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Neurology Now:
Special Report: Alzheimer's Special Report

Picturing and Predicting Your Brain's Future: Advanced imaging can now detect changes that foreshadow Alzheimer's years before the disease appears

Shaw, Gina

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Gina Shaw is a health and science writer whose articles have appeared in Redbook and Glamour as well as on WebMD.

what if your doctor could forecast Alzheimer's disease in your future — years before you might begin to show any symptoms?

Scientists already know that positron emission tomography, known as PET scanning, can accurately diagnose Alzheimer's disease in people who already have clear symptoms of memory impairment. In fact, PET officially became the “gold standard” of Alzheimer's diagnosis in 2004 when the federal government expanded Medicare coverage to include PET screening for patients who show signs of dementia. And it's becoming increasingly clear that PET can also help predict the development of Alzheimer's in people who have been diagnosed with mild cognitive impairment, a recently identified condition characterized by memory problems without other dementia symptoms.

But research is now pushing that predictive frontier back even further — using PET to detect subtle changes in the brains of cognitively healthy older people, and forecasting their chances of developing Alzheimer's disease or other dementias in the future.

Would you really want to know, at the age of 65, that you are likely to develop Alzheimer's by the time you turn 70? If you hope to stave off the effects of the disease, the answer is absolutely yes, says Jorge Barrio, M.D., professor of medical and molecular pharmacology at the University of California–Los Angeles. “Alzheimer's is an insidious disease: by the time you discover you have symptoms, it's too late. When dementia is too advanced, we have little to no chance of intervening.”

But in the early stages of the disease, before the brain's neurons have begun to die, it's a different story. Dr. Barrio and other Alzheimer's experts are hopeful that experimental drugs now in the research pipeline can help preserve healthy brain function — if accurate tests can be developed to pinpoint the patients who need those treatments.

“The evidence so far certainly tells us that if you can identify individuals early, when there are some abnormalities in the brain but the structural damage is less extensive, these people have the greatest likelihood of showing response to treatments,” says Ronald Van Heertum, M.D., director of Columbia University's Kreitchman PET Center. “If we can keep pushing the envelope of diagnosis back to well before symptoms develop, it is more likely that new treatments will have benefit.”

How is it that PET scanning can predict the brain's future? Unlike the still images of physical structures found in standard MRI (magnetic resonance imaging), PET scans show the body “in action,” visualizing different levels of metabolic or chemical activity.

In a PET scan, the patient is injected with a radioactive substance called a tracer that attaches to a specific natural compound in the body. As the tracer is drawn to particular areas of the body, the PET scan lights up with different colors and levels of brightness that can tell doctors how well certain organs are functioning and show signs of damage or disease.

For instance, one type of PET tracer is designed to bind to beta-amyloid, the protein that builds up in the brains of people with Alzheimer's and is thought to damage and ultimately kill brain cells. Using this tracer, doctors can see if there are abnormal levels of beta-amyloid in the brain.

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The most commonly used PET tracer, though, binds to glucose and shows how the body metabolizes it. Studies have shown that the brains of people with Alzheimer's disease metabolize glucose at lower levels than the brains of healthy people.

Among people with the ApoE4 gene variation, a known genetic risk factor for common late-onset Alzheimer's occurring after age 65, abnormally low rates of glucose metabolism have been found in important areas of the brain even in relatively young adulthood. Building on earlier research that found abnormally low glucose levels in cognitively healthy older ApoeE4 carriers, a 2004 study showed the same also held true for healthy young adults. This is important because it documents the earliest brain changes yet seen in persons at risk for Alzheimer's.

Researchers are racing to determine how best to use PET scans in the early diagnosis of Alzheimer's. In a major nationwide study, Dr. Van Heertum and colleagues are testing whether PET and other brain imaging tools can be combined with biomarkers, such as levels of proteins like beta-amyloid in cerebrospinal fluid and blood, to help pinpoint the earliest changes that lead to Alzheimer's.

Combining PET imaging with biomarkers for early detection of Alzheimer's has already shown promise. In December 2005, researchers at Washington University in St. Louis and the University of Pittsburgh announced intriguing early findings based on combined PET scanning and measurement of beta-amyloid in the brain and cerebrospinal fluid: when patients had higher levels of plaques in the brain, they also had lower levels of beta-amyloid in their cerebrospinal fluid. That may indicate beta-amyloid is not circulating properly from the brain into the cerebrospinal fluid, and instead is accumulating excessively in the brain where it will eventually damage neurons, says Mark Mintun, M.D., professor of radiology at Washington University.

The study used an imaging agent that “sticks to amyloid plaques in the brain,” he says. “In a person lacking amyloid, the agent washes out of the brain in 30 to 60 minutes. In a person with amyloid, it stays longer, creating a strong contrast that PET scans can detect easily. When this test is positive, it's dramatically visual.”

Scientists are also developing other PET tracers that they hope will help open the window of Alzheimer's diagnosis. At UCLA, Dr. Barrio has developed a tracer that's a marker of serotonin receptor 1A. “These receptors happen to sit on the neurons that die first in Alzheimer's disease, the ones whose destruction produces the earliest symptoms of the disease,” explains Dr. Barrio. When these neurons die, the hippocampus — a part of the brain important for learning and memory — begins to atrophy and shrink. “Using this marker, we've found that there is a very good correlation between the [neuron damage] measured by PET scanning and Alzheimer's disease progression,” he says. “At first you can see the [damage] without the death of neurons. Then, neuronal death occurs over a period of several years. And then, the symptoms come next.”

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“What I think is so exciting about all this,” says Dr. Van Heertum, “is that we're really now able to develop imaging techniques that will also help in the future with our treatment approach — refining what will be the most appropriate treatment for particular patients and monitoring those patients to see how treatment is working.”

Someday soon, Dr. Barrio predicts, anyone at elevated risk — for example, someone over age 55 or 60 who has a family history of the disease — may be asked to consider a PET scan to help detect presymptomatic Alzheimer's.

“To me,” he says, “the most important aspect of this is not just to diagnose a disease. It's being able to answer the patient's next question: ‘What can you do for me?’”

What's more, he would like to change the way this disease is viewed.

“We need to treat Alzheimer's disease the same way we treat cancer and heart disease: with a focus on early detection and prevention,” he says. “And the future is exciting in terms of therapies that are preventive.”

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A Century of Alzheimer's

1901

Dr. Alois Alzheimer examines 51-year-old Auguste D. and diagnoses what he coins “presenile” dementia.

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1906
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Dr. Alzheimer discovers plaques and tangles as hallmarks of new disease in autopsy of Auguste D.'s brain.

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1910
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Dr. Emil Kraepelin rewards protégé by naming “Alzheimer's disease” for him.

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1936

Scientists find same plaques and tangles in middle-aged and elderly brains.

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1963

Researchers link cognitive decline to plaques and tangles.

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1974

Old term “senile dementia” replaced by diagnosis of “Alzheimer's disease.”

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1975

Verbal cognitive test introduced as standard diagnostic tool.

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1979

Alzheimer's Association formed to help patients and caregivers.

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1980

Rita Hayworth's diagnosis makes Alzheimer's widely known worldwide.

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1983
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President Reagan approves task force for Alzheimer's research.

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1984

Beta-amyloid identified as component of plaques between neurons.

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1990

Tau protein identified as component of tangles within neurons.

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1991

First gene implicated in early-onset Alzheimer's.

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1992

First gene implicated as risk factor in late-onset Alzheimer's.

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1993
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FDA approves first Alzheimer's drug, tacrine (Cognex), for mild to moderate symptoms.

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1994

Former President Reagan announces diagnosis of Alzheimer's.

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1996
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Donepezil (Aricept) approved by FDA as safer treatment for mild to moderate symptoms and becomes most popular Alzheimer's drug.

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1999

First Alzheimer's vaccine tested in mice but side effects halt human trials.

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2003

Memantine (Namenda) approved by FDA as first drug to treat moderate to severe Alzheimer's symptoms.

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2004

U.S. government approves PET brain scans to diagnose Alzheimer's.

©2006 American Academy of Neurology

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