Neurocognition among older HIV-infected adults

Data reveal how aging and HIV act synergistically and place older adults at particular risk

At the beginnings of the HIV epidemic in the 1980s, if someone had suggested writing an article about older HIV infected adults the reception would have been mixed at best. Back then this was a disease that primarily struck down the young in the very prime of their lives. But over the past 30 years, the face of this epidemic has changed as increasingly HIV has targeted women, minorities and — the focus of this article — older adults. Now the CDC estimates that approximately 50 percent of HIV-infected adults are over the age of 50, with increasing numbers in their seventies and beyond. We have long known that HIV affects the brain. Early work using data drawn from the CDC revealed that HIV associated neurocognitive disorders, now known by the acronym HAND, were not evenly distributed across the age spectrum. Instead it was the very young and the very old that were at disproportionate risk.

Percentage of persons with HIV encephalopathy as initial AIDS-defining illness

As these data reveal, it was often HIV associated cognitive problems that heralded the onset of more advanced disease and the transition to a diagnosis of what was then termed “full blown AIDS.” What is it then that places older adults at particular risk?

If we consider the fact that HIV accelerates biological aging and T cell senescence, we can begin to appreciate how aging and HIV act synergistically to accelerate physiologic aging. For older HIV patients the disease process tends to progress more rapidly; morbidity/mortality rates among older patients are more dire than for younger patients. Brain imaging has allowed us to take a closer look, in vivo, into how HIV alters brain function. Compelling evidence from researchers at Washington University supports the idea that HIV accelerates brain aging. Ances and colleagues (2010) used SPECT scans, a type of functional neuroimaging, to assess brain blood flow in 26 study participants with HIV and 25 uninfected controls. HIV+ participants showed reduced blood flow in the brain at levels that were equivalent to those seen among uninfected individuals who were 15 years older. In other words, these data indicate that HIV causes your brain to age at a faster rate than is normal. We know that once HIV enters the brain, pathological changes occur as the brain marshals a concerted immune response. It is estimated that there may be up to a five-fold increase in the presence of certain metabolites that reflect brain inflammation in older HIV infected adults, a finding that bears a striking resemblance to the pathogenesis seen in Alzheimer’s disease.

The neurocognitive effects of HIV and the cognitive changes associated with the normal aging process are actually quite similar. Early work conducted by our group in the late 1980s compared the neuropsychological performance of a group of young patients with a mean age of 35 years with a group of older HIV uninfected normal controls with an average age of 75. As can be seen in Figure 2, there was a remarkable similarity in both level and pattern of performance between these groups.

Pattern of neuropsychological perfomance across diagnostic groups

These data provide a useful heuristic for those of you who may be working with HIV-infected patients and are uncertain as to how HAND presents. In many respects the nature of the neurocognitive changes that can be seen in HIV bear a striking resemblance to that seen in the normal aging process. These impairments become even more severe in older patients, suggesting a “double whammy” of advancing age and HIV on cognitive function.   

What does this mean for older HIV+ patients? The question as to whether impaired performance on neuropsychological measures translates to “real-world” functional decline and difficulty performing everyday tasks such as taking one’s medication and driving has become a topic of great interest. Using laboratory-based measures that are designed to simulate real-world experiences, investigators from our University of California, Los Angeles (UCLA) group as well as others such as from the UCSD HNRP found that older adults with HIV have more difficulties carrying out activities such as medication adherence and driving, and that these difficulties become even more pronounced when patients present with cognitive problems. These data suggest that older adults are not only at greater risk for cognitive failures, but also for functional disability. 

When working with older HIV infected patients, you may notice that not all present with the same degree of cognitive problems, which begs the question: "What factors place some patients at greater risk whereas others appear unscathed?" Cognitive reserve, or “brain reserve,” may contribute to the differences observed in cognitive performance between older patients with equivalent levels of immune dysfunction.  Patients with higher levels of education and/or a more cognitively active lifestyle are thought to be less susceptible to neurological insult and dementing illnesses. Factors that are unique to the individual, such as history of head trauma, developmental abnormalities and genetic factors such as apolipoprotein E4 are putative factors thought to deplete ones’ cognitive reserve. Earlier studies comparing well-educated HIV patients to matched seronegative controls on neuropsychological performance failed to find much in the way of significant differences between the groups. In contrast, among the less educated, the HIV+ patients performed far worse on neuropsychological testing than did the normal controls, suggesting that higher levels of educational attainment delay the onset of cognitive impairment. A recent neuroimaging study led by one of us (ADT) found that after matching older HIV+ adults on neuropsychological test performance, individuals with higher levels of cognitive reserve displayed more neuroimaging abnormalities compared to individuals with low levels of cognitive reserve, again supporting the idea that cognitive reserve protects against the neurobehavioral manifestations of HIV-associated neuropathology. This suggests that older patients with higher levels of cognitive reserve are able to withstand a greater degree of underlying neurological disease before it becomes overtly apparent. Clinicians working with such patients must be alert to this as their patients may actually be worse off than what meets the eye.

Advances in the pharmacological treatment of HIV, particularly the widespread use of combination antiretroviral therapy (cART), had a transformational effect on the field. Before the introduction of cART, HIV was not unreasonably often viewed as a death sentence. But now, HIV is better conceptualized as a chronic disease not unlike diabetes. Similarly to what is true of diseases like prostate cancer, it increasingly appears that many older HIV positive patients will die with HIV, rather than from, HIV.

But there's a catch. To borrow a phrase from Surgeon General C. Everett Koop, "Drugs don't work if people don't take them." Our group has devoted considerable effort over the past decade towards elucidation of the causes of treatment non-adherence. We have found that older patients, as a group, are far more adherent that are younger adults. This is likely due to a number of factors including a more stable lifestyle and past experience with medication usage for other maladies. But we have also found that older patients with cognitive dysfunction are at particular risk for poor adherence as older, cognitively impaired patients have difficulty remembering to take their medications and difficulty planning and executing a strategy to help them in this regard. As such, clinicians working with cognitively impaired HIV-infected elders must be particularly vigilant to ensure that their patients remain medically compliant.

A major side effect of cART that includes protease inhibitors is changes in lipid metabolism, which can contribute to cerebral atherosclerotic changes and increase the likelihood of developing other types of cerebrovascular disorder such as stroke. Research conducted by Jessica Foley along with other members of our group have shown that older HIV patients present with a greater number of cerebrovascular risk factors than younger patients, and these risks are associated with worse cognitive performance, particularly among those whose hypertension and other vascular risk factors are pharmacologically untreated. There is also reason to believe that HIV may accelerate other age-linked neurological disorders as well.

As we noted at the onset of this essay, few among us who were working in the trenches back in the 1980s could have imagined a day when HIV infected folks would be dying of old age rather than from the ravages of AIDS. As the graying of the HIV epidemic brings with it new challenges for clinicians and researchers alike. Critically important questions regarding how HIV alters the normal aging process, how aging alters the natural history of HIV infection, and how HIV and its treatment may cause or interact with the other neurocognitive disorders that emerge among elders remain unanswered and are clear targets for the next wave of neuroAIDS research.

Resources on aging and HIV

About the authors

Charles H. Hinkin, PhDCharles H. Hinkin, PhD, obtained his PhD in clinical psychology from the University of Arizona in 1991. After completing a postdoctoral fellowship in neuropsychology at UCLA, Dr. Hinkin then joined the UCLA faculty where he has remained to this day. He is currently professor-in-residence in the Department of Psychiatry & Biobehavioral Sciences in the UCLA School of Medicine and serves as the director of the Neuropsychology Assessment Service at the West Los Angeles VA Medical Center. A board certified neuropsychologist, Hinkin is a recognized expert in the neuropsychology of HIV and has more recently focused on study of HCV and HIV/HCV co-infection. Since the late 1980’s his research program has focused on explicating the cognitive and psychiatric effects of HIV-infection. For the past 10 years, his group has examined predictors of medication adherence among HIV infected adults, including study of older HIV infected adults and comorbid conditions such as substance use, psychiatric disorder, and HCV co-infection. His professional time is devoted in equal measure towards teaching, research and patient care. When not working he can be found hanging out and traveling with his daughters Maya (age 11) and Shanti (age 8) as well as trying to keep active by running the odd marathon, scuba and golf.

April D. Thames, PhDApril D. Thames, PhD, is currently completing her postdoctoral fellowship in clinical neuropsychology at UCLA’s Semel Institute for Neuroscience and Human Behavior. During fellowship, Dr. Thames has focused her research program on the neurological and neuropsychological effects of HIV among under-represented groups, particularly older adults and ethnic minorities. She is principal investigator on three grants targeting: (1) neuroimaging and neurocognitive correlates of HIV and Hepatitis C; (2) the impact of stereotype threat and perceived discrimination on neuropsychological performance among African Americans; and (3) neurological and functional consequences of HIV in geriatric HIV infected adults. Addressing health disparities is both a research interest as well as an area of professional concern. She is actively involved in teaching and mentoring predoctoral interns and undergraduate students in research. In her spare time, she enjoys running, swimming and spending quality time with family and friends.

References

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