Disease detector: chemical test may spot Alzheimer's.

Doctors could soon have a definitive diagnostic test for Alzheimer's disease, thanks to some tiny but sophisticated sensors. These nanoscale particles isolate extremely small quantities of protein clumps associated with the neurodegenerative disease.

The researchers tested cerebrospinal fluid, which bathes the spinal cord and parts of the brain. They took samples from 15 people confirmed after death to have had the brain plaques characteristic of Alzheimer's disease and from 15 people who were free of the disease. The samples were collected from living people as well as from individuals who had died. With two exceptions, patients who might have been misdiagnosed, the nanoparticle test distinguished the two groups by detecting the prevalence of protein clumps called amyloid beta-diffusible ligands (ADDLs) in the Alzheimer's patients, the researchers say.

ADDLs are "invisible to conventional neuropathology, but their presence or absence may be the real determinants of memory loss," says team member William L. Klein of Northwestern University in Evanston, Ill.

For the test, Dimitra G. Georganopoulou, also of Northwestern, and her colleagues used iron particles coated with antibodies that stick to ADDLs. They mixed the iron particles into each sample and later used a magnetic field to extract them. The particles dragged along any ADDLs in the sample.

To enable them to quickly detect the protein clumps after this extraction, the scientists had included in each sample gold particles carrying antibodies to ADDLs. The gold particles are unaffected by the magnetic field, so they came out of the sample only when piggybacked on ADDLs.

The gold particles also earned hundreds of copies of a DNA strand that would bind to complementary strands on a glass plate. By scanning the plate surface with a focused beam of light, the researchers could spot gold anchored to the plate, signaling the ADDLs' presence. The nanoparticle test can sense just a few dozen molecules of ADDL in a sample, making it a million times as sensitive as any other technique, the team reports in an upcoming Proceedings of the National Academy of Sciences.

Previous research had found ADDLs in the brains of people with Alzheimer's, and scientists expected them also to be present in the cerebrospinal fluid, but no test was sensitive enough to find them there.

"Being able to successfully measure [ADDLs] in cerebrospinal fluid is a huge step forward;' says David S. Knopman, a neurologist at the Mayo Clinic in Rochester, Minn. He adds that if the technique pans out, it could be important as an early test for Alzheimer's. Diagnoses based on brain scans and memory tests are wrong about 15 percent of the time, though scientists are working to improve those methods (see p.93).

Kaj Blennow of the University of Goteborg in Sweden says the study's data are hard to interpret because some samples were taken before the participants died, and some afterward. "The research community will certainly be waiting eagerly for further studies on ADDLs in cerebrospinal fluid," he says.

Georganopoulou's team is preparing a study of 400 people. The researchers aim to make the test sensitive enough to detect ADDLs in blood or urine samples.