Our major findings are: 1) carotid lesions and top CIMT quintile were significantly associated with Stroop interference time but not with SDMT. 2) The magnitude of these associations were comparable to the effect of AIDS on these tests and larger than the effect of HIV without AIDS. 3) On all but one analysis, there was no association between HAART use and cognitive score.
There are only 2 previous studies of the association of carotid lesions and cognition in persons with HIV. The first included only 47 patients with HIV (Yaldizi et al. 2006
). The second had substantial numbers of subjects but only examined men (Becker et al. 2009
). Thus our study extends the work of Becker et al (2009)
by demonstrating that cardiovascular variables are associated with cognitive function in women with HIV. Whereas Becker et al. (2009)
found that the associations were not longer significant when age was included as a covariate, we found significance for carotid lesions with Stroop interference time even when age was included as a covariate.
At least one other study has investigated the influence of cardiovascular variables on cognitive function in HIV. Wright et al. (2010) showed an association between prior cardiovascular disease, hypertension, and hypercholesterolemia on measures of motor speed in 292 participants from the SMART study. However, only 122 women were studied, carotid measures were not available, and the neuropsychological evaluation was limited to the color trails test.
This is the largest study of the association of cardiovascular markers with cognition in women with HIV. The association of carotid lesions with cognitive impairment has not been demonstrated in such a young cohort; indeed the mean age of our participants is 9 years less than in the study of Becker et al. (2009)
and 15 years younger than the youngest non-HIV study. Very few studies have investigated the prevalence of carotid lesions in persons under 40 years of age. If subclinical carotid disease proves to be prevalent in early middle age in patients with and/or without HIV, as suggested by these data, it could have substantial public health significance.
We recognize that a limitation of our finding is that only 2 neuropsychological tests were included in our analyses, and a significant result in the fully controlled models, was found for the Stroop interference tests but not for SDMT. Although multiple brain regions are involved in solving any neuropsychological test, the interference part of the Stroop test requires persistence of concentration and is a sensitive measure of frontal lobe function. In contrast, the DSMT is more a test of complex scanning and visual tracking and may be less sensitive to some types of frontal lobe dysfunction. As the frontal lobes appear to be the major site of brain dysfunction associated with vascular disease, it is not surprising to see a dissociation in the effect of cardiovascular variables on test score. Future studies assessing the effects of cardiovascular variables on cognition will need to include an array of sensitive neuropsychological tests that probe function in multiple brain regions.
The recent report of Robertson et al. (2010)
has forced a reconsideration of the benefits and risks of HAART in relation to cognitive function. Analysis of the effects of HAART on cognition is extremely challenging as even within drug classes some drugs may occasionally be associated with deleterious effects on cognition whereas other drugs in the same class are less likely to have such an effect (see the possible deleterious effects of efavirenz (Ciccarelli et al, 2011
)). Future longitudinal studies are needed to replicate and extend the findings of Robertson et al (2010)
on whether certain HAART regimens have deleterious effects on cognition. If true, one possible explanation is that certain anti-retroviral drugs exacerbate atherosclerosis and that atherosclerosis somehow leads to cognitive impairment. Our cross-sectional study in general did not show an association between ARVs and worse cognitive score.
Our finding of no association of HIV-serostatus with score on at least one neuropsychological test is consistent with two studies from the Men’s AIDS Cohort Study (MACS) that showed no difference in cognitive scores either cross-sectionally (Cole et al. 2007
; Becker et al. 2009
) or longitudinally (Cole et al. 2007
) between HIV+ patients and SN participants. Several earlier studies, most with small numbers of subjects, had showed no difference in cognitive scores between asymptomatic participants in the early stages of HIV and SN participants (Mason et al. 1998
; Damos et al. 1997
; Odiase et al. 2007
; Stern et al. 1998
What is the mechanism by which carotid lesions might influence cognition? Although hypertension and other cardiovascular risk factors might lead to increased numbers of strokes and thus to cognitive impairment, we do not believe this is likely mechanism. Clinically-recognized strokes occurred in only 37 of our subjects. MRI data were not available to determine whether silent infarcts may have occurred. A previous study of the relationship between carotid stenosis and cognitive impairment in elderly patients without HIV found that strokes on MRI did not account for the cognitive impairment (Mathiesen et al. 2004
). Although cardiovascular risk factors increase the risk for Alzheimer’s disease and Alzheimer pathology can predate clinical symptoms by years (Craft et al. 2009
), we believe that it is unlikely that preclinical Alzheimer disease would account for measurable psychological differences among early middle-aged subjects. We believe that the mechanism by which hypertension and other cardiovascular factors may impair brain function has not yet been identified.
This is the largest study of the association of cardiovascular markers with cognition in women with HIV. Strengths include the large number of women with carotid ultrasonography and the well matched control group without HIV. Weaknesses include the limited battery of neuropsychological tests, the cross sectional analyses, and the lack of brain imaging. We are now administering every two years a more complete neuropsychological battery so that we will be able to study the association of the cardiovascular variables with change in neuropsychological function over time. Comparison of the women’s data with a men’s cohort would also be desirable. A hypothesis proposing a mechanism by which these cardiovascular risk factors leads to brain dysfunction might also suggest cardiovascular measures that are more proximate to the mechanism of cognitive impairment than the measures used in this study.