Change agent: Creating new scans to track brain diseases

Seven weeks after weight-loss surgery, a group of women have seen significant changes in their body shapes and sizes. They’re each down 20 to 30 pounds, but that’s not the only change their bodies are going through.

The women’s weight loss is caused by a change in appetite, which results from changes in brain function, explains UAB neuroradiologist Robert Kessler, M.D. (pictured above in UAB's Advanced Imaging Facility). On positron emission tomography (PET) scans, Kessler can see an obvious transformation in the women’s brains, particularly in dopamine neurotransmission.

Using a specialized brain PET scan that he has developed, Kessler can visualize levels of dopamine receptors — molecules that help transmit the brain’s messages of motivation and reward. Before surgery, the women had increased levels of the receptors, which appear on the PET scans as glowing white patches throughout the brain. But after their surgeries, these changes have faded; the women’s brains exhibit a more balanced map of dopamine receptors. In real-world terms, Kessler thinks, these tempered receptor levels reflect a shift to a more normal reward perception, helping the women control their appetites after surgery.

Obesity — and the drive to overeat — isn’t the only pathology that Kessler can see when he peers into people’s brains with a PET scan. During the past 30 years, he has helped illuminate changes to the brain that might underlie schizophrenia, drug addiction, depression and dementia, among other disorders. By looking at a person’s brain PET scan and carefully measuring the levels of neurotransmitter function, Kessler can tell whether someone is more prone to taking risks than average, whether they’re more of a “slacker” or a “go-getter,” and whether or not they have “the ability to experience rewarding stimuli in a normal manner or if they have lost that ability,” he said.

Find out how a cyclotron works, and what makes UAB’s new cyclotron unique among U.S. academic medical centers, in the video above and in this feature from UAB Magazine.

Kessler, who joined the UAB faculty in 2013 as director of neurochemical brain imaging and PET neurotracer development in the Department of Radiology, says these specialized PET scans are paving the way toward a new level of understanding of brain diseases.

“At a very basic scientific level, there’s no other technology that can look at the human brain and inform you about specific molecules and receptors,” Kessler said. At UAB, he’s taking advantage of the university’s TR24 cyclotron — the largest at any U.S. academic medical center — to develop new PET scans. And he has launched collaborations with UAB researchers across the psychiatric and neurological sciences to help them apply his techniques to even more questions.

Focusing on Receptors

As a medical student, resident and fellow in the 1970s, Kessler first became interested in the human brain at a time that clinicians had few methods to visualize the organ. Surgeons could physically see the outer layers of the brain when they opened the skull for an operation, or pathologists could dissect an autopsied brain; but viewing the activity — in a living human — of the molecules that make up the brain’s electrical pathways wasn’t possible.

In 1977, Kessler joined a lab at the National Institutes of Health just as this was changing. One of his mentors there became the first to use a PET scan to visualize the activity of the brain. The earliest scans, rather than pinpointing specific receptors as Kessler does now, were designed to simply show which cells in the brain were undergoing metabolism — a sign of activity — at any given moment.

But the basic idea has been the same for more than three decades now: A patient gets an injection of a radioactive tracer into their bloodstream. Depending on the design of the tracer, it accumulates in particular organs or cells of the body. Then, a PET machine is used to measure the location of the accumulated radioactivity.

“It quickly became clear to me that PET was going to become an important tool for understanding the brain,” Kessler said. “And we began to use it to look at everything from brain tumors and schizophrenia to aging and dementia.”

As Kessler immersed himself in the new technology, first at NIH and then at Vanderbilt University, he helped develop new tracers that would pave the way for the rest of his career: 18F-Fallypride, and later 18F-FPEB. Rather than building up in all metabolizing brain cells, these radioactive molecules bind specifically to dopamine and glutamate receptors.

Among the first questions Kessler asked with 18F-Fallypride was ‘What are the effects of antipsychotic drugs on the brains of patients with schizophrenia?’ A new class of antipsychotic drug had recently been developed; the drugs had fewer side-effects than older versions, but researchers didn’t know why. Kessler and his collaborators discovered that the new drugs targeted different areas of the brain than the old drugs, offering not only an explanation for the differences, but a way to test future drugs for their efficacy.

Dopamine had also already become known as a chemical that mediates reward-seeking behavior and pleasure. So Kessler’s lab began to look at how levels of the dopamine receptor and the effects of dopamine release on dopamine receptors might relate to drug abuse, impulse control, addiction and the ability to feel pleasure.

“People who are depressed lose their ability to enjoy rewards and experience the pleasures of life; people who are addicted have very distorted reward functions where they crave just one reward,” Kessler said. “We showed that dopamine plays a key role in all of these.”

These are 18F-Fallypride PET images of dopamine D2 type receptors, averaged across several normal subjects. There are high levels of these receptors (red color) in deep brain structures and lower levels in the cortex. These include the basal ganglia and thalamus (A), amygdala and temporal cortex (B), and substantia nigra (C). These regions are concerned with movement, emotion and cognition.

The Future of Brain PET

PET scans offer the most direct way to observe what happens at a molecular level in the brain when someone develops, or recovers from, a psychiatric disorder or addiction, Kessler says. Drug developers and pharmaceutical companies now use PET scans to fine-tune prospective new treatments, he notes. If they know they need to lower the number of dopamine receptors in one area of the brain, for instance, they can use PET scans to determine which drugs, and drug dosages, effectively achieve this.

One of the ongoing challenges in the field, Kessler says, is developing new tracers. With UAB’s new cyclotron, Kessler says he has the tools at his fingertips to continue developing and perfecting tracers that bind to different receptors in the brain. He’s already begun work with the neurotransmitter glutamate; like dopamine, glutamate can be studied through PET tracers that bind to glutamate receptors. And glutamate is thought to have roles in autism, Huntington’s disease, Parkinson’s and anxiety disorders, among other things.

This fall, Kessler launched a study examining glutamate receptors in the brains of addicts as they voluntarily withdraw from methamphetamine. The findings — if they show key differences from normal brains — could lead to new drugs to help meth addicts quit their addiction. Studies on Parkinson’s, depression and Alzheimer’s disease are also in the works with UAB collaborators.

Although “this is a tough area to work in for many reasons,” Kessler said — from the vagaries of chemical half-lives to the sheer complexity of the brain itself — he wouldn’t have it any other way. “You just can’t get this kind of information anywhere else.”

Image post 8: mapping live brains

This image from UAB Research illustrates the improving brain maps that promise to reveal the mechanisms behind complex, neurological diseases.


























A MRI technology called diffusion tractography captured this image of a living rat brain. Tractography is a 3-D modeling technique that visually represents nerve pathways in the brain using data collected by diffusion tensor imaging (DTI).

DTI visualizes nerve pathways known collectively as white matter that connect the various parts of the brain via long bundles of nerve cells. It shows whether or not bundles of white matter fibers run in the same direction, but not in which direction. Tractography does that.

Since developed by researchers at Washington University School of Medicine in St. Louis, it has given the field a more detailed look at brain structures, especially living brains. Taken together, these new MRI technologies promise to improve understanding of neurological disorders like schizophrenia and Alzheimer's disease and the consequences of head trauma. They also may one day help neurosurgeons better avoid cutting nerves during surgeries.

In particular, tractography reveals connections that can be measured in living human subjects and measurements that can be made simultaneously across the entire brain. The Human Connectome Project is capitalizing on these strengths to build more accurate brain maps. The image was created in the lab of Hyunki Kim, Ph.D., associate professor in the departments of Radiology and Biomedical Engineering and faculty in the UAB Comprehensive Cancer Center.

Image post 5: eye nerves shed light on memory disorders

While most posts from The Mix feature a science story, we have also begun sharing images coming out of UAB research. Below is a brief description of what we are looking at and how related work may contribute to a better understanding of Alzheimer's disease.

Pictured here is a retinal ganglion (center), a kind of nerve cell near the eye’s retina that helps to process light into the images we perceive. It had been injected with a fluorescent dye, which made it glow green along with the cells connected to it electrically. In each of our eyes, 125 million photoreceptors capture light. They then trigger nerve messages in 1.5 million retinal ganglion cells, long extensions of which bundle together to form the optic nerve.

Captured by Christianne Strang, Ph.D., research instructor in the Department of Vision Sciences within the UAB School of Optometry, this image represents signaling mechanisms between the retina and surrounding nerve cells. Strang's lab seeks to understand how photoreceptors connect to surrounding nerve pathways, as well as the degree to which they signal using the neurotransmitter acetylcholine.

Within nerve pathways, each nerve cell sends an electric pulse down an extension of itself called an axon until it reaches a synapse, a gap between itself and the next cell in line. When it reaches an axon’s end, the pulse triggers the release of chemicals called neurotransmitters that float across the gap. Upon reaching the other side, they either cause the downstream nerve cell to “fire” and pass on the message, or stop the message. Certain neurological diseases, including Alzheimer’s, have been linked to a decrease in acetylcholine signals in nerve pathways related to vision and memory.

As for rest of the color scheme, the pictured eye tissue has also been treated with dyes that interact with choline acetyltransferase (blue), which helps to produce acetylcholine, and synaptophysin (red), which reveals the location of synapses. The work was done in the lab of Kent Keyser, Ph.D., professor in the School of Optometry.