Mechanistic signatures of comorbid PTSD with cognitive impairment implicate cortisol-induced neural toxicity.
Authors
Affiliations (11)
Affiliations (11)
- Department of Biomedical Engineering, State University of New York at Stony Brook, Stony Brook, NY, USA.
- Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
- Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY, USA.
- Program in Public Health, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA.
- Department of Family, Population, and Preventive Medicine, Renaissance School of Medicine at Stony Brook, Stony Brook, NY, USA.
- World Trade Center Health Program, Commack, NY, USA.
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA.
- Department of Biomedical Engineering, State University of New York at Stony Brook, Stony Brook, NY, USA. [email protected].
- Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA. [email protected].
- Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY, USA. [email protected].
- Santa Fe Institute, Santa Fe, NM, USA. [email protected].
Abstract
The men and women who worked in rescue and recovery operations at the 9/11 World Trade Center site are developing cognitive impairment (CI) at mid-life, decades before CI is usually detected. To date, one of the most consistent risk factors for CI in this population is symptoms of post-traumatic stress disorder (PTSD). However, little is known about the mechanistic cascade that drives stress-related neurological changes to accelerate cognitive decline in the human brain. We used machine learning to identify distinct brain signatures from functional magnetic resonance imaging between trauma-exposed healthy controls (TEHC; N = 30; 21 men), PTSD without CI (PTSD-CI; N = 19; 16 men), and PTSD with CI (PTSD + CI; N = 22; 18 men). We compared the spatial gradient of each functional signature to the distribution of mRNA expression in the brain. We applied structural equation modeling (SEM) to infer mechanistic cascades specific to each group. While modest accuracy was achieved for the PTSD-CI versus TEHC signature (0.67), clear differentiation was observed for PTSD + CI versus TEHC (0.73) and PTSD + CI versus PTSD-CI (0.85). Consistent significant correlations were found between PTSD + CI signatures and ZNF48, TOMM40, and GRIN1 expression distributions. The cortisol-induced neurotoxicity pathway was consistently found with the PTSD + CI signature, while the p53 signaling pathway was observed across all PTSD signatures. Our results reinforce peripheral biomarkers from a previous transcriptomic study and suggest functional biomarkers in PTSD and PTSD-related CI. Furthermore, our SEM results suggest that PTSD and PTSD-related CI may diverge at the mechanistic level, with neurotoxicity being specific to CI.