Increased CSF neurogranin concentration is specific to Alzheimer disease

Abstract

Objective: To assess the specificity of the dendritic protein neurogranin (Ng) in CSF from patients with a broad range of neurodegenerative diseases including a variety of dementias, tauopathies, and synucleinopathies.

Method: An optimized immunoassay was used to analyze CSF Ng in a retrospective cohort of 331 participants with different neurodegenerative diseases, including healthy controls (n = 19), biomarker-proven Alzheimer disease (AD) (n = 100), genetic AD (n = 2), behavioral variant frontotemporal dementia (n = 20), speech variant frontotemporal dementia (n = 21), Lewy body dementia (n = 13), Parkinson disease (n = 31), progressive supranuclear palsy (n = 46), multiple system atrophy (n = 29), as well as a heterogeneous group with non-neurodegenerative cognitive impairment (n = 50). CSF Ng concentrations and correlations of CSF Ng with total tau, phosphorylated tau, and β-amyloid 42 concentrations, Mini-Mental State Examination score, and disease duration in the different groups were investigated.

Results: Median CSF Ng concentration was higher in patients with AD compared to both controls (p < 0.001) and all other disease groups (all p < 0.001) except speech variant frontotemporal dementia. There were no significant differences in CSF Ng concentrations between any other neurodegenerative groups and controls. In addition, we found strong correlations between Ng and total tau (p < 0.001) and phosphorylated tau (p < 0.001).

Conclusions: These results confirm an increase in CSF Ng concentration in patients with AD as previously reported and show that this is specific to AD and not seen in a range of other neurodegenerative diseases.

Figure 1. Increased CSF Ng concentrations in patients with AD

Boxplots showing CSF Ng concentrations across different diagnostic groups. Ng concentrations were significantly higher in the AD group compared to control participants. The lower, upper, and middle lines correspond to the 25th centile, 75th centile, and median, respectively. The whiskers extend to the minimum and maximum Ng data points. For genetic AD, the lower and upper lines of the box correspond to the individual CSF Ng concentrations. The differences between the groups were assessed using Kruskal–Wallis test followed by the Dunn multiple comparisons test. ***Compared to control, p < 0.001; ***compared to AD, p < 0.001. AD = Alzheimer disease (includes typical and atypical); bvFTD = behavioral variant frontotemporal dementia; genetic AD = those with confirmed PSEN1 mutations; HC = healthy controls; LBD = Lewy body dementia; MSA = multiple system atrophy; Ng = neurogranin; non-ND = non-neurodegenerative patients with mood disorder; PD = Parkinson disease; PSP = progressive supranuclear palsy; svFTD = speech variant frontotemporal dementia (includes patients with progressive nonfluent aphasia, semantic dementia, and primary progressive aphasia).

Figure 2. Elevated CSF Ng concentrations in patients with AD-indicative CSF profiles

Scatter plots displaying CSF Ng concentrations in patients with non-AD-indicative (n = 109) and AD-indicative (n = 151) CSF profiles, as well as with gray zone values (n = 52). The middle line shows the median. The lower and upper lines correspond to interquartile range. The differences between the groups were assessed using Kruskal–Wallis test followed by the Dunn multiple comparisons test. A p value <0.01 was considered statistically significant. AD = Alzheimer disease; Ng = neurogranin.