Neurogranin and YKL-40: independent markers of synaptic degeneration and neuroinflammation in Alzheimer's disease

Konstantin Hellwig, Hlin Kvartsberg, Erik Portelius, Ulf Andreasson, Timo Jan Oberstein, Piotr Lewczuk, Kaj Blennow, Johannes Kornhuber, Juan Manuel Maler, Henrik Zetterberg, Philipp Spitzer, Konstantin Hellwig, Hlin Kvartsberg, Erik Portelius, Ulf Andreasson, Timo Jan Oberstein, Piotr Lewczuk, Kaj Blennow, Johannes Kornhuber, Juan Manuel Maler, Henrik Zetterberg, Philipp Spitzer

Abstract

Introduction: Neuroinflammation and synaptic degeneration are major neuropathological hallmarks in Alzheimer's disease (AD). Neurogranin and YKL-40 in cerebrospinal fluid (CSF) are newly discovered markers indicating synaptic damage and microglial activation, respectively.

Methods: CSF samples from 95 individuals including 39 patients with AD dementia (AD-D), 13 with mild cognitive impairment (MCI) due to AD (MCI-AD), 29 with MCI not due to AD (MCI-o) and 14 patients with non-AD dementias (non-AD-D) were analyzed for neurogranin and YKL-40.

Results: Patients with dementia or MCI due to AD showed elevated levels of CSF neurogranin (p < 0.001 for AD-D and p < 0.05 for MCI-AD) and YKL-40 (p < 0.05 for AD-D and p = 0.15 for MCI-AD) compared to mildly cognitively impaired subjects not diagnosed with AD. CSF levels of neurogranin and YKL-40 did not differ between MCI not due to AD and non-AD dementias. In AD subjects no correlation between YKL-40 and neurogranin was found. The CSF neurogranin levels correlated moderately with tau and p-tau but not with Aβ42 or the MMSE in AD samples. No relevant associations between YKL-40 and MMSE or the core AD biomarkers, Aβ42, t-tau and p-tau were found in AD subjects.

Conclusions: Neurogranin and YKL-40 are promising AD biomarkers, independent of and complementary to the established core AD biomarkers, reflecting additional pathological changes in the course of AD.

Figures

Fig. 1
Fig. 1
Increased levels of cerebrospinal fluid (CSF) neurogranin and YKL-40 in Alzheimer’s disease. Scatterplots of CSF neurogranin (a) and YKL-40 (b) in patients with mild cognitive impairment not due to Alzheimer’s disease (MCI-o, black squares), mild cognitive impairment due to AD (MCI-AD, circles with a cross), Alzheimer’s disease dementia (AD-D, black circles), and non-Alzheimer’s disease dementia (non-AD-D), consisting of frontotemporal lobar degeneration (withe circles), vascular dementia (semi-filled squares), dementia with Lewy bodies (white squares), and dementia of unknown origin (semi-filled circles). Data are presented as median and interquartile range. Differences between the groups were calculated with the Kruskal–Wallis test followed by Dunn’s posttest. *p < 0.05, **p < 0.01, ***p < 0.001
Fig. 2
Fig. 2
Neurogranin is correlated with total tau (t-tau), phosphorylated tau (p-tau), and β-amyloid (Aβ40), especially in subjects without Alzheimer’s disease (non-AD). Cerebrospinal fluid levels of neurogranin in the non-AD group (a, c, e, g, and i) and patients in the AD group (b, d, f, h, and j) are plotted against YKL-40 (a, b) and core AD biomarkers (c–j). Correlations were calculated using Spearman’s rank correlation coefficient
Fig. 3
Fig. 3
Neurogranin and YKL-40 are not correlated with Mini Mental State Examination (MMSE) scores. Cerebrospinal fluid levels of neurogranin (a, b) and YKL-40 (c, d) are plotted against MMSE scores in the non-AD group (a, c) and the AD group (b, d). Correlations were calculated using Spearman’s rank correlation coefficient
Fig. 4
Fig. 4
Neurogranin distinguishes Alzheimer’s disease (AD) from non-AD subjects well. Receiver operating characteristic curves of neurogranin (black circles), YKL-40 (black triangles), and the product of neurogranin × YKL-40 (white circles) for the discrimination between samples within the non-AD group and the AD group. AUC area under the curve

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