Potential Neuroprotective Effects of Natural Anti-NMDAR1 Autoantibodies Against Psychiatric Symptoms Associated with Traumatic Brain Injuries

Importance: Traumatic brain injury (TBI) increases the risk of developing psychiatric symptoms such as post-traumatic stress disorder (PTSD), depression and anxiety, however biological risk and resiliency factors that explain the significant heterogeneity in outcomes are limited. Although 5-10% of the population carries natural autoantibodies to the NMDA receptor (anti-NMDAR1) it is unknown if carrying anti-NMDAR1 autoantibodies modifies risk for psychiatric outcomes after TBI. Objective: Since TBI facilitates infiltration of circulating natural anti-NMDAR1 autoantibodies into the brain, we tested the hypothesis that natural anti-NMDAR1 autoantibody levels in plasma may modify risk for development of psychiatric symptoms after TBI. Design Settings and Participants: Data were analyzed from 1025 Marine Resiliency Study-II participants, a longitudinal study that included plasma collection and assessments for TBI, PTSD (Clinician Administered PTSD Scale-IV), depression (Beck Depression Inventory-2) and anxiety symptoms (Beck Anxiety Inventory) before and after a combat deployment to Afghanistan (2010-2013). Plasma anti-NMDAR1 autoantibody levels were quantified using a luciferase-based immunnoassay. Outcomes were post-deployment symptoms and the predictor was a continuous or dichotomous measure of anti-NMDAR1 autoantibody level. Covariates included pre-deployment symptoms, deployment history and experiences. Results: TBI (606 with TBI, 419 without TBI) was associated with significantly greater depression, PTSD and anxiety symptoms post-deployment. In individuals with no TBI history, anti-NMDAR1 autoantibody levels were not associated with symptoms. In individuals that endorsed a TBI however, higher pre-deployment plasma levels of natural anti-NMDAR1 autoantibodies were significantly associated with lower predicted post-deployment depression and PTSD symptoms, but not anxiety. In the TBI group, high autoantibody group membership lowered predicted post-deployment CAPS-IV and BDI-2 scores by 22 and 25% respectively (Cohen's d=0.25-0.32). After deployment, prevalence of moderate-severe depression was significantly lower in participants with high anti-NMDAR1 autoantibodies (.8% [2/256 participants]) compared with participants with low anti-NMDAR1 autoantibodies (3.5% [27/763 participants]), as was prevalence of taking psychotropic medications. Conclusions and Relevance: Natural anti-NMDAR1 autoantibodies may be a "resilience" factor for TBI-associated increases in depression and PTSD symptoms, supporting the hypothesis that natural anti-NMDAR1 autoantibodies could have neuroprotective effects. Mechanistic studies are warranted to understand if plasma natural anti-NMDAR1 autoantibodies reach the CNS to suppress glutamate excitotoxicity associated with TBI.