Publications & Posters

CSF and plasma amyloid-β temporal profiles and relationships with neurological status and mortality after severe traumatic brain injury


S. Mondello1, A. Buki2, J. Randall3, G. Provuncher3, D. Hanlon3, D. Wilson3, D. Italiano1, F. Tomasello1, A. Jeromin4Institute(s): 1University of Messina, Messina, Italy, 2University of Pecs, Pecs, Hungary, 3Quanterix Corporation, Lexington, United States, 4NextGen Science Dx, Gainesville, United States

INTRODUCTION. Recent experimental and human studies have shown that traumatic brain injury (TBI) results in significant changes in the concentration and dynamics of amyloid-ß (Aß) in the human brain (1, 2). This condition is believed to accelerate Aß-related pathophysiologic processes and affect neuronal function in patients with severe TBI.

OBJECTIVES. To assess amyloid-ß1-42 (Aß42) concentrations and time-course in CSF and in plasma of patients with severe TBI and their relationship to injury characteristics, neurological status and clinical outcome.

METHODS. A total of 12 patients with severe TBI [Glasgow Coma Scale (GCS) =8] and 20 controls were included in this prospective study. We evaluated levels of Aß42 in paired CSF and plasma samples taken from each TBI patient at admission and daily up to 7 days. Aß42 concentrations were assessed by utilizing an ultrasensitive digital ELISA approach. This method is based on isolating single immunocomplexes labeled with an enzyme in arrays of femtoliter wells, sealing the arrays in the presence of the enzyme substrate, and fluorescently imaging the array. Isolation of single immunocomplexes in this w ay gives rise to a dramatic increase in sensitivity over bulk, ensemble detection methods. The limit of detection was 0.02 pg/mL in plasma. Data collected included demographic and clinical variables as w ell as survival 6 months post-injury.

RESULTS. CSF Aß42 levels w ere significantly lower in TBI patients acutely after injury as compared to controls (median 105.9 vs. 537.6 pg/ml, p< 0.0001) with lower levels in patients who died 6 months post injury than in those who were alive. Conversely, plasma Aß42 levels were significantly increased in TBI as compared to controls (median 17.0 vs.7.3 pg/ml, p< 0.0001) with higher levels in patients who survived. A trend analysis using the Jonckheere-Terpstra test showed that both CSF and plasma Aß42 levels strongly correlated with mortality (P< 0.0001). CSF and plasma Aß42 concentrations within the first 24 hrs after injury did not correlate with TBI characteristics. A positive correlation between changes in CSF Aß42 concentrations and neurological status as assessed by GCS was identified. CSF Aß42 levels tended to increase as neurological status improved and decrease when neurological status deteriorated. There was no correlation between CSF and plasma Aß42 levels.

CONCLUSIONS. These results suggest that determination of Aß42 may be valuable to obtain prognostic information in patients with severe TBI as well as in monitoring the response of the brain to injury.

REFERENCE(S). 1. Magnoni S, Brody DL. Arch Neurol. 2010 Sep;67(9):1068-73. 2. Tran HT, Sanchez L, Esparza TJ, Brody DL. PLoS One. 2011;6(9):e25475.

GRANT ACKNOWLEDGMENT. Supported by Department of Defense (DAMD17-03-1-0772 and DAMD17-03- 1-0066)