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Neurology Today:
doi: 10.1097/01.NT.0000430535.81353.ab
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Why Are Some HIV Patients Aging Faster with Accelerated Cognitive Declines?

Valeo, Tom

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ARTICLE IN BRIEF

Investigators report that — based on MRI data of brain networks when patients are at rest — HIV may lead to patterns of degradation in brain function similar to those associated with advancing age, possibly placing older HIV-positive patients at an increased risk for developing cognitive impairment.

A decline in functional connectivity within three brain networks may accelerate cognitive aging in people who are HIV-positive, according to neuroimaging studies described in a paper published Feb. 27 ahead of the print edition of Neurology.

The loss of functional connectivity within the default mode network, which is active when the brain is not focused on a task; the executive control network, which is active when the brain is focused intently on relevant information; and the salience network, which identifies the significance of perceptions by attaching an emotional charge to them, may be equivalent to 30-40 years of normal brain aging, the authors wrote.

No significant changes were found in two other brain networks of the HIV-positive subjects — the sensorimotor network, which integrates sensory and motor information into a sense of the bodily self, and the dorsal attention network, which directs focus to relevant information. [For additional information networks, see “More About Resting-State Functional Connectivity MRI.”]

“What we're seeing is that different networks seem to be affected in different diseases,” said senior author Beau M. Ances, MD, PhD, assistant professor in the department of neurology at Washington University in Saint Louis. “The default mode network, for example, has been shown to be involved in Alzheimer's, schizophrenia, and frontotemporal dementia.”

Dr. Ances said his “dream goal” would be to use the activity in these networks to improve diagnosis and tailor therapies for each patient.

“If we start characterizing these networks using this method, we might be able to distinguish what's going on with each patient,” he said. “That could influence the type of therapy provided.”

Distinguishing the accelerated brain aging found in HIV patients from Alzheimer's disease would be particularly helpful, he added, since the two conditions display similarities as well as distinct differences.

“When we scan older HIV patients who are having memory problems, the question is, are their problems due to Alzheimer's or to HIV?” Dr. Ances said. “By looking at networks we can start to disentangle whether the effects are due to HIV or early Alzheimer's. If it's HIV, then antiretroviral treatments would be appropriate. If it's Alzheimer's, then maybe donepezil would be better.”

Figure. DR. BEAU M. ...
Figure. DR. BEAU M. ...
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STUDY DESIGN

The researchers used resting-state functional connectivity MRI (rs-fcMRI) data, which is gathered while the brain is not engaged in a specific task, to search for signs of decline in the five brain networks. Although antiretroviral drugs have enabled HIV patients to survive into old age, such patients appear to be subject premature brain aging. Postmortem analysis of HIV patients in their 40s, for example, has found evidence of brain plaques, although not the neuritic plaques found in Alzheimer's, as Dr. Ances and colleagues demonstrated in a 2012 paper in the Archives of Neurology. Although they found amyloid-beta in the brains of their subjects, the deposits were not revealed by the PET tracer known as Pittsburgh Compound B, or PiB, which binds to the neuritic plaques characteristic of Alzheimer's but not to soluble plaques.

“It may be that the plaques are about to develop,” Dr. Ances said.

In the current study, the researchers gathered rs-fcMRI data from 52 HIV-positive subjects and 52 HIV-negative controls of similar age. The HIV-positive subjects showed a loss of positive resting-state correlations between the right lateral parietal cortex and other nodes within the default mode network, including the medial prefrontal cortex and the posterior cingulate cortex. They also showed loss of normal negative correlations between the right lateral parietal cortex and anterior portions of the lateral parietal cortex that comprise the salience network.

“Our results suggest that HIV may lead to patterns of degradation in brain function similar to those associated with advancing age, possibly placing older HIV-positive patients at an increased risk for developing cognitive impairment,” the authors state in their paper.

Figure. DR. DAVID M....
Figure. DR. DAVID M....
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PRIOR RESEARCH

The research builds on the findings reported in a 2012 paper in the Journal of Neuroscience by Dr. Ances and colleagues based on rs-fcMRI data from 510 elderly subjects whose cognitive status ranged from normal to mild Alzheimer's disease. The researchers focused on the same five brain networks studied in the Neurology paper, and observed loss of connectivity in the default network beginning with very mild symptoms of Alzheimer's disease. Declines in functional connectivity within and among other networks became more apparent as symptoms of Alzheimer's increased.

The researchers hypothesize that the inflammatory response triggered when HIV enters the brain causes synaptic neuronal pruning, leading to an overall decrease in neuronal function. These changes could diminish glutamate cycling, thereby reducing metabolic demand.

“When a person gets infected with HIV, the virus gets across the blood-brain barrier and it remains in the brain for life,” Dr. Ances said. “Even with treatment, low levels of virus probably create chronic inflammation in the brain, and that leads to immunosenescence. Even with medications that help suppress the virus, the body is fighting the virus, so the body is constantly revved up. However, the actual mechanism remains unknown.”

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WHAT'S CAUSING PREMATURE DECLINE?

Others in the field also suspect inflammation as a contributing factor to the premature cognitive decline of HIV-positive patients. A 2011 paper in AIDS, for example, observed that changes caused by brain inflammation remain ubiquitous among that population. “Together these findings indicate that despite the widespread use of HAART (highly active antiretroviral therapy), HIV-associated cognitive impairment and brain injury persist in the setting of chronic and stable disease,” the authors stated.

One of the authors, Ronald Cohen, PhD, director for the Center on Cognitive Aging at University of Florida in Gainesville, believes that inflammation helps to explain why HIV infection is now recognized as causing cortical dysfunction as well as the more familiar problems such as motor disorders, mood changes, and diminished concentration that are associated with subcortical disruption.

“HIV was once thought to be a subcortical disorder that affected the basal ganglia and other deep structures,” said Dr. Cohen, who also retains his position at Brown University, where until recently he was a professor, and director of the Neuropsychological Research Centers for Behavioral Medicine at The Miriam Hospital. “Over the past decade there has been a growing recognition of white matter connectivity problems and disturbances from HIV. What's not clear is the basis for these changes. What this paper looks at is one way of getting at the idea that functional connections across cortex are being affected.”

Such problems are the result of antiretroviral therapies that have enabled HIV-positive people to live into old age and experience cortical atrophy, white matter hyperintensities, and other problems common among the elderly. The question, according to Dr. Cohen, is why this type of aging seems to happen faster in the HIV population.

“The aging we're seeing among HIV patients is not different from the changes found in older individuals, but it's happening earlier,” he said.

The imaging studies done by the authors of the Neurology paper provide “interesting insights,” Dr. Cohen said, because they offer a look at the brain at rest.

“The evidence of specific networks affected in HIV is an interesting finding in own right,” he said, “but using functional connectivity is compelling because there's no demand being placed on the brain, so you can get a picture of what the brain is doing in the absence of a cognitive task. The results are not influenced by a person's inherent abilities.”

But he added that the results don't clearly distinguish how the accelerated brain aging of HIV patients differs from normal brain aging.

“There's evidence of default network abnormalities across a wide variety of disorders,” Dr. Cohen said. “What's not clear to me is to what extent the findings described are specific to HIV. There are clear differences between HIV and Alzheimer's disease, but the cognitive disturbances in HIV patients look a lot like Alzheimer's pathology. There's not a lot of evidence of the type of amyloid disturbances you would see in classic Alzheimer's, but having said that, there's some question about whether Alzheimer's is a single disease, multiple diseases, or a disease with multiple etiologies.”

The difficulty involved in distinguishing accelerated aging from Alzheimer's and other forms of dementia poses a growing challenge to clinicians who treat HIV patients, according to David M. Simpson, MD, professor of neurology and director of the Clinical Neurophysiology Laboratories and director of the Neuro-AIDS Program at Mount Sinai School of Medicine in New York.

“Our HIV population is getting older,” he said. “I just saw a patient with HIV who is 83 years old, and he was complaining of cognitive problems — loss of short-term memory, forgetting phone numbers, increasing irritability. Are these problems caused by HIV or Alzheimer's, or an interaction between the two?”

Dr. Simpson appreciates the Neurology paper for extending knowledge about how HIV affects brain function and contributes to cognitive impairment, but he also recognizes that distinguishing the effects of HIV from typical aging remains a problem.

“HIV plays a role, certainly, but the impairment does not appear to be entirely related to viral infection. There probably are secondary pathways downstream that may be impairing cognitive function — something related to inflammatory mediators, cytokines, calcium- or NMDA-channel abnormalities. But we don't truly understand the direct mechanism or the pathophysiology of HIV dementia and cognitive impairment,” he said.

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MORE ABOUT RESTING-STATE FUNCTIONAL CONNECTIVITY MRI

MRI provides vivid and detailed images of brain structures. Diffusion tensor imaging uses the movement of water molecules in the brain to infer the presence of the axonal tracts that connect brain structures. But resting-state functional connectivity MRI (rs-fcMRI) reveals the functional relationships among those structures — how they work together to form networks.

The authors of the Feb. 27 online edition of the Neurology paper investigated five networks:

* The default mode network (DMN), which is active when the brain is not focused on a task, links brain regions, including the posterior cingulate cortex, with the precuneus and the medial prefrontal cortex.

* The executive control network (CON), which is active when the brain is planning a sequence of actions and imagining the consequences, links the prefrontal cortex, the anterior cingulate cortex, the basal ganglia, and other structures.

* The salience network (SAL), which includes structures primarily in the frontal lobes, identifies the significance of stimuli by attaching an emotional charge to them.

* The sensorimotor network (SMN), which integrates sensory and motor information into an awareness of the bodily self, links the somatosensory cortex, the granular insula, the posterior parietal cortex, and other regions.

* The Dorsal Attention Network (DAN), which includes the intraparietal sulcus and the junction of the precentral and superior frontal sulcus, links the frontal and parietal lobes.

Using rs-fcMRI to analyze these networks in the resting state — when the brain is not engaged in a specific task — reveals their background state, without the influence of impairments that could confound the results.

“Individuals with impairments like Alzheimer's disease may use different strategies to respond to tasks, and that could affect the results,” said the study author Beau M. Ances, MD, PhD, assistant professor in the department of neurology at Washington University in Saint Louis. “In contrast, rs-fcMRI, which does not require subjects to perform a task, allows for more consistent imaging even of impaired subjects as long as they do not move a lot. This method can then be compared to functional tasks designed to test certain domains that may be affected by a lesion or disease.”

—Tom Valeo

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FOR FURTHER READING:

•. Thomas JB, Brier MR, Snyder AZ, Vaida FF, Ances BM.Pathways to neurodegeneration: Effects of HIV and aging on resting state functional connectivity. Neurology 2013; E-pub 2013 Feb. 27.
•. Ances BM, Benzinger TL, Clifford DB, et al.HIV associated neurocognitive disorder (HAND) is not associated with increased fibrillar amyloid deposits using 11C-PiB in middle-aged HIV+ participants. Arch Neurol 2012;69(1):72–77.
•. Brier MR, Thomas JB, Ances BM, et al.Loss of intra- and inter-network resting state functional connections with Alzheimer's disease progression. J Neurosci 2012;32(26):8890–8899.
•. Harezlak J, Buchthal S, Navia B, et al.HIV Neuroimaging Consortium. Persistence of HIV-associated cognitive impairment, inflammation, and neuronal injury in era of highly active antiretroviral treatment. AIDS 2011;25(5):625–633.

•. The Neurologic AIDS Research Consortium: http://bit.ly/WKurMa.
•. The National NeuroAIDS Tissue Consortium: www.hivbrainbanks.org
•. Neurology Today archive on Neuro-AIDS: http://bit.ly/Wh16Yt.

©2013 American Academy of Neurology

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