Being able to detect high blood pressure can help doctors treat the condition before it causes a stroke or other serious illness. Similarly, the ability to measure blood sugar allows for the diagnosis and control of diabetes before it causes irreversible damage to a patient's blood vessels, kidneys, or other organs.
Alzheimer's disease (AD), however, is usually diagnosed only after clinical symptoms, such as memory loss and confusion, become apparent-and even then a diagnosis cannot be made with complete certainty. In most cases, these symptoms develop 10 to 20 years after plaques of beta-amyloid peptide (Aß) begin to accumulate inside a person's brain.
Now, with the help of some recently developed neuroimaging techniques, scientists can visualize Aß inside the brain before the disease becomes debilitating. Using these new techniques could help doctors predict the course of the disease, gauge the efficacy of various treatments, and one day possibly prevent or even reverse cognitive decline.
The first chemical that has been used successfully to detect the presence of Aß inside the brain of patients living with AD was developed by a group of researchers lead by William Klunk and Chet Mathis of the University of Pittsburgh. Named Pittsburgh Compound-B, or PIB for short, the chemical provides a tool to visualize beta-amyloid in the brain of living human subjects, with the help of positron emission tomography (PET). Mathis says the compound can help determine the efficacy of anti-amyloid drug therapies in clinical trials, and in the future, it may also be used as a diagnostic agent for AD.
Before the development of this brain imaging technology, AD could be diagnosed with certainty only by examining brain tissue itself during an autopsy, Mathis says. PIB is a variation of one of the tissue dyes used to positively diagnose AD after death, he explains. But he points out that, unlike the tissue dyes, PIB can enter the brain in living humans, bind to the beta-amyloid plaques, and be detected by PET.
PET imaging with PIB has already been used in more than 200 clinical studies at 12 institutions worldwide, Mathis says. He admits, however, that it is unlikely to become a general diagnostic tool for at least another five years. The main reason for the wait is that conducting PET studies requires very expensive equipment.
Colored positron emission tomography (PET) scans show differences in the brain of a normal patient, left, and a patient with Alzheimer's disease (AD). The scan of the patient with AD indicates reduced function and blood flow in both sides of the brain, which is common in Alzheimer's. Dr. Robert Friedland / Photo Researchers, Inc.
In an attempt to make the detection of early AD more widely available using amyloid imaging, some of the same researchers who invented the PIB method are also developing a so-called hybrid tracer-a chemical that could be used not only with PET but with single-photon emission computed tomography (SPECT) as well.
"At present, SPECT is the key biomedical imaging modality that is available in most nuclear medicine departments around the world," says lead researcher Yanming Wang of the University of Illinois at Chicago. "We are extensively evaluating some dual agents in animal models, and completion of this project will allow us to identify a lead (preferred) compound that can potentially be used in human subjects in the near future for both PET and SPECT studies."
Another amyloid-imaging technique that has recently been tested in animals involves the use of magnetic resonance imaging (MRI) equipment. In a study published in the April 2005 issue of Nature Neuroscience, Makoto Higuchi and colleagues at the RIKEN Brain Science Institute in Japan injected a group of mice, specially bred with amyloid plaques in their brains, with a fluorine-labeled, amyloid-binding compound.
Using a high-magnetic-field MRI machine, the researchers were able to detect the amyloid plaques inside the living animals' brains. "This work is the first to visualize brain amyloid by fluorine-MRI, and it permits high-contrast imaging of the pathology with theoretically no background signals, because no fluorine atoms are present in the body," Higuchi says.
PET vs. SPECT vs. MRI
Magnetic resonance imaging has a higher resolution than PET, Higuchi adds, and there are other advantages to MRI: "It does not require radioactivity from the tracer, and thus can circumvent costly production and complex safety control of radioactive materials."
However, this technique cannot yet be applied to humans. "We need to inject the tracer at a considerably high dose, which might cause subacute or chronic toxicity," Higuchi says. Moreover, the MRI scanners most hospitals currently employ are not sensitive enough to detect signals from amyloid-binding fluorine.
Most hospitals are also unable to use the amyloid-imaging technique developed at the University of Pittsburgh, using PET scanners and the PIB compound, because of its high cost. Nevertheless, this method is already being utilized (in a few well-equipped centers) in the evaluation of some experimental treatments of AD.
Although PET has a higher resolution than SPECT, it is very unlikely that medical insurance companies will pay for PET scans to diagnose AD in the foreseeable future, Wang says. Successful development of a hybrid tracer, which could be used with either PET or SPECT, "would bridge the gap between the two imaging modalities," he argues, and the clinical application of such a dual tracer "could be streamlined from the development stages in research laboratories directly to patients in clinics worldwide."