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Molecular fingerprint predicts HIV-associated dementia

A new study using a cutting edge research technique called "proteomics protein fingerprinting" shows that HIV patients with dementia have distinct protein patterns in their blood, setting them apart from patients with no symptoms of dementia. The study suggests a possible way to screen HIV patients for the first signs of cognitive impairment.

"Characterizing dementia in this way is a very new and exciting approach," says study author Loyda Melendez, Ph.D., of the University of Puerto Rico Medical Sciences Campus in San Juan. "It's a ways off, but our research tells us that we might eventually be able to use a blood test to look for signs of HIV-associated dementia (HAD)." Dr. Melendez' group collaborated with researchers led by Howard E. Gendelman, M.D., of the University of Nebraska Medical Center in Omaha. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the June 24, 2003, issue of Neurology1.

About 10 to 15 percent of people living with HIV eventually develop HAD. The condition causes loss of memory and thinking abilities. Patients also may have motor deterioration and/or changes in their behavior and personality.

Researchers do not know how HIV infection leads to HAD. In this study, the researchers tested a unique hypothesis that HIV attacks immune cells in the blood that travel to the brain, rather than infecting the nerve cells. In a healthy individual, those blood immune cells, called monocytes, nourish the brain. However, studies have suggested that in a person with HAD, the corrupted immune cells may release substances that damage brain cells.

Dr. Valerie Wojna, M.D., and Dr. Melendez developed a cohort of Hispanic women at the University of Puerto Rico Medical Sciences Campus. Within 3 months complete neurological testing was done and blood samples were obtained from 31 Puerto Rican women aged 21-45 years. Nine of the women had HIV with relatively high levels of cognitive impairment, 12 had HIV without dementia, and 10 control subjects were HIV-negative and had no cognitive impairment.

Researchers at Nebraska then used a relatively new technique known as proteomics, which maps out patterns of activity for particular groups of proteins, essentially providing a molecular "fingerprint" unique to each patient.

Proteomic analysis showed that of the 177 proteins examined in the study, 38 proteins exhibited different activity levels in the HAD groups than in people without dementia. All of the patients with the distinct protein pattern were HAD-positive, but not all HAD patients had the profile.

The findings suggest that physicians may one day be able to screen for HAD using a simple blood test. A blood test would be quicker, less expensive, and more specific than currently used magnetic resonance imaging techniques and clinical evaluations. Even further down the road, researchers might be able to identify specific proteins responsible for causing the dementia. If researchers can find ways to inhibit those proteins, they might be able to prevent the onset of dementia.

Studies need to be done to more fully describe the protein profile for HAD, says Dr. Gendelman. "Our results are encouraging, but proteomics is still in its infancy. We've taken the first step in a very long journey to find better ways to diagnose HAD and other diseases."

The researchers have followed the same group of patients and healthy subjects for one year, and they plan to continue following them for another year, Dr. Melendez says. They also hope to double the number of study subjects in the future, in order to improve the statistical significance of their results, and to begin including men in the studies.

In addition to continuing the current work, the researchers plan to purify and sequence the proteins that are altered in HAD and to see how the protein patterns change over time as patients improve or decline. They also hope to examine whether genetic factors influence HIV dementia.

The study represents some of the first published results from one of the National Institutes of Health (NIH)'s Specialized Neuroscience Research Programs (SNRPs). The SNRP awards are designed to help minority institutions develop state-of-the-art neuroscience research programs, prepare the next generation of neuroscience investigators, and create opportunities for collaborations among researchers at minority institutions and other NIH grantees. Directing the SNRP program and coordinating the research between the Medical Sciences Campus and the University of Nebraska is Edmundo Kraiselburd, Ph.D., professor and director of the Unit of Comparative Medicine.

"The publication of such important results from this team of investigators in HIV-1/AIDS indicates that the NINDS-designed SNRP program, matching promising investigators from minority institutions with experienced scientists from larger medical centers, was well designed and is hitting its benchmarks for success," commented Eugene Major, Ph.D., an AIDS investigator and Acting Deputy Director of the NINDS.

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