Amyloid-Beta Changes Seen in Injured Brains

By Michael Smith
ST. LOUIS, 29 aug 2008-- In patients with brain injury, recovery is correlated with increased levels of some of the peptides associated with Alzheimer's disease, researchers here said. The finding emerged from the first direct measurement of amyloid-beta levels in the interstitial fluid of the brains of living humans, according to David Brody, M.D., Ph.D., of Washington University and colleagues. The analysis, using a technique called microdialysis, showed that levels of amyloid-beta rose as patients' neurological status improved and fell when it worsened, Dr. Brody and colleagues reported in the Aug. 29 issue of Science. He and colleagues undertook the study -- in 18 patients already undergoing invasive intracranial monitoring after either brain trauma or aneurysmal subarachnoid hemorrhage -- to increase their understanding of the dynamics of amyloid-beta peptides.
Amyloid-beta (especially the 42-amino acid form) plays a central role in the development of Alzheimer's, and people with brain injuries are known to be at higher risk of later developing the illness.
"Amyloid-beta is normally present in the cerebrospinal fluid and it was generally believed to be a normal component of the brain extracellular fluid," he said. "This is the first time that has been demonstrated."
The key finding of the analysis was the close link between neurological status, as measured by the Glasgow Coma Score, and levels of amyloid-beta, he said.
Because the clinical significance of a one-point change in the coma score isn't clear, the researchers assessed changes in the amyloid-beta levels only when the score changed by two or more points.

The correlation "was markedly strong," they found, with a Spearman r of 0.82, which was significant at P<0.0001, and remained "quite robust" when the analysis allowed one-point coma score changes. (The Spearman r was 0.52, which was also significant at P<0.0001).
The correlation was present both in patients with traumatic injury and subarachnoid hemorrhage, Dr. Brody and colleagues reported.
Levels of amyloid-beta were also correlated with physiological markers, they said. Specifically, they were:
Positively correlated with glucose in the brain interstitial fluid (where the Spearman r was 0.45, significant at P<0.0001).
Negatively correlated with the lactate/pyruvate ratio, with a Spearman r of minus 0.40, which was significant at P<0.0001.
Negatively correlated with elevated intracranial pressure (greater than 20 mm Hg) with a Spearman r of minus 0.56, which was significant at P<0.0001.
Negatively correlated with extremes of cerebral temperature, with a Spearman r of minus 0.26, which was significant at P<0.0001.
One implication of the finding is that the level of amyloid-beta reflects brain activity.
The "most likely" explanation, Dr. Brody said, is that the levels rose as patients improved "because synaptic activity in their brains increased concomitantly with the improvement in neurological status."
The study is only a first step in understanding how amyloid-beta levels vary over time, Dr. Brody said. Among other things, the researchers were unable to measure what was happening within the cells of the damaged brains, so that analysis is incomplete.
One immediate clinical implication, he said, is that amyloid-beta levels "could be used as a marker for neurological status," which is now difficult for clinicians to measure.
The study was supported by the NIH, a Burroughs Wellcome Career Award in the Biomedical Sciences, and the Cure Alzheimer's Fund. Eli Lilly and Co. provided antibodies. The researchers reported no conflicts.
Primary source: ScienceSource reference:Brody DL, et al "Amyloid-b dynamics correlate with neurological status in the injured human brain" Science 2008; 321: 1221-24.