War and aging play particular havoc with the human brain, a fact that has mobilized and energized researchers and clinicians at the UCSF-affiliated San Francisco Veterans Affairs Medical Center (SFVAMC). From world-renowned treatment programs in post-traumatic stress disorder to stroke, traumatic brain injury and dementia research, SFVAMC scientists understand the need for answers as they grapple with the human cost of distress and disability.
Post-Traumatic Stress Disorder
“In 1989,” recalls Charles Marmar, MD, SFVAMC chief of mental health, “I came to the San Francisco VA to develop the program in post-traumatic stress disorder — PTSD. Today, we treat about 2,000 veterans per year.” Marmar, who is also professor and vice chair of psychiatry at UCSF, notes that “for older veterans with chronic PTSD, a major challenge is dealing with secondary symptoms, including anger, alienation, withdrawal, depression and the tendency to self-treat these conditions with alcohol. Nonetheless, there are safe and effective treatments.”
Marmar conducts extensive research in PTSD among military personnel, police and civilians. One current study is looking at whether D-cycloserine, a safe drug already approved for human use, can help make cognitive behavioral therapy for PTSD more effective and longer-lasting in fewer treatment sessions.
The PTSD treatment program at SFVAMC is directed by Thomas Neylan, MD, whose research specialty is the connection between PTSD and sleep disturbance. “People with chronic PTSD are chronically on guard — they spend a lot of time appraising their environment for danger, in a state of what we call hyperarousal,” he says. “And so they have insomnia.”
As a psychiatrist with a bent toward neurobiology, Neylan, who is also an associate professor of psychiatry at UCSF, is “trying to understand the engine in hyperarousal, what fuels it, and how we can help veterans with those symptoms and make them feel better.”
“In 2005, I started seeing returning vets from Iraq and Afghanistan in my clinic,” says Karen Seal, MD, MPH, a staff physician at SFVAMC and an assistant adjunct professor of medicine at UCSF. “I began noticing how many were coming back with psychosocial problems, including post-traumatic stress disorder and substance abuse disorders.”
Research confirmed her observation: In one study, about one-third of returning vets had a mental health diagnosis. At the same time, she says, “there’s a real stigma attached to such a diagnosis, and many vets are reluctant to seek treatment.” To address this paradoxical situation, “we now have an integrated OIF/OEF clinic at SFVAMC that combines primary care with combat stress services and social services in one visit,” says Seal. “It’s a one-stop clinic for veterans who need help with any combat-related difficulties.”
Thomas Neylan, MD, discusses the neurobiology of PTSD.
Traumatic Brain Injury
The so-called signature wound of the conflicts in Iraq and Afghanistan is traumatic brain injury, or TBI. The most insidious form of the syndrome, closed-head TBI, often has no physical symptoms. “It’s an invisible injury,” says SFVAMC neurosurgeon Grant Gauger, MD. “But it’s no less damaging to the lives of those affected.” Mild, chronic TBI can lead to personality changes, inability to focus or make plans, and difficulty in controlling emotion — symptoms that can overlap with those of PTSD.
Gauger notes that like PTSD, mild TBI cannot be detected in the brain by using the conventional imaging technology available to most physicians. It is diagnosed only through neuropsychiatric examination, “which places an additional stigma on the men and women who suffer from it.” Gauger, who is also a clinical professor of neurological surgery at UCSF, is researching innovative methods for detecting mild TBI, using high-strength magnetic resonance (MR) techniques.
“If we can turn it from a psychiatric disease into a physical malady with reliable, reproducible biomarkers, that will help relieve the stigma and encourage patients to seek treatment,” he says.
Brain Imaging
For neurological and neuropsychiatric researchers at SFVAMC, a key facility is the Center for the Imaging of Neurodegenerative Diseases (CIND), which is directed Michael Weiner, MD, who is also a professor of radiology, medicine and psychiatry at UCSF.
CIND, which is built around two powerful MR units, is the only MR facility in the entire VA system devoted exclusively to human brain imaging, notes Weiner. He stresses that the CIND research group includes not only medical personnel, but physicists and computer scientists as well, “who are largely focused on developing new ways of obtaining sharper, more detailed images by enhancing the ability of our machines to acquire and process data. Thanks to them, our laboratory is able to make more and better discoveries.”
Among the current projects at CIND: identifying brain biomarkers for PTSD, which would help turn a stigmatizing psychiatric diagnosis into a medical condition. CIND is also home to research projects on Gulf War syndrome, Parkinson’s disease, Lou Gehrig’s disease and other neurodegenerative conditions.
Alzheimer’s Disease and Other Dementias
Weiner is the principal investigator for the Alzheimer’s Disease Neuroimaging Initiative, a $40 million, nationwide clinical trial. Its purpose is to establish a physical biomarker for the progression of Alzheimer’s disease that is based on changes in the brain as the disease progresses. Currently, Alzheimer’s progression is determined solely through neuropsychiatric tests.
“The problem is that these tests have a lot of variability from one day to the next,” says Weiner. “The beauty of MR is that it’s consistent from day to day, and thus measurable. So you could say it’s a no-brainer that brain imaging would be useful in clinical trials of Alzheimer’s drugs.”
“Most of my research is aimed at trying to understand who is at risk for developing cognitive impairment and dementia, and how we can modify that risk,” says Kristine Yaffe, MD, chief of geriatric psychiatry at SFVAMC and professor of psychiatry, neurology, and epidemiology and biostatistics at UCSF. “Can we prevent dementia? Are there ways to slow down cognitive decline as we age? Those are the questions that excite me.”
Yaffe says that she and her colleagues in the SFVAMC Mental Health Service are working to build the geriatric psychiatry program at the VA Medical Center. “We’ve been trying to make this a more comprehensive, multidisciplinary program to provide services to older veterans who might have medical problems, memory disorders, psychiatric issues, and cognitive and neurologic disorders.”
The good news, she says, is that “there are a number of things we can do that seem to help lower the risk of cognitive impairment as we age: Control weight, get sufficient exercise, treat chronic physical disease and, perhaps most important, keep challenging the mind.”
Basic Neurological Research
As a doctor, SFVAMC Chief of Neurology and Rehabilitation Raymond Swanson, MD, employs simple tools to diagnose complex neurological conditions, such as when he uses a hammer or a pen to check reflexes. As a researcher, he hopes to create better treatments for those conditions — for example, stroke, which has a very short time window for effective treatment.
“In my laboratory, we are looking at ways to extend that treatment window, and to develop new therapies that can be used at much longer time intervals after onset of symptoms,” says Swanson, who is also professor and vice chair of neurology at UCSF. He and his research team are investigating promising compounds that might prevent brain damage hours after a stroke or diabetic coma. He says that as a physician-researcher, he has the best of both worlds. “It allows me to target the research questions that will really help patients.”
AIDS
Lynn Pulliam, PhD, was the first in the world to show that HIV dementia, which strikes about 15 percent of people with HIV, can be caused when white blood cells called monocytes carry HIV into the brain, releasing toxins that kill brain cells.
“This infection of the brain occurs very early in HIV infection,” says Pulliam, who is associate chief of staff for research at SFVAMC and professor of laboratory medicine and medicine at UCSF. “Why do some people live with it and some develop dementia? That’s what we’re studying now.”
She notes that there is more than one route to HIV dementia. “In the developed world, if you live with HIV infection for a long time, there are proteins that HIV can secrete into the brain.” One protein called Tat interferes with the production of the enzyme neprolysin, which in turn causes the protein amyloid beta to build up in the brain. Amyloid beta is associated with dementias such as Alzheimer’s disease.
Currently, Pulliam and her team are working to develop ways of predicting who might develop this form of HIV dementia. One clue is a molecule called Sn, which is elevated in the bodies of individuals with active HIV infection. “A high viral load with Sn-expressing monocytes could facilitate HIV infection,” she explains. “We are looking at whether or not those monocytes could be easily transported to the brain.”
