Association Of Cerebrospinal Fluid Neurogranin Levels With Cognition And Neurodegeneration In Alzheimer’s Disease

Objective: Alzheimer’s disease(AD)is a progressive neurodegenerative disease with complex and diverse pathophysiological mechanisms.Synaptic dysfunction is an early pathologic substrate of AD and is linked to cognitive symptoms in AD.Neurogranin(Ng)is a postsynaptic neuronal protein that has demonstrated utility as a cerebrospinal fluid(CSF)marker of synaptic dysfunction in AD.CSF Ng levels are increased in AD,including in the predementia stage of the disease.This study was designed to investigate the correlation between CSF Ng levels and cognition and neurodegeneration in AD and to investigate the utility of CSF Ng for diagnosis and monitoring of AD.Methods: Participants were individuals with a clinical diagnosis of cognitively normal(CN)controls(n=111),mild cognitive impairment(MCI)patients(n=193)and AD patients(n=95)in the Alzheimer’s Disease Neuroimaging Initiative(ADNI)cohort.Clinical follow-up data were available for 187 subjects with MCI(80 remained stable(sMCI),107 progressed to AD(pMCI)).Tests of inter-group differences were performed using Kruskal-Wallis test.Linear regression models were constructed to examine the cross-sectional associations between CSF Ng levels and CSF core biomarkers(CSF amyloid-β(Aβ),phosphorylated-tau(p-tau),and total-tau(t-tau))at baseline.Associations between CSF Ng levels and longitudinal cognitive,metabolic and structural data were assessed using linear mixed-effects model.The receiver-operator curves(ROC)and the area under the curves(AUC)were used to investigate the diagnostic and prognostic utility of CSF Ng levels.Cox proportional hazard regression models were used to determine whether the baseline CSF Ng levels predict future cognitive impairment.Results: Mean CSF Ng levels were higher in AD patients and pMCI subjects compared with stable MCI(sMCI)subjects or CN controls.Mean CSF Ng levels were higher in sMCI subjects compared with CN controls.When comparing by Aβ status,Ng values were differentially increased in Aβ+ CN and Aβ+ MCI individuals.The diagnostic accuracy of CSF Ng in differentiating patients with AD from CN was comparable to that of the core CSF biomarkers.CSF Ng levels correlated with CSF p-tau and t-tau levels within each diagnostic group.High baseline CSF Ng levels correlated with longitudinal reductions in cortical glucose metabolism within each diagnostic group and hippocampal volume within MCI group during follow-up.In addition,high baseline CSF Ng levels correlated with cognitive decline as reflected by decreased cognitive scale scores.The CSF Ng levels offered prognostic utility for future cognitive decline in CN controls,the mean AUC was 0.73.Elevated CSF Ng levels was associated with a 3.66-fold increased risk of MCI(95% Confidence Interval(CI): 1.74-7.70,P = 0.001).Conclusion: CSF Ng offers diagnostic utility for AD and complements the collective ability of established AD biomarkers to predict future cognitive decline in cognitively normal individuals and,therefore,will be a useful addition to the current panel of AD biomarkers.