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March 28, 2005

Finding Alzheimer’s Sooner
By Kate Jackson
For The Record
Vol. 17 No. 7 P. 42

Developing the ability to effectively diagnose and treat the disease earlier—even before symptoms appear—is the key to heading off a major healthcare crisis for aging America.

The financial toll of Alzheimer’s disease (AD) will bankrupt the healthcare system if major advances are not made quickly in diagnosing and treating the devastating condition, predicts one expert. According to William Thies, PhD, vice president of medical and scientific affairs for the Alzheimer’s Association, some estimates suggest that the total price tag for AD tops $100 billion per year for direct and indirect costs of care, including loss of productivity of patients and caregivers and the direct medical costs. It’s one of the most expensive diseases Medicare pays for—and it pays for a great deal of it, he notes, because the disease strikes the older population.

Adding to the imperative to develop effective diagnostic and treatment measures, he observes, is the aging of the post–baby-boom population in the coming 15 years, moving them into the age group at which they are most likely to develop AD.

“If we see the same distribution of AD across that age bracket that we have now, we could have two or three times as much AD by the middle of the century, and the price of that is simply going to be unbearable, not to mention the cost of the human suffering,” Thies laments. The only thing that’s going to short-circuit this debacle, he insists, is an investment in research now. “There’s a relatively short window—we’ve got 10 or 15 years to head this off.”

It sounds like a dark forecast, yet Thies quickly relates that his vision is rosy. “I see the future being one of continued improvement in our ability to analyze brain function through a combination of imaging and chemistry,” he adds. “When you put chemistry and energy and computers together, you get an amazingly powerful tool.”

Thies is so confident that imaging will be a potent weapon in the fight against AD that he predicts a revolution in imaging techniques that will prove just as exciting as the one that took place in the past 20 years. Positron emission tomography (PET) and magnetic resonance imaging (MRI), he and other experts agree, promise to reveal changes that will not only make earlier diagnosis possible but will also spur the development of targeted medications and provide a means for gauging their effectiveness. It’s a contribution to the understanding of the disease’s natural history that Thies says can’t be underestimated. The advances neuroimaging are beginning to permit could transform the treatment of AD. “In the world of the future,” explains Thies, “clinicians will start examining people in later middle age for risk factors for dementia and family history and perhaps even taking a baseline scan. For people who may be at risk, doctors will begin administering medications and tracking their effectiveness in much the same way that they now offer cholesterol-lowering agents and use blood tests as indicators of their effectiveness.”

Imaging procedures are often part of the workup for patients suspected of having dementia, says Thies, but they’re performed to rule out things such as stroke or brain tumors, not truly for diagnostic purposes. CT scans or, more commonly today, MRIs are read for these rule-outs, he explains, but they can also give experienced neuroradiologists a hint about the presence of the disease. There’s a fair amount of literature to indicate that people with dementia have smaller hippocampi, says Thies, and if you have software that allows you to measure volume, the scan may have some diagnostic value. That’s a question, he says, that’s been taken up by the National Institute on Aging (NIA), which, in a very large neuroimaging study, is using MRI and PET in an attempt to explore the natural history of the course of the disease by following normal patients and those with mild cognitive impairment (MCI) and AD.

Earlier Identification
Researchers are eager for the findings of such studies because information that may lead to earlier identification of the disease will allow patients to benefit from more prompt treatment. There are a number of medicines that are at least somewhat useful in treating symptoms of AD, but they’re often not given early enough to maximize their use. “You probably get a return closer to normal with treatment early in the process of the disease than you do later,” explains Thies, so information that would lead to an early definite diagnosis would be a breakthrough that could alter the course of the disease or improve quality of life for patients. “There are a lot of planning issues that are best done when the patient is still able to contribute,” he observes—for example, placement in care facilities and end-of-life decision making or, on a more positive note, those that revolve around meeting goals and fulfilling aspirations. Those who get an early diagnosis may be able to participate in such decisions while they are still fairly functional. “For example,” Thies says, “a person who’s always dreamed about going around the world may want to do that sooner rather than later, and if they get a late diagnosis, then they don’t have that option.”

Early diagnosis, Thies adds, will also help patients make the most of disease-modifying medications that are now being evaluated for their ability to stop or slow the disease’s progression. “It’s only a matter of time before we have those medications, so we’d like to be able to transition them to a prevention scheme as early as possible, and that’s going to require us to be able to identify the disease process before symptoms occur.”

Biological markers of disease progression would allow not only for earlier treatment but also for better tracking of medication effectiveness. Researchers hope imaging can provide a more precise and consistent measure of brain status than the behavioral measures, which are difficult to quantify, may be inconsistently applied, require highly trained personnel, and may produce a great deal of variation, says Thies.

Because PET and MRI are key tools in the fight against AD, the Alzheimer’s Association is funding a considerable amount of research involving imaging, including some of the earliest FDG-PET work in AD, studies in volumetric MRI, and a newer technique, functional MRI, which measures oxygen utilization. Volumetric MRI, Thies is quick to point out, is not experimental, but the interpretation of the different volumes and the best way to separate people who are normal and at risk for dementia from those with dementia is still a work in progress. Functional MRI, Thies adds, is behind that on the progress curve.

Imaging Improvements
Recent developments in imaging for AD, says Thies, have been hugely significant. “Ten years ago, there was a limited amount of literature, and it was all about volumetric MRI.” That, he says, was just the beginning of the appreciation that whole brain shrinkage occurred in people who are severely demented. Now, not only is that understanding being fine-tuned, but imaging is revealing volumes that are changing in the brain well before the total brain volume changes, explains Thies. The newer techniques look not only at volume but also at function, and they’re far enough along, he says, that, while there’s no consensus about it, some early adopters would insist that their role in making a diagnosis is very significant.

The latest exciting scientific leap to be layered on top of that advance is a series of disease-specific imaging probes, Thies explains. He points to the much-reported research performed at the University of Pittsburgh where scientists have developed a molecule that binds preferentially to amyloid—one of two unusual altered proteins that accumulate in the brains of people with AD and lights up on a PET scan. William E. Klunk, MD, PhD, and colleagues developed the molecule, called Pittsburgh Compound-B (PIB), that adheres to abnormal clumps of protein in the brain known as amyloid plaques. These plaques, along with other abnormal protein aggregates, are characteristic features in the brains of individuals with AD.

The key component of the plaques, beta-amyloid, is thought to be responsible for the death of brain cells in individuals with AD. According to the Alzheimer’s Association, “Klunk and colleagues presented PET scan data from a preliminary study of five people with MCI. They found that the subjects fall into two distinct groups. One group has evidence of amyloid deposition that is indistinguishable from normal controls, and the other group has evidence of amyloid deposition that is indistinguishable from AD patients.” Not all individuals with MCI progress to Alzheimer’s, and researchers theorize that one’s risk of progressing to AD may be associated with one’s level of amyloid in the brain.

Amyloid Measurement
The Pittsburgh researchers’ method allows measurement of the amount of amyloid that’s accumulated in any one brain, explains Thies. Researchers, he says, are trying to correlate that amount with the presence or absence of dementia to determine whether this might be a diagnostic technique and, more important, if it could be used to track the effectiveness of drugs that limit the accumulation of amyloid in an attempt to modify the disease’s course. Other researchers, he notes, are working on other specific probes, some that measure the brain inflammation that occurs in AD and some that are indicators of increased immune response.

Everyone, says Susan Molchan, MD, program director for AD clinical trials at the NIA, is excited about this research and PIB but notes that the research is too preliminary to know how useful it might be. “We know some people who have amyloid plaque deposits and don’t seem to be cognitively impaired,” Molchan said, “so its presence doesn’t mean one has dementia.” The difference is subtle, she explains, because when the amyloid is coalesced into full plaques, dementia is more certain. In the case of earlier, more diffuse forms of amyloid, dementia is not always present.

She’s also intrigued by the work of an Arizona group of researchers that has found that PET scans can pick up signs of lower glucose (or brain) metabolism in young people at risk for AD, even those who, by virtue of their having an apoE4 allele (gene component), appear to be at some increased risk of AD. Other researchers, she says, have found decreases in metabolism and blood flow before an actual diagnosis of dementia, usually in older age groups. The metabolic changes in the brain get lower and lower as these patients experience more cognitive impairment. But the Arizona researchers, she indicates, found changes in the parietal lobe and other areas of the brain affected by AD in totally asymptomatic people in their 30s. “We’re not sure yet what it all means,” Molchan says, “but it shows promise in terms of early diagnosis and measurement of the effects of medication.”

Missing Piece
Despite the numerous advances, a part of the puzzle is still clouded. Missing are large longitudinal studies that will offer insights into the course of the disease. “If you look at most of the imaging studies in the literature, they’re sort of snapshot studies in which the investigators will find 20 people who are normal at the moment and 20 people who have dementia, then image both groups and look for the differences,” says Thies. “What we don’t have is the study that takes a group of 500 normal people and tracks them for 10 years until a portion of them become demented so that we can actually see the natural history of the evolution of the disease.” Without that, he explains, there is no standards curve that reveals an individual’s risk at any given time. The NIA’s Alzheimer’s Disease Neuroimaging Initiative is trying to fill that gap, says Thies, explaining that the Alzheimer’s Association is actively trying to support its funding and adoption because it’s designed to generate some of that longitudinal data.

Neuroimaging Initiative
The Alzheimer’s Disease Neuroimaging Initiative, announced in October 2004, is a $60 million, five-year public-private partnership to test whether the progression of MCI and early AD can be measured using serial MRI, PET, and other biological markers combined with clinical and neuropsychological assessment. The study will take place at nearly 50 sites in the United States and Canada, with recruitment of 800 adults aged 55 to 90 beginning in the spring. Approximately 200 normal older individuals and 400 people with MCI will be followed for three years, and 200 people with early AD will be followed for two years.

The overriding goal of the NIA initiative, says Molchan, is the development of biomarkers. “We’re in critical need of biomarkers, and the fact that we don’t have them is really going to slow down our drug pipeline.” There are promising drugs, she observes, but no biomarker that can be used to signal whether the drug is working. Molchan believes that drugs that eventually will work to slow down AD will probably need to be given early in the illness, probably even before symptoms have appeared and too much brain damage has occurred.

Consequently, she says, researchers are looking for signs of the disease in MRI and PET scans, as well as in blood and cerebrospinal fluid, at every early stage of the disease. “For this large initiative, we wanted to have some imaging techniques that were quite well-established as being able to show change in time as people get worse, and we have that to some degree with MRI and PET,” says Molchan. “With this initiative, we’re going to collect genetic information. We’ll be establishing cell lines for DNA, as well as collecting blood and cerebrospinal fluid specimens, so we’ll have a huge amount of information to put together with the clinical, neuropsychiatric, and imaging data.”

Earl A. Zimmerman, MD, heads another important initiative in neuroimaging for AD—the Neurosciences Advanced Imaging Research Center at Albany Medical Center, which was created to discover new and unique technologies and methodologies to diagnose AD and other neurogenerative diseases. It’s one of the 50 sites participating in the NIA study. Using a new GE 3 Tesla MRI system, the center researchers are using molecular imaging to identify biomarkers in AD patients, specifically in a cohort of individuals developed by Zimmerman of normal individuals, people with MCI, early AD, Parkinson’s disease, and other dementias. According to Zimmerman, molecular imaging is a key tool that will allow researchers to explore and improve the pathology of AD.

Zimmerman, who’s been studying AD for more than 20 years, feels that researchers are very close to a true molecular therapy with what he calls the amyloid-busting drugs. “The more we can directly image the molecular pathology,” he says, “the farther we’ll get in the search for markers that will permit early detection and disease modification.”

According to Thies, imaging techniques are getting better, and the combination of chemistry with imaging is going to be an important framework for future advances. “The ability to develop very specific problems that get to a certain step in a disease process, and to be able to measure the activity in that step through imaging and interpret it in a computer,” Thies envisions, “is going to be revolutionary over the next 20 to 25 years.”

— Kate Jackson is a staff writer at For The Record.

For More Information
• Alzheimer’s Association
www.alz.org

• Alzheimer’s Disease Clinical Studies
www.clinicaltrials.gov

• National Institute for Biomedical Imaging and Bioengineering
www.nibib1.nih.gov

• National Institute on Aging
www.nia.nih.gov

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