- Researchers have found significant damage in the brains
of HIV-positive patients whose viral load is effectively suppressed by
anti-retroviral therapy. In one of the first studies of its kind, researchers
from the San Francisco Veterans Affairs Medical Center (SFVAMC) used a
combination of MRI brain imaging, recording of electrical brain activity,
and behavioral tests to compare the size and function of brains of HIV-positive
patients on antiretroviral therapy with those of healthy subjects.
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- Although it is not known whether any or all of the damage
occurred before patients started drug therapy, even minor damage that is
present now should serve as a warning, says Linda Chao, PhD, the study's
lead author and an assistant adjunct professor with the Magnetic Resonance
Unit of the SFVAMC and the Departments of Psychiatry and Radiology at University
of California, San Francisco (UCSF). "People are starting to get lax
about AIDS now," Chao says. "You see people on antiretroviral
medications and they seem fine. But the take-home message of our study
is that antiviral medications might not be stopping brain damage. When
we put patients' brains under closer scrutiny, we saw that they were affected."
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- "The results of our study raise the concern of brain
injury in HIV subjects who are on treatment, even among those who are virally
suppressed," says the study's senior investigator, Michael Weiner,
PhD, of the Magnetic Resonance Unit, SFVAMC, and the Departments of Radiology,
Psychiatry, Medicine and Neurology at UCSF. "What we don't know is
whether or not these changes occurred some time ago, prior to effective
treatment, or whether these changes represent ongoing injury."
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- The study appears in the November 14 issue of NeuroReport.
HIV or human immunodeficiency virus, the pathogen that causes AIDS or acquired
immunodeficiency syndrome, can produce neurological abnormalities in any
part of the nervous system, including the brain. Symptoms of HIV brain
damage may include depression, memory loss, a slowing of mental and physical
response time and sluggishness in limb movement. These symptoms can progress
to a severe disorder known as HIV dementia, an advanced stage of neurological
damage that, before the advent of antiretroviral drug therapy, afflicted
some 20 percent of HIV patients. These patients experienced such symptoms
as severe memory loss and cognitive impairment, tremors, hyperactive reflexes,
immobility, and loss of speech.
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- Now that antiretroviral drugs have become widely accessible
in the U.S., the prevalence of HIV dementia and other neurological problems
associated with HIV have sharply declined. But the drugs do not eliminate
the virus: they merely suppress it. And while HIV can make its way through
the blood-brain barrier (the body's natural defense mechanism that prevents
many blood-borne substances from passing into brain tissue), antiretroviral
drugs are largely excluded by the barrier.
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- Taking the first steps to determine how the virus may
be affecting the brains of people taking antiretroviral drugs, Chao and
her research team compared 39 people who tested positive for HIV who had
been taking antiretroviral drugs for at least three months with 39 control
subjects not infected by the virus. The HIV-positive group was further
divided into two subgroups: a "virally suppressed" group whose
16 members had no detectable virus in blood samples, and a "viremic"
group whose 23 members had substantial virus in blood samples. Whether
virally suppressed or viremic, all subjects in these groups were healthy
with no symptoms of HIV infection.
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- Study participants ranged in age from 25 to 57 years.
All had from 12 to 20 years of education, and no one with a history of
substance abuse or psychiatric or neurological disorders was included in
the study. Due to inherent difficulties in determining when HIV infection
has taken place, this information was not available for study participants.
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- Three separate techniques were used to assess neurological
health of study participants:
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- Recording of brainwaves during task performance. Researchers
recorded subjects' contingent negative variation (CNV), a type of brainwave,
while subjects performed a reaction time test. The CNV is considered to
be a measure of anticipation and preparation potential as well as an indication
of a person' s ability to initiate physical action.
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- Neuropsychological testing. Participants performed a
battery of tests designed to assess memory and mental agility.
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- MRIs. Magnetic resonance imaging was used to measure
the size of various parts of the brains of 31 HIV patients and 35 control
subjects. The biggest difference in test results between groups came from
the contingent negative variation brainwave recordings. When Chao charted
the magnitude of brainwaves during the computer task performance test,
she found that while CNV activity among HIV-negative participants surged
shortly after appearance of the first image, it remained nearly flat among
both the viremic and virally suppressed HIV-positive participants. Lack
of CNV response is generally an indication of damage or destruction to
brain cells in the basal ganglia, a part of the brain that coordinates
motor behavior and one of two brain structures where HIV tends to concentrate.
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- Chao also found that among control subjects, the stronger
their CNV activity, the faster their response time. But there was no correlation
between CNV activity and response time among HIV-positive participants.
Nevertheless, HIV- positive participants had just as good response times
as control subjects. There is a possible explanation, says Chao: the flat
CNVs recorded among the HIV-positive participants are possibly an indication
that HIV has damaged the normal neurological linkage between a stimulus
(for example, a hand touching a hot pan) and a reaction (pulling the hand
away). But the fact that response times were equal could mean that alternate
neurological pathways that compensate for the disruption have developed
in the brains of the HIV- positive subjects.
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- To assess where HIV-triggered damage might be occurring
in the brain, Chao examined the relationship between the strength of CNV
activity during the reaction-time test, with MRIs of study subjects' caudate
nuclei, a substructure of the basal ganglia. She found that the weaker
the CNV among HIV-positive participants the more reduced the caudate volume.
"The basal ganglia is a part of the brain known to carry one of the
highest viral burdens," she says. Because there is also evidence that
the CNV partially originates in this part of the brain, finding this correlation
[between weak CNVs and reduced caudate volume] is a nice tie-in that gives
us more confidence in our conclusions about where and how damage is occurring."
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- MRI measurements also revealed that the volume of the
brain structure known as the thalamus was smaller both in viremic and in
virally suppressed participants than in controls, an indication of damage
in this region. The thalamus serves as a relay station for sensory information.
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- Results of the behavioral tests were mixed. On several
tests, there were no differences between the three groups. And on all tests
virally suppressed patients scored as well as the control group. But on
three tests, scores of viremic participants were significantly lower than
those of virally suppressed participants and the controls. "People
with lower scores like these might not be able to do such things as type
as fast as before, and they might not have as good attention or mental
flexibility as the people who scored higher," Chao says. "But
unless they were challenged daily, this is something they probably wouldn't
notice, because these are the kinds of things that are more easily compensated
for."
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- Previous studies have already shown that when viral load
is reduced by antiretroviral therapy, behavioral performance improves.
But in running several kinds of tests and comparing their results, the
research team was able to scrutinize their findings in a new light. To
determine whether injury is ongoing, Weiner says, follow-up studies that
assess HIV-positive patients over a longer time period are needed.
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- Contact: Liese Greensfelder lgreensfelder@pubaff.ucsf.edu
415-476-2557 University of California - San Francisco
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- http://www.eurekalert.org/pub_releases/2003-11/uoc--bdf111303.php
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