Inside the Brain

The latest research at Banner Alzheimer's Institute

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Pierre Tariot, MD, and Eric Reiman, MD, head up the Banner Alzheimer's Institute, bringing their expertise in brain imaging to find new ways to treat Alzheimer's. (www.davecruz.com)

The abbreviated labels identify brain regions (PF: Pre-frontal, Te: Temporal, Pa: Parietal, PC: Posterior cingulate) known to show decreased activity in patients affected by Alzheimer's disease, particularly at late stages of the illness. (Banner Alzheimer's Institute)

(Top) As shown in purple and dark blue, patients with Alzheimer's disease have progressively reduced glucose metabolism (an indicator of brain activity) in certain locations. As shown in light blue, healthy people at genetic risk for Alzheimer's have lower brain activity in the same locations; (Bottom) These images, taken from a PET scan using fluorodeoxyglucose, show the coronal, transaxial and sagittal dimensions in a patient with mild cognitive impairment.

In fact, Alzheimer's – like a medieval plague – continues to gather in size and force. Since 1980, the number of Alzheimer's sufferers has doubled to its present 4.5 million. An estimated $100 billion is spent annually just to care for these patients.

There is at least some good news, as medical researchers tap new technologies to learn more about the disease and find better ways to treat it. Last year in Switzerland, for instance, researchers used sophisticated functional brain imaging techniques to confirm the link between a gene called "Kibra" and memory performance in humans.

In the United States, meanwhile, brain imaging technologies, such as PET scans and MRI, are being increasingly used to learn more about this terrible illness. And, Banner Alzheimer's Institute (BAI), based in Phoenix, is in the forefront of such research.

Overview of Facilities

A nonprofit healthcare network with 20 hospitals and long-term care facilities in seven western states, Banner Health employs nearly 25,000 employees. BAI is a recent addition to the system, having opened its doors last July.

BAI's five areas of concentration include its:

• Memory Disorders Clinic
• Brain Imaging Center
• Family and Community Services program
• Clinical research programs
• Genomics research

The three main research components for BAI are brain imaging, clinical trials and genomics.

The Memory Disorders Clinic, for instance, provides comprehensive diagnostic, treatment and disease management recommendations for people suffering from memory or thought-related problems. It also offers education, social and emotional support for those afflicted with the disorder and their families.

Patients are thoroughly evaluated, including a comprehensive review of medical symptoms and histories. Lab tests might also be prescribed, including neuropsychological testing and brain imaging. Treatment options are then reviewed.

Clinical research focuses on working with qualified candidates for promising experimental treatments that are conducted in conjunction with the National Institutes of Health (NIH) and U.S. FDA. Genomics research is applied to evaluate the genetic role in the development and progress of Alzheimer's, as well as its treatment.

Finally, BAI uses brain imaging to determine why certain people fall prey to Alzheimer's, to track the course of the disease and to determine which treatments will be most effective. PET scans, MRI and advanced computer analysis are all employed to determine the value of specific prevention therapies.

The Leaders and Their Vision

BAI is led by Executive Director Eric M. Reiman, MD, and Associate Director Pierre N. Tariot, MD. Reiman is a researcher and brain imaging expert, and Tariot is a recognized expert on drug therapy research for Alzheimer's and other forms of dementia.

Reiman, who also heads the state- and NIH-funded Arizona Alzheimer's Consortium, says BAI's three goals are to: (1) end Alzheimer's without losing a generation, (2) set a new standard of care for patients and families and (3) continue to forge a model of statewide collaboration in biomedical research.

The Consortium consists of 120 researchers from 10 Arizona institutions, and capitalizes on its complementary resources in brain imaging, computational image-analysis, genomics, cognitive sciences and clinical and neuropathology research to gain headway in understanding Alzheimer's. Reiman has led brain imaging research at Banner Good Samaritan since its launch in 1991.

To achieve its goal, BAI will launch a clinical trials program in conjunction with its organizational partners from the Arizona Alzheimer's Consortium.

"Each year, we'll aim to enroll 1,000 patients for evaluation of promising disease-slowing treatments, and 1,000 genetically healthy persons in primary prevention studies," Reiman says. "This will continue to establish the roles of PET and MRI in the evaluation of disease-slowing and prevention therapies, and permit a clinical trial to be performed on the same imaging systems with no hardware upgrades during the trial. This will increase the statistical power to observe effects on subjects."

Directing the Memory Disorders Clinic, Tariot is responsible for family and community services and the clinical trials program. "One aspect of our mission is to educate people about and refer them to research opportunities," he explains.

In addition, Tariot says, "Because this is a critical strategic issue, we partner with other regional institutions to promote awareness about dementia and the importance of available research. This outreach effort includes a unique registry in which people interested in research can enroll or be linked with existing studies, or to pre-enroll for future studies. The clinical trials program offers patients access to experimental treatments that hold hope for slowing progression of illness or improving cognitive function. In many cases, studies involve imaging outcomes and rely on advances in genetics for enrichment purposes and/or better understanding of therapeutic responses."

Tariot's team plans to offer prevention studies for non-demented people who have varying degrees of genetic susceptibility for dementia. "Most of these studies will also incorporate imaging, as well as biomarkers outcomes," he explains.

"In many cases, the treatment and prevention trials are specifically designed to rely on imaging and biomarkers as therapeutic surrogates for "proof of concept' studies, on the basis of which early decisions can be made about whether to bring promising therapies into larger, more conventional Phase III trials," Tariot says. "Our goal is to slice years off the time it will take to identify the most promising treatment and prevention interventions."

Brain Imaging Research

Traditional Alzheimer's evaluations have been conducted through questioning and personal observation. But because the PET scan offers a more scientific approach to monitoring the illness, Banner has been using its 3-D imaging to better evaluate potential treatments for patients.

Specifically, the PET scan follows chemical processes in the brain, providing a clear evaluation of the health and functionality of various organs.

When patients are injected with a harmless radioactive glucose/water solution "tracer," the PET scan is able to follow and measure the manner in which the body processes it. Computerized images of bodily organs are also produced, enabling physicians to distinguish healthy from unhealthy tissue.

In short, brain imaging helps researchers to study and identify patients who may be predisposed to Alzheimer's, and to follow the progress of the disease in those who are already afflicted. Banner researchers are even using PET to detect the early stages of Alzheimer's several years before memory and thinking problems arise.

Reiman says Banner was the first non-academic institution to install a cyclotron and establish a PET research program. "Our researchers and collaborators have used PET and MRI to make pioneering contributions to the study of normal human memory, emotion, pain, hunger and satiation, obesity and the predisposition to Alzheimer's. Findings have been published in such leading scientific journals as Nature, Nature Neuroscience, PNAS and The New England Journal of Medicine."

Reiman explains how the process works. "FDG PET reveals characteristic and progressive reductions in regional glucose metabolism in patients with Alzheimer's disease. Clinically, this radiotracer technique has been approved to distinguish Alzheimer's disease from frontotemporal dementia (a less common cause of disabling cognitive impairment) should uncertainties remain following a comprehensive medical evaluation. Scientifically, this technique can be used to track progressive brain changes in patients with Alzheimer's disease, patients with mild cognitive impairment and cognitively normal persons at genetic risk for Alzheimer's. It can also be used to evaluate promising disease-slowing and prevention therapies."

In addition to demonstrating how PET might be used to evaluate disease-slowing treatments for Alzheimer's patients, Banner's researchers and colleagues have also demonstrated that research can be done with only one-tenth the number of patients that would be needed using clinical endpoints. "This information can be used to help make strategic investment decisions about the performance of much more expensive multi-center pivotal trials," says Reiman.

Of special interest are developments in early detection of the Alzheimer's susceptibility gene, known as APOE4 allele. Reiman and colleagues have used PET to detect and track early brain changes that indicate the presence of this trait in cognitively normal people.

They've also suggested ways that PET might be used to evaluate the promising prevention therapies designed to slow down brain changes without needing to study thousands of healthy volunteers, and waiting many years to determine whether they develop problems with memory and thought.

"For instance," Reiman explains, "we've identified characteristic brain changes in young adult carriers of the APOE4 allele almost five decades before the possible onset of symptoms. This shows that the higher a person's genetic risk, the greater the reductions in PET measurements of glucose metabolism in Alzheimer's regions. PET might also evaluate primary prevention therapies in 100 late-middle-aged APOE4 carriers through a two-year study."

BAI has also set specific testing targets, according to Reiman. "We intend to conduct at least one clinical trial of a promising disease-slowing treatment every two years, and at least one clinical trial of a promising primary prevention therapy every three years. Our goal is to find effective ways to end Alzheimer's within the next 12 years."

According to Reiman, there have even been some developments in the methodology. "Several groups have recently developed promising PET radiotracer methods to visualize amyloid plaques, one of the cardinal neuropathological features of Alzheimer's disease, in the living human brain. Additional studies are needed to further establish their role in the clinical diagnosis, detection and tracking of Alzheimer's and the evaluation of amyloid-modifying treatments."

— Christopher J. Bachler is a freelance writer based in Pennsylvania. Questions and comments can be directed to editorial@rt-image.com.