomarker for synaptic loss and prediction of cognitive decline in Alzheimer’s disease (AD), according to results from a study published in JAMA Neurology.
Neurogranin is an abundant neuronal protein likely involved in calcium-mediated signalling pathway modulation and synaptic plasticity. Previous evidence points to higher levels of neurogranin in the CSF of patients with AD, suggesting it may be a potential biomarker of synaptic loss.
For this study, David Holtzman, MD, of the Department of Neurology at Washington University School of Medicine in St. Louis, MO, and colleagues conducted a longitudinal, cross-sectional observation study to assess correlations between baseline CSF biomarker levels and cognitive decline in healthy controls and participants with symptomatic AD.
In total, 95 patients with early symptomatic AD and 207 healthy controls (mean age, 73.1 years) were included in the study. Participants with Clinical Dementia Rating (CDR) scores of 0.5 (2.04 ng/mL) ≥1 (1.98 mg/mL) had higher mean CSF neurogranin levels than those with non-AD dementia (1.08 ng/mL, P<.001) or a CDR Score of 0 (1.47 ng/dL, P<.001). Likewise, participants with a CDR score of 0.5 (0.006) or ≥1 (0.007) had higher mean neurogranin/Aβ42 levels than those with non-AD dementia (0.0013, P<.001) or CDR scores of 0 (0.003, P<.001).
CSF neurogranin was comparable to other biomarkers for diagnostic accuracy in differentiating between healthy controls and participants with AD. For instance, the mean area under the curve (AUC) for neurogranin was 0.71 compared to 0.81 for p-tau181, 0.85 for tau, 0.77 for Aβ42, and 0.74 for VILIP-1. Similarly, the AUC for the ratios were 0.81 for neurogranin/Aβ42, 0.86 for p-tau181/Aβ42, 0.88 for tau/Aβ42, and 0.85 for VILIP-1/Aβ42.
In participants with preclinical AD, CSF neurogranin correlated with atrophy of the hippocampus (adjusted r=-0.36, P=.03), entorhinal (r=-0.46, P=.006), parahippocampus (r=-0.47, P=.005), amyloid load (r=0.39, P=.02), and whole-brain volume (r=-0.38, P=.02). CSF neurogranin levels were also predictive of future cognitive impairment (aHR 1.89, 95% CI: 1.29 to 2.78, P=.001) and the rate of cognitive decline by annual CDR-SB scores (β estimate 0.29, P=.001), semantic memory scores (β estimate -0.06, P=.04), global composite memory scores (β estimate -0.11, P=.001), and episodic memory scores (β estimate -0.18, P<.001).
“Because most of our AD cohort includes individuals with very mild dementia (CDR score of 0.5), some of whom may elsewhere be classified as having MCI or pre-MCI, neurogranin may be a useful diagnostic marker for even the earliest symptomatic stages of the disease,” the authors wrote.
In an accompanying editorial, Steven T. DeKosky, MD, and Todd Golde, MD, PhD pointed out that CSF neurogranin levels increase over time in patients developing symptomatic AD, with levels elevated during the preclinical period. They hypothesized that evidence of reversal or cessation of neurogranin levels following therapy would indicate protection of nervous tissue.
However, they noted that the utility of these biomarkers is limited by the need for serial lumbar punctures and most importantly a disease-modifying treatment for AD.
- Tarawneh R, D’Angelo G, Crimmins D, et al. Diagnostic and Prognostic Utility of the Synaptic Marker Neurogranin in Alzheimer Disease. JAMA Neurol. 2016. doi:10.1001/jamaneurol.2016.0086.
- DeKosky ST, Golde T. Cerebrospinal Biomarkers in Alzheimer Disease—Potential Roles as Markers of Prognosis and Neuroplasticity. JAMA Neurol. 2016. doi:10.1001/jamaneurol.2016.0090.