Patients with posttraumatic stress disorder may exhibit coordinated molecular changes involving redox metabolism, neuronal signaling, immune activation, and accelerated biological aging. Researchers identified distinct plasma protein and metabolite signatures associated with chronic posttraumatic stress disorder.
In a study, they analyzed plasma samples from 393 World Trade Center responders, including 232 patients with posttraumatic stress disorder (PTSD) and 161 trauma-exposed controls. Using the SomaScan platform, they measured 9,404 protein analytes and performed targeted metabolomic profiling of 145 metabolites. The primary outcome of the study was differential protein and metabolite expression associated with PTSD. Secondary analyses evaluated integrated proteomic-metabolomic networks, enriched biological pathways, replication across previous omics studies, and organ-specific proteomic aging.
Researchers identified 121 significantly altered protein analytes corresponding to 114 unique proteins and seven differentially expressed metabolites. Among the most prominent findings were alterations in the proteins NCAN, BCAN, NCAM1, and GDF15 as well as increases in the metabolites lactate, glutamic acid, cystathionine, hydroxylysine, proline, and sphingomyelin and decreases in serotonin among the patients with PTSD. The researchers reported that these molecular signatures were associated with alterations in energy metabolism, amino acid metabolism, oxidative stress, and neuronal signaling.
Integrative analyses demonstrated coordinated relationships between metabolites involved in redox and amino acid metabolism and proteins associated with synaptic function, oxidative stress, extracellular matrix remodeling, and immune activity. Gene ontology analyses also identified the enrichment of pathways related to neuronal development and repair, glial differentiation, axon regeneration, immune activation, extracellular matrix organization, and oxidative stress.
In proteomic aging analyses, the researchers uncovered accelerated biological aging among the patients with PTSD, who exhibited accelerated proteomic aging signatures involving the pancreas, lungs, and organismal-level aging models compared with trauma-exposed controls. The findings remained consistent across multiple sensitivity analyses adjusting for body mass index, smoking status, World Trade Center exposure, drug use, medical comorbidities, and depressive symptom severity. The researchers also reported broad concordance with previous proteomic and metabolomic studies of PTSD, including the replication of several previously identified protein associations.
The researchers acknowledged several limitations. The cross-sectional case-control design precluded conclusions about causality or temporal relationships. The study population consisted exclusively of World Trade Center responders and represented an enriched sample of patients with chronic PTSD, which may limit generalizability to other populations. In addition, plasma-based biomarkers may not fully reflect biological processes within specific organs or the brain, and residual confounding could not be excluded.
Overall, the findings suggested that chronic PTSD may be associated with coordinated redox-metabolic alterations and accelerated biological aging across multiple organ systems. The researchers noted that longitudinal studies will be needed to determine whether these molecular signatures predict disease progression, treatment response, or long-term health outcomes.
"Together, these findings indicate that PTSD is accompanied by coordinated, multisystem molecular dysregulation that extends well beyond the central nervous system," wrote lead study author Pei-Fen Kuan, PhD, of the Department of Applied Mathematics and Statistics at Stony Brook University, and colleagues.
The study authors declared no competing interests.
Source: Nature Communications
