fMRI Measures Effect of Treatment on HIV-related Cognitive Impairment

Researchers are using neuroimaging to assess the response of the central nervous system to HIV infection and the drugs used to treat it.

Dennis Kolson, M.D., Ph.D. University of Pennsylvania

Beau Ances, M.D., Ph.D. University of California, San Diego

While antiretroviral drug regimens have significantly prolonged the lives of individuals infected with HIV, long-term use has been associated with an increase in the prevalence of HIV-related brain and central nervous system disorders. To evaluate the effect of different highly active antiretroviral treatments (HAART) on HIV-associated cognitive impairment, researchers have turned to functional magnetic resonance imaging (fMRI).

Since the development of HAART, clinicians have noted that central nervous system-related deficits are not as severe as the frank dementia seen prior to the advent of these medications. However, the symptoms are still significant enough to have an impact on quality of life, researchers said.

Beau Ances, M.D., Ph.D., an assistant professor of neurosciences at the HIV Neurobehavioral Research Center at the University of California, San Diego (UCSD), is using fMRI to study whether drugs with higher penetration across the blood/brain barrier lead not only to improvement in neurocognition but also to improvement measured by neuroimaging. He said he hopes that results from this trial will allow clinicians to tailor regimens for particular patients.

"Even though patients with HIV can now live relatively healthy lives with the help of these medications, about 20 to 30 percent of them will eventually develop neurocognitive impairment," said Dr. Ances. "These patients often present with slowed movements and mild memory loss. While we know that these drugs are beneficial, we also know that certain drugs can be toxic to the peripheral nervous system. We need to be sure that as new drugs are developed, they do not cause injury to the central nervous system."

HIV Quickly Infiltrates Nervous System

Researchers from Johns Hopkins University School of Medicine in Baltimore and Washington University School of Medicine in St. Louis also are investigating the central nervous system effect on subjects given high- versus low-penetration antiretrovirals. The fMRI studies will be performed only at UCSD.

When a person is infected with HIV, the disease gets into the brain within "a couple of hours to a couple of days," said Dr. Ances. After infiltrating the central nervous system, the virus can cause inflammation, nerve cell damage and abnormalities in the brain's white matter. Each of these can affect nerve cell function within the brain, causing learning and memory deficits, impairment of cognitive or motor skills and even dementia.

To date, about 50 patients with documented HIV infection and associated neurocognitive impairment have been studied at UCSD using fMRI. A total of 120 patients will be enrolled in the study. In order for researchers to compare drugs that affect the central nervous system to those that do not, study participants' baseline brain function will be evaluated with a neurological examination and lumbar puncture. Functional neuroimaging measures such as changes in cerebral blood flow and metabolism will be assessed in subjects as they perform simple tasks such as fingertapping or watching a flashing checkerboard.

The importance of these neuroimaging studies is that they are the only way, in living patients, to assess the brain's response to this disease and its treatment, said Dr. Ances. "It's so important to gather these data and use them to develop the best techniques to treat these people."

Antiretroviral Drugs Alone Inadequate to Protect Brain

Since 1992, Dennis Kolson, M.D., Ph.D., an associate professor of neurology at the University of Pennsylvania, has been researching the clinical manifestations of HIV infection and how the virus damages the brain. He said that after more than 10 years of neuroimaging studies, such as MR imaging and MR spectroscopy, HIV researchers have discovered two very important concepts.

"The first is that effective antiretroviral therapy offers some degree of protection of the brain, preserving it to some degree, or at least slowing the rate of progression of deficits of neurological function and cognition," said Dr. Kolson. "Drugs that penetrate more deeply into the brain are more effective at protecting the brain.

"The second conclusion is that antiretroviral drugs are not adequate on their own to protect the brain," Dr. Kolson continued. "We are most likely going to need additional drugs, which will have to be used early in infection in order to have a long-term effect."

Cognitive impairment among people infected with HIV was not considered a major problem a decade ago because people with the disease were not living as long, said Dr. Kolson. However, as people live longer with HIV/AIDS, their likelihood of developing cognitive impairment increases, he said.

"The cognitive impairment is a consequence of effectively prolonging people's lives and the effect of taking these drugs long-term, as well as the effect of HIV itself in an older population," he said.

Researchers said they hope the new study will give them a better idea of what the antiretroviral drugs are doing and enable them to develop more effective drugs for addressing brain issues. A number of research laboratories, including Dr. Kolson's, are studying model systems of HIV infection of brain cells to determine how such cells are damaged and how strategies can be developed to protect the different cells in the brain. Combining such basic research with clinical neuroimaging studies, like those being conducted by Dr. Ances and collaborators, will hopefully lead to the development of more effective approaches to protecting the brain from the damaging effects of HIV, Dr. Kolson said.

"It's no longer okay to just extend the length of life for people with HIV," said Dr. Kolson. "We now have to develop the best treatments to help the quality of life as well."

  
Neuronal damage caused by HIV.
A healthy rat brain cell culture is shown in panel (a), with neurons labeled in red and astrocytes (supporting cells) labeled in green. Panel (b) shows a similar culture that was exposed to HIV-infected human cells for 24 hours, resulting in a dramatic loss of the neuron population. Cell nuclei are labeled blue. Such model systems are used to study the mechanisms by which HIV infection causes damage in the brains of infected individuals.
Photo courtesy of Dennis Kolson, M.D., Ph.D.

Neuroradiology at RSNA 2008
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