Two of the holy grails of Alzheimer’s disease research are early diagnosis and drug therapies to modify the disease outcome. Achieving these goals would dramatically alter the current state of treating this progressive, degenerative disorder that attacks the brain's nerve cells, or neurons, and robs individuals of their memory and ability to reason, communicate, and carry out daily activities. Today, the only way to diagnose the disease definitively is through an autopsy.
What researchers do know is that two types of abnormal lesions clog the brains of individuals with Alzheimer's disease: beta-amyloid plaques – sticky clumps of protein fragments and cellular material that form outside and around neurons; and neurofibrillary tangles – insoluble twisted fibers composed largely of the protein tau that build up inside nerve cells.
To shed light on how the disease begins and the path it takes, researchers at Massachusetts General Hospital in Boston have combined mouse models, an existing optical imaging technology – multiphoton microscopy (MPM) – and unique visualization agents. Their work provides an important step in evaluating Alzheimer’s progression, hastening the discovery of beneficial drugs to treat the disease and change its course.
“We have a limited understanding of the disease’s progression,” says Brian Bacskai, Associate Professor of Neurology at Massachusetts General Hospital in Boston. “Multiphoton microscopy allows us to see what’s happening as the mouse gets sick and to potentially provide therapeutic interventions.”
High Resolution Imaging
The technique has several advantages over other imaging methods. The infrared light used in MPM penetrates deeply into living tissue without damaging it. Traditional approaches use stains that require ultraviolet light that can damage living cells. MPM provides a resolution of 1 µm – 1,000-fold greater than the resolution achieved with positron emission tomography (PET). When combined with special imaging agents, the multiphoton microscope reveals individual blood vessels, neurons, and plaques in the brain. All of this can be done in a living, intact mouse brain but the approach does require optical access to the brain, which means surgically implanting a cranial window in place of a region of skull.
To image plaques in humans, researchers use PET. While it is more sensitive in identifying plaques and can image the entire brain, PET does not show individual plaque deposits. “With PET you get an average plaque load for a given cubic millimeter of brain,” says Bacskai, while “MPM shows you exactly what the brain looks like but you can only image a tiny chunk of brain.” Although MPM only images to a depth of approximately 500 µm, amyloid deposits are found in superficial cortex, near the brain’s surface.
Reducing Plague Build-Up
In a recent study, Bacskai and his group used MPM to monitor the clearance of amyloid-β peptide from CAA. While CAA is commonly associated with Alzheimer’s, it is also responsible for some strokes in the elderly. “This is a shockingly understudied condition,” says Bacskai, adding that 80 percent of Alzheimer’s cases have CAA.
The researchers found that by administering an antibody continually into the brain over a 2-week period, the CAA was cleared from the blood vessels with no evidence of hemorrhage. This was in contrast to a single dose of antibody administered directly to the brain, which resulted in an initial clearance of CAA but then a significant rate of regrowth of the deposits. By determining the growth pattern of CAA, the group showed that immunotherapy can be tailored to treat both Alzheimer’s and CAA.
Their findings could be significant since the first major clinical trial using an active immunotherapeutic approach with a compound called AN1792 (a synthetic form of the amyloid beta protein) was halted due to brain inflammation in about 6 percent of participants. “When certain antibodies to Aβ interact with CAA, it can cause little and sometimes big hemorrhages,” says Holtzman. “Brian’s work may be a way to get around this problem.”
Testing New Drugs and Imaging Agents
The work being done by Bacskai’s group also provides a springboard for testing a broader range of drugs. “If we can figure out the key steps in the progression of the disease, then we can try to modulate these steps and see if it translates into changes in disease course,” explains Steven Greenberg, Director of Hemorrhagic Stroke Research at Massachusetts General Hospital and a Bacskai collaborator. “This work will shorten the process of identifying a stable of plausible candidate drugs that could modify how the disease progresses.”
In another recent study, Bacskai and his group found that curcumin, a small fluorescent compound in the Indian spice tumeric, can disrupt existing amyloid plaques and partially restore brain structures distorted by the disease in the mouse brain.
Although researchers cannot use MPM to image humans, MPM research can provide critical information about compounds that could be relevant to clinical imaging. In the case of an imaging agent called Pittsburgh compound B (PiB) developed by William Klunk and Chester Mathis at the University of Pittsburgh’s School of Medicine, Bacskai and his team demonstrated in the mouse model that PiB enters the brain quickly, links to amyloid deposits within minutes, and clears rapidly from the brain. The researchers concluded that the finding would translate directly to successful imaging in humans. A 25-center clinical trial is under way to test PiB as a method of labeling amyloid plaques.
A Role in Human Imaging
This work is supported in part by the National Institute of Biomedical Imaging and Bioengineering and the National Institute on Aging.
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