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Observational Study
. 2020 May 12;11(1):2360.
doi: 10.1038/s41467-020-15930-5.

PTSD is associated with neuroimmune suppression: evidence from PET imaging and postmortem transcriptomic studies

Shivani Bhatt  1 , Ansel T Hillmer  2   3   4 , Matthew J Girgenti  3   5 , Aleksandra Rusowicz  3 , Michael Kapinos  4 , Nabeel Nabulsi  2   4 , Yiyun Huang  2   4 , David Matuskey  2   3   4 , Gustavo A Angarita  3   4 , Irina Esterlis  1   3   4   5 , Margaret T Davis  3 , Steven M Southwick  3   5 , Matthew J Friedman  6 ; Traumatic Stress Brain Study Group; Ronald S Duman  3 , Richard E Carson  2   4 , John H Krystal  3   5 , Robert H Pietrzak  3   5 , Kelly P Cosgrove  7   8   9   10   11
Collaborators, Affiliations
Observational Study

PTSD is associated with neuroimmune suppression: evidence from PET imaging and postmortem transcriptomic studies

Shivani Bhatt et al. Nat Commun. .

Abstract

Despite well-known peripheral immune activation in posttraumatic stress disorder (PTSD), there are no studies of brain immunologic regulation in individuals with PTSD. [11C]PBR28 Positron Emission Tomography brain imaging of the 18-kDa translocator protein (TSPO), a microglial biomarker, was conducted in 23 individuals with PTSD and 26 healthy individuals-with or without trauma exposure. Prefrontal-limbic TSPO availability in the PTSD group was negatively associated with PTSD symptom severity and was significantly lower than in controls. Higher C-reactive protein levels were also associated with lower prefrontal-limbic TSPO availability and PTSD severity. An independent postmortem study found no differential gene expression in 22 PTSD vs. 22 controls, but showed lower relative expression of TSPO and microglia-associated genes TNFRSF14 and TSPOAP1 in a female PTSD subgroup. These findings suggest that peripheral immune activation in PTSD is associated with deficient brain microglial activation, challenging prevailing hypotheses positing neuroimmune activation as central to stress-related pathophysiology.

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Conflict of interest statement

Dr. John Krystal acknowledges the following relevant financial interests. He has a patent for glutamate modulator, riluzole, in augmentative treatment of anxiety disorders that was licensed by Biohaven Medical Sciences. His annual income from consultation for any of several pharmaceutical companies is not expected to exceed $10,000 in 2019. He holds stock in Biohaven Pharmaceuticals, Sage Pharmaceuticals, and Spring Care. He also receives over $10,000 from Society of Biological Psychiatry for his services as editor of the journal, Biological Psychiatry. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Prefrontal-limbic TSPO availability was associated with PTSD severity.
Lower [11C]PBR28 VT was significantly associated with greater PTSD severity (R2 = 0.51, p = 0.003; β = −0.43, p = 0.046), quantified by normalized total severity scores on CAPS in the PTSD group (n = 23). Coefficient of determination and standardized coefficients were assessed using linear regression. Displayed composite prefrontal-limbic [11C]PBR28 VT values are genotype- and sex-adjusted, with gray shading indicating 95% confidence intervals.
Fig. 2
Fig. 2. Prefrontal-limbic circuit TSPO availability was lower in the PTSD vs. control group.
[11C]PBR28 VT in the prefrontal-limbic circuit composed of amygdala, anterior cingulate cortex, hippocampus, insula, and vmPFC, was lower (F5,41 = 2.46, p = 0.049) in the PTSD (pink triangles, n = 23) compared to control (green circles, n = 26) group. A 14% difference in [11C]PBR28 VT between groups was observed in insula (p = 0.036) and vmPFC (p = 0.023). Group differences were assessed using MANOVA and within-ROI comparisons assessed using ANOVA. Displayed [11C]PBR28 VT values are adjusted for genotype and sex, with group-wise mean indicated by black point. AMYG: amygdala, ACC: anterior cingulate cortex, HIPP: hippocampus, INS: insula, VMPFC: ventromedial prefrontal cortex. *p < 0.05, not corrected for multiple comparisons.
Fig. 3
Fig. 3. CRP was negatively associated with prefrontal-limbic TSPO availability and positively associated with PTSD severity.
a Lower [11C]PBR28 VT was significantly associated with higher levels of CRP (R2 = 0.52, p = 0.005; β = −0.92, p = 0.029) in the PTSD group (n = 21). Displayed [11C]PBR28 VT values are adjusted for genotype and sex. b Higher CRP was significantly associated with greater PTSD severity (R2 = 0.21, p = 0.037) in the PTSD group (n = 21). Coefficient of determination and standardized coefficients were assessed using linear regression. Gray shading indicates 95% confidence intervals.
Fig. 4
Fig. 4. Expression of TSPO, TNFRSF14, and TSPOAP1 genes was lower in areas comprising the prefrontal cortex in a postmortem brain sample.
a In females with PTSD (n = 11) relative to female controls (n = 11), TSPO expression was significantly lower in BA11 (−2.30-fold lower (±0.10), p = 0.01), but not in BA25. Prefrontal cortex TSPO expression was not significantly lower in PTSD (n = 22) relative to controls (n = 22) combined across sex. b Relative expression of TNFRSF14 was significantly lower in BA11 (−1.60-fold (±0.03), p = 0.01) and in BA25 (−1.30-fold (±0.02), p = 0.04) in the female PTSD subgroup (n = 11 per subgroup). Relative expression of TSPOAP1 was significantly lower in BA11 (−1.60-fold (±0.06), p = 0.04) in the female PTSD subgroup (n = 11 per subgroup). Apparent lower relative expression did not reach statistical significance for TSPO and TSPOAP1 in BA25 in the female subgroup, and for TSPO, TNFRSF14, and TSPOAP1 in BA11 in PTSD vs. controls combined across sex. Mann-Whitney U tests were used to assess differences in fold change. Displayed values are shown as fold change (−log2(ddCT))-1, representing the fold change in transcript expression, or the ratio of the average dCT in the PTSD relative to average dCT in the control group. Error bars indicate the log-corrected SD of dCT calculated from the comparison PTSD sample. *p < 0.05, after Bonferroni correction for multiple comparisons for two exploratory genes.
See this image and copyright information in PMC

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