Published Oct. 10 by the online Proceedings of the National Academy of Sciences, the research offers a new way to measure the impact of AIDS on the living brain, and reveals that the brain is still vulnerable to infection when patients are receiving highly active antiretroviral therapy (HAART).
"Two big surprises came out of this study," explained Paul Thompson, Ph.D., first author and associate professor of neurology at the David Geffen School of Medicine at UCLA. "First, that AIDS is selective in how it attacks the brain. Second, drug therapy does not appear to slow the damage. The brain provides a sanctuary for HIV where most drugs cannot follow."
Thompson's laboratory used a new 3-D brain-mapping technique developed at UCLA to analyze the MRIs of 26 people diagnosed with AIDS, and then compared the scans to those of 14 HIV-negative people. The brain scans measured the thickness of gray matter in various regions of the cerebral cortex.
The University of Pittsburgh diagnosed and scanned the AIDS patients; all 26 subjects had lost at least half of their T-cells, the immune cells targeted by HIV. None had experienced AIDS-related dementia, and 13 were on HAART.
The striking differences between the AIDS patients' and the control subjects' brain scans were easy to see on the detailed 3-D images. Areas of tissue loss glowed red and yellow, while intact regions shone blue and green.
The researchers were surprised to discover that AIDS consistently injured the brain's motor, language and judgment centers, but left other areas alone. Specific patterns of tissue damage directly correlated with patients' physical and mental symptoms, including impaired motor coordination and slowed reflexes.
"The brain scan really catches AIDS red-handed, allowing us to see precisely where the damage is," Thompson observed. "For the first time, we can understand why motor skills deteriorate with AIDS, because the virus attacks the motor centers on top of the brain."
"We saw up to a 15-percent tissue loss in the brain centers that regulate motor skills, such as movement and coordination," added Thompson. "This helps explain the slowed reflexes and disruption of balance and gait that often affect people with early AIDS."
The UCLA team also linked thinning of the language cortex and reasoning center to depletion of T-cells from the immune system. The finding may shed light on why AIDS is often accompanied by mild vocabulary loss, judgment problems and difficulty planning. As the disease advances, these symptoms can worsen into memory loss and dementia similar to Alzheimer's disease.
"Tissue loss follows T-cell loss, meaning that people with poor immune function also show severe brain damage," explained Thompson. "This was a revelation. We used to consider these separate phenomena, because HIV harms the brain and immune system in different ways. Now we see they are intrinsically linked."
"This is an exciting finding, not only because we can now see the effects of HIV/AIDS on the cortex, but also because it reinforces the importance of using sophisticated neuroimaging measurements as biomarkers for the effects of the virus on the brain," said James Becker, Ph.D., professor of psychiatry, neurology and psychology at the University of Pittsburgh. "Techniques such as these may also prove useful in evaluating the effects of HIV-medications on the brain."
The researchers were most startled to see no difference in tissue loss between the patients taking HAART and those who were not.
"This was the most terrifying aspect of our findings," said Thompson. "Even though antiretroviral drugs rescue the immune system, AIDS is still stalking the brain. A protective blood barrier prevents drugs from entering the brain, transforming it into a reservoir where HIV can multiply and attack cells unchecked."
The scientists hail brain imaging as a useful method for monitoring AIDS and evaluating new drugs' effect on disease progression. The technique can be powerfully applied to gauge patients' response to therapy, even before the onset of dementia or opportunistic infections.
"Brain mapping can help physicians monitor patients with more accurate detail than they can obtain by counting T-cells," said Thompson. "The scans also can test new drugs' ability to penetrate the brain during clinical trials."
One in 100 people aged 15 to 49 is infected with HIV, the fourth leading cause of death worldwide. In 2004, 40 million people were living with the disease. Forty percent of AIDS patients suffer from progressive neurological symptoms, typically leading to death.
The study was funded by the National Institute of Aging, National Institute of Biomedical Imaging and Bioengineering, and the National Center for Research Resources. Coauthors included Rebecca Dutton, Kiralee Hayashi and Arthur Toga, Ph.D., at UCLA, and Dr. Oscar Lopez and Dr. Howard Aizenstein at the University of Pittsburgh.
Journal
Proceedings of the National Academy of Sciences