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CATIE News - Brain decline linked to cardiovascular disease
2010 Aug 25 - Although HIV infection is generally explained as a virus that damages the immune system,
it can also affect many organs and tissues, including the brain.
Inflammation
While potent anti-HIV therapy (commonly called ART or HAART) can greatly reduce virus levels in the blood, small amounts
of HIV continue to be produced within the body's lymph nodes and tissues. This low-level production of HIV causes the immune system to be in an activated state.
The activation of the immune system is a normal response to infection. Once an infection has been brought under control, the immune
system dampens down activation. However, because HIV infection persists, the immune system appears to be continuously activated-even in people who use ART for many
years. Such prolonged activation may in turn affect a broad range of the body's organs and tissues. This is because the immune system has cells that rove around
the body and can take up residence in organs and tissues. There, activated immune cells can affect the surrounding tissues of organs, disturbing the health and functioning of these organs.
Enter the brain
One organ that may be negatively affected by prolonged HIV infection is the brain. Since the earliest days of the HIV pandemic, researchers
recognized that, in some cases, HIV infection could eventually result in behavioural and cognitive changes-including difficulty thinking clearly, problems with memory,
confusion, delirium, and, in extreme cases, dementia. Now that ART is widely available, AIDS-related dementia is rare in high-income countries. But emerging research
suggests that subtle impairment of the brain's thinking abilities occurs even in HIV-positive people who are adherent to therapy and who do not engage in substance
use. These findings have spurred further research into HIV's impact on the brain.
No brain is an island
Scientists in high- and middle-income countries who study the brain have been trying to understand the issue of declining neurocognitive ability
despite the use of ART and ways to reverse it. One team of researchers has completed its preliminary analysis, which will appear in a future issue of the
journal Neurology . The researchers found that, even in people with high CD4+ cell counts, neurocognitive decline was more likely to occur
in people with pre-existing cardiovascular disease than in people with traditional risk factors for HIV-related dementia. If this finding is
confirmed, further emphasis on improving cardiovascular health for HIV-positive people can be expected.
Study details
As part of a larger study of episodic treatment interruption called SMART, researchers interested in HIV-neurocognitive issues conducted a sub-study with 292
participants from the following countries:
- Canada
- Australia
- Brazil
- Thailand
- United States
Participants completed different tests to help researchers understand the brain's ability to solve problems, think clearly, process information and remember.
These results were compared to those that had previously been collected from healthy HIV-negative people. Additionally, detailed medical records and results of laboratory analyses of blood
were also considered when analyzing the data.
The average profile of participants when they entered the study was as follows:
- 42% females, 58% males
- proportion with 12 years education or less - 54%
- CD4+ count - 536 cells
- lowest-ever CD4+ count - 225 cells
- proportion with a viral load of 400 copies/ml or less - 88%
Results
Overall, the researchers stated, neuropsychological testing suggested that people in the sub-study had "below-average performance compared to a
healthy [HIV-negative] population." Furthermore, about 14% of participants had more serious neurocognitive impairment. There were no significant differences in neuropsychological
test results among different countries.
The researchers found that about one-quarter of participants had depression, with people in Canada, Australia and the U.S. more likely to have
depression (41%) than people in Thailand (14%).
Cardiovascular connection
People who entered the study with pre-existing cardiovascular disease were six times more likely to have neurocognitive impairment than those
who had no cardiovascular problems. This finding remained even when the study team took into account the following factors:
- age
- gender
- race or ethnicity
- educational levels
- country of residence
- having had AIDS in the past
Furthermore, this six-fold increased risk for neurocognitive impairment was statistically significant.
Other findings: People who entered the SMART study with higher-than-normal levels of total cholesterol or higher-than-normal blood pressure also
had a greater risk for neurocognitive impairment.
Oddly, factors that in other studies had previously been linked to neurocognitive impairment-lowest-ever CD4+ count, high viral load, diabetes,
or the ability of ART to penetrate the brain-were not associated with this problem in the present sub-study.
Why the connection?
HIV infection is associated with persistent activation of the immune system. An activated immune system releases chemical signals-cytokines-that
can adversely affect the health of many organs and tissues, including blood vessels, kidneys and bones.
One previous study found that HIV infection appeared to prematurely age a person's blood vessels 15 years above their current age. This aging of
blood vessels may mean that less oxygen- and nutrient-rich blood reaches brain cells. In turn, with poorer blood flow, perhaps fewer waste products are removed from brain cells.
These findings may explain the decreased neurocognitive function in the present study with a relatively young population. The study authors note that neurocognitive decline
associated with cardiovascular disease does not usually occur in HIV-negative people until they are "at least in their sixth decade."
Limitations
The present neurological sub-study of SMART has a cross-sectional design. Such studies can only provide a snapshot of people's health at
one point in time. Moreover, cross-sectional studies can find statistical associations between factors and events, but they cannot prove cause and effect-in this case,
that cardiovascular disease causes neurocognitive impairment.
An advantage of cross-sectional studies is that they are relatively cheaper and faster to implement than a study that monitors a large group
of people over many years. The findings from cross-sectional studies are still useful and can be used to formulate studies of a more robust design to explore important research questions.
Bear in mind
Despite the limitations of the present SMART sub-study, its findings are important and echo results of other studies of accelerated aging and HIV.
Furthermore, the present study underscores the importance of cardiovascular health not just for the heart but also for the brain.
Resources
- For tips on understanding and improving cardiovascular health in HIV infection, see CATIE's In-Depth Fact Sheet " HIV and cardiovascular disease: keeping your heart and blood vessels healthy ," available at:
www.catie.ca/facts
- The Winter 2010 issue of CATIE's Positive Side magazine features a first-person article by activist Maggie Atkinson on the topic of neurocognitive problems in HIV. You can read about her experience and what she learned about protecting her brain in " A Mind of Her Own," which can be found at:
www.positiveside.ca/e/V11I2/Mind_e.htm
-Sean R. Hosein
REFERENCES:
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- Levy JA, Shimabukuro J, Hollander H, et al. Isolation of AIDS-associated retroviruses from cerebrospinal fluid and brain of patients with neurological symptoms. Lancet . 1985 Sep 14;2(8455):586-8.
- Carne CA, Tedder RS, Smith A, et al. Acute encephalopathy coincident with seroconversion for anti-HTLV-III. Lancet . 1985 Nov 30;2(8466):1206-8.
- Appay V, Sauce D. Immune activation and inflammation in HIV-1 infection: cause and consequences. Journal of Pathology . 2008 Jan;214(2):231-41.
- Grossman Z, Meier-Schellersheim M, Paul WE, et al. Pathogenesis of HIV infection: what the virus spares is as important as what it destroys. Nature Medicine . 2006 Mar;12(3):289-95.
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- Boasso A, Hardy AW, Anderson SA, et al. HIV-induced type I interferon and tryptophan catabolism drive T cell dysfunction despite phenotypic activation. PLoS One . 2008 Aug 13;3(8):e2961.
- Simioni S, Cavassini M, Annoni JM, et al. Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS . 2010 Jun 1;24(9):1243-50.
- Ances BM, Vaida F, Yeh MJ, et al. HIV infection and aging independently affect brain function as measured by functional magnetic resonance imaging. Journal of Infectious Diseases . 2010 Feb 1;201(3):336-40.
- Wright EJ, Grund B, Robertson K, et al. Cardiovascular risk factors associated with lower baseline cognitive performance in HIV-positive persons. Neurology . 2010; in press .
- Hatano H, Delwart EL, Norris PJ, et al. Evidence of persistent low-level viremia in long-term HAART-suppressed HIV-infected individuals. AIDS. 2010; in press.
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CATIE-News is written by Sean Hosein, with the collaboration of other members of the Canadian AIDS Treatment Information Exchange, in Toronto.
From Canadian AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca
Source: CATIE: CANADIAN AIDS TREATMENT INFORMATION EXCHANGE
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