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'hypercholesterol, hypertension, prior CVD associated with poor neurologic performance in SMART' factors: 'reported Increased vascular aging in HIV, inflammation, Hepatitis, immunosenescence, insulin resistance......
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292 SMART Study participants had a median CD4 cell count of 536 cells/mm3, 88% had an HIV viral load ≤400 copies/mL......
MAIN FINDING: 'Prior CVD was associated with neurocognitive impairment. Prior CVD, hypercholesterolemia, and hypertension were associated with poorer neurocognitive performance.....'
"Twenty-four percent of participants met the study definition of depression....Fourteen percent of patients met the study definition of NCI..... 51% of participants had z scores <-1 in 2 or more cognitive domains... A QNPZ-5 score below 0 denotes below-average neurocognitive performance"
"Older age was associated with worse test performance in raw test scores except for TG, but not with any of the z scores, which are standardized by age. Women and black participants had lower estimated mean QNPZ-5 scores"
"Our findings suggest that cardiovascular risk factors and disease may be key drivers of impairment in HIV-positive persons with high CD4 cell counts, more so than HIV-related HAD risk factors. These findings are important because HIV-positive populations have a high number of CVD risk factors including smoking,3 hypertension,3 diabetes,3 hyperlipidemia,3 metabolic syndrome,27 insulin resistance,28 and antiretroviral use.29.....
The mechanisms that might link lower neurocognitive performance with CVD and cardiovascular risk factors in HIV-positive populations are likely multifactorial. In HIV-negative populations increasing evidence suggests that cardiovascular risk factors contribute to the pathogenesis of both vascular dementia and AD.4-6,30 Theoretically the pathogenesis of these 2 dementing illnesses may overlap. Recently it was proposed that insulin resistance, which underlies several of the abovementioned cardiovascular risk factors, may be one of the primary convergent mechanisms that links these risk factors to both vascular dementia and AD.31"
"Raised inflammatory markers, including IL-6 and C-reactive protein, are risk factors for dementia32 and are common to CVD,33 the metabolic syndrome,34 aging, and HIV, including treated HIV infection.35 However, we do not have inflammatory markers for study analysis."
"The changes in the adaptive immune system of HIV-infected patients receiving long-term antiretroviral therapy resemble those seen in the elderly.36 Key factors that may contribute to immune senescence in HIV-infected patients include persistent immune activation, inflammation, and poor CD4 cell response to antiretroviral treatment.36 A recent study of HIV-infected patients measured coronary artery calcium accumulation and found an increased vascular age in over 40% of patients, with a mean increase of 15 years over their chronological age.37 Increased vascular aging would help to explain why we found an association between lower neurocognitive performance and cardiovascular risk factors/CVD in a relatively young study population whereas cognitive decline and dementia associated with these factors in HIV-negative populations usually do not occur until at least the sixth decade. Similarly, the early expression of Parkinson disease in HIV infection has been reported recently.38"
Cardiovascular risk factors associated with lower baseline cognitive performance in HIV-positive persons - pdf attached
NEUROLOGY 2010;75:864-873
Published online before print August 11, 2010
E.J. Wright, MBBS, B. Grund, PhD, K. Robertson, PhD, B.J. Brew, MBBS, MD, M. Roediger, MS, M.P. Bain, BSc, M Clin Psych, M Clin Neuropsych, F. Drummond, MBChB, MRCA, DA (UK), M.J. Vjecha, MD, J. Hoy, MBBS, C. Miller, MPH, A.C. Penalva de Oliveira, MD, PhD, W. Pumpradit, MD, J.C. Shlay, MD, MSPH, W. El-Sadr, MD, MPH, R.W. Price, MD For the INSIGHT SMART Study Group
From The Alfred Hospital (E.J.W., J.H.), Melbourne; The Burnet Institute (E.J.W.), Melbourne; Monash University (E.J.W., J.H.), Melbourne, Australia; University of Minnesota (B.G., M.R., C.M.), Minneapolis; Department of Neurology (K.R.), University of North Carolina School of Medicine, Chapel Hill; Departments of Neurology and HIV Medicine (B.J.B., M.P.B.), St Vincent's Hospital, Sydney; University of New South Wales (B.J.B.), Sydney; National Centre in HIV Epidemiology and Clinical Research (F.D.), University of New South Wales, Sydney, Australia; Washington Veterans Affairs Medical Center (M.J.V.), Washington, DC; Departamento de Neurologia (A.C.P.d.O.), Instituto de Infectologia Em’lio Ribas, S‹o Paulo, Brasil; HIV-NAT (W.P.), Bangkok, Thailand; Denver Public Health (J.C.S.), Denver, CO; International Center for AIDS Care and Treatment Programs (W.E.-S.), Mailman School of Public Health, Columbia University, New York, NY; and Department of Neurology (R.W.P.), University of California, San Francisco.
Address correspondence and reprint requests to Dr. Edwina Wright, Infectious Diseases Unit, Alfred Hospital, Commercial Road, Melbourne, Victoria 3004, Australia e.wright@alfred.org.au
Abstract.
Objective: To determine factors associated with baseline neurocognitive performance in HIV-infected participants enrolled in the Strategies for Management of Antiretroviral Therapy (SMART) neurology substudy.
Methods: Participants from Australia, North America, Brazil, and Thailand were administered a 5-test neurocognitive battery. Z scores and the neurocognitive performance outcome measure, the quantitative neurocognitive performance z score (QNPZ-5), were calculated using US norms. Neurocognitive impairment was defined as z scores <-2 in two or more cognitive domains. Associations of test scores, the QNPZ-5, and impairment with baseline factors including demographics and risk factors for HIV-associated dementia (HAD) and cardiovascular disease (CVD) were determined in multiple regression.
Results: The 292 participants had a median CD4 cell count of 536 cells/mm3, 88% had an HIV viral load ≤400 copies/mL, and 92% were taking antiretrovirals. Demographics, HIV, and clinical factors differed between locations. The mean QNPZ-5 score was -0.72; 14% of participants had neurocognitive impairment. For most tests, scores and z scores differed significantly between locations, with and without adjustment for age, sex, education, and race. Prior CVD was associated with neurocognitive impairment. Prior CVD, hypercholesterolemia, and hypertension were associated with poorer neurocognitive performance but conventional HAD risk factors and the CNS penetration effectiveness rank of antiretroviral regimens were not.
Conclusions: In this HIV-positive population with high CD4 cell counts, neurocognitive impairment was associated with prior CVD. Lower neurocognitive performance was associated with prior CVD, hypertension, and hypercholesterolemia, but not conventional HAD risk factors. The contribution of CVD and cardiovascular risk factors to the neurocognition of HIV-positive populations warrants further investigation.
"Overall, the mean QNPZ-5 score was -0.72; in each location, the mean z score was below 0 (p < 0.001), denoting below-average performance compared to a healthy, matched population. Fourteen percent of patients met the study definition of NCI (z scores <-2 in 2 or more cognitive domains); 51% of participants had z scores <-1 in 2 or more cognitive domains....
Older age was associated with worse test performance in raw test scores except for TG, but not with any of the z scores, which are standardized by age. Women and black participants had lower estimated mean QNPZ-5 scores (by 0.21 and 0.48) after adjustment for the other covariates."
Our primary neurocognitive performance outcome measure was the QNPZ-5, calculated as the average of the 5 z scores from the individual tests in the battery. A QNPZ-5 score below 0 denotes below-average neurocognitive performance. For the purpose of this study, we defined neurocognitive impairment (NCI) as z scores <-2 in at least 2 cognitive ability domains. Ability domains assessed were 1) speed/fine motor skills (GPB and FTT), 2) attention/speed of processing (CT1), 3) abstraction/executive function (CT2), and 4) gross motor skills (TG). The cutoff was chosen to reflect criteria for abnormal neurocognitive performance that are a required component for the diagnosis of HAD.19
We administered the Center for Epidemiologic Studies-Depression scale (CES-D)20 to screen for depression at baseline. The CES-D has been used in international studies in HIV-infected15 populations. We used the recommended cutoff score of ≥16 to define depression (sensitivity 86%-100%, specificity 53%-84%).21
Abbreviations: AD = Alzheimer disease; ART = antiretroviral therapy; BP = blood pressure; CES-D = Center for Epidemiologic Studies-Depression scale; CT = Color Trails; CVD = cardiovascular disease; FTT = Finger Tapping Test; GPB = Grooved Pegboard; HAD = HIV-associated dementia; NCI = neurocognitive impairment; QNPZ-5 = quantitative neurocognitive performance z score; SMART = Strategies for Management of Antiretroviral Therapy; TG = Timed Gait.
In advanced untreated HIV disease, HIV-associated dementia (HAD) develops in approximately 15% of patients1 and combination antiretroviral therapy (ART) has effectively reduced the incidence of HAD.2 The Strategies for Management of Antiretroviral Therapy (SMART) study randomized participants to intermittent, CD4-guided ART or continuous ART.3 In a neurology substudy, a neurocognitive test battery was administered. We hypothesized that neurocognitive performance would be superior in patients receiving continuous ART via its attendant benefits upon both peripheral and CNS immunity.
We present a cross-sectional analysis of 292 HIV-infected persons coenrolled in the SMART neurology substudy at sites in Australia, North America, Brazil, and Thailand. We sought to explore factors associated with neurocognitive performance. These included demographics, ART, HAD, and cardiovascular risk factors and cardiovascular disease (CVD). In HIV-negative populations, smoking,4 hypertension,5 high cholesterol,6 obesity,5 and diabetes5 are the cardiovascular risk factors associated with increased risk of poor cognitive function, vascular dementia, and Alzheimer disease (AD). Prior myocardial infarction,7 coronary artery bypass grafting,8 and stroke5 are also associated with poor cognitive function. In HIV-positive populations, diabetes has been associated with HAD,9 and increased carotid intima media thickening10 has been associated with poorer neurocognitive performance. CVD risk factors were common in the SMART study3: we hypothesized that they would be associated with lower baseline neurocognitive performance. We sought to describe and compare neuropsychological test results obtained in Australia, North America, Brazil, and Thailand and hypothesized that test scores, but not the standardized z scores, would differ across locations.
RESULTS
Baseline characteristics. Baseline characteristics of the 292 study participants by their location of enrollment are shown in table 1 and table e-1. Participant characteristics differed across locations, including their demographics, HIV, and general medical history.
Baseline neurocognitive test scores are summarized by location in table 2 and the figure. Overall, the mean QNPZ-5 score was -0.72; in each location, the mean z score was below 0 (p < 0.001), denoting below-average performance compared to a healthy, matched population. Fourteen percent of patients met the study definition of NCI (z scores <-2 in 2 or more cognitive domains); 51% of participants had z scores <-1 in 2 or more cognitive domains. For each of the 5 tests, mean z scores differed between locations (all p ≤ 0.02). There was no evidence, however, for regional differences in mean QNPZ-5 scores (p = 0.53), and no one region performed consistently higher or lower across all tests. In pairwise comparisons, there were no significant differences in test scores between Australia/North America and Thailand, except for the GPB (figure). Table 2 also shows the variability in test scores between clinical sites (between-site SD) in relation to the between-patient SD, estimated in hierarchical mixed models. For all tests except GPB, the between-site SD was about one-third to one-half of the between-patient SD, and remaining differences between locations (countries) were not statistically significant relative to the differences between sites (p > 0.05 in the hierarchical models).
The mean CES-D score was 11.2. Overall, 71 participants (26%) met the study definition of depression (table 2). The proportion of participants with depression was highest in Australia/North America (41%) and lowest in Thailand (14%).
Association between baseline factors and neurocognitive performance.
The z scores for all 5 tests, but not the QNPZ-5 scores, differed by location after adjustment for age, gender, race/ethnicity, education, and selected other factors (table 3). Older age was associated with worse test performance in raw test scores except for TG, but not with any of the z scores, which are standardized by age. Women and black participants had lower estimated mean QNPZ-5 scores (by 0.21 and 0.48) after adjustment for the other covariates.
Patients with preexisting CVD had 6.2-fold higher odds of having NCI(p = 0.01, 95% CI 1.4-26.4), after adjustment for age, gender, race/ethnicity, education, location, prior AIDS, and total cholesterol (table 3). Prior CVD was also associated with lower QNPZ-5 scores (by -0.7; p = 0.02), as were use of antihypertensive agents (by -0.4, p = 0.03), higher total cholesterol (by -0.03 per 10 mg/mL, p = 0.02), and hepatitis B (by -0.7, p = 0.05); estimated mean QNPZ-5 scores were lower for women, black participants, and, borderline, for those with depression (p = 0.07) (table 3). Smoking, diabetes, higher body mass index, higher low-density lipoprotein, and use of lipid-lowering drugs were not independently associated with NCI or lower QNPZ-5 scores but were associated with lower z scores or worse test scores for some of the tests (table 3 and table e-2). Higher high-density lipoprotein was associated with lower z scores on GPB and CT1, but not with NCI or QNPZ-5 scores. In a sensitivity analysis, we included the Framingham CVD risk score as a factor instead of fitting cholesterol and BP-lowering drugs separately: there was no evidence for an association of the Framingham score with either the QNPZ-5 or NCI (data not shown). There was no evidence that major abnormalities on the baseline ECG, hepatitis C, or alcohol abuse were independently associated with any of the neurocognitive performance measures (table 3, footnote).
There was no evidence for an association of baseline or nadir CD4 cell counts, viral load, diabetes, or the CNS penetration effectiveness rank of ART regimens with QNPZ-5 scores or NCI.
DISCUSSION
Our cross-sectional study of baseline neurocognitive performance included 292 SMART study participants from Australia, North America, Brazil, and Thailand with CD4 cell counts >350 cells/mm3. At baseline, 14% of participants had NCI and prior CVD was the single associated factor. Participants with prior CVD, higher total cholesterol, and those using antihypertensive drugs had lower estimated mean baseline neurocognitive performance, but neither HIV-related risk factors commonly associated with HAD nor the CNS penetration effectiveness rank of ART were associated with NCI or neurocognitive performance measured by the QNPZ-5. The 10 participants (3.4%) with prior CVD in our study had experienced myocardial infarction, coronary heart disease, congestive heart failure, or peripheral vascular disease, but not stroke.
Our findings suggest that cardiovascular risk factors and disease may be key drivers of impairment in HIV-positive persons with high CD4 cell counts, more so than HIV-related HAD risk factors. These findings are important because HIV-positive populations have a high number of CVD risk factors including smoking,3 hypertension,3 diabetes,3 hyperlipidemia,3 metabolic syndrome,27 insulin resistance,28 and antiretroviral use.29
The mechanisms that might link lower neurocognitive performance with CVD and cardiovascular risk factors in HIV-positive populations are likely multifactorial. In HIV-negative populations increasing evidence suggests that cardiovascular risk factors contribute to the pathogenesis of both vascular dementia and AD.4-6,30 Theoretically the pathogenesis of these 2 dementing illnesses may overlap. Recently it was proposed that insulin resistance, which underlies several of the abovementioned cardiovascular risk factors, may be one of the primary convergent mechanisms that links these risk factors to both vascular dementia and AD.31
Raised inflammatory markers, including IL-6 and C-reactive protein, are risk factors for dementia32 and are common to CVD,33 the metabolic syndrome,34 aging, and HIV, including treated HIV infection.35 However, we do not have inflammatory markers for study analysis.
The changes in the adaptive immune system of HIV-infected patients receiving long-term antiretroviral therapy resemble those seen in the elderly.36 Key factors that may contribute to immune senescence in HIV-infected patients include persistent immune activation, inflammation, and poor CD4 cell response to antiretroviral treatment.36 A recent study of HIV-infected patients measured coronary artery calcium accumulation and found an increased vascular age in over 40% of patients, with a mean increase of 15 years over their chronological age.37 Increased vascular aging would help to explain why we found an association between lower neurocognitive performance and cardiovascular risk factors/CVD in a relatively young study population whereas cognitive decline and dementia associated with these factors in HIV-negative populations usually do not occur until at least the sixth decade. Similarly, the early expression of Parkinson disease in HIV infection has been reported recently.38
None of the conventional HIV-related HAD risk factors was associated with NCI or lower neurocognitive performance and the reason for this is unclear. The median CD4 cell count was high (536 cells/mm3) but there was also no association of NCI with nadir CD4 counts. There was no evidence for an association of diabetes with impairment or poorer neurocognitive performance, although the lack of evidence may have been due to the low number of participants with diabetes. There was also no evidence for an association of the ART CNS penetration effectiveness rank with any of the neurocognitive performance scores. ART regimens with CNS penetration effectiveness ranks ≥2 have been associated with improved neurocognitive performance26; in our study, 25% of participants had CNS penetration effectiveness ranks ≥2. Contrary to expectations, participants with prior AIDS had a slightly increased estimated mean QNPZ-5 score (by 0.24, p = 0.05, table 3). This may be a statistical artifact due to confounding; in univariate analysis, those with and without prior AIDS had similar QNPZ-5 scores (p = 0.60 for difference), but those with prior AIDS had more CVD risk factors, including a higher body mass index (mean 25 vs 23) and more use of BP-lowering drugs (18% vs 9%).
Mean z scores differed significantly between locations for each of the 5 neurocognitive tests; moreover, differences between locations persisted after adjusting for differences in age, sex, race, and education and other factors (table 3). At first glance, this leads to the hypothesis that the standard US norms were not appropriate for Brazil or Thailand. Within countries, however, z scores also varied considerably between clinical sites (table 2, hierarchical model). Further adjustment for age, race, sex, and education decreased between-site variability in raw test scores, but had only minimal effect on the between-site variability in z scores (data not shown). The latter suggests that our US norm z scores reasonably standardized the test scores for these 4 demographic factors, and that the remaining variability between countries may be largely due to other unmeasured factors such as nutritional status, urban vs rural residency, cultural/ethnic factors, and test administration. It may be that if we had been able to more accurately measure and adjust for the education of participants, for example by assessing their reading level39 instead of using years of education, we may have seen less between-country variability.
Twenty-four percent of participants met the study definition of depression; this proportion is commensurate with some studies but lower than others.15
Antidepressant use was not assessed.
One should interpret our study definition of NCI (z scores <-2 in 2 or more domains) with caution because 1) NCI was not confirmed clinically; 2) we used US norms in Brazilian and Thai populations; and 3) we assessed 4 cognitive domains only.19 Moreover, NCI may not always represent HAD or other HIV-associated neurocognitive disorders because there is an overlap between the neurocognitive impairment associated with cerebrovascular disease40 and HIV-associated CNS disease.
Study limitations include a moderate sample size, which limits the power to detect associations; a modest test battery; study-trained staff rather than neuropsychologists administering the neurocognitive tests; and the lack of local reference norms in Brazil and Thailand. Also, hypertension was not assessed directly, but extrapolated from the use of BP-lowering drugs. Finally, we evaluated multiple outcomes; some of the observed associations might be false-positives, in particular where statistical significance was borderline.
Our findings suggest that, in HIV-infected persons with high CD4 cell counts, cardiovascular-related insults may be more detrimental to neurocognitive functioning than factors more directly related to HIV. Given the high prevalence of cardiovascular risk factors in HIV-infected populations, this finding is important and warrants further investigation.
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