341. Preliminary investigation of peripheral immune markers and synaptic density in trauma-exposed youth seeking mental health treatment

Abstract

Abstract Background Animal studies show that stress triggers immune dysregulation, leading to elevated levels of pro-inflammatory cytokines and microglial activation. This response is linked to excessive synaptic pruning and reduced synaptic density, potentially raising vulnerability to mental illness. In humans, childhood trauma has been linked with elevated levels of plasma peripheral pro-inflammatory cytokines. At the same time, our previous work showed that childhood trauma is linked with lower synaptic density. This raises an important question about the relationship between peripheral inflammation, childhood trauma, and synaptic density. Aims & Objectives Our aims are to 1) investigate the relationship between immunologically challenged peripheral immune markers and synaptic density, and 2) investigate the relationship between immunologically challenged peripheral immune markers and childhood trauma and associated psychopathology in a sample of youth seeking mental health treatment. Method We recruited a subset of 50 youth (age 16-24) seeking mental health treatment from the Toronto Adolescent and Youth (TAY) Cohort study. Participants completed PET imaging with [18F]SynVesT-1, a probe for the synaptic vesicle glycoprotein 2A (SV2A), a validated proxy for measuring synaptic density. T1-weighted MRI scans were used to delineate 6 regions of interest (ROIs) implicated in stress disorders: the prefrontal, anterior cingulate, and temporal cortices, amygdala, striatum and hippocampus. Time-activity curves were analyzed using a simplified reference tissue model 2 (SRTM2) with the centrum semiovale as the reference region to estimate non-displaceable binding potential (BPND), serving as an index of synaptic density. PET scans were accompanied by optional venous blood draws, which underwent in vitro lipopolysaccharide (LPS) stimulation to generate a panel of immunologically challenged immune markers. Participants also completed psychiatric interviews to determine if they met criteria for any DSM-5 psychiatric conditions, and the Achenbach Adult/Youth Self Report (ASR) to measure psychopathology. Results Fifty participants consented to the PET study, of whom 33 (20.9 years old, 14M, 19F) had blood drawn for analysis. Eighty-eight percent of participants met DSM-5 criteria for each of depression and anxiety, and 46% for each of PTSD and substance use disorders. LPS stimulation significantly increased levels of multiple cytokines (TNF-α, IL-1β, IL-6, TNFRI, IFN-γ, CCL2). Participants with PTSD (n=15) had marginally elevated levels of LPS-stimulated TNFRI (Tumor Necrosis Factor Receptor I) compared to those without PTSD (n=18); p=0.061. LPS-stimulated levels of TNFRI were also marginally positively correlated with psychopathology scores on the Anxious-Depressed subscale of the ASR (r=0.333, p=0.059). Finally, a greater fold change in TNFRI from baseline to LPS condition was associated with lower [18F]SynVesT-1 BPND in prefrontal cortex (r = -0.376, p = 0.031), anterior cingulate cortex (r = -0.351, p = 0.045), and striatum (r = -0.358, p = 0.041). Discussion & Conclusions This is the first study to investigate the relationship between trauma, psychopathology, peripheral inflammation, and synaptic density. We find that greater immunoreactivity is linked with greater psychopathology and lower synaptic density. Immunological studies, however, require a much larger sample, therefore these preliminary findings should be interpreted with caution. We continue to increase the sample size to gain a better understanding of this mechanism.