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Brain scan, cerebrospinal fluid analysis may help predict Alzheimer's

By Michael Purdy

Nov. 15, 2005 — A combination of brain scanning with a new imaging agent and cerebrospinal fluid (CSF) analysis has left neuroscientists encouraged that they may finally be moving toward techniques for diagnosing Alzheimer's disease before its clinical symptoms become apparent.

"When clinical symptoms start, the disease process has already been at work in the patient for many years and possibly even decades," explains Anne Fagan Niven, Ph.D., research associate professor of neurology at Washington University School of Medicine in St. Louis. "Up to 30 percent of neurons in vulnerable areas are already dead, and you can't get them back. So finding markers that can help us identify patients prior to symptoms is really our big push now."

With colleagues Mark Mintun, M.D., professor of radiology, and David Holtzman, M.D., the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology, Fagan studied a group of 24 people that included individuals diagnosed with very mild and mild Alzheimer's disease, and cognitively normal subjects. As expected, in patients with cognitive impairments, believed to be attributable to Alzheimer's disease, researchers found low CSF levels of amyloid beta 42 (A-beta 42), the principal ingredient of the brain plaques that are characteristic of Alzheimer's disease. In the same individuals, brain scans with a new imaging agent that reveals the presence of amyloid plaques in the brain were positive.

What scientists didn't anticipate was that three cognitively normal subjects would have both low CSF levels of A-beta 42 and positive results from the brain scans. Fagan stressed that although this aspect of their findings was very intriguing, it doesn't prove that the three normal subjects will one day develop clinical Alzheimer's disease.

"For now, definitive diagnosis of Alzheimer's disease still cannot be made until autopsy," she says. "It's going to take a number of years for us to fully assess these results, because all we can do now is follow the participants closely to see if they eventually develop Alzheimer's dementia."

Fagan presents the results of the study at 10:15 a.m. on Nov. 15 at this year's annual meeting of the Society for Neuroscience in Washington, D.C. The study will also appear in an upcoming issue of Annals of Neurology.

Many prior studies have found that A-beta 42 levels drop in the cerebrospinal fluid of Alzheimer's disease patients. A-beta 42 is naturally produced in the brain, and researchers suspect that the creation of amyloid plaques may be linked to breakdowns of the processes that degrade or normally clear A-beta 42 from the brain via the CSF and the bloodstream.

However, natural variations occur in CSF A-beta 42 levels in healthy subjects, and the amount this level drops in Alzheimer's patients also varies. And that left no distinct level scientists could identify as a diagnostic marker characteristic of Alzheimer's disease.

Fagan wanted to see if useful distinctions could be made by combining data on CSF A-beta 42 levels with results from brain scans with a new imaging agent, PIB (for Pittsburgh compound B). Developed by researchers at the University of Pittsburgh, PIB temporarily sticks to amyloid plaques in the brain but washes clean in 30 to 60 minutes. Scientists can detect this sticking with a PET scanner.

Using PIB data available from ongoing studies of research volunteers at the Memory and Aging Project at the Alzheimer's Disease Research Center at Washington University, Fagan compared PIB scan results and levels of CSF A-beta 42.

"When I realized that everyone who was PIB positive also had lower CSF A-beta 42 levels, I had one of those 'aha!' moments that makes it so exciting to be a scientist," Fagan says.

Other CSF factors, such as levels of another form of A-beta and of a molecule found in the brain cell tangles created by Alzheimer's disease, did not correlate with positive PIB scan results.

"The hope is that 10-20 years from now, we'll give people a PIB scan, draw and analyze their CSF, and combine that with other factors to get a global score for their personal risk of Alzheimer's disease," Fagan says. "We have disease-modifying treatments on the way to clinical trials right now, and tests that can help us detect Alzheimer's earlier will both help us put those treatments to better use and assess the results they produce in patients."

Fagan AM, Mintun MA, Mach RH, Dence CS, Shah AR, LaRossa G, Spinner ML, Klunk WE, Mathis CA, Morris JC, Holtzman DM. Correspondence between in vivo amyloid imaging and CSF A-beta 42 levels in humans: implications for antecedent biomarkers of Alzheimer's disease. Society for Neuroscience annual meeting, November 15, 2005.

Funding from the National Institute on Aging supported this research.