Amyloid-beta dynamics correlate with neurological status in the injured human brain

Abstract

The amyloid-beta peptide (Abeta) plays a central pathophysiological role in Alzheimer's disease, but little is known about the concentration and dynamics of this secreted peptide in the extracellular space of the human brain. We used intracerebral microdialysis to obtain serial brain interstitial fluid (ISF) samples in 18 patients who were undergoing invasive intracranial monitoring after acute brain injury. We found a strong positive correlation between changes in brain ISF Abeta concentrations and neurological status, with Abeta concentrations increasing as neurological status improved and falling when neurological status declined. Brain ISF Abeta concentrations were also lower when other cerebral physiological and metabolic abnormalities reflected depressed neuronal function. Such dynamics fit well with the hypothesis that neuronal activity regulates extracellular Abeta concentration.

Fig. 1

Aβ dynamics in human brain ISF assessed with intracerebral microdialysis after acute injury. (A, C, and E) Computerized tomography scans demonstrating location of microdialysis catheters; the radio-opaque gold tips of the catheters are indicated by red arrows. (B, D, and F) Brain ISF Aβ concentrations (blue triangles) measured hourly or bihourly in individual patients. Urea (green circles) was measured in several of the same microdialysis samples. Time (x axis) reflects interval from initiation of microdialysis. (G) Trends over time in brain ISF Aβ (***P = 0.0002, Wilcoxon signed rank test). (Left) Individual patient values. Closed triangles: traumatic brain injury patients with catheters placed in right frontal lobe white matter regions with no apparent focal injury (n = 9); x-symbols: traumatic brain injury patients with catheters placed in pericontusional brain tissue (n = 3); open circles: subarachnoid hemorrhage patients with catheters placed in right frontal lobe white matter (n = 6). (Right) Median, interquartile interval across all 18 patients. (H) Brain ISF urea was essentially stable. (Left) Individual patient values; (right) median, interquartile interval.

Fig. 2

Brain ISF Aβ versus ventricular CSF Aβ. (A) Schematic demonstrating placement ofmicrodialysis catheters into subcortical white matter and external ventricular drains into the frontal horn of the lateral ventricle. (B) Simultaneous measurements of Aβ concentrations from brain ISF obtained by microdialysis and from ventricular CSF Aβ in a patient with traumatic brain injury. (C) Assessment of fractional recovery of Aβ during microdialysis. In vivo zeroflow extrapolation from one neurologically normal subject who had microdialysis performed for 24 hours after surgical clipping of an unruptured aneurysm. Triangles and circles represent independent measurements 12 hours apart. This method revealed ~30% recovery at a flow rate of 0.3 μl/min. In vitro recovery at 0.3 μl/min at room temperature (n = 10 catheters) was essentially identical (inset). Error bars (inset) are SEs. (D) Aβ concentrations in 140 paired samples from five patients in which both ventricular CSF and microdialysis measurements were possible. Box: median and interquartile range; whiskers: 5 to 95% confidence interval; circles: outliers. (E) Changes from initial values of Aβ over time in ventricular CSF versus changes from initial values over time in brain ISF. (F) Aβ_1–42 concentrations compared with total Aβ_1−x concentrations in brain ISF (left) and ventricular CSF (right). The correlation in brain ISF was stronger than in ventricular CSF (P = 0.029, difference test).

Fig. 3

Correlations of brain ISF Aβ concentrations with other microdialysis parameters and physiological measures. (A) Brain ISF glucose versus brain ISF Aβ measured in the same microdialysis samples (n = 388 paired measurements). (B) Brain ISF lactate/pyruvate ratio versus brain ISF Aβ (n = 374). (C) Intracranial pressure (ICP) versus brain ISF Aβ (n = 565). (D) Absolute value of the difference between measured temperature cerebral temperature and normal cortical temperature, 37.2°C (27) versus brain ISF Aβ (n = 324). Each point represents a single paired measurement. Data are from 11 to 17 patients. Not all patients had all parameters measured at all time points (see supporting online material). Shaded regions represent mean ± 1 SD of estimated normal values (5, 27, 28).

Fig. 4

Brain ISF Aβ and neurological status. (A to D) Examples of the time course of changes in brain ISF Aβ concentrations and changes in neurological status, as reflected by Glasgow Coma Score (GCS). Aβ changes appear to track (A and B), and in some cases even precede (C), neurological status changes. (E) Correlation of change in brain ISF Aβ from baseline with changes in neurological status across 13 patients in which serial GCS measurements could be reliably obtained (n = 173 paired measurements). (F) Model of brain ISF Aβ dynamics in the setting of acute brain injury.