The Hawaii Aging with HIV Cohort was designed to capture a representative set of individuals in Hawaii living with HIV-1. The demographic constitution of the cohort closely matches that reported by the Hawaii State Department of Health regarding sex, ethnicity, risk profile, and distribution by island, suggesting a modest degree of representative recruitment.29
In this cohort, older age is associated with an increased risk of HAD after adjusting for other important differences between groups. A trend for greater severity of HAD is also observed. While based on a relatively small number of participants with HAD, these findings add strength to the previous assertions by confirming epidemiologic observations in a structured research protocol designed to test cognition across age groups.
The overall rate of MCMD in this cohort is 36%, somewhat higher than rates described in other seropositive populations in the post-HAART era.6
In our cohort, this higher frequency may represent not only the changing epidemiology of HIV-1-related cognitive impairment but also an added contribution associated with aging. Given the high degree of reliance on neuropsychological testing abnormalities in our research case definition and only one time point of testing, it is also possible that this rate overestimates true MCMD in the cohort. Longitudinal data are being acquired. Older individuals are also less likely to have normal neurocognitive test findings, although many participants in both groups had only mild abnormalities on neuropsychological testing, insufficient to meet MCMD criteria. These mild abnormalities may represent subtle neurocognitive impairment associated with HIV-1 or limitations in the normative data. Our analysis was not designed to characterize subtle neuropsychological findings; however, we are currently acquiring additional data from seronegative controls to address this issue.
The high frequency of comorbid illness among seropositive participants is exemplified by the rates of “possible” compared to “probable” modifiers to our research diagnoses. Coexisting factors were expected and have been described in other HIV-1 cohorts.6,11
In our study, commonly identified examples of such confounders included the following: motor or sensory findings on examination that could have affected testing (14.3% of possible cases), high degree of depressive symptoms or situational stressors (45.5% of possible cases), and past or present substance abuse (66.2% of possible cases). More than one confounder was identified in 44.2% of possible cases. While our protocol required both the presence of such cofactors and some suggestion that it could have affected testing, it is possible that this categorization was overly conservative, thus overestimating the contribution of these factors. The frequency of such factors supports a multifaceted etiology to cognitive impairment among most HIV-1 patients and limits our ability to isolate pure age or HIV-1 effects.
The etiology of the observed increase in HAD associated with older age is not clear. Important factors not identified could be critical. While speculative, mechanisms common to other degenerative diseases, such as AD, could contribute to a greater degree of cognitive impairment.30
In addition, characteristics of seropositive patients who survive into advanced age (not age itself) may be important mediators. For example, factors associated with HIV-1 infection prior to HAART, such as prolonged or greater past immunosuppression, could be vital. In such cases, HAD may have been present prior to immune reconstitution and could contribute to increased prevalence (rather than incidence) of HAD.
Comorbid illness could also appreciably modulate frequency of HAD in older patients where coexisting diseases are more prevalent.31
These factors could explain the unexpected lack of correlation between duration of HIV-1 and HAD among older participants. Historical data in our study are limited by a potential recall bias and diagnostic lag bias among older seropositive participants.32
Taken together, these hypotheses can be understood using a cerebral reserve model of HAD in older individuals.33
In this model, multiple factors such as increased prevalence of comorbid illness among older patients, presenile presentation of CNS degenerative disorders, and differential responses among older and younger patients to the chronicity of immune activation and duration of infection prior to HAART each may contribute to an increased risk of neurologic pathology, decreased cerebral reserve, and increased risk for clinical neurocognitive impairment among older seropositive patients.
Several limitations to this work need to be considered. The AAN HAD criteria were developed before the widespread use of HAART and before aging became an emergent issue in HIV-1 care. It is possible that the characteristics of cognitive impairment in the post-HAART era and particularly among older adults differ, potentially decreasing both sensitivity and specificity of these criteria. Some HAD participants had marked neurologic and neuropsychological testing abnormalities sufficient to meet HAD diagnostic criteria yet lacked confirmation of cognition-related functional decline in work, IADLs, or ADLs. However, important limitations in assessing functional change impair our ability to objectively capture these data, particularly among patients who are retired or otherwise no longer working. In fact, most of such individuals within our cohort were no longer working (82%), typically due to other HIV-1-related concerns, and 63% reported receiving disability coverage. Many individuals had changed their work status before HAART-associated immune reconstitution and had not been re-challenged with a similar work experience, limiting their ability to assess work capabilities. In some cases, individuals endorsed functional impairment but indicated a noncognitive etiology. Consequently, a change in ADLs and IADLs due to noncognitive aspects of HIV may confound our ability to identify changes associated with cognition. Further, many participants were unwilling or unable to provide appropriate proxy contacts for reporting of function due to confidentiality issues. This limits our ability to identify objective changes in ADLs and IADLs. Longitudinal follow-up of these individuals will further clarify our findings.
The normative data used in this study are from several sources to maximize goodness of fit to our cohort. All normative data were acquired on the mainland United States rather than in Hawaii, increasing the risk of a possible ethnicity/acculturation bias. Adjusting for ethnicity did not significantly affect our statistical results; however, limitations exist in using this approach. Self-identified ethnicity may not fully capture variation among normative data across populations and across age groups, although addition of education should decrease this potential risk. An interaction between age and race may further confound our findings whereby normative data are more appropriate for younger compared to older non-Caucasian populations (cohort affect). Further research into culture and ethnicity appropriate normative data is needed. We are currently capturing matched data in seronegative populations in Hawaii to address a need for local normative data and more appropriate data for our older HIV subset. As the HIV population in the United States ages, it may be important to expand current normative datasets for neuropsychological measures commonly used in HIV populations to include a greater representation of older age groups.
Future analyses will address other covariates when a larger sample of participants has been enrolled. Medication use, for example, will be further evaluated to assess HAART class affects. Evaluation of coexisting medical conditions would be useful, particularly age-associated and antiretroviral medication-associated cerebrovascular risk factors. Ischemic disease may be particularly concerning due to attenuated protective astrocytic activation in response to ischemic injury in older compared to younger human brains.34
As we enter the third decade of HIV-1 treatment in the United States, encountering patients with advanced age and HIV-1 will become increasingly common. These data suggest increased frequency of cognitive dysfunction among older seropositive patients. Based on our current knowledge of HAD, this may have implications for mortality, morbidity, and functional life expectancy. Future research should investigate the underlying etiologies and search for modifiable risk factors to decrease morbidity in this unique and emerging population.