QUINOLINIC ACID IS INCREASED IN CSF AND ASSOCIATED WITH MORTALITY AFTER TRAUMATIC BRAIN INJURY IN HUMANS

We tested the hypothesis that quinolinic acid, a tryptophan-derived N- methyl-D-aspartate agonist produced by macrophages and microglia, woul d be increased in CSF after severe traumatic brain injury (TBI) in hum ans, and that this increase would be associated with outcome. We also sought to determine whether therapeutic hypothermia reduced CSF quinol inic acid after injury. Samples of CSF (n = 230) were collected from v entricular catheters in 39 patients (16 to 73 years Old) during the fi rst week after TBI, (Glasgow Coma Scale [GCS] < 8). As part of an ongo ing study, patients were randomized within 6 hours after injury to eit her hypothermia (32 degrees C) or normothermia (37 degrees C) treatmen ts for 24 hours. Otherwise, patients received standard neurointensive care. Quinolinic acid was measured by mass spectrometry. Univariate an d multivariate analyses were used to compare CSF quinolinic acid conce ntrations with age, gender, GCS, time after injury, mortality, and tre atment (hypothermia versus normothermia). Quinolinic acid concentratio n in CSF increased maximally to 463 +/- 128 nmol/L (mean +/- SEM) at 7 2 to 83 hours after TBI. Normal values for quinolinic acid concentrati on in CSF are less than 50 nmol/L. Quinolinic acid concentration was i ncreased 5- to 50-fold in many patients. There was a powerful associat ion between time after TBI and increased quinolinic acid (P < 0.00001) , and quinolinic acid was higher in patients who died than in survivor s (P = 0.003), Age, gender, GCS, and treatment (32 degrees C versus 37 degrees C) did not correlate with CSF quinolinic acid. These data rev eal a large increase in quinolinic acid concentration in CSF after TBI in humans and raise the possibility that this macrophage-derived exci totoxin may contribute to secondary damage.