VGF Peptides in Cerebrospinal Fluid of Patients with Dementia with Lewy Bodies

Abstract

In a previous proteomic study, we identified the neurosecretory protein VGF (VGF) as a potential biomarker for dementia with Lewy bodies (DLB). Here, we extended the study of VGF by comparing levels in cerebrospinal fluid (CSF) from 44 DLB patients, 20 Alzheimer's disease (AD) patients, and 22 cognitively normal controls selected from the Amsterdam Dementia Cohort. CSF was analyzed using two orthogonal analytical methods: (1) In-house-developed quantitative ELISA and (2) selected reaction monitoring (SRM). We further addressed associations of VGF with other CSF biomarkers and cognition. VGF levels were lower in CSF from patients with DLB compared to either AD patients or controls. VGF was positively correlated with CSF tau and α-synuclein (0.55 < r < 0.75), but not with Aβ1-42. In DLB patients, low VGF levels were related to a more advanced cognitive decline at time of first presentation, whereas high levels of VGF were associated with steeper subsequent longitudinal cognitive decline. Hence, CSF VGF levels were lower in DLB compared to both AD and controls across different analytical methods. The strong associations with cognitive decline further points out VGF as a possible disease stage or prognostic marker for DLB.

Keywords: VGF; cerebrospinal fluid; dementia with Lewy bodies; synaptic dysfunction.

Figure 1

CSF VGF in DLB, AD and controls. (A) CSF levels of VGF373-417 measured with ELISA and (B) VGF measured with SRM. The line through the middle of each box corresponds to the median and the lower and the upper lines to the 25th and 75th percentile, respectively. The whiskers extend from the 5th percentile on the bottom to the 95th percentile on the top. Differences between groups were assessed with GLM corrected for age and sex. AD = Alzheimer’s disease; DLB = dementia with Lewy bodies; GLM = general linear model; SRM = selected reaction monitoring; VGF = neurosecretory protein VGF. * p < 0.05, ** p < 0.01, *** p < 0.001.

Figure 2

CSF VGF levels and global cognitive score in DLB. (A) Associations between baseline CSF levels of VGF373-417 levels measured with ELISA and subsequent global cognition in the DLB patient group (n = 44), (B) VGF measured with SRM. Associations are shown using linear regression lines, with all DLB patients classified into two groups with a split-half approach using the median value as cut-off point, according to their CSF VGF levels. For the linear mixed model statistical analysis, continuous CSF VGF levels were used.