The results of this evaluation designed to determine interaction effects between aging and HIV infection indicate that HIV infection and advancing age appear to generally function independently of each other on neuropsychological testing performance although limited interactions of small magnitude cannot be excluded. Our previous published work in this cohort identified a 2-fold increased risk for meeting American Academy of Neurology 1991 Criteria for HIV-associated Dementia in age greater than 50. In our previous work, we employed cut-points to define impairment and included neurological and behavioral data to designate diagnoses based on a consensus panel that included neurologists and neuropsychologists. In contrast, here, we a comparing group means and frequency of poor performance on neuropsychological tests only for HIV and age groups in models that include interaction variables. The current work more clearly defines HIV effects on the neuropsychological performance aspect of the neurological syndrome associated with HIV. This work extends the existing literature by demonstrating that age and HIV status appear to largely act independently on neuropsychological performance even when a substantial number of cases are over 50 years of age.
When viewed with an understanding of these methodological differences, these data are congruent with other independent assessments in large multicenter studies where high rates of impaired neuropsychological scores are noted in HIV with general increased risk associated with aging (Heaton et al., 2009
; Robertson et al., 2007
). Similarly, these findings do not differ greatly from other studies where interaction effects were either not found, or only modest in magnitude (Becker, et al., 2004
; Cherner, et al., 2004
; Hardy, et al., 1999
; Kissel, et al., 2005
; van Gorp, et al., 1994
There are several other factors that contribute to our finding. Most importantly, our seronegative controls were carefully selected to match many of the non-HIV socioeconomic factors seen in our HIV population by selecting subjects from similar arenas and most importantly, their family and social networks. In contrast, our previous publication utilized published normative data to define impairment rates that informed consensus conference diagnostic categorization. In the current study, we utilize our internal HIV-negative groups to evaluate HIV effects (Valcour, et al., 2004
). This approach likely minimizes differences by HIV status but may be more informative regarding pure HIV effects on neuropsychological performance. Specifically, the presence of co-existing morbidity in HIV-negative individuals in this study could also impact performance on our tests in a manner that would minimize HIV group findings.
The evaluation of cognitive diagnoses in the setting of HIV requires careful inclusion of behavioral and gross motor findings in addition to neuropsychological performance. It is possible that age modulates the influence of HIV on these behavioral and clinical motor signs and symptoms in a manner that was not detected in this study of neuropsychological outcomes. Indeed, a previous evaluation of motor findings using the United Parkinson Disease Rating Scale (UDPRS) in this cohort revealed higher scores in aged individuals with HIV that was further increased in subjects with dementia (Valcour et al., 2008
As described by Wilkie et al (Wilkie et al., 2003
) and a National Institutes of Mental Health workgroup (Butters et al., 1990
), examination of group mean scores may not be sensitive to HIV effects, since it is suspected that only a proportion of these individuals will ultimately develop cognitive dysfunction and relevant findings may be obscured due to inclusion of individuals with less overall risk. Even in the pre-cART era, when HIV infection was largely untreated, only a portion of individuals developed clinically important cognitive dysfunction, suggesting that host or viral factors are critical (McArthur, et al., 1993
). In the present study we managed this concern by also utilizing cut-points to evaluate proportions of individuals in each group who may be exhibiting neuropsychological impairment. This had little impact in our outcome, but the emergence of interaction effects was noted only on a phonemic fluency test. Another study that used this approach also did not identify interaction effects on cognitive tests, though a significant interaction was noted between age and CSF HIV RNA levels whereby older individuals with detectable CSF HIV RNA had twice the rate of impairment than did their older counterparts who had undetectable CSF HIV RNA. These findings provide some biological evidence that age may modulate HIV effects on the brain in a manner that does not result in overt behavioral decrements on neuropsychological testing (Cherner, et al., 2004
). . It should also be noted that the age range of our cohort was limited by HIV demographic characteristics in the US with only 9% of our HIV cases over the age of sixty. Once older cohorts are enrolled, reconsidering this issue may reveal more significant synergy between age and HIV status.. Although our statistical approach adjusted for these variables, a finding that our younger group was less educated, had more non-Caucasian members, and were women may have attenuated our ability to identify interaction effects.
Our work best matches the pre-cART analyses carried out by van Gorp et al, who in 1994 reported a lack of interaction effect between aging and HIV in the Multicenter AIDS Cohort Study (MACS) (van Gorp, et al., 1994
). Although the sample size exceeded 1,000 individuals in both the HIV-positive and negative arms, only five subjects were age 55 or greater. In a smaller clinical-based study of symptomatic patients published simultaneously, an interaction effect was identified in the Grooved Pegboard test. Similarly, Hardy et al identified interaction effects among patients with AIDS, but not in HIV-positive individuals without AIDS (Hardy, et al., 1999
Becker et al examined rates of neuropsychological testing abnormalities among older participants compared to younger individuals in the Allegheny County Neuropsychological Survey, which included 290 HIV-positive and 114 seronegative individuals. They identified 37% of older (n=22, > 50 years of age) compared to 31% of younger individuals (< 50 years old) tested in an impaired range, with most of the older patients having greater degrees of impairment (23% defined as dementia compared to 9% in the younger group). In this work, a dementia designation was based on neuropsychological performance rather than clinical diagnostic characterization and 40% of clinically asymptomatic patients were deemed to have dementia.
In summary, this cross-sectional evaluation of HIV-age group interaction effects utilizing HIV-negative controls selected to be similar to HIV-positive groups failed to identify important interactions. Although seemingly in contrast, these findings are in fact congruent with research-based evaluations and epidemiological data demonstrating increased risk for cognitive impairment with advancing age given differences in methodology, differences in normative data selection, and the typical inclusion of behavioral and motor neurological examination findings in studies that employ diagnostic approaches. Our work highlights the importance on non-HIV-related and HIV-related coexisting morbidities in the evaluation of cognitive performance and the need for appropriate comparative groups in such work. Future work may be best informed by careful assessment of coexisting morbidities, enrollment of control subjects with similar socio-demographic factors, and the thoughtful inclusion of behavioral and gross motor neurological examination findings in definitions of outcomes.