Sci. Aging Knowl. Environ., 1 October 2003
Amyloid-loving molecule could furnish the first diagnostic test for Alzheimer's disease
Key Words: biomarker radioligand cerebral amyloid angiopathy multiphoton microscope
Every news story suggesting that actor Charlton Heston suffers from Alzheimer's disease (AD) is jumping the gun. Yes, Heston likely does have the memory-sapping illness, but with current technology, doctors can't make a definitive diagnosis until after his death. That limitation could soon vanish, thanks to a compound that gloms onto the telltale plaques that characterize AD. In a new study, researchers use the molecule to pinpoint plaques in the brains of living mice, a finding that opens the way for an AD diagnostic test in patients.
Tests of cognition can provide strong evidence that someone has AD, but only an autopsy can confirm that the patient's brain teems with the hallmark -amyloid plaques and tau tangles. The lack of a good test for the illness not only frustrates patients' doctors and families but also hinders researchers working to develop treatments that slow or reverse plaque buildup. For years, scientists have sought molecules that flag amyloid or tau. Last year, psychiatrist William Klunk of the University of Pittsburgh and colleagues reported a candidate. The molecule, known as Pittsburgh compound B (PIB), adheres specifically to -amyloid plaques. The researchers envisioned tagging PIB with radioactive carbon, injecting it into a patient's bloodstream, and then searching for the radioactive compound using a brain-scanning technique called positron emission tomography. Unfortunately, the radioactive signal fades fast, declining by half every 20 minutes, so the researchers needed to find out how quickly PIB moves from the blood to the brain--and how long it remains attached to -amyloid plaques. If they were lucky, any label that stuck specifically would hang around long enough to be detected.
To address these issues, Klunk joined forces with neuroscientist Brian Bacskai of Massachusetts General Hospital in Charlestown and others to study mice that had been genetically altered to amass amyloid. The researchers anesthetized the animals, surgically replaced a small section of their skulls with a clear cover, and injected PIB into a tail vein. Using a microscope positioned over the viewing window, the scientists tracked the glowing molecules' travel. Within 1 minute, the compound had leached into the brain and begun adhering to plaques. Within 15 minutes, most PIB that was not stuck to amyloid had dissipated, leaving a constellation of brightly glowing plaques. Additional experiments indicated that the compound remains glued to plaques for at least 3 days. The results suggest that PIB marks plaques within the brief detection window for carbon radioactivity, says Bacskai.
"I think it's an excellent paper," says neuroscientist Frank LaFerla of the University of California, Irvine. "If what they found in mice is applicable to humans, it should allow early diagnosis of AD." Bacskai says that the procedure would also help researchers gauge whether experimental compounds stem AD's assault on the brain. "It's very difficult to do a clinical trial in humans if you can't be sure your patient population has the disease," he says. Klunk and colleagues have already begun evaluating PIB in humans. Glowing plaques could light the way to the first treatments for AD.
October 1, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150