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Molecular Imaging Sheds New Light On Progression Of Alzheimer’s Disease

The groundbreaking discovery by University of Pittsburgh researchers Chester Mathis, PhD, and William Klunk, MD, PhD, is being watched with great interest.

Pittsburgh Compound B (PIB) binds to the abnormal amyloid plaque in the brain. When imaged with a PET scan, PIB shows researchers actual pathological changes in the brain that could turn out to be the best and earliest signs of the disease.


Pittsburgh at the forefront of Alzheimer’s research

Researchers at the University of Pittsburgh Medical Center (UPMC) are revolutionizing the fight against Alzheimer’s disease (AD). Scientists and researchers at the University of Pittsburgh recently discovered a new agent, dubbed “Pittsburgh Compound B,” which allows researchers to visualize for the first time in living people the brain plaque suspected of causing the memory-stealing disease. Previously, the presence of plaque could be confirmed only during autopsy.

Pittsburgh Compound B (PIB) binds to the abnormal amyloid plaque in the brain. When imaged with a PET scan, PIB shows researchers actual pathological changes in the brain that could turn out to be the best and earliest signs of the disease. It may be possible that these changes could be detected as many as 10 years before patients experience serious memory loss.

The groundbreaking discovery by University of Pittsburgh researchers Chester Mathis, PhD, and William Klunk, MD, PhD, is being watched with great interest. Along with Drs. Klunk and Mathis, researchers like Steven DeKosky, MD, director of the Alzheimer Disease Research Center at UPMC, are currently collaborating with investigators around the world to further study PIB and other compounds, as well as potential new treatments for Alzheimer’s.

Pittsburgh Compound B was developed after more than a decade of work by University Drs. Klunk and Mathis. Dr. Klunk is an associate professor of psychiatry who studies Alzheimer’s disease, while Dr. Mathis specializes in developing radiopharmaceuticals — compounds that are injected into the body and temporarily emit radioactive particles that can be captured by PET imaging to reveal anatomical clues.

Working with three classes of dyes used to detect plaque in the lab, Drs. Klunk and Mathis worked for years testing hundreds of compounds before developing PIB.

“This is in the early stages of development,” says Dr. DeKosky. “But if our success continues, it’s possible there could be a commercially available product for the early diagnosis of Alzheimer’s within the next decade.”

Using PIB, doctors may someday be able to follow the progression of the disease and identify people who are at increased risk for AD long before any symptoms occur.

“Until the development of Pittsburgh Compound B, there was no way to measure a decrease in AD plaque or possible remission of the disease,” says Dr. DeKosky. “What makes PIB remarkable is that, for the first time, doctors may be able to tell definitively if treatment is working.” Dr. DeKosky says before this discovery by Drs. Mathis and Klunk, no one was able to develop a tracer that binds to the specific abnormal protein in AD. All of the other imaging studies simply show shrinkage in parts of the brain or brain activity changes in different regions.

“For the last 20 years, we’ve talked about finding a noninvasive way to make a definite and specific diagnosis and being able to quantify the amount of plaque in the brains of people who have AD,” says Dr. DeKosky. “If we can make a specific diagnosis through imaging, then we can track the effectiveness of new drugs and other treatments. There is nothing out there right now anywhere near as direct, that can tell us definitively whether or not a drug reaction and response helps the disease.”

Furthermore, use of the compound may also tell researchers whether the hypotheses upon which therapies are being developed are correct. “That’s important, as is identifying early-stage patients before it’s too late,” says Dr. DeKosky.

“The future is very exciting, and it’s satisfying to know that we were at the forefront of advancing the science,” says Dr. Mathis. “Right now we’re setting the stage to use Pittsburgh Compound B in collaboration with a number of companies that are trying to target therapies for AD. If these therapies do what we hope they will do, then it will become more important to determine if a person has AD at an earlier stage.”

Dr. Mathis says another very important goal will be to nail down amyloid plaque’s exact role in Alzheimer’s disease. While most doctors suspect that it causes Alzheimer’s, there isn’t yet 100 percent agreement on the theory. If amyloid plaque turns out not to be a central cause, Dr. Mathis says, such a finding could completely redirect research.

Finally, PIB and improved radiotracers now under development at the University of Pittsburgh will allow researchers to follow amyloid deposits in Alzheimer’s patients and older people without the disease, helping to better define the normal aging process in the brain.

Alzheimer’s is a very complex disease, one that is just beginning to be understood. It steals the mind and memory. It devastates families and makes strangers out of life-long partners. Approximately 4 million Americans have Alzheimer’s, and if left unchecked, it will strike as many as 14 million during the next 50 years. UPMC’s new research may stem the advance of this debilitating disease.

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Unraveling Alzheimer’s secrets

clipped from www.telegram.com

Kerley, 52, has spent much of her life in the shadow of an illness that gradually destroys memory, personality and the ability to think, speak and live independently. Her mother, grandmother and a maternal great-aunt all developed Alzheimer’s disease. Her mother, 78, is in a nursing home in the advanced stages of dementia, helpless and barely responsive.

Currently, the diagnosis is not made until symptoms develop, and by then it may already be too late to rescue the brain.

A radioactive dye called PIB (for Pittsburgh Compound B) has made it possible to use PET scans to find deposits of amyloid, an Alzheimer’s-related protein, in the brains of live human beings.

It may lead to earlier diagnosis, help doctors distinguish Alzheimer’s from other forms of dementia

“PIB is being used today to help determine whether drugs that are meant to prevent or remove amyloid from the brain are working, so we can find drugs that prevent the underlying pathology of the disease.”

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Unraveling Alzheimer’s secrets

Scientists searching for ways to detect disease early

By Denise Grady
The New York Times

For a perfectly healthy woman, Dianne Kerley has had quite a few medical tests in recent years: MRI and PET scans of her brain, two spinal taps and hours of memory and thinking tests.

Kerley, 52, has spent much of her life in the shadow of an illness that gradually destroys memory, personality and the ability to think, speak and live independently. Her mother, grandmother and a maternal great-aunt all developed Alzheimer’s disease. Her mother, 78, is in a nursing home in the advanced stages of dementia, helpless and barely responsive.

“She’s in her own private purgatory,” Kerley said.

Kerley is part of an ambitious new scientific effort to find ways to detect Alzheimer’s disease at the earliest possible moment. Although the disease may seem like a calamity that strikes suddenly in old age, scientists now think it begins long before the mind fails.

“Alzheimer’s disease may be a chronic condition in which changes begin in midlife or even earlier,” said Dr. John C. Morris, director of the Alzheimer’s Disease Research Center at Washington University in St. Louis, where Kerley volunteers for studies.

Currently, the diagnosis is not made until symptoms develop, and by then it may already be too late to rescue the brain. Drugs now in use temporarily ease symptoms for some, but cannot halt the underlying disease.

Many scientists believe the best hope of progress, maybe the only hope, lies in detecting the disease early and devising treatments to stop it before brain damage becomes extensive. Better still, they would like to intervene even sooner, by identifying risk factors and treating people preventively – the same strategy that has markedly lowered death rates from heart disease, stroke and some cancers.

So far, Alzheimer’s has been unyielding. But research now under way may start answering major questions about when the disease begins and how best to fight it.

A radioactive dye called PIB (for Pittsburgh Compound B) has made it possible to use PET scans to find deposits of amyloid, an Alzheimer’s-related protein, in the brains of live human beings. It may lead to earlier diagnosis, help doctors distinguish Alzheimer’s from other forms of dementia and let them monitor the effects of treatment. Studies with the dye have already found significant deposits in 20 percent to 25 percent of seemingly normal people over 65, suggesting that they may be on the way to Alzheimer’s, though only time will tell.

“PIB is about the future of where Alzheimer’s disease needs to be,” said Dr. William E. Klunk, a co-discoverer of the dye at the Alzheimer’s research center at the University of Pittsburgh. “PIB is being used today to help determine whether drugs that are meant to prevent or remove amyloid from the brain are working, so we can find drugs that prevent the underlying pathology of the disease.”

Though PIB is experimental now, studies began in November that are intended to lead to government approval for wider use.

Currently, for the most common form of Alzheimer’s disease, which occurs after age 65, there is no proven means of early detection, no definitive genetic test. But PIB tests might be ready before new treatments emerge, making it possible to predict who will develop Alzheimer’s – without being able to help.

Researchers are also using MRI scans to look for early brain changes, and testing blood and spinal fluid for amyloid and other “biomarkers” to see if they can be used to predict Alzheimer’s or find it early.

Studies of families in which multiple members have dementia are helping to sort out the genetic underpinnings of the disease.

Finally, experiments are under way to find out whether drugs and vaccines can remove amyloid from the brain or prevent its buildup, and whether doing so would help patients. The new drugs, unlike the ones currently available, have the potential to stop or slow the progress of the disease. At the very least, the drug studies will be the first real test of the leading theory of Alzheimer’s, which blames amyloid for setting off a chain of events that ultimately ruin the brain.

Alzheimer’s was first recognized 100 years ago, and in all that time science has been completely unable to change the course of the disease. Desperate families spend more than $1 billion a year on drugs approved for Alzheimer’s that generally have only small effects, if any, on symptoms. Patients’ agitation and hallucinations often drive relatives and nursing homes to resort to additional powerful drugs approved for other diseases such as schizophrenia, drugs that can deepen the oblivion and cause severe side effects such as diabetes, stroke and movement disorders.

Alzheimer’s is the most common cause of dementia (artery disease, Parkinson’s and other brain disorders can also lead to dementia). Five million people in the United States have Alzheimer’s, most of them over 65. It is the nation’s sixth leading cause of death by disease, killing nearly 66,000 people a year and probably contributing to many more deaths. By 2050, according to the Alzheimer’s Association, 11 million to 16 million Americans will have the disease.

“Sixteen million is a future we can’t countenance,” said William H. Thies (pronounced thees), the association’s vice president for medical and scientific relations. “It will bankrupt our health care system.”

The costs are already enormous, $148 billion a year – more than three times the cost of chronic lung disease, even though Alzheimer’s kills only half as many people.

To a great extent, increases in dementia are the price of progress: More and more people are living long enough to get Alzheimer’s, some because they survived heart disease, strokes or cancer. It is a cruel tradeoff. The disease is by no means inevitable, but among people 85 and older, about 40 percent develop Alzheimer’s and spend their so-called golden years in a thicket of confusion, ultimately becoming incontinent, mute, bedridden or forced to use a wheelchair and completely dependent on others.

“It makes people wonder whether they really want to live that long,” Klunk said.

The potential market for prevention and treatment is enormous, and drug companies are eager to exploit it. If a drug could prevent Alzheimer’s or just reduce the risk, as statins such as Lipitor do for heart disease, half the population over 55 would probably need to take it, Thies said.

If new drugs do emerge, they will come from studies in patients who already have symptoms, Thies said. But he said the emphasis would quickly shift to treating people at risk, before symptoms set in. Many researchers doubt that even the best preventive drugs will be able to heal the brains of people who are already demented.

Researchers are especially eager to study people like Kerley, because the children of Alzheimer’s patients have a higher-than-average risk of dementia themselves, and tracking their brains and minds may open a window onto the earliest stages of the disease.

 
 
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