Circulating biomarkers and neuroanatomical brain structures differ in older adults with and without post-traumatic stress disorder

Abstract

The aim of this study was to advance post-traumatic stress disorder (PTSD) understanding in older adults (48-77 years) by determining if circulating cytokines (IL-1β, IL-2, IL-4, IL-6, IL-12p70, IL17A and TNFα), brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF-A) and neuroanatomical brain volumes (grey and white matter, hippocampus, and amygdala) significantly differed in those with versus without PTSD. While none of the tested cytokines showed a significant difference, serum BDNF and VEGF-A levels were found to be significantly higher in the PTSD cohort. The assay used for BDNF quantification was important, with differences in general BDNF detected, but not when pro- and mature BDNF were measured specifically. Additionally, BDNF genotyping revealed a significant difference in Val66Met genotype distribution by PTSD diagnosis, with Val66Met carriers generally having lower circulating levels of BDNF compared to their Val66Val counterparts, regardless of PTSD diagnosis. Neuroanatomically, an all-female subset was examined to find total grey and white matter volumes and left and right hippocampal volumes were significantly smaller in those with PTSD. Collectively, these results show that both novel (VEGF-A) and established targets (BDNF and neuroimaging) may serve as useful biomarkers for older adults with PTSD.

Keywords: BDNF; Cytokines; Hippocampus; PTSD; VEGF-A; Val66Met.

Fig. 1

Violin plots depicting BDNF levels in plasma and serum between PTSD and non-PTSD cohorts measured as (a) BDNF (via xMAP multiplex technology), (b) Mature BDNF (via ELISA technology), (c) ProBDNF (via ELISA technology) and (d) Mature BDNF and ProBDNF added together (via ELISA technology) (Mann Whitney U test). Coloured circles represent individual sample concentrations (the coloured triangle in non-PTSD plasma plots identifies a participant with an outlier proBDNF value in each test set); Unfilled circles represent samples below the assay detection limit which were assigned values of half the lower limit of quantification (LLOQ) for analysis; Solid faded circles represent samples with concentrations estimated from the analysis software (detectable but below the LLOQ); Line represents the sample set mean; White square represents the sample set median; NS = not significant (p > 0.05). (e) Spearman’s rank correlations of BDNF measurements between testing methods in plasma and serum. Correlations with significance of p ≤ 0.002 are shown in white text with red asterisk; all other non-significant correlations are shown in black text; r_s(45) in plasma, r_s(46) in serum.

Fig. 2

PTSD and non-PTSD cohorts by BDNF Val66Met (rs6265) polymorphism. (a) Genotype distribution by PTSD diagnosis (Fisher-Freeman-Halton Exact test = 7.284, p = 0.015). Violin plots of plasma and serum levels of (b) BDNF (xMAP), (c) Mature BDNF (ELISA) and (d) ProBDNF (ELISA) by both PTSD diagnosis and genotype. Overall group differences were determined using the Kruskal-Wallis H test. Pairwise differences, when significant after Bonferroni correction for multiple tests, are indicated within the graphs by a bar and p-value. Coloured circles represent individual sample concentrations; Unfilled circles represent samples below the assay detection limit which were assigned values of half the lower limit of quantification (LLOQ) for analysis; Solid faded circles represent samples with concentrations estimated from the analysis software (detectable but below the LLOQ); Line represents the sample set mean; White square represents the sample set median; NS = not significant (p > 0.05), *indicates p values still significant after Bonferroni multi-comparison correction (p ≤ 0.013).

Fig. 3

Violin plots depicting VEGF-A levels in plasma and serum between PTSD and non-PTSD cohorts measured via xMAP multiplex technology (Mann Whitney U test). Coloured circles represent individual sample concentrations; Line represents the sample set mean; White square represents the sample set median; NS = not significant (p > 0.05).

Fig. 4

Neuroanatomical volumes by PTSD diagnosis. (a) Overview diagram depicting targeted regions: total white matter (light grey), total grey matter (dark grey), hippocampus (green) and amygdala (red). Violin plots depicting (b) total white matter, (c) total grey matter, (d) hippocampus (left and right) and (e) amygdala (left and right) volumes by PTSD cohort (Independent sample t-test). Circles represent individuals; Line represents the sample set mean; White square represents the sample set median; NS = not significant (p > 0.05).