Alzheimer's patients can't effectively clear sticky plaque component

December 09, 2010

Neurologists finally have an answer to one of the most important questions about Alzheimer's disease: Do rising brain levels of a plaque-forming substance mean patients are making more of it or that they can no longer clear it from their brains as effectively?

"Clearance is impaired in Alzheimer's disease," says Randall Bateman, MD, assistant professor of neurology at Washington University School of Medicine in St. Louis. "We compared a group of 12 patients with early Alzheimer's disease to 12 age-matched and cognitively normal subjects. Both groups produced amyloid-beta (a-beta) at the same average rate, but there's an average drop of about 30 percent in the clearance rates of the group with Alzheimer's."

Scientists calculate this week in Science Express that it would take 10 years for this decrease in clearance to cause a build-up of a-beta equal to those seen in the brains of Alzheimer's patients.

The results have important implications for both diagnosis and treatment, according to the authors. Scientists are now interested in learning how a-beta, a byproduct of normal metabolism, is moved out of the brain for breakdown and disposal. As these details come in, they will be essential for physicians working to diagnose the disease before symptoms develop and for drug developers, who can target the problems with pharmaceuticals.

A-beta was recognized long ago as a key component of the brain plaques found during autopsies of Alzheimer's patients. One of the ways the brain clears away the a-beta normally produced by brain cell activity is by moving it to the spinal fluid for disposal. Studies have suggested that a drop in spinal fluid levels of a-beta may be a presymptomatic indicator of Alzheimer's disease, possibly because a-beta is getting stuck in the brain and starting to accumulate there.

Recent failures of therapies designed to clear a-beta from the brain have led some neurologists to speculate that a-beta may not be causatively linked to Alzheimer's. According to Bateman, though, the new data show that Alzheimer's is associated with disruption of the brain's ability to handle a-beta normally.

"These findings support the idea that impaired a-beta clearance is fundamentally linked to Alzheimer's disease," Bateman says.

For the new study, scientists used stable isotope-linked kinetics (SILK), a process Bateman and his colleagues developed, to assess a-beta clearance and production rates.

During SILK, researchers give test subjects an intravenous drip of the amino acid leucine that has been very slightly altered to label it.

Over the course of hours, cells in the brain pick up the labeled leucine and incorporate it into the new copies they make of a-beta and other proteins. Scientists take periodic samples of the subjects' cerebrospinal fluid through a lumbar catheter, purify the a-beta from the samples and determine how much of the a-beta includes labeled leucine.

Tracking the rise of a-beta with labeled leucine over time gives scientists the subject's a-beta production rate. When the percentage of a-beta containing labeled leucine plateaus, researchers stop introducing labeled leucine. Periodic sampling of the patients' CSF continues, allowing scientists to get a measurement of how quickly the nervous system clears out the labeled a-beta.

Average clearance rate for a-beta differed significantly between the 12 normal subjects and the 12 with early Alzheimer's, but some normal subjects had lower clearance rates close to or slightly within the range seen in Alzheimer's patients.

"Cognitive tests show no signs of dementia in these participants now, but we'll be interested to see if a lower clearance rate is a predictive marker for future diagnosis of Alzheimer's disease," Bateman says.
-end-
Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Yarasheski KE, Bateman RJ. Decreased clearance of CNS amyloid-beta in Alzheimer's disease. Science Express, Dec. 9, 2010.

Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Washington University School of Medicine

Related Brain Articles from Brightsurf:

Glioblastoma nanomedicine crosses into brain in mice, eradicates recurring brain cancer
A new synthetic protein nanoparticle capable of slipping past the nearly impermeable blood-brain barrier in mice could deliver cancer-killing drugs directly to malignant brain tumors, new research from the University of Michigan shows.

Children with asymptomatic brain bleeds as newborns show normal brain development at age 2
A study by UNC researchers finds that neurodevelopmental scores and gray matter volumes at age two years did not differ between children who had MRI-confirmed asymptomatic subdural hemorrhages when they were neonates, compared to children with no history of subdural hemorrhage.

New model of human brain 'conversations' could inform research on brain disease, cognition
A team of Indiana University neuroscientists has built a new model of human brain networks that sheds light on how the brain functions.

Human brain size gene triggers bigger brain in monkeys
Dresden and Japanese researchers show that a human-specific gene causes a larger neocortex in the common marmoset, a non-human primate.

Unique insight into development of the human brain: Model of the early embryonic brain
Stem cell researchers from the University of Copenhagen have designed a model of an early embryonic brain.

An optical brain-to-brain interface supports information exchange for locomotion control
Chinese researchers established an optical BtBI that supports rapid information transmission for precise locomotion control, thus providing a proof-of-principle demonstration of fast BtBI for real-time behavioral control.

Transplanting human nerve cells into a mouse brain reveals how they wire into brain circuits
A team of researchers led by Pierre Vanderhaeghen and Vincent Bonin (VIB-KU Leuven, Université libre de Bruxelles and NERF) showed how human nerve cells can develop at their own pace, and form highly precise connections with the surrounding mouse brain cells.

Brain scans reveal how the human brain compensates when one hemisphere is removed
Researchers studying six adults who had one of their brain hemispheres removed during childhood to reduce epileptic seizures found that the remaining half of the brain formed unusually strong connections between different functional brain networks, which potentially help the body to function as if the brain were intact.

Alcohol byproduct contributes to brain chemistry changes in specific brain regions
Study of mouse models provides clear implications for new targets to treat alcohol use disorder and fetal alcohol syndrome.

Scientists predict the areas of the brain to stimulate transitions between different brain states
Using a computer model of the brain, Gustavo Deco, director of the Center for Brain and Cognition, and Josephine Cruzat, a member of his team, together with a group of international collaborators, have developed an innovative method published in Proceedings of the National Academy of Sciences on Sept.

Read More: Brain News and Brain Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.