Indiana University Research & Creative Activity

Mind/Brain

Volume 30 Number 2
Spring 2008

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Andrew Saykin
Andrew Saykin
Photo © Ann Schertz Photography

brain scan
Brain scan created using IU's High Performance Computing Systems
Courtesy Andrew Saykin

Committed to Memory

by Eric Schoch

Early one winter morning in a research building at the Indiana University School of Medicine, a cheerful gray-haired woman is lying motion-less in an MRI machine, wearing goggles. There she will stay for the next 90 minutes, making her contribution to the search for the causes of, and treatments for, Alzheimer's disease.

And maybe for schizophrenia too. And for epilepsy, for so-called "chemo-brain," and even for traumatic brain injury.

Happily, the woman in the MRI doesn't have any of these problems, including Alzheimer's. But on the other side of a shielded window, a control room is crowded with more than a half dozen people working to answer questions about all these diseases and more.

Among them is Andrew J. Saykin Jr., one of the nation's experts in using the latest brain-imaging technologies. Saykin has been conducting such tests over the course of a 25-year career that has taken him from Hahnemann Medical College in Philadelphia to the University of Pennsylvania to Dartmouth College in New Hampshire, and most recently to Indiana University. In this morning's proceedings, he and his colleagues will be putting the patient through a battery of MRI (magnetic resonance imaging) and PET (positron emission tomography) sequences, many of them "investigational," as Saykin puts it.

"These are probably the standard of care of the future, being validated now," he says.

Developing tomorrow's medical care is the sort of thing IU School of Medicine leaders had in mind when they recruited Saykin in the fall of 2006 as Raymond C. Beeler Professor of Radiology and director of the IU Center for Neuroimaging. Saykin didn't come alone. His wife, neuropsychologist Gwen Sprehn, joined the IU Department of Neurology. Brenna McDonald, assistant professor of radiology, and John West, a computer systems engineer for the neuroimaging center, also made the move from Dartmouth. Saykin recruited computer scientist Li Shen from the University of Massachusetts to become an assistant professor of radiology as well.

All this recruitment is an outgrowth of the growing emphasis at the School of Medicine, and IU, on neuroscience research that is funded with part of a $26 million grant to IU from the Lilly Endowment made in December 2004. Out of that grant, one of the Endowment's series of intellectual capital grants to state colleges and universities, $10 million went to recruit neuroscience researchers in Bloomington and Indianapolis.

Saykin's recruitment brought a scientist with broad interests. Type "Saykin" into the search box of the biomedical database PubMed (www.ncbi.nlm.nih.gov/sites/entrez/), and you'll find his journal articles on schizophrenia, testing evaluation, cognition and chemotherapy, obsessive-compulsive disorder, clinical use of functional magnetic resonance imaging, volume and shape of the hippocampus, mild cognitive impairment, bipolar disorder, Alzheimer's disease, traumatic brain injury, and more. In some of these studies, Saykin's role was to help others use imaging technology, but he led the studies on Alzheimer's, mild cognitive impairment, chemotherapy, and schizophrenia. And all of the work is tied to his interest in memory.

"I'm particularly interested in memory--different types of memory and how they are compromised in different disease states, and how they respond to different types of treatments,'' Saykin says. "Basically, we're looking at an exquisite and delicate organ that permits us to think, feel, behave, and plan, and that organ system can be compromised by many different kinds of disease process and injuries."

The goal of the neuroimaging center is to study that organ system, those diseases, and possible treatments, using its advanced imaging tools meshed with the power of genomics. A growing cadre of IU faculty (and students), newcomers and veterans, is coalescing around the center, creating formal and ad-hoc interdisciplinary groups whose members vary based on the work--oncologists on chemotherapy, psychiatrists on schizophrenia, neurologists on alcohol addiction.

"For every brain disorder there's a genetic story, and there's a story in terms of structural, functional, or chemical changes in the brain. So it would be crazy not to benefit from what we learn studying schizophrenia and not apply it to Alzheimer's," Saykin says.

The need for such research is obvious from the numbers concerning just one disease, Alzheimer's. An estimated 4.5 million Americans have Alzheimer's disease now, and the national cost of caring for them is $100 billion annually. If no treatments are developed that would prevent the disease in at least some people, it's estimated that by 2050, 13.2 million Americans will have Alzheimer's disease.

A progressive and ultimately fatal disease, Alzheimer's destroys the brain's capabilities for memory, thought, and controlling behavior. The build-up of beta-amyloid protein deposits (plaque) between nerve cells and the development of fibers of the protein tau inside of brain cells (tangles) appear related to the development of Alzheimer's, but the causes and mechanisms aren't yet well understood. What is understood is the need to discover and treat these processes a lot sooner than we do now.

"We probably need to intervene five, 10, 20 years before a diagnosis of early Alzheimer's disease," says Saykin. "There's good reason to think that a lot of processes are percolating in the background for many years."

To that end, Saykin and colleagues are working on a long-term study of a group of older individuals, ranging from those with no signs of any cognitive problems to those with Alzheimer's. Somewhere in between is a group with what's been defined as "amnestic mild cognitive impairment" (MCI), involving problems with memory in the absence of broader problems with areas such as language, attention, reasoning, judgment, reading, and writing that might compromise daily functioning.

Researchers are paying a lot of attention because mild cognitive impairment imparts a significant risk of progressing to Alzheimer's. The key is to determine the differences between the normal effects of aging, or stress, and worsening problems that are likely to lead to Alzheimer's disease or another dementia. Those with amnestic MCI, who have memory problems in particular, are at 50 percent risk of developing Alzheimer's disease or another dementia within five years.

Saykin and his colleagues have identified another group, however, that may hold even more promise for developing methods for early detection and prevention of Alzheimer's. This group, he says, have cognitive complaints--they feel themselves slipping in memory in minor but troublesome ways, such as forgetting where they put things, or what somebody said in a conversation, or the plot of a movie. Yet they don't demonstrate problems when they take neuropsychological tests, so many physicians would classify them as merely "the worried well."

In a 2006 article in the journal Neurology, Saykin and colleagues reported an MRI study of such "cognitive complainers," MCI patients and people with no memory complaints--all over age 60--found that the cognitive complainers did in fact have some loss of brain gray matter, including the hippocampus, a region that's important to memory and where Alzheimer's disease is known to cause damage.

"We think some of them are pre-MCI," Saykin says. "We think we have an earlier identification of people on that pathway to dementia. On the other hand, some of them seem to be stable and have stopped complaining."

Long-term studies are needed--imaging, physiological, genetic--to predict who is going on what trajectory, who is a candidate for testing agents that may block that progression to Alzheimer's.

The availability of such imaging tools is a dramatic change from when Saykin started along his personal career trajectory.

A Massachusetts native, Saykin received his doctoral degree in psychology in 1982 from Hahnemann Medical College. Early in his graduate studies at Hahnemann, the college developed a neuropsychology track, and Saykin was "one of the first three 'guinea pigs' who went into it," he says. "This program, developed by Sandra Koffler, was a career changing opportunity for me."

Neuropsychologists work to connect brain structure and neural activity with behavior, memory, and psychological disorders. As he began learning more about the brain and seeing neurological patients, Saykin says, he realized that new imaging technologies were going to offer great opportunities.

At the time there was no definitive way to know whether a particular psychological test was calling on the strengths of a particular part of the brain other than to study patients with focal tumors or strokes. Ask a subject to study a shopping list, provide a distraction, then find out how much of the shopping list the subject can remember. Then try to decide which lobes of the brain are involved.

"It was always frustrating to have a panel of experts try to decide, is this more right frontal/left frontal, left temporal/right temporal, and so on. It would come down to a matter of opinion," Saykin recalls.

Down the street from Hahnemann, however, the University of Pennsylvania was operating one of the nation's first PET scanners. Saykin went to see the director of the cerebrovascular research center at Penn and offered his opinion that that anyone getting one of these new PET scans ought to undergo neuropsychological testing so that their cognitive state could be associated with the imaging results. He was pointed in the direction of a pair of researchers at Penn, Ruben and Raquel Gur, who were doing early functional brain imaging studies using a different type of scanner, employing radioactive Xenon gas.

"I became intrigued with the idea of being able to do neuropsychological testing while measuring activity in the brain. I guess I'm still intrigued by that," Saykin says.

Which is why, years later at IU School of Medicine, a cheerful gray-haired lady is spending 90 minutes in an MRI machine, with goggles on.

Her tests will include a conventional MRI brain anatomy scan, but with higher precision than standard clinical scans. A functional MRI scan shows which parts of the brain are active when the subject is tested--in this case, the woman is shown a list of words one after the other, pressing one button when the word is new, and a second button when a word is repeated. She will also undergo diffusion tensor imaging (DTI) which measures the brain's white matter fiber tracks--essentially the communications pathways in the brain, MRIs to measure blood flow and brain chemistry, and a PET scan to measure brain metabolism.

All of these tests provide huge volumes of data and an accompanying challenge to analyze it. Advanced scans provide hundreds of thousands of "voxels"--essentially three-dimensional versions of the two-dimensional pixels familiar to digital photographers. To further complicate things, genetic information is added in. For example, IU scientists are using an imaging process to identify beta amyloid protein deposits in the brain. There are many genes that appear to be involved in a biological cascade of activity that results in those beta amyloid deposits. A microarray can identify hundreds of thousands of genetic variations that may link certain genetic patterns with the protein deposits that show up in the brain scans.

A few hundred thousand imaging data points here, and a few hundred thousand genetic data points there, and it's time to call in the statisticians, mathematicians, computer scientists, and other such specialists, says Saykin.

"Now that we have these tremendously rich datasets, we have to have very smart strategies for properly interrogating the data without--as a statistician friend used to say--torturing that data to the point of false confessions."

What Saykin hopes will emerge, instead, is a comprehensive model of the brain that encompasses its structure, its neural activity and blood flow, its biochemistry and genomics, all the factors that will help us understand what happens in disease and injury, and what results when we respond with treatment, whether pharmaceutical, surgical, or psychological. With that knowledge, we may be able to keep the breast cancer patient feeling mentally sharp, return the injured soldier to a normal life, stop the seizures of an epileptic child, and halt the processes that can cruelly rob us of our memories even as we learn how to live longer lives.

Eric Schoch is a writer and manager of science communications for the IU School of Medicine in Indianapolis.