Amyloid-ss Dynamics Correlate with Neurological Status in the Injured Human Brain

The amyloid-β peptide (Aβ) 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 Aβ concentrations and neurological status, with Aβ concentrations increasing as neurological status improved and falling when neurological status declined. Brain ISF Aβ 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 Aβ concentration. Aβ is the principal constituent of the hallmark amyloid plaques found in Alzheimer’s disease and is the target of many potential treatments for the disease (1). However, little is known about the concentration and dynamics of this secreted peptide in the extracellular space of the human brain where these plaques form. In vitro and animal studies have shown that neuronal and synaptic activity dynamically regulate soluble extracellular Aβ concentrations (2–4). Whether similar regulation of Aβ levels occurs in the human brain is unknown. We used intracerebral microdialysis (5) to obtain serial brain interstitial fluid (ISF) samples in 18 intensive care unit (ICU) patients who had sustained acute brain injury and were undergoing invasive intracranial monitoring for clinical purposes. In all patients, Aβ1−x was detected in hourly or bihourly intracranial microdialysis samples. None had a diagnosis of Alzheimer’s disease or dementia, demonstrating that Aβ is a normal constituent of human brain extracellular fluid (6). The Aβ1−x enzyme-linked immunosorbent assay (ELISA) used detects Aβ species from amino acid 1 to amino acid 28 or greater (3,7). There were rising trends in brain ISF Aβ concentrations over several hours to days in most patients, though the specific pattern of these trends was variable (Fig. 1, B, D, and F;Fig. 2B; and Fig. 4, A to D). Median brain ISF Aβ1−x at 60 to 72 hours was 59% higher than at 0 to 12 hours (Fig. 1G) (P = 0.0002, Wilcoxon signed rank test). Urea concentrations in the same samples, which control for the stability of