Advanced imaging allows researchers to examine further in the brain, hoping to unlock the secret to the disease.
A diagnosis of Alzheimer’s disease is many things. It’s an entrance to a growing community, one numbering more than 5 million in the United States and expanding every 71 seconds. It’s a public health epidemic, with more than 10 million Baby Boomers expected to develop Alzheimer’s in their lifetime. It’s a public cost nightmare, with the direct and indirect costs of Alzheimer’s and other dementias to Medicare, Medicaid, and businesses amounting to more than $148 billion each year.
Most of all, a diagnosis of Alzheimer’s often signals a loss of hope. Alzheimer’s disease is a debilitating condition of memory loss and dementia, one that is rooted in brain dysfunction. It’s a condition with no cure and no major treatment, and it’s the seventh leading cause of death in the United States. But in addition to all these things, Alzheimer’s is now a field of hope and opportunity in research. And medical imaging and nuclear medicine are leading the way.
“Alzheimer’s research is very exciting at this point,” said William Thies, PhD, vice president of Medical and Scientific Relations at the Alzheimer’s Association. “We’re on the verge of some developments that will fundamentally change the way we think of Alzheimer’s. There’s a strong imaging component to this, and to the last couple of large conferences we’ve put on. We can see a time when we’ll move away from fatalism and view it as a manageable chronic disease. It’s exciting, and it’s palpable in the field.”
The overarching need for Alzheimer’s treatment is for early detection and disease-modifying drugs. As it stands, Alzheimer’s is a devastating condition, and no means of stopping its destructive onslaught exist. Current medications for Alzheimer’s focus on reducing symptoms, but have no power over the underlying cause and progression. Clinical trials are investigating disease-modifying drugs to rectify this situation, but the next generation of medications is still far from entering the market.
In the absence of drugs that will prevent Alzheimer’s from developing and stop the degenerative progress, the focus has turned to early diagnosis and detection. Alzheimer’s pathology begins many years before symptoms like dementia occur. The need to identify Alzheimer’s before behavior changes then is critical. When drugs become available, this early diagnosis will enhance their efficacy. Until then, early detection helps patients plan for the future.
“If it’s possible to identify patients who will develop dementia, it enables earlier treatment of symptoms,” said Lisa Mosconi, PhD, research assistant professor at the Center for Brain Health at New York University School of Medicine. “But it also gives people time to plan for the future in terms of finances and legal arrangements. A lot of people don’t want to know, but a lot of people do for that reason. What we can also do with early detection is try to lower the impact of factors known to have negative effects on cognition, like blood pressure, cholesterol, diabetes, and vascular damage. It gives us things we can focus on immediately.”
Mosconi recently conducted a study published in the March 2008 issue of the Journal of Nuclear Medicine taking advantage of advances in imaging technology in order to work toward this goal. While previous imaging technology was low-resolution, limiting study to the outside of the brain, advanced positron-emission topography (PET) scanning, along with tracers that include F-18 fluorodeoxyglucose (FDG), can examine structures deep within the brain, pinpointing areas of concern for developing Alzheimer’s.
Her study, performed with Mony De Leon, PhD, professor and director of the Center for Brain Health and conducted in concert with research centers across the world, included 548 subjects who had mild cognitive impairment (MCI), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), or Alzheimer’s disease. Researchers used optimized FDG-PET analysis techniques, meaning a standardized software package of disease-specific PET patterns. The rationale behind using FDG-PET is its measurement of brain glucose metabolism. Decreases in this rate are indicative of brain cell dysfunction and are associated with dementia.
Using these standardized PET patterns, researchers were able to correctly classify more than 90% of subjects. The study confirms that different areas of the brain are affected with different types of dementia.
“The power of our study is that it’s not just early diagnosis, but it offers a differential diagnosis,” said Mosconi. “Different dementia disorders have different biological causes. And treatments now and in the future will be available for specific dementia disorders and symptoms. If you use one treatment for a patient and they don’t have that dementia, it won’t help. And it will take a long amount of time to tell.”
The optimized PET analysis methods the researchers offer are an attempt to cut down on one of the main problems with diagnosis and differentiation from imaging: subjectivity.
“The main clinical limitation right now in diagnosis is based on the nuclear medicine physician’s experience,” said Mosconi. “That person will look at a PET scan and visually determine if it looks normal or not. We’re trying to make the process more objective and less dependent on clinic al expertise. We offer technicians and physicians a database of normal images as a clear and clean reference to facilitate the process.”
Advanced imaging methods hold a promise of less subjectivity for a field plagued with it. The nature of Alzheimer’s is such that change is slow, particularly in early stages, and erratic. Physicians who attempt to merely observe patient behavior and determine if Alzheimer’s is present are at a disadvantage.
“Normal people have good and bad days, and it’s exactly the same with Alzheimer’s,” said Thies. “Depending on where they fall in their own cycle when they see their doctor or the trial staff, they may look better or worse but it could be false. That’s why it’s so important to find something with less variability. That’s the appeal of imaging technology in clinical trials, and hopefully later in the general clinical setting.”
The goal is to find imaging that can effectively discover Alzheimer’s with pinpoint accuracy. In addition to improved methods of analysis, like that offered by Mosconi, researchers are looking at different substances within the brain and different tracers to use.
Carolyn Cidis Meltzer, MD, FACR, William P. Timmie Professor and Chair of Radiology and associate dean for research in the Emory University School of Medicine, is examining beta amyloid protein in the brain, and advanced imaging tracers or agents that bind to it. Beta amyloid is a small, sticky protein that accumulates in brains of those with Alzheimer’s. Many believe beta amyloid is a key factor in brain cell death in the disease.
“The commonly held theory is that amyloid protein is deposited in the brain in abnormal quantities in Alzheimer’s patients,” said Meltzer. “Using a tracer that binds to amyloid protein, we can theoretically have more specificity and sensitivity at an earlier stage in diagnosing Alzheimer’s.”
The radioactive tracer that Meltzer and her colleagues use in PET imaging is the C-11 compound, known as the Pittsburgh Compound B (PIB), developed by Chet Mathis, PhD, director of the PET facility at the University of Pittsburgh. Patients in Meltzer’s clinical trails are very well characterized through this process, and Meltzer hopes to continue to collect more data, following patients longitudinally, observing who develops Alzheimer’s, and comparing this diagnosis with their scans.
“Once we really understand what amyloid PET scans mean for prediction, if we combine the image data with other information about patients, then I think it can have enormous impact on clinical care,” said Meltzer. “It can be a clinically useful part of the patient’s workup, for those patients who present with advanced cognitive difficulties and those who are identified as high risk from their genetic profile, family history, and other risk factors. In the short term, individuals will be better able to do life planning. In the long term, hopefully this approach can enhance the effectiveness of disease-modifying therapy under development.”
Imaging in the Long Term
Meltzer’s drive for longitudinal research on imaging methods is a crucial one.
“The field has had a number of interesting snapshot studies, comparing and separating 25 folks with normal presentation and 25 with Alzheimer’s, for example,” said Thies. “These are interesting first tests. But they’re not ultimately going to give us the kind of confidence and usefulness we need that moves things along in routine clinical practice. We’re looking excitedly to newer studies that are giving us the longitudinal data largely missing from the field.”
One of these studies is the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a 5-year study with a patient population in the hundreds that uses PET scans with the Pittsburgh Compound B.
ADNI was launched by the National Institute on Aging (NIA) as a $60 million public/private partnership and is led by Michael W. Weiner, MD, professor of medicine, radiology, and psychiatry at the University of California, San Francisco, and director of the Center for Imaging of Neurodegenerative Diseases at the VA Medical Center. Researchers are testing whether serial MRI, PET imaging, other biological markers (in blood, urine, and CSF), and clinical and neuropsychological assessment can be combined to measure the progression of MCI and mild Alzheimer’s disease. The Alzheimer’s Association awarded its largest grant ever in 2006 to expand the study and add a PIB-PET scan component.
Some additional research being conducted in the field takes on PET imaging methods for both Alzheimer’s and other types of dementias.
Another lead researcher from the ADNI project, Bill Jagust, MD, professor in the School of Public Health at the University of California, Berkeley, conducts imaging studies through a joint initiative with neuroscience and public health researchers. At the Jagust Lab, researchers use PIB compound with PET imaging to study amyloid deposits, PET imaging to evaluate dopamine function in aging brains, and imaging interactions between Alzheimer’s and cerebrovascular disease.
Christos Davatzikos, PhD, of the Department of Radiology at the University of Pennsylvania, is conducting research using computer-based image analysis techniques with the goal of better diagnosis of mild cognitive impairment. Advanced high-dimensional pattern classification methods were used to analyze areas of brain atrophy with MRI images, and reduced blood blow to the brain with PET images. By combining the two, the researchers were able to determine complex spatial patterns of brain abnormality characteristic of the condition, and distinguish between patients with MCI and healthy participants with 100% accuracy.
Imaging for the Future
While research using PET imaging to forward the field of Alzheimer’s varies from study to study in methods and goals, two things are similar among all of them. Among researchers and field experts, there is a palpable mood of excitement, but also a strong frustration.
“When I first started getting into the area of dementia, it was just about understanding the disease and following patients,” said Meltzer. “The thought that 20 years later we would be talking about deciphering the cause of neurodegenerative disorders, and would have technology like we do now, was unfathomable. Many fields are coming together to get to this point and answer these questions. So it’s a very exciting time.”
At the same time, the advances promised by PET imaging and other Alzheimer’s research are threatened by a shortsighted lack of funding.
“It’s the worst time I can actually remember,” said Thies. “There’s a profound mismatch between funding for Alzheimer’s disease and the need. We’re anticipating a huge increase in patients over the next 40 years, from around 5.5 million now to 16 million. That’s unmanageable. We can’t afford to take care of that many people with the system and manpower we have now.”
The significant advances in Alzheimer’s research, driven by imaging studies, are pointing the way toward a future where Alzheimer’s doesn’t have to mean a debilitating end to dignity and health. But that can happen only if funding sources realize the critical juncture the field finds itself in.
“It’s an absolutely impossible scenario for us to watch play out,” said Thies. “The current rate of funding is completely inadequate for the public health threat. Ultimately, the federal government will go bankrupt paying for the growing Alzheimer’s population, all because they didn’t provide the front-end research investment necessary.”
Amy Lillard is a contributing writer for Axis Imaging News. For more information, contact .