The present study sought to investigate the differential impact of age and cerebrovascular risk factors on neurocognitive function in HIV-infected individuals. A secondary but related aim was to determine whether pharmacological treatment of cerebrovascular risks mitigated cognitive dysfunction. To our knowledge the present study is the first to address whether cerebrovascular risks are particularly deleterious to neurocognitive function in an HIV-infected sample, although this is well established in the aging and dementia literature. We hypothesized that increased age and the presence of cerebrovascular risks in HIV-positive individuals would be associated with greater fronto-subcortical dysfunction.
Results indicated that cerebrovascular risk factors are predictive of processing-speed declines in HIV+ participants, above and beyond the effects of age. Our findings therefore suggest that the relative contribution of cerebrovascular illness to processing-speed reduction may be greater than that of age alone within HIV-positive populations. These results are consistent with previous literature, which has documented the effects of cerebrovascular risk factors and disease on frontal-subcortical cognitive functioning in healthy older adults and in dementing populations (Erkinjuntti, 2005
; Gregg et al., 2000
; Gunstad et al., 2007
; Sacktor et al., 2007
). Neuroimaging of patients with vascular illness frequently reveals subcortical lesions, even in the absence of clinically documented cerebrovascular insults (Erkinjuntti, 2005
), which may have the effect of slowing speed of neuronal transmission thus precipitating slowing of information processing speed. Furthermore, compared to reports in the general population, white matter lesions are more common among HIV-seropositive individuals, and are suggested to increase with age but not with higher levels of HIV-related CNS pathology. Based on these considerations, it has been posited that cerebrovascular disease plays an even greater role in the cognitive compromise of aging HIV-infected individuals when compared to the normal aging population (McMurtray et al., 2007
). Moreover, a recent study demonstrated that white matter hyperintensities generally caused by small-vessel ischemic disease were more prevalent in HIV-seropositive individuals with greater mean systolic blood pressure (mm Hg). The frontal lobes were most significantly affected, with reduced cortical volume in those with moderate white matter hyperintensities (McMurtray et al., 2008
The interaction between age and risk did not significantly contribute to processing-speed reductions. Our inability to document an age-risk interaction effect for this variable could reflect the fact that cerebrovascular risks are of greater importance than age, and/or account for a portion of the age effects. There is, however, mounting evidence for age-related (Hartley, Speer, Jonides, Reuter-Lorenz, & Smith, 2001
; Petersen, Smith, Kokmen, Ivnik, & Tangalos, 1992
; West, Ergis, Winocur, & Saint-Cyr, 1998
; Willis, 1996
; Winocur, Moscovitch, & Stuss, 1996
), cerebrovascular-related (Gregg et al., 2000
; Gunstad et al., 2007
; Sacktor et al., 2007
), and HIV-related changes in fronto-subcortical neurocognitive functioning (Levine, Stuss, & Milberg, 1997
; Sacktor et al., 2007
; Stuss, Craik, Sayer, Franchi, & Alexander, 1996
), alongside evidence of subcortical pathology and inefficient frontal lobe functioning in older adults (Boone et al., 1992
; Schacter, Savage, Alpert, Rauch, & Albert, 1996
), individuals with cerebrovascular risks (Erkinjuntti, 2005
; Gregg et al., 2000
; Gunstad et al., 2007
), and HIV-positive people (Hinkin et al., 1995
; McArthur et al., 1990
; Navia, 1997
; Navia, Jordan, & Price, 1986
). Therefore a shared neuroanatomical substrate has been identified which could be particularly vulnerable to the combined effects of these factors. Previous research has also shown that older adults with medical problems are at greater risk for cognitive dysfunction (Uchiyama, Mitrushina, Satz, & Schall, 1996
), and thus older individuals with HIV/AIDS and
cerebrovascular risks might be anticipated to be at even greater risk for neurocognitive impairment. Despite these observations, the literature has yet to establish a synergistic effect of age and cerebrovascular risks on processing speed, and our lack of an interaction finding may reflect the relatively greater importance of risk for cerebrovascular compromise to neurodegeneration.
It is also possible that the unequal sample sizes in older and younger groups (n= 71 in the younger group and n= 27 in the older group) may have contributed to the absence of an age–risk interaction for the processing-speed domain in this study. The lack of effect may also be explained by the greater number of younger than older individuals presenting with cerebrovascular risk, which could dilute any potential interaction. It should also be noted that the age range of our sample was somewhat truncated (from 32 to 69 years of age), particularly for the older participants (from 50 to 69 years of age). Therefore, the effect of age on processing speed in this study may have been underpowered, as it is well accepted that significant cognitive deterioration becomes more apparent in later decades. Larger samples with broader representation of the age spectrum will be necessary to determine whether the combined effects of HIV infection, risk factors, and older age contribute to cognitive decline.
Results did reveal an interaction effect between age and cerebrovascular risk factors on the verbal fluency domain, although a greater impact of cerebrovascular risks on verbal fluency function was demonstrated for the younger (rather than older) HIV-infected group. The inability to document greater deficits among HIV-infected individuals affected by the combined impacts of cerebrovascular risk and older age is surprising, given that both factors in isolation have been shown to reduce frontal-striatal cognitive function (as described in further detail above). It is possible that the additive effects of these conditions are obscured due to the overlapping nature of these two processes. Nevertheless, it is believed that deficits in working memory and processing speed underlie age-related decline on measures of verbal fluency (Borstein et al., 1992
; Bryan & Luszcz, 2000
; Sacktor et al., 2007
; Sheline et al., 2006
), and current findings may therefore be related to the processing-speed main effect described above. Previous investigation of verbal fluency within the broader HIV-infected population is well in line with our current results, and has demonstrated deficits in verbal fluency among individuals with HIV when compared to controls (HIV+ < HIV−; Bornstein et al., 1992
; Iudicello et al., 2007
; Levine, Berger, Didona, & Duncan, 1992
; Marsh & McCall, 1994
). Moreover, various cerebrovascular risk factors, including diabetes mellitus, HTN, and cardiac disease, have been shown to affect verbal fluency (Backman et al., 2004
; Brady, Spiro, & Gaxiano, 2005
; Brady, Spiro, McGlinchey-Berroth, Milberg, & Gaziano, 2001
; Verhaeghen, Borchelt, & Smith, 2003
; Wahlin, Nilsson, & Fastborn, 2002
) and, in one study in particular, the strongest relationship of risk to cognitive outcomes in general was demonstrated for verbal fluency performance (Brady et al., 2001
). It also appears that higher number of cardiovascular risk factors (including age, blood pressure, diabetes mellitus, current cigarette smoking, and cardiovascular disease) is related to greater decline in verbal fluency performance (Brady et al., 2001
). Moreover, both phonemic and semantic components of verbal fluency have been associated with cerebrovascular risk factors. In particular, several studies of diabetes mellitus (Vanhanen et al., 1997
; Verhaeghen et al., 2003
; Wahlin et al., 2002
) have shown impairment in phonemic fluency to be more pronounced than impairment in semantic fluency, even after accounting for preclinical dementia and impending death (Wahlin et al., 2002
). However, in the case of older untreated hypertensive participants, impairment in semantic fluency in the absence of phonemic fluency has also been implicated (Brady et al., 2005
). Our results suggest that among younger HIV-specific participants, cerebrovascular risks are associated with combined semantic and phonemic verbal fluency decrements, and this finding is consistent with prior studies of seronegative participants. Given that this represents the first study to address the effects of aging and cerebrovascular risk within an HIV-infected sample, these results should be interpreted with caution and further evidence will be necessary to provide support for the findings reported here.
While we did not specifically examine the independent cognitive effects of cerebrovascular conditions of interest (e.g., diabetes versus hypertension) due to our sample size limitations, it should be noted that diabetes mellitus in particular has been implicated in studies of cognitive function among seropositive individuals. Even after adjusting for age and other vascular factors, research has revealed that diabetes is significantly associated with HIV-associated dementia (HAD), particularly in HIV patients over 60 years of age. Valcour and colleagues (Valcour et al., 2004a
) have reported that fasting glucose levels were positively correlated with increasing neurocognitive impairment. Additionally, insulin resistance is a common complication in HIV and was found to be associated with neurocognitive impairment among older seropositive and seronegative patients. Strikingly, the level of neurocognitive impairment was similar to that of HAD (Valcour et al., 2006
When we examined subgroup differences between pharmacologically treated versus untreated at-risk HIV-seropositive participants, we found significant differences in processing speed and learning/memory, and trend differences in executive functioning, with untreated HIV participants performing more poorly than untreated HIV participants. As a result we elected to investigate whether differences between participants with and without cerebrovascular risk would be more pronounced when including only untreated participants. Results of this follow-up analysis indicated significant group differences in processing speed, learning/memory, and executive functioning, with untreated at-risk individuals performing less well than seropositive controls in all cases. Effect sizes were more robust when pharmacological treatment of cerebrovascular risk was considered, in contrast to analyses comparing at-risk individuals to seropositive controls. See for an illustration of these results. Even when covarying for the effects of prior history of stimulant abuse or dependence, these results continued to remain significant. These results are particularly noteworthy, and suggest the important role of pharmacological intervention in preventing more severe frontal-subcortical cognitive dysfunction.
Cognitive performances for cerebrovascular at-risk subgroups and seropositive controls. Note: Standard Error of the Mean noted above each bar.
Limitations and future research
An important limitation to the current study concerns the self-reported nature of cerebrovascular risk determination. We recognize the importance of collecting blood sugar and serial blood pressure data for accurately evaluating the presence of cerebrovascular risk, and recommend that future research conduct rigorous medical confirmation of the presence of cerebrovascular risks. Although self-report methods have limitations with respect to validity, previous studies have reported high agreement between self-reported diagnosis and medical records (Azar, Murrell, & Mast, 2005
; Bush, Miller, Golden, & Hale, 1989
; Simpson et al., 2004
). After researchers considered such factors as advanced age and existing cognitive impairment, excellent agreement remained between self-report and medical diagnosis among patients with cancer, stroke, myocardial infarction, and Parkinson’s disease (Simpson et al., 2004
). Furthermore, we did not consider whether the duration
of the medical condition associated with cerebrovascular risk affects results. Although it is possible that risk duration may influence cognitive outcomes, previous studies of diabetes have failed to reveal cross-sectional durational differences in neurocognitive performance on measures of learning, memory, and problem solving, or differences over 3 years across a variety of cognitive performances (Fischer, de Frias, Yeung, & Dixon, 2009
; Ryan, 2005
). Moreover, our cerebrovascular risk sample was limited to individuals with hypertension and/or diabetes only; other pertinent risks for cerebrovascular disease, such as obesity and sleep apnea, should be evaluated and the relative contributions of variant risks factors should be addressed. Future research should also employ larger samples with more evenly distributed groups in order to better evaluate the extent to which the effects of these three combined conditions are particularly deleterious. It should also be emphasized that our cerebrovascular risk group included only individuals with diabetes or hypertension, and clearly the scope of risk factors is far more extensive than this study could address. Including individuals with more diverse risk factors and examining differences between subsets of at-risk individuals will likely be revealing in identifying factors of greater or lesser consequence to cognitive compromise. We would also like to acknowledge the limitations associated with not having included a seronegative control group in this study. This investigation remains unequipped to selectively address effects that are specific to HIV, and rather centers on the broader study of cerebrovascular versus aging effects on cognition within the population of HIV+ individuals. Therefore future research should include a seronegative control group in order to better address possible synergistic effects of cerebrovascular risks and HIV illness on cognitive ability. Finally, as described earlier in detail, we elected to utilize sample-standardized raw scores in our analyses rather than demographically corrected standard scores, although we certainly appreciate the limitations associated with use of these unadjusted values. However, we believe that use of uncorrected scores reduces unintended masking of age findings attributable to over-correction for age, and is in line with previous work that has recommended use of unadjusted raw scores to improve diagnostic validity (Kraemer et al., 1998
; Mungas et al., 2009
), and sensitivity to differences in brain structure and function (Brandt, 2007
). Despite these considerations, we appreciate that our study is unable to compare the synergistic effects of age and risk factors with those found in the general population.
Conclusions and implications for the practicing neuropsychologist
The results from this study indicate a significant impact of cerebrovascular risk factors among HIV-infected individuals, and this effect may be of greater importance to processing-speed reductions than advancing age. The impact of cerebrovascular risk on cognitive functioning appears to be more pronounced and more widespread in pharmacologically untreated patients. The increasing presence of vascular risk factors such as hypertension and myocardial infarction among the HIV-infected population is likely to be attributable to treatment with HAART alongside the rising mean age of individuals with HIV (Bergersen, 2006
; DAD, 2003
; Goodkin et al., 2001
; Mary-Krause et al., 2003
; Valcour et al., 2004a
). As individuals with HIV infection continue to age, the risk for small-vessel ischemic disease is likewise expected to rise, since one recent study demonstrated that, among HIV-seropositive individuals, age was found to be correlated with both decreased white matter lesion volume and leukoaraiosis severity (McMurtray et al., 2007
). Given the similarities in symptom presentation, as persons with HIV/AIDS become older, the distinctions among normal age-related cognitive decline, HIV-associated neurocognitive impairment, vascular cognitive impairment, and other age-related dementias will become increasingly difficult to ascertain.
Generating a neuropsychological profile of cerebrovascular risk factors for HIV-positive individuals is especially important for practicing neuropsychologists, as it will facilitate identification of patients requiring additional monitoring. Neuropsychologists should be cognizant of the potential physiological compromises that can arise from the combination of HIV and cerebrovascular risks and should be alert to alterations and/or fluctuations in cognitive status that signal a cerebrovascular process warranting further medical evaluation (Marcotte, Grant, Atkinson, & Heaton, 2001
). A clear understanding of the trajectory of neuropsychological compromise associated with HIV illness will allow neuropsychologists to examine whether existing impairments have been further exacerbated by cerebrovascular risk-related illnesses, and to help focus treatment efforts.
Furthermore, recognizing patients who might benefit from pharmacological treatment of cerebrovascular risks will be of vital importance in preventing additional neurocognitive compromise in an already vulnerable population. Clinical treatment of HIV-infected individuals should include a detailed review of vascular risk factors. Neuropsychologists should additionally consider referral to other disciplines specializing in cardiovascular and cerebrovascular illness for evaluation of appropriate pharmacological treatment agents to be administered prophylactically against cognitive deterioration.
It should also be emphasized that cognitive impairment of this nature can lead to substantial difficulty in executing even the most simple functional abilities as well as instrumental activities of daily living (e.g., adhering to medications, preparing meals, managing finances). Therefore, in approaching work with HIV-infected older adults who are at risk for cerebrovascular disease, neuropsychologists should consider incorporating cognitive rehabilitative techniques into treatment to address the multiple cognitive impairments arising from the combined effects of HIV infection and cerebrovascular risk. For example, teaching patients to use such external aids as memory notebooks, alarms, and/or pill counts for remembering and maintaining complex medication regimens can assist with overall quality of living.