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. 2012 Apr;135(Pt 4):1268-80.
doi: 10.1093/brain/awr286. Epub 2011 Nov 23.

Tau elevations in the brain extracellular space correlate with reduced amyloid-β levels and predict adverse clinical outcomes after severe traumatic brain injury

Sandra Magnoni  1 , Thomas J Esparza, Valeria Conte, Marco Carbonara, Giorgio Carrabba, David M Holtzman, Greg J Zipfel, Nino Stocchetti, David L Brody
Affiliations

Tau elevations in the brain extracellular space correlate with reduced amyloid-β levels and predict adverse clinical outcomes after severe traumatic brain injury

Sandra Magnoni et al. Brain. 2012 Apr.

Abstract

Axonal injury is believed to be a major determinant of adverse outcomes following traumatic brain injury. However, it has been difficult to assess acutely the severity of axonal injury in human traumatic brain injury patients. We hypothesized that microdialysis-based measurements of the brain extracellular fluid levels of tau and neurofilament light chain, two low molecular weight axonal proteins, could be helpful in this regard. To test this hypothesis, 100 kDa cut-off microdialysis catheters were placed in 16 patients with severe traumatic brain injury at two neurological/neurosurgical intensive care units. Tau levels in the microdialysis samples were highest early and fell over time in all patients. Initial tau levels were >3-fold higher in patients with microdialysis catheters placed in pericontusional regions than in patients in whom catheters were placed in normal-appearing right frontal lobe tissue (P = 0.005). Tau levels and neurofilament light-chain levels were positively correlated (r = 0.6, P = 0.013). Neurofilament light-chain levels were also higher in patients with pericontusional catheters (P = 0.04). Interestingly, initial tau levels were inversely correlated with initial amyloid-β levels measured in the same samples (r = -0.87, P = 0.000023). This could be due to reduced synaptic activity in areas with substantial axonal injury, as amyloid-β release is closely coupled with synaptic activity. Importantly, high initial tau levels correlated with worse clinical outcomes, as assessed using the Glasgow Outcome Scale 6 months after injury (r = -0.6, P = 0.018). Taken together, our data add support for the hypothesis that axonal injury may be related to long-term impairments following traumatic brain injury. Microdialysis-based measurement of tau levels in the brain extracellular space may be a useful way to assess the severity of axonal injury acutely in the intensive care unit. Further studies with larger numbers of patients will be required to assess the reproducibility of these findings and to determine whether this approach provides added value when combined with clinical and radiological information.

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Figures

Figure 1
Figure 1
Verification of the accuracy of sequential ELISA methods using mock microdialysis samples. Symbols indicate measured sample points. Dashed lines indicate linear best fits and 95% CIs. (A) NF-L sequential ELISA after Aβ1-x ELISA versus NF-L as the first ELISA: r2 = 0.99, slope 95% CI 0.90–0.99, y-intercept 95% CI −17.6 to 8.1. (B) Tau sequential ELISA after Aβ1-x ELISA versus tau as the first ELISA. r2 = 0.99, slope 95% CI 0.99–1.05, y-intercept 95% CI −20.5 to 2.3. (C) Tau sequential ELISA after NF-L ELISA versus tau as the first ELISA. r2 = 0.99, slope 95% CI 0.99–1.03, y-intercept 95% CI −17.7 to 3.4. (D–F) Bland-Altman plots for the data presented in panels (A–C).
Figure 2
Figure 2
Examples of microdialysis-based measurements of tau and Aβ dynamics in the injured human brain. (A) CT scan of the brain from a patient in the non-contusional group. Microdialysis catheters tip (red arrow) apparent in normal-appearing right frontal subcortical white matter.(B) Brain interstitial fluid Aβ (left y-axis) and tau (right y-axis) levels as a function of time (h) since placement of the microdialysis catheter. (C and D) CT scan plus brain interstitial fluid Aβ and tau levels from another non-contusional patient. (E–H) CT scans plus brain interstitial fluid Aβ and tau levels from two patients with traumatic frontal contusions. Microdialysis catheter tips (red arrows) apparent near the frontal lobe contusions.
Figure 3
Figure 3
Tau and Aβ measurements in non-contusional versus pericontusional groups. (A) Mean tau levels during the initial 24 h of microdialysis sampling were higher in patients with catheters placed in pericontusional regions: Error bars represent median and 25–75th percentiles (**P = 0.005, Mann–Whitney U-test). (B) Mean Aβ levels during the initial 24 h of microdialysis sampling were lower in pericontusional group (**P = 0.0012). (C) Tau levels decreased with time in all patients (*P = 0.0078 for non-contusional group, P = 0.016 for pericontusional group, Wilcoxon paired rank tests). (D) Aβ levels rose over time in all but one non-contusional patient (P = 0.29) and all but one pericontusional patient (*P = 0.031). NS = not significant.
Figure 4
Figure 4
Correlations between tau and other microdialysis analytes. (A) Inverse correlation between initial Aβ levels and initial tau levels. (B) No correlation between the per cent change in Aβ levels and per cent change in tau levels. (C) Inverse correlation between initial brain interstitial fluid glucose levels and initial tau levels. (D) No significant correlation between initial brain interstitial fluid pyruvate levels and initial tau levels. (E) No correlation between initial brain interstitial fluid lactate levels and initial tau levels. (F) No correlation between initial brain interstitial fluid glutamate levels and initial tau levels. (G) No significant correlation between initial brain interstitial fluid lactate/pyruvate levels and initial tau levels. Shaded regions represent mean  ± 1 standard deviation of estimated normal values (Reinstrup et al., 2000; Hillered et al., 2005). NS = not significant.
Figure 5
Figure 5
Close correspondence between microdialysis measurements of tau and NF-L. (A) Example of microdialysis-based measurements of brain interstitial fluid tau (left y-axis) and NF-L (right y-axis) dynamics in a non-contusional patient. (B) Positive correlation between initial tau and NF-L levels in 16 patients.
Figure 6
Figure 6
Tau levels, but not levels of other microdialysis analytes, predicted overall clinical outcomes 6 months after injury. (A) Significant correlation between tau levels in the first 12 h after catheter placement and overall clinical outcomes. Better outcomes indicated by higher Glasgow Outcome Score-Extended scores. (B) Non-significant correlation between initial Aβ levels and clinical outcomes. (C) No correlation between initial brain interstitial fluid glucose levels and clinical outcomes. (D) Non-significant correlation between initial brain interstitial fluid lactate/pyruvate levels and clinical outcomes. (E) Non-significant correlation between initial brain interstitial fluid glutamate levels and clinical outcomes. NS = not significant.
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