Monitoring of β-Amyloid Dynamics after Human Traumatic Brain Injury

Epidemiological evidence links severe or repeated traumatic brain injury (TBI) to the development of Alzheimer's disease (AD). Accumulation of amyloid precursor protein (APP) occurs with high frequency after TBI, particularly in injured axons, and APP may be cleaved to amyloid- (A) peptides playing key pathophysiological roles in AD. We used cerebral microdialysis (MD) to test the hypothesis that interstitial A levels are altered following TBI and are related to the injury type, cerebral energy metabolism, age of the patient, and level of consciousness. In the present report, we evaluated 10 mechanically ventilated patients (7 male, 3 female, ages 18-76 years) with a severe TBI, who had intracranial pressure and MD monitoring. Each MD sample was analyzed for hourly routine energy metabolic biomarkers (MD-lactate, MD-pyruvate, MD-glucose, and MD-lactate/pyruvate ratio), cellular distress biomarkers (MD-glutamate, MD-glycerol), and MD-urea. The remaining MD samples were analyzed for A1-40 (A40; n=765 samples) and A1-42 (A42; n=765 samples) in pooled 2h fractions up to 14 days post-injury, using the Luminex xMAP technique, allowing detection with high temporal resolution of the key A peptides A40 and A42. Data are presented using medians and 25th and 75th percentiles. Both A40 and A42 were consistently higher in patients with predominately diffuse axonal injury compared with patients with focal TBI at days 1-6 post- injury, A42 being significantly increased at 113-116h post-injury (p<0.05). The A levels did not correlate with the interstitial energy metabolic situation, age of the patient, or the level of consciousness. These results support that interstitial generation of potentially toxic A species may occur following human TBI, particularly related to axonal injury.