Plasma Serotonin 2A Receptor Autoantibodies Predict Rapid, Substantial Decline in Neurocognitive Performance in Older Adult Veterans with TBI.

Aim: Traumatic brain injury (TBI) was associated with increased plasma serotonin 2A receptor (5-HT2AR) autoantibodies in adults who experienced neurodegenerative complications. We tested whether the baseline presence of plasma serotonin 2A receptor (5-HT2AR) autoantibodies was a significant predictor of the two-year rate of cognitive decline in middle-aged and older adult TBI.

Methods: Plasma from thirty-five middle-aged and older adult veterans (mean 65 years old) who had suffered traumatic brain injury was subjected to protein-A affinity chromatography. One-fortieth dilution of the resulting immunoglobulin (Ig) G fraction was tested for binding (in ELISA) to a linear synthetic peptide corresponding to the second extracellular loop region of the human 5-HT2A receptor. All available patients completed baseline and two-year follow-up neurocognitive tests of memory (St Louis University Mental Status), processing speed (Digit Symbol Substitution Test) and executive function (Trails-making Test, Part B). Change in cognitive performance was computed as (two-year - baseline) raw test score.

Results: Eighteen patients completed both baseline and two-year follow up neurocognitive tests. TBI patients harboring plasma 5-HT2AR autoantibodies at the baseline examination (n=13) did not differ significantly in their baseline clinical characteristics (age, education level) compared to TBI patients lacking baseline plasma autoantibodies (n=5). Plasma serotonin 2AR antibody-positive patients experienced a significantly greater post-baseline decline in performance on the St Louis University Mental Status test (P=0.0118) and in the Digit Symbol Substitution Test (P=0.011), but not in Trails-making Part B (P=0.129) compared to serotonin 2AR antibody-negative patients. In multivariable linear regression analyses that adjusted for age, baseline presence of plasma 5-HT2AR autoantibody was a significant predictor of the two-year rate of decline in memory, and processing speed. Binding of plasma autoantibody to the serotonin 2A receptor peptide in the enzyme linked immunosorbent assay was also significantly higher (at 1/160th titer of the protein-A eluate= 1 μg/mL IgG) in TBI patients harboring vs. those not harboring baseline plasma 5-HT2AR autoantibodies.

Conclusion: These data suggest that plasma 5-hydroxytryptamine 2A receptor autoantibodies which were increased in approximately two-thirds of middle-aged and older adults following traumatic brain injury predicts rapid and substantial declines in cognitive function (memory and processing speed), independent of age.