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Physical exercise is associated with less neurocognitive impairment among HIV-infected adults
 
 
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J. Neurovirol. June 2013
 
Catherine A. Dufour & Maria J. Marquine & Pariya L. Fazeli & Brook L. Henry & Ronald J. Ellis & Igor Grant & David J. Moore & the HNRP Group
 
"In summary, NCI still affects nearly half of the HIV+ population. Our results suggest that exercise is associated with less NCI among HIV-infected persons and may have specific impact on working memory and speed of information processing. Future intervention studies would help better determine whether exercise is an effective tool to address the neurocognitive deficits associated with this disease…..Unadjusted analyses showed that the exercise group had significantly lower rates (p<0.05) of impairment in working memory, speed of information processing, executive function, and motor function. Adjusted models showed that exercise was significantly associated with lower impairment rates (p<0.05) in working memory and speed of information processing (Fig. 2), but not in the other cognitive domains."
 
"The major benefit of exercise to the brain may be reduced neurocognitive risk factors, such as high blood pressure and hyperlipidemia. Metabolic syndrome associated with ART use is also associated with increased risk for developing diabetes, hypertension, obesity, and dyslipidemia (Aboud et al. 2007; Grinspoon and Carr 2005). All of these phenomena are cerebrovascular risk factors that may in turn cause NCI (Gorelick et al. 2011). Studies have shown that aerobic exercise can improve body composition, reduce waist circumference and weight, and improve lipid levels in those with HIV infection (O'Brien et al. 2010).
 
Exercise interventions would likely reduce waist circumference and BMI, factors that our group has previously shown to be associated with NCI (McCutchan et al. 2012). In summary, our findings are consistent with the notion of cerebrovascular disease as a possible mechanism underlying the association between exercise and neurocognition.
 
It is worth noting, however, that exercise has direct impacts on the brain as well. Studies have also shown that exercise reduces oxidative stress and inflammatory markers, and increases neurogenesis, angiogenesis, and synaptogenesis in the brain (Lista and Sorrentino 2010; Ahlskog et al. 2011)"
 
Abstract

 
Neurocognitive impairment (NCI) remains prevalent in HIV infection. Randomized trials have shown that physical exercise improves NCI in non-HIV-infected adults, but data on HIV-infected populations are limited. Community-dwelling HIV-infected participants (n = 335) completed a comprehensive neurocognitive battery that was utilized to define both global and domain-specific NCI.
 
Participants were divided into "exercise" (n = 83) and "no exercise" (n = 252) groups based on whether they self-reported engaging in any activity that increased heart rate in the last 72 h or not. We also measured and evaluated a series of potential confounding factors, including demographics, HIV disease characteristics, substance use and psychiatric comorbidities, and physical functioning. Lower rates of global NCI were observed among the exercise group (15.7 %) as compared to those in the no exercise group (31.0 %; p < 0.01). A multivariable logistic regression controlling for potential confounds (i.e., education, AIDS status, current CD4+ lymphocyte count, self-reported physical function, current depression) showed that being in the exercise group remained significantly associated with lower global NCI (odds ratio = 2.63, p < 0.05). Similar models of domain-specific NCI showed that exercise was associated with reduced impairment in working memory (p < 0.05) and speed of information processing (p < 0.05). The present findings suggest that HIV-infected adults who exercise are approximately half as likely to show NCI as compared to those who do not. Future longitudinal studies might be best suited to address causality, and intervention trials in HIV-infected individuals will determine whether exercise can prevent or ameliorate NCI in this population.
 
Results
 
Table 2 shows the demographic, HIV disease, and health status characteristics by group (i.e., exercise and no exercise). The exercise group reported significantly more formal education, lower prevalence of AIDS, higher current CD4+ count, less current major depressive disorder, and a higher PHS (better self-reported physical functioning).
 
As shown in Fig. 1, the exercise group had significantly lower rates of global NCI than the no exercise group, and the rate of cognitive impairment was approximately doubled in the no exercise group (df=1, χ2=7.99, p<0.01, odds ratio (OR)=2.28, confidence interval (CI)=1.30-4.80). A comparable analysis in our subset of participants with undetectable viral load (n=233) showed similar findings (χ2=4.02, p<0.05, OR=2.08, CI=1.01-4.31). In our overall sample, a multivariable logistic regression model on global NCI was significant (χ2=13.61, p=0.03) and showed that exercise continued to be significantly associated with global NCI (χ2=6.02, p<0.01, OR=2.63) after adjusting for potential confounding factors that differed between groups. Figure 2 shows the rate of NCI in each domain by group. Unadjusted analyses showed that the exercise group had significantly lower rates (p<0.05) of impairment in working memory, speed of information processing, executive function, and motor function. Adjusted models showed that exercise was significantly associated with lower impairment rates (p<0.05) in working memory and speed of information processing (Fig. 2), but not in the other cognitive domains.
 
Follow-up analysis
 
In order to more stringently adjust for the potential effect of demographic variables on NCI, we selected a subgroup of participants from the no exercise group (n=83; age: M=47.5, SD=8.7; education: M=14.2, SD=2.8; 79.5 % male; 59.0 % non-Hispanic White) that were matched on demographic characteristics (i.e., age, years of education, gender, and ethnicity) to the exercise group (n=83). This subgroup of participants in the no exercise group continued to have significantly lower CD4 counts (median=485, IQR=233-702), higher rates of current major depressive disorder (15.7 %), and higher instances of AIDS (79.3 %) than the exercise group (ps<0.05), with no other significant group differences on covariates. The rate of global NCI in the no exercise group (28.9 %) continued to be double that of the exercise group (χ2=4.21, p=0.04, OR=2.19, CI=1.03-4.68), and exercise remained a significant predictor of global impairment after adjusting for potential confounding factors that differed between groups (i.e., current CD4, current major depressive disorder, AIDS status).
 
Discussion
 
The present study is among the first to examine the direct relationship between exercise and neurocognition among HIV+ individuals. We found that self-reported recent engagement in exercise was significantly associated with lower rates of global NCI in a large cohort of HIV+ individuals. Further, this association continued to be significant even after examining a number of potential confounds, including demographic factors, HIV disease characteristics, substance use disorders, past and current depression, mental health status, and physical functioning. Among the cognitive domains examined, lower rates of impairment in working memory and speed of information processing were significantly associated with exercise. These findings support exercise as a modifiable lifestyle behavior that may reduce or potentially prevent NCI in HIV+ persons. It is also relevant to note that our findings correspond to a growing body of studies that support the hypothesis that exercise has a positive effect on neurocognition (e.g., Heyn et al. 2004; Lautenschlager et al. 2008; Rosenberg et al. 2012).
 
Our results are consistent with prior findings indicating an association between exercise and cognition among persons living with HIVand extend the current literature by showing that this association is present in a diverse, large group of HIV+ patients who have completed a comprehensive neurocognitive assessment (Fillipas et al. 2006; Honn et al. 1999).
 
The only intervention study on this topic among HIV+ adults was limited by a small sample size (i.e., 17-18 participants per group) and the use of a self-report measure of cognitive symptoms, which might be impacted by responding bias and poor insight (Fillipas et al. 2006). A prior observational study found only a limited association between exercise and neurocognition in a group of young (M=33 years), medically asymptomatic HIV+ adult males (Honn et al. 1999). Although it included a comprehensive neurocognitive battery, the authors did not report data on cognitive domains, but rather individual tests. However, similar to our present findings, this study reported that current exercise was associated with performance on a cognitive test of working memory that requires speeded information processing.
 
Our analyses, when adjusted for potential confounds, showed that exercise was significantly associated with lower impairment in working memory and speed of information processing domains. Similar associations have been reported in randomized control exercise interventions of HIV-uninfected persons (Smith et al. 2010). These cognitive domains are thought to be mediated by frontal and subcortical brain systems which are typically most affected by cerebrovascular disease (DeCarli et al. 1995; Kennedy and Raz 2009; Raz et al. 2003), suggesting that this factor could potentially mediate the relationship between exercise and improved cognition in HIV infection. The major benefit of exercise to the brain may be reduced neurocognitive risk factors, such as high blood pressure and hyperlipidemia. Metabolic syndrome associated with ART use is also associated with increased risk for developing diabetes, hypertension, obesity, and dyslipidemia (Aboud et al. 2007; Grinspoon and Carr 2005). All of these phenomena are cerebrovascular risk factors that may in turn cause NCI (Gorelick et al. 2011). Studies have shown that aerobic exercise can improve body composition, reduce waist circumference and weight, and improve lipid levels in those with HIV infection (O'Brien et al. 2010). Exercise interventions would likely reduce waist circumference and BMI, factors that our group has previously shown to be associated with NCI (McCutchan et al. 2012). In summary, our findings are consistent with the notion of cerebrovascular disease as a possible mechanism underlying the association between exercise and neurocognition.
 
It is worth noting, however, that exercise has direct impacts on the brain as well. Studies have also shown that exercise reduces oxidative stress and inflammatory markers, and increases neurogenesis, angiogenesis, and synaptogenesis in the brain (Lista and Sorrentino 2010; Ahlskog et al. 2011). Further, it is possible that pain, neuropathy, or some other factor we did not examine may both limit exercise and impair cognition. Alternatively, our results could be interpreted to mean that lower neurocognitive functioning may be a barrier to participating in exercise. The relationship may be complex and bidirectional in that exercise could influence NCI, and in turn, NCI could influence one's ability to engage in exercise.
 
Our study has several limitations. We measured exercise by self-report, which might be subjected to bias. Our questionnaire was short and did not specify the frequency or quantity of exercise in various categories (e.g., leisure vs. work-related exercise). Moreover, we did not quantify exercise over a long time span. However, studies across many domains have suggested that shorter recall periods may lead to more accurate self-report of various behaviors (Jerant et al. 2008; Napper et al. 2010). Therefore, estimates of exercise time over a relatively short and recent epoch (the previous 72 h) may be more precise compared to longer periods. We cannot infer causality due to the cross-sectional nature of these data, and an interventional study is needed to fully demonstrate the impact of exercise on neurocognition. However, the influence of exercise on NCI is supported in the literature by prospective randomized controlled trials of exercise interventions that have been shown to improve cognition among HIV-uninfected individuals (Heyn et al. 2004). Differences in demographics and systemic function between participants in the exercise and no exercise groups might confound the relationship between exercise and neurocognition. In order to adjust for these potential confounds, we examined many covariates and included any that significantly differed between groups in our models. Further, we re-ran our core models in a subgroup of participants matched on demographic characteristics. The strength of this study includes the assessment of a large, well-characterized cohort and the extensive and well-validated neurocognitive battery (Heaton et al. 1995).
 
Although we have shown that self-reported exercise is associated with better cognitive function, additional research is needed to determine the intensity and frequency of exercise needed to achieve the best neurocognitive outcomes. A better understanding of the relationship between exercise and NCI may be possible if patients are followed longitudinally or if objective measurements of exercise are used, such as pedometers, accelerometers, or supervised exercise. Future studies should also examine the ability of exercise interventions to improve cognitive function in the HIV+ population. In addition to objectively measuring exercise, it has been shown that pedometers can motivate an increase in daily physical activity across all age groups and even in older, sedentary individuals (Kang et al. 2009). Recent studies have also demonstrated significant benefits from using mobile phone interventions to influence exercise behavior. Hurling and colleagues (2007) used a text messaging intervention in adults and were able to increase moderate exercise by 2 h per week, and reduce body fat percent in 9 weeks. Text messaging interventions have even been shown to modify behavior in cognitively impaired schizophrenia patients (Pijnenborg et al. 2010). Thus, using techniques that include pedometer-motivated exercise or a text messaging interface may increase exercise engagement and lead to improved neurocognitive performance in HIV+ individuals.
 
In summary, NCI still affects nearly half of the HIV+ population. Our results suggest that exercise is associated with less NCI among HIV-infected persons and may have specific impact on working memory and speed of information processing. Future intervention studies would help better determine whether exercise is an effective tool to address the neurocognitive deficits associated with this disease.

 
 
 
 
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