Potential Neuroprotective Effects of Natural Anti-NMDAR1 Autoantibodies Against Psychiatric Symptoms Associated with
Melonie Vaughn1, Dean Acheson1,2, Susan Powell1,3
1Department of Psychiatry, University of California San Diego, La Jolla, California, CA 92093, United States of America.
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.
