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Relationship of blood pressure and antihypertensive medications to cognitive change in the BVAIT, WISH, and ELITE clinical trials

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Relationship of blood pressure and antihypertensive medications to cognitive change in the BVAIT, WISH, and ELITE clinical trials

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Content RELATIONSHIP OF BLOOD PRESSURE AND ANTIHYPERTENSIVE MEDICATIONS TO COGNITIVE CHANGE IN THE BVAIT, WISH, AND ELITE CLINICAL TRIALS by Victor Mao Ye A Thesis Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE (APPLIED BIOSTATISTICS AND EPIDEMIOLOGY) August 2015 Copyright 2015 Victor Mao Ye ! ii! TABLE OF CONTENTS DEDICATION iii ACKNOWLEDGMENTS iv ABSTRACT v INTRODUCTION 1 METHODS 4 RESULTS 10 DISCUSSION 15 CONCLUSION 20 REFERENCES 21 TABLES 25 FIGURES 31 ! iii! DEDICATION This work is dedicated to my parents for all of their endless love and support. Also, to Hannah for always being there for me. ! iv! ACKNOWLEDGMENTS I would like to thank my advisor Dr. Wendy Mack for being a great mentor, allowing me to join her research, and for being incredibly supportive and helpful. In addition, I would like to thank my committee members Dr. Howard Hodis and Dr. Roksana Karim for their expertise and guidance. I would like to thank Dr. Stanley Azen for introducing me to the Applied Biostatistics and Epidemiology master’s program at USC. Lastly, I would like to thank the Summer Institute for Training in Biostatistics (SIBS) program at Emory University for showing me how useful and fun biostatistics can be. ! v! ABSTRACT Background: Hypertension has been previously linked to cognitive decline in some populations. Based on this association, antihypertensive medications have been hypothesized to reduce cognitive decline. We evaluated the relationship of blood pressure and antihypertensive medications to cognitive change using data from three clinical trials conducted in the Atherosclerosis Research Unit at the University of Southern California: B-Vitamin Atherosclerosis Intervention Trial (BVAIT), Women’s Isoflavone Soy Health (WISH), and Early Versus Late Intervention Trial with Estradiol (ELITE). Methods: A total of 1334 patients (1057 postmenopausal women, 277 men), with an average (SD) age of 60.6 (8.0) were included in the secondary analysis of the three clinical trials. The dataset was analyzed using multiple linear regression, adjusting for age, baseline cognitive score, race, gender, and trial. Cognitive change scores (endpoint minus baseline) were calculated after 2.5 years of follow-up for global cognition, verbal memory, executive function, and visual memory. Different regression models were used to assess the association of these changes in cognition with systolic blood pressure (mean and SD measured over the trial), diastolic blood pressure (mean and SD), and pulse pressure. In the regression models evaluating the association of antihypertensive medication and changes in cognition, two separate analyses were performed, one with mean systolic blood pressure as a model covariate, and the other excluding systolic blood pressure. Results: Higher levels of systolic blood pressure and pulse pressure were statistically significantly associated with a decline in global cognition (p=0.013 and p=0.004, respectively). Pulse pressure was also significantly negatively associated with changes in verbal memory and visual memory (p=0.04 and p=0.03, respectively). In the models including SBP, diuretic use was ! vi! significantly positively associated with change in global cognition (p=0.02); central agonist use (clonidine and guanfacine) was significantly positively associated with changes in global cognition and verbal memory (p=0.01 and p=0.03, respectively). Alpha blockers, combined alpha/beta blockers, ACE inhibitors, angiotensin II receptor blockers, beta blockers, and calcium channel blockers were not significantly associated with cognitive change (all p>0.05). Conclusion: In this ethnically diverse population of primarily postmenopausal women, we found that higher systolic blood pressure and pulse pressure were associated with some aspects of cognitive decline, and that central agonists and diuretics may reduce cognitive decline. Central agonists, in particular clonidine and guanfacine, were found to have a blood pressure independent effect on cognition. Further research will be needed to understand which classes of antihypertensive medications, and their associated mechanisms, are best suited to prevent cognitive decline in certain patient populations. ! 1! INTRODUCTION As the world population ages, understanding the risks and causes of cognitive impairment has become an increasingly important global health issue. Cognitive decline can describe a wide spectrum of mental impairments, including decline from normal aging as well as mild cognitive impairment (MCI) and dementia. 1 Dementia refers to cognitive impairments that affect activities of daily living; in 2000, dementia was estimated to affect 25 million people worldwide, and in 2009 the cost of care for dementia was estimated at $412 billion. 2,3 In examining the risk factors for cognitive decline, the relationship with blood pressure has been well studied over the past few decades, with several studies suggesting an association between high blood pressure and decreased cognition. 4–7 Since hypertension affects over a third of the world’s population, including 65-75% of people over age 65, the link between hypertension and cognitive function is an important public health problem, and highlights an important avenue for prevention of cognitive decline and dementia. 8,9 Hypertension has previously been linked to an increased risk of developing dementia or Alzheimer’s disease (AD) in some populations, such as persons with MCI. This relationship was reported in the Canadian Study of Health and Aging, which followed 990 subjects diagnosed with MCI for 5 years. 10 Among subjects with executive dysfunction alone, those with hypertension had significantly higher risk of progressing to dementia compared to those with normal blood pressure. Another study, the Uppsala longitudinal study of adult men (a 40-year follow-up of a population-based cohort of 50 year old men with normal cognition) studied the vascular risk factors for incident dementia and Alzheimer’s disease and found that high systolic blood pressure (SBP) increased the risk of vascular and all-type dementia, but not Alzheimer’s disease. 11 These associations between blood pressure and dementia and Alzheimer’s disease have ! 2! since been studied in many different populations, and because of their importance, they are still being studied today. The association of elevated blood pressure with dementia has prompted studies of blood pressure effects on early cognitive decline. Much of this research has focused on the relationship between high mid-life or late-life blood pressure and late-life cognitive decline. The Hoorn Study, a longitudinal population-based study with mean (SD) baseline age of 57.7 (5.5) years, reported that individuals with poor information-processing speed after 15 years of follow-up had higher levels of SBP at baseline than those with good information processing speed. 12 This relationship, however, gradually attenuated with increasing age, suggesting that the timing of blood pressure treatment strategies could be important. Another landmark study, the Honolulu- Asia Aging study, conducted among 3735 Japanese-American men in Hawaii, concluded that midlife SBP was a significant predictor of reduced cognitive function later in life. 13 The authors suggested that early control of blood pressure could be important in preventing cognitive decline. The Women’s Health and Aging Study II was another large longitudinal study focusing on women with a follow-up of 9 years. 14 In the group of women aged 70-75 years old, high pulse pressure was associated with lower verbal learning after follow-up, while in the group aged 76- 80 years old, high SBP was associated with decreased executive function. The authors suggested that late-life hypertension could be associated with declines in cognitive function as well. In a recent 20-year study on the effects of midlife hypertension and cognitive change, however, it was concluded that midlife hypertension, not late-life hypertension was associated with cognitive decline. 15 While it is not yet conclusive on whether midlife or late-life blood pressure is more strongly associated with cognitive decline, it is apparent that blood pressure is indeed associated with cognitive function. ! 3! Because of this association between blood pressure and cognitive decline, it has been hypothesized that blood pressure medications could improve cognitive function or prevent cognitive decline. In the Epidemiology of Vascular Aging study, a longitudinal study in the elderly, cognitive decline was lower in treated compared to untreated hypertensive patients. 16 A lower rate of cognitive decline among patients with antihypertensive treatment was reported in another longitudinal study focusing on an elderly population. 17 In a posthoc analysis of the Gingko Evaluation of Memory study (GEM), a clinical trial testing whether ginkgo supplementation could prevent dementia in older adults at least 75 years of age with normal cognition or MCI, diuretics, angiotensin II receptor blockers, and ACE inhibitors use was associated with reduced risk of incident AD dementia in subjects with normal cognition. 18 Only diuretics were associated with reduced risk in those with MCI. A few randomized clinical trials (RCTs) testing the effects of antihypertensive medications on cognitive decline, dementia, and Alzheimer’s disease have also focused on hypertensive patients or patients with high risk of cardiovascular events. 19–21 In a recent systematic review of various antihypertensive medications (including diuretics, ACE-I, and ARBs) and their effects on cognitive decline and dementia, two RCTs demonstrated that antihypertensive medications have a significant beneficial effect on cognition, while five RCTs reported no significant effects. 22 The authors of the review suggested that the significant associations between blood pressure medications and cognitive decline and dementia may have simply resulted from medication-related stroke prevention rather than a direct effect on cognition, since the populations of those RCTs reporting significant medication effects had high risk of cardiovascular events, or a previous stroke or transient ischemic attack. In contrast, the populations of three of the RCTs that did not find significant effects were those with high blood ! 4! pressure but no previous history of stroke or transient ischemic attack. One of the non-significant RCTs had a population of patients with stroke within the previous 90 days, however, and another had a population of patients with coronary, peripheral, or cerebrovascular disease or diabetes with end-organ damage. Overall, the review concluded that anti-hypertensive therapy, particularly calcium channel blockers, ARBs, and ACE inhibitors, may decrease the risk of cognitive decline and dementia, but further RCTs with longer follow up and cognition as the primary outcome are needed. Other researchers have also hypothesized that ARBs in particular may prevent cognitive decline, as evidenced by an autopsy study demonstrating that use of ARBs was associated with less AD-related pathology. 23 We analyzed data from three randomized controlled trials performed in the Atherosclerosis Research Unit of the University of Southern California from 2001-2013. Our aim was to investigate the relationship between blood pressure and change in cognition measured over 2.5 years in healthy individuals across the three clinical trials. We also tested the association between specific blood pressure medications taken during the studies with changes in cognition. METHODS Participants and study design. This study is a secondary analysis of three randomized controlled trials performed at the Atherosclerosis Research Unit of the University of Southern California. All three studies used similar primary and secondary outcomes, and the variables of interest in this study were measured under the same protocol across all trials. The B-Vitamin Atherosclerosis Intervention Trial (BVAIT) investigated whether reduction of plasma total homocysteine levels with daily B vitamin supplementation (5 mg folic acid+0.4 mg vitamin B12+50 mg vitamin B6) in healthy adults would reduce progression of ! 5! early atherosclerosis. 24 BVAIT was a double-blind placebo controlled clinical trial randomizing 506 participants, ages ranging from 40 to 89 years old, without diabetes and cardiovascular disease, and with initial plasma total homocysteine levels >8.5 µmol/L. Eligible consenting subjects were randomized to high-dose B vitamin supplementations or placebo for a planned 2.5 year treatment period. Clinic visits occurred every 3 months and included measurements of vital signs and evaluation of medication and supplement use. B-vitamin supplementation did not significantly influence the progression of early-stage subclinical atherosclerosis, measured with carotid artery intima-media thickness (CIMT, the primary trial outcome). However, in a subgroup analysis, B-vitamin supplementation compared to placebo reduced CIMT progression among individuals baseline fasting total homocysteine level ≥ 9.1 µmol/L. The Women’s Isoflavone Soy Health (WISH) trial tested isoflavone soy supplementation in healthy postmenopausal women and effect on progression of subclinical atherosclerosis (measured as CIMT), cognitive decline, bone mineral density, and breast tissue density. 25 WISH was a double-blind, placebo-controlled trial randomizing 350 postmenopausal women aged 45- 92 years, without diabetes and CVD. Eligible subjects were randomized to either daily isoflavone soy protein supplementation or placebo for a planned 2.5 years. The soy supplement, which was given in two equally divided doses daily, was 25 g soy protein consisting of 85 mg aglycone weight naturally-occurring isoflavones (150 mg total isoflavone), genistein 45 mg aglycone weight (80 mg total weight), daidzein 35 mg aglycone weight (60 mg total weight) and glycitein 5 mg aglycone weight (10 mg total weight). Clinic visits occurred every month for the first 6 months, and then every other month for the remainder of the trial. Vital sign measurements and current medications were ascertained at every visit. Cognitive assessments were completed at baseline and final follow-up visit after 2.5 years. Trial results indicated that ! 6! isoflavone soy protein did not significantly reduce subclinical atherosclerosis (CIMT) progression in postmenopausal women. In a subgroup analysis, healthy women <5 years postmenopausal who received the intervention had an average 68% lower carotid intima-media thickness progression rate compared to placebo participants. The Early Versus Late Intervention Trial with Estradiol trial (ELITE) tested the menopausal hormone timing hypothesis. 26 Specifically, ELITE examined the effects of the timing of estrogen administration relative to menopause in healthy postmenopausal women on progression of subclinical atherosclerosis and cognitive decline. ELITE was a randomized double-blind placebo-controlled prospective trial with a 2 X 2 factorial design, randomizing 643 participants. The two factors in the trial were defined by time since menopause (<6 [early postmenopause]or ≥ 10 years [late postmenopause]). Subjects with an intact uterus were randomized to oral micronized 17B-estradiol 1 mg/day with 4% vaginal micronized progesterone gel 45 mg/day for 10 days each month or to placebos. Subjects without an intact uterus were randomized to oral micronized 17B-estradiol 1 mg/day alone or to placebo. The primary outcome was the rate of change in right distal common carotid artery far wall intima-media thickness (CIMT) measured on ultrasonograms, completed every 6 months. Secondary outcomes included measurement of cognition and coronary artery atherosclerosis. Follow-up occurred every month for the first 6 months of the trials, and then every other month until trial completion. The trial was initially planned for 2.5 years of randomized follow-up. Blood Pressure Assessment Blood pressure (in mmHg) was measured at every visit in the right arm after participants had been seated for at least 5 minutes. Mean SBP and DBP were calculated as the average of ! 7! three measurements. Pulse pressure was calculated as the difference between SBP and DBP at each visit. Medication Assessment At each visit, participants brought all current prescription and non-prescription medications. Medication names, dosages, frequencies, and start and end dates were recorded and entered into a medication database. A uniform coding system was used for all three trials. Blood pressure medications were categorized according to the 2015 American Heart Association classifications. 27 Blood pressure medications were classified as alpha blockers (doxazosin mesylate, prazosin hydrochloride, terazosin hydrochloride), central agonists (alpha methyldopa, clonidine hydrochloride, guanabenz acetate, guanfacine hydrochloride), combined alpha/beta blockers (carvedilol, labetolol hydrochloride), ACE inhibitors (benazepril hydrochloride, captopril, enalapril maleate, fosinopril sodium, lisinopril, moexipril, perindopril, quinapril hydrochloride, ramipril, trandolapril), ARBs (candesartan, eprosartan mesylate, irbesarten, losartin potassium, telmisartan, valsartan), beta blockers (acebutolol, atenolol, betaxolol, bisoprolol fumarate, carteolol hydrochloride, metoprolol tartrate, metoprolol succinate, nadolol, penbutolol sulfate, pindolol, propranolol hydrochloride, solotol hydrochloride, timolol maleate), calcium channel blockers (amlodipine besylate, bepridil, diltiazem hydrochloride, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil hydrochloride), and diuretics (chlorthalidone, chlorothiazide, furosemide, hydrochlorothiazide, indapamide, metolazone, amiloride, hydrochloride, spironolactone, triamterene, bumetanide). ! 8! Demographics and Mood Assessment Demographic information collected at baseline included race, formal education, age, and gender. Mood was assessed with the Center for Epidemiologic Studies- Depression scale. 28 Cognitive outcome measures The primary cognitive outcome was the change in cognitive function, measured at baseline and after 2.5 years. All three trials scheduled a baseline and 2.5 year follow-up cognitive testing. ELITE also had a 3 rd cognitive assessment at approximately 5 years post-baseline; for consistency with the BVAIT and WISH trials, only the 2.5-year follow-up testing was used in this analysis. A comprehensive neuropsychological battery that emphasized standardized tests sensitive to age-associated change in middle-aged and older adults measured cognitive function in the form of cognitive scores. 29 The executive function score was designed to represent working memory, visual expression, and visuospatial skills, and was assessed by the combination of scores from the Symbol Digit Modalities Test, Trail Making Test, Shipley Abstraction, Letter-Number Sequencing, Block Design, Judgment of Line Orientation, Category Fluency, and Boston Naming Test. The verbal memory and visual memory factor scores represented aspects of episodic memory. The verbal memory score included verbal learning factors from list-learning tasks and verbal logical memory factor from paragraph recall tasks, assessed by the combination of scores from the California Verbal Learning test (immediate recall and delayed recall), and the East Boston Memory Test (immediate recall and delayed recall). The visual memory score was assessed from facial recognition tasks, including Faces I immediate recall and Faces II delayed recall. Global cognitive function was a composite score of all of the aforementioned tests. Details on each of these cognitive tests have been published. 30 ! 9! We generated Z scores for each of the 14 individual cognitive tests. The neuropsychological tests were standardized within each trial using baseline means and standard deviations from all subjects contributing baseline cognitive data in that trial. 31 A composite score for each cognitive factor was calculated as a weighted average of the standardized scores of the individual tests in the factor (weighted by the inverse of the correlations between tests). Cognitive change scores were computed as endpoint minus baseline composite scores. Statistical Analysis All participants of the three clinical trials who had complete baseline and 2.5 year cognitive function scores were included in this analysis. We first evaluated associations between blood pressure and cognitive change using multiple linear regression. Mean SBP, mean DBP, and mean pulse pressure were calculated as the mean over all trial visits for each participant. As a measure of blood pressure variability, standard deviations of SBP and DBP were calculated as the standard deviation of these measures across all trial visits for each participant. Average resting blood pressure was evaluated as mean SBP and mean DBP. Average stroke volume was assessed as the mean pulse pressure, calculated as the mean of SBP minus DBP. A separate regression model was developed for each composite score: global cognition, verbal memory, executive function, and visual memory. An analysis of the association between blood pressure and cognitive change stratified by gender was also performed. Age, baseline cognitive composite score, CES-D, education level, race, gender, and trial were all considered as potential confounders. Only age, baseline cognitive score, race, gender, and trial consistently altered the regression coefficient of interest (in the association between blood pressure measures and cognitive change) by more than 10% and were included in the final models. !10! We next evaluated the relationship between cognitive change and blood pressure medication using multiple linear regression. Blood pressure medication was evaluated as a binary variable for each medication as “taken” or “not taken” during the trial. For consistency, the same confounders used in the previous model of blood pressure and cognition were used. Because the relationship between medication and cognition may be confounded by SBP, two separate analyses were performed, one with mean SBP added in the model and the other with mean SBP excluded from the model. Significance was set at two-sided p <0.05 for analyses based on global cognition and cognitive factor change scores. Effect modification was evaluated by adding interaction terms of age group and antihypertensive medication. Age group was categorized as a binary variable as under age 65 or age 65 and older. Linear regression model assumptions regarding homoscedasticity and normality of residuals were evaluated and met. All data were analyzed using Statistical Analysis System software version 9.4 (SAS institute, Inc., Cary, North Carolina). RESULTS Baseline Characteristics of Participant Population Table 1 shows the baseline characteristics of the three RCTs. A total of 1499 individuals were initially randomized; 165 participants were excluded from this analysis due to missing either baseline or 2.5 year follow-up cognitive testing, resulting in a total of 1334 participants included in the final analysis. Participants were primarily non-Hispanic whites (67.4%) with a mean (SD) age of 60.6 (8.0). The racial composition of the remaining participants was Asian (9.2%), Black (9.8%), and Hispanic (12.7%). The majority of the participants were female (79.2%) due to WISH and ELITE enrolling only postmenopausal women. Most of the !11! participants were well educated, with 26.9% having a bachelor’s degree and 36.6% having a graduate or professional degree. Mean baseline levels of SBP and DBP (119.4 mmHg and 75.1 mmHg, respectively) indicated participants were relatively healthy and normotensive. Across all three trials, 33.6% of participants were taking antihypertensive medications during the trial; most were taking diuretics (20.4% of the entire study population) or ACE inhibitors (14.8%). Alpha blockers (1.0% of the entire study population), central agonists (0.9%), and combined alpha/beta blockers (0.8%) were the least commonly taken blood pressure medications. The BVAIT trial had the highest proportion of participants on antihypertensive medications at baseline (41.6%). Association of blood pressure with change in cognitive function We used cognitive factors as a measure of change in cognitive function from baseline to about 2.5 years after intervention. Table 2 shows the average (SD), minimum and maximum time from baseline to follow-up cognitive assessment in years for each trial by gender. Table 2 also shows the mean change in each composite score by trial and gender. Women in BVAIT had less improvement in cognitive function than women in ELITE and WISH, with the exception of the visual function score. Cognitive change scores in men were slightly lower than those of women in the BVAIT trial. Compared to cognitive change scores of women across all three trials, the men in the BVAIT trial had less improvement in cognitive function in each composite score. Table 3 shows the associations of blood pressure with change in cognitive scores, adjusted for baseline cognitive score, age, race, gender and trial. SBP was statistically significantly inversely associated with 2.5-year change in global cognition (p=0.013). A 1 mmHg increase of SBP was associated with a -0.007 change in global cognition over 2.5 years !12! (95% CI = -0.012, -0.001). Pulse pressure, which is a function of SBP, was also significantly negatively associated with global cognition (p=0.004), with an increase of 1 mmHg of pulse pressure associated with an average of 0.011 lower score in global cognitive change (95% CI=- 0.018, -0.003). These results suggest that higher SBP and pulse pressure were associated with a decline in cognitive function. Pulse pressure was also significantly negatively associated with changes in verbal memory and visual memory (p=0.04 and p=0.03, respectively), showing that as the difference between SBP and DBP increased, the change in verbal and visual memory worsened (Table 3). An increase of 1 mmHg of pulse pressure was associated with an average 0.008 lower change in verbal memory composite (95% CI=-0.016, -0.0002) and an average 0.006 lower change in visual memory composite scores (95% CI=-0.011, -0.0005). Although not all statistically significant, all of the blood pressure measures were negatively associated with changes in global cognition and visual memory (Table 3). As expected from previous literature, SBP is a significant inverse correlate for change in global cognition. Pulse pressure also appears to be correlated to global cognition, verbal memory, and visual memory. On the other hand, DBP was not significantly associated with changes in cognition. The standard deviation measures of SBP and DBP, as markers of within-subject variability in blood pressure over the 2.5-year period, were also not statistically significantly associated with changes in any of the cognitive factors, suggesting that variability in blood pressure is not related to changes in cognitive function. Table 4 shows the associations of blood pressure with change in cognitive scores, stratified by gender and adjusted for baseline cognitive score, age, race, and trial. In women, there was a statistically significant inverse association between mean SBP and global cognitive !13! change (p=0.006), as well as between mean pulse pressure and global cognitive change (p=0.001). There was also a significant inverse association between mean pulse pressure and verbal memory change (p=0.041). However, there were no statistically significant associations between blood pressure and cognitive change in men. The lack of significance in the analysis of men is likely due the small sample size of men in the study. The results for women in Table 4 are likely driving the significant associations found in Table 3. Association of antihypertensive medication and cognitive function (including SBP) Table 5 shows the adjusted associations of antihypertensive medications with change in cognitive scores, including adjustment for mean SBP. In the model including SBP, central agonists were statistically significantly positively associated with change in global cognition (p=0.01) and verbal memory (p=0.03), indicating that central agonists were associated with improvements in these cognitive functions. Use of central agonists was associated with an average 0.811 greater change in global cognition (95% CI=0.225, 1.396) and an average 0.657 greater change in verbal memory (95% CI= 0.080, 1.233). Diuretics were also significantly positively associated with global cognition (p=0.02), indicating that taking diuretics during the clinical trials was associated with improvements in global cognition. Use of diuretics was associated with an improvement in 0.168 global cognitive points. Diuretics were marginally significantly associated with an increase in verbal memory (p=0.07). Although not statistically significant, alpha blockers, combined alpha/beta blockers, ACE inhibitors, and calcium channel blockers were positively associated with an improvement in global cognition (Table 5). Conversely, ARBs and beta-blockers had a non-significant inverse association with change in global cognition. Although not all significant, all of the medications !14! had a positive association with improvements in visual memory and verbal memory, with the only exception being the negative association between beta-blockers and verbal memory. Associations between blood pressure medications and executive function did not follow the above patterns. ACE inhibitors, ARBs, beta-blockers, calcium channel blockers, and diuretics were all not associated with executive function. Association of antihypertensive medication and cognitive function (without SBP) Table 6 shows the adjusted associations of antihypertensive medications with changes in cognitive composite scores, without the inclusion of mean SBP. Central agonists remained significantly positively associated with changes in global cognition (p=0.01) and verbal memory (p=0.03). Use of central agonists was positively associated with an average 0.779 greater change in global cognitive points (95% CI=0.192, 1.365) and an average 0.638 greater change in verbal memory cognitive points (95% CI=0.062, 1.214). In this model without SBP, there was no longer a statistically significant association between diuretics and global cognition. Interaction of age with antihypertensive medications To determine whether the effect of antihypertensive medications on cognitive function differed in older and younger patients, age was categorized into two baseline age groups: ages ≥65 and ages <65. Interaction between age group and antihypertensive interactions was tested for all of the cognitive scores (Figures 1a-d). For the global cognitive function model, there was a significant interaction between age group and ACE inhibitors (p=0.04) and age group and ARBs (p=0.04). However, ACE inhibitors and ARBs in both age groups were not statistically significantly associated with changes in global cognitive function (Figure 1a). Those in the !15! younger age group taking ACE inhibitors had an average 0.180 change in global cognitive points (95% CI=-0.021, 0.382; p=0.08), while those in the older age group taking ACE inhibitors had an average -0.156 change in global cognitive points (95% CI=-0.415, 0.103; p=0.24). Those in the younger age group taking ARBs had an average -0.222 change in global cognitive points (95% CI=-0.496, 0.053; p=0.11), while those in the older age group taking ARBs had an average 0.269 change in global cognitive points (95% CI=-0.106, 0.645; p=0.16). The results suggest that in terms of global cognition, there is a difference in effect of ACE inhibitors and ARBs between the younger and older age groups. In the verbal memory, executive function, and visual memory models, there were no significant interactions between age group and any of the antihypertensive medications (all p>0.05). The analysis suggests that there was no difference in the effect of any of the antihypertensive medications by age group (Figures 1b-d). DISCUSSION In this sample of 1,334 participants across three clinical trials (BVAIT, ELITE, and WISH), the population consisted of relatively young and healthy persons with an average age of 60.6 years old. Almost 80% of the study participants were women, which provides additional insight to the health of women, as 59% of patients worldwide with dementia are female. 2 It was also an ethnically diverse sample, with many different minority groups substantially represented. SBP was significantly associated with and global cognitive decline measured over 2.5 years. Pulse pressure was also significantly associated with global cognitive decline, verbal cognitive decline, and visual cognitive decline. These results expand previous research by examining specific cognitive scores, as well as global cognition. Ultimately, these results agree !16! with previous literature and indicate that in this population, measures of blood pressure (SBP and pulse pressure) are associated with cognitive decline. However, because the study had a protocol follow-up time of only 2.5 years, no conclusions can be made as to whether mid-life or late-life hypertension affects cognitive decline. Given that an association between SBP and cognitive decline was found in this relatively healthy population with an average blood pressure in a healthy range, it seems that these changes in cognition may be sensitive to small increases in blood pressure. In the analysis of the association of antihypertensive medications and cognitive decline, only diuretics and central agonists were positively associated with improvements in cognition. Diuretics are one of the most commonly prescribed antihypertensive medications, with 20.4% of the study participants taking this class of blood pressure medication. Diuretics had a positive effect on cognition in the study when including SBP in the model. This result coincides with a study conducted in Cache County, Utah of patients aged 65 and older, in which diuretics (especially potassium-sparing diuretics) were found to be associated with reduced incidence of dementia. 32 It also agrees with some of the results from the GEM study, which indicated that diuretics, ARBs, and ACE inhibitors had a positive effect on cognition. However, the GEM study had a much older population, with an average age of 78.6 and the inclusion criteria of at least 75 years old. As mentioned earlier, the systematic review of this topic concluded that calcium channel blockers, ARBs, and ACE inhibitors are the most promising antihypertensive medications for preventing cognitive decline and dementia. It is important to note that the average age of all of the studies in the review was also 74, an older population than our study. Since diuretics are such a commonly used medication, further research should be done to !17! determine whether these medications can help prevent cognitive decline, especially in a younger population as represented in our study population. Conversely, central agonists, also known as centrally acting alpha-2 adrenergic receptor (ADRA2A) agonists, are not a commonly prescribed medication for hypertension —there were only 12 participants in the final study population taking this class of blood pressure medication (11 clonidine, 1 guanfacine). Clonidine and guanfacine are psychoactive medications and have also been shown to be effective for children with Attention Deficit Hyperactivity Disorder (ADHD) and Tourette’s syndrome. 33,34 The significant positive effect of these drugs on cognition with such a small sample size suggests that these medications could have a large effect on cognition. Improvements in cognition from guanfacine were first seen in a study of aged monkeys. 35 Further research using delayed response tests in nonhuman primates has shown that guanfacine can improve working memory. 36,37 Clonidine has also been shown to induce a protracted improvement in aspects of working memory in healthy nonhuman primates. 38 These early studies suggest that ADRA2A agonists, like clonidine and guanfacine, could potentially improve cognition in humans. In our study, central agonists were significantly associated with improvements in cognition in the models without SBP, suggesting that the mechanism of action of these drugs is independent of blood pressure. The lack of a positive cognitive effect for diuretics when SBP was removed from the model provides further evidence that central agonists have a blood pressure-independent effect on cognition. ADRA2A agonists bind to presynaptic alpha-2 adrenergic receptors in the vasomotor center of the medulla oblongata, thus inhibiting the release of norepinephrine and resulting in decreased arterial blood pressure. 39 However, these drugs also have another mechanism by which they can affect cognition. ADRA2A agonists act on the locus !18! coeruleus, which is a nucleus found in the pons and the brain’s main site of norepinephrine production. 40 Norepinephrine has been shown to play an important role in regulating the prefrontal cortex, which has effects on working memory and executive functions. 41 Thus, the positive effect of central agonists on cognition may have been a result of its prefrontal cortex action, rather than its effect on blood pressure. Most of the research involving ADRA2A agonists and cognition focuses on guanfacine because it is has less hypotensive and sedative side effects than clonidine, and early evidence showed that it is has a stronger positive effect on working memory in nonhuman primates. 36 Much of the current research on the effect of these drugs on cognition in humans has been conducted on those with disease or illness, not healthy individuals. For instance, some studies have shown that central agonists improve working memory in those with traumatic brain injury and schizotypal disorder. 42,43 However, one notable study on healthy individuals was a double- blind placebo controlled clinical trial of 60 healthy male volunteers randomized into three arms (1 or 2 mg of guanfacine or placebo), which found no improvement of prefrontal memory or executive functions with guanfacine. 44 The most recent study of the effects of guanfacine on cognition was a RCT completed at Yale University testing the hypothesis that low doses of guanfacine can improve deficits in prefrontally-mediated working memory and executive control function in healthy elderly subjects, but results have not yet been published (NCT Number: 00935493). Further research needs to be done to understand the mechanism of these central agonists and whether they can help prevent cognitive decline in humans. The age of antihypertensive use may also play a role in its effect on cognition, as noted by the Hoorn Study discussed previously, which suggested that the timing of vascular treatments could be critical in preventing cognitive decline. In our study, we did find a significant !19! interaction between ARBs and ACE inhibitors with age group in the change in global cognition model. These results suggest that age could play a role in how these medications affect cognition. As researchers further investigate the question about whether midlife or late-life hypertension contributes to cognitive decline, we also need to answer the question about whether earlier use of antihypertensive medications could help prevent cognitive decline. Our study and many previous studies indicate evidence for the positive effect of antihypertensive medications on cognition, but further research needs to better understand which types of medications are best suited for different patient populations. Most of the RCTs conducted on the effect of antihypertensive on cognition thus far showed non-significant results. 22 However, the potential for antihypertensive treatments to help prevent cognitive decline and even AD and dementia is promising and could have a significant impact on the quality of life for many patients at an individual level as well as more globally at a public health level. This question needs to be further studied because of the aging population worldwide and its major public health implications. !20! CONCLUSION Our study was a unique study of a diverse population of mostly women. Compared to most studies addressing the effect of blood pressure and antihypertensive medication on cognition, our sample was relatively young and diverse ethnically. We found that increased SBP and pulse pressure were associated with cognitive decline, and that central agonists and diuretics could help reduce cognitive decline. ADRA2A agonists, particularly guanfacine and clonidine, show promise in their ability to improve cognition in this study, and their mechanism of action may in fact be blood pressure independent. Further research will be needed to understand how central agonists work to improve cognition, and which antihypertensive medications are best suited to prevent cognitive decline in certain patient populations. !21! REFERENCES 1 Gąsecki D, Kwarciany M, Nyka W, Narkiewicz K. Hypertension, brain damage and cognitive decline. Curr Hypertens Rep 2013; 15: 547–58. 2 Wimo A, Winblad B, Aguero-Torres H, von Strauss E. The magnitude of dementia occurrence in the world. Alzheimer Dis Assoc Disord; 17: 63–7. 3 Wimo A, Winblad B, Jönsson L. The worldwide societal costs of dementia: Estimates for 2009. Alzheimer’s Dement 2010; 6: 98–103. 4 Whitmer RA, Sidney S, Selby J, Johnston SC, Yaffe K. Midlife cardiovascular risk factors and risk of dementia in late life. 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Lack of effects of guanfacine on executive and memory functions in healthy male volunteers. Psychopharmacology (Berl) 2005; 182: 205–13. !25! TABLES Table 1. Baseline characteristics of the three RCTs included in the secondary analysis* BV AIT (n=452) ELITE (n=568) WISH (n=314) Total (n=1334) Demographic Characterics Female, n (%) 175 (38.7) 568 (100) 314 (100) 1057 (79.2) Age, years 61.2 ± 9.7 60.0 ± 6.9 60.6 ± 7.1 60.6 ± 8.0 CES-D Scale 5.8 ± 5.5 7.8 ± 7.1 7.0 ± 6.2 6.9 ± 6.4 Education, n (%) High School Graduate or less 27 (6.0) 21 (3.7) 16 (5.1) 64 (4.8) Trade/Business School 25 (5.5) 14 (2.5) 16 (5.1) 55 (4.1) Some College 123 (27.3) 149 (26.2) 95 (30.3) 367 (27.5) Bachelor's Degree 121 (26.8) 164 (28.9) 74 (23.6) 359 (26.9) Graduate/Professional Degree 155 (34.4) 220 (38.7) 113 (36.0) 488 (36.6) Race, n (%) White non-hispanic 303 (67.0) 398 (70.1) 198 (63.1) 899 (67.4) Black non-hispanic 62 (13.7) 49 (8.6) 19 (6.1) 130 (9.8) Hispanic 46 (10.2) 74 (13.0) 49 (15.6) 169 (12.7) Asian or Pacific Islander 39 (8.6) 47 (8.3) 36 (11.5) 122 (9.2) Native American 2 (0.4) 0 0 2 (0.2) Other 0 0 12 (3.8) 12 (0.9) Blood Pressure Measurements (mmHg) Systolic Blood Pressure 126.8 ± 12.4 115.1 ± 9.9 116.5 ± 10.8 119.4 ± 12.2 Diastolic Blood Pressure 78.5 ± 6.7 73.3 ± 5.6 73.5 ± 6.0 75.1 ± 6.6 Pulse Pressure 48.3 ± 11.3 41.8 ± 7.0 43.0 ± 8.2 44.3 ± 9.4 Medications Taken During Trial, n (%) Any Blood Pressure Medication 188 (41.6) 181 (31.9) 79 (25.2) 448 (33.6) Alpha Blockers 11 (2.4) 1 (0.2) 1 (0.3) 13 (1.0) Central Agonists 7 (1.6) 3 (0.5) 2 (0.6) 12 (0.9) Combined Alpha/Beta blockers 4 (0.9) 5 (0.9) 1 (0.3) 10 (0.8) ACE inhibitors 79 (17.5) 88 (15.5) 30 (9.6) 197 (14.8) ARBs 29 (6.4) 51 (9.0) 12 (3.8) 92 (6.9) Beta blockers 62 (13.7) 47 (8.3) 26 (8.3) 135 (10.1) Calcium Channel blockers 42 (9.3) 46 (8.1) 23 (7.3) 111 (8.3) Diuretics 115 (25.4) 110 (19.4) 47 (15.0) 272 (20.4) *All continuous variables are described by the mean ± SD ! 26! Table 2. Changes in cognitive function by gender across the three RCTs* ELITE (N=568) WISH (N=314) Female (N=1057) Total (N=1334) Male (N=277) Female (N=175) Baseline Cognitive Function Baseline Global Cognitive Score 0.189 ± 1.6 -0.049 ± 1.8 0.040 ± 1.8 0.043 ± 1.7 0.026 ± 1.8 0.060 ± 1.8 Baseline Verbal Memory Score -0.130 ± 1.3 0.210 ± 1.4 0.041 ± 1.3 0.015 ± 1.3 0.061 ± 1.3 0.022 ± 1.3 Baseline Executive Function Score 0.171 ± 1.2 -0.122 ± 1.4 0.010 ± 1.4 0.046 ± 1.3 -0.001 ± 1.4 0.035 ± 1.3 Baseline Visual Function Score -0.055 ± 1.1 0.166 ± 1.1 0.019 ± 1.1 -0.006 ± 1.1 0.035 ± 1.1 0.017 ± 1.1 Time to Follow-up Cognitive Assessment, years Mean 2.69 ± 0.2 2.72 ± 0.2 2.75 ± 0.2 2.74 ± 0.2 2.74 ± 0.2 2.73 ± 0.2 Minimum 1.28 1.61 2.39 1.78 1.61 1.28 Maximum 3.68 3.74 4.20 3.40 4.2 4.20 Change in Cognitive Function after Follow-up Change in Global Cognitive Score 0.161 ± 1.0 0.186 ± 1.2 0.327 ± 1.1 0.366 ± 1.1 0.315 ± 1.1 0.283 ± 1.1 Change in Verbal Memory Score 0.075 ± 1.0 0.089 ± 1.2 0.331 ± 1.1 0.096 ± 1.2 0.221 ± 1.2 0.191 ± 1.1 Change in Executive Function Score -0.127 ± 0.6 -0.047 ± 0.7 -0.003 ± 0.7 -0.035 ± 0.7 -0.020 ± 0.7 -0.042 ± 0.7 Change in Visual Function Score 0.141 ± 0.8 0.268 ± 0.9 0.243 ± 0.8 0.345 ± 0.8 0.278 ± 0.8 0.249 ± 0.8 *All continuous variables are described by the mean ± SD BV AIT (N=452) ! 27! Table 3. Adjusted association of blood pressure measurements and cognitive change* Global Cognitive Change Verbal Memory Change Executive Function Change Visual Memory Change β (95% CI) P-value β (95% CI) P-value β (95% CI) P-value β (95% CI) P-value -0.007 -0.004 -0.001 -0.003 (-0.012, -0.001) (-0.0094, 0.001) (-0.004, 0.0039) (-0.007, 0.0006) -0.003 0.0001 -0.003 -0.0007 (-0.012, 0.006) (-0.0094, 0.009) (-0.009, 0.003) (-0.007, 0.006) -0.011 -0.008 0.001 -0.006 (-0.018, -0.003) (-0.0157, -0.0002) (-0.004, 0.006) (-0.011, -0.0005) -0.003 -0.002 -0.003 -0.0005 (-0.013, 0.006) (-0.012, 0.008) (-0.009, 0.004) (-0.008, 0.007) -0.003 -0.004 0.00003 -0.002 (-0.016, 0.010) (-0.016, 0.009) (-0.008, 0.008) (-0.011, 0.007) 0.094 0.834 0.032 0.897 0.668 *All regression models were adjusted for baseline cognitive score, age, race, gender, and trial. The β coefficient unit is defined as change in cognitive score per 1 mmHg increase in blood pressure Mean SBP 0.013 0.146 0.683 Mean DBP 0.495 0.978 0.295 Std. Dev. Of DBP 0.629 0.577 0.994 Mean Pulse Pressure 0.004 0.043 0.776 Std. Dev. Of SBP 0.492 0.718 0.428 ! 28! Table 4. Adjusted association of blood pressure measurements and cognitive change stratified by gender* Men β (95% CI) P-value β (95% CI) P-value β (95% CI) P-value β (95% CI) P-value -0.0005 -0.002 0.0003 -0.002 (-0.011, 0.010) (-0.011, 0.008) (-0.006, 0.007) (-0.010, 0.005) 0.0009 -0.003 0.005 -0.006 (-0.012, 0.014) (-0.016, 0.009) (-0.003, 0.014) (-0.016, 0.004) Women β (95% CI) P-value β (95% CI) P-value β (95% CI) P-value β (95% CI) P-value -0.009 -0.005 -0.001 -0.004 (-0.015, -0.003) (-0.011, 0.001) (-0.005, 0.003) (-0.008, 0.001) -0.015 -0.009 -0.001 -0.006 (-0.024, -0.007) (-0.018, -0.0004) (-0.007, 0.005) (-0.012, 0.001) Global Cognitive Change Verbal Memory Change Executive Function Change Visual Memory Change Mean SBP 0.006 0.130 0.614 0.123 *All regression models were adjusted for baseline cognitive score, age, race, and trial. The β coefficient unit is defined as change in cognitive score per 1 mmHg increase in blood pressure Mean Pulse Pressure 0.001 0.041 0.758 0.080 Mean Pulse Pressure 0.897 0.635 0.224 0.246 Mean SBP 0.920 0.729 0.940 0.535 ! 29! Table 5. Adjusted association between antihypertensive medication and cognitive change, including SBP* β (95% CI) P-value β (95% CI) P-value β (95% CI) P-value β (95% CI) P-value 0.294 0.392 0.091 0.209 (-0.282, 0.870) (-0.175, 0.958) (-0.292, 0.474) (-0.200, 0.617) 0.811 0.657 0.271 0.298 (0.225, 1.396) (0.080, 1.233) (-0.119, 0.661) (-0.118, 0.714) 0.171 0.211 0.289 0.139 (-0.470, 0.813) (-0.420, 0.842) (-0.137, 0.715) (-0.316, 0.593) 0.055 0.072 -0.006 0.054 (-0.106, 0.216) (-0.086, 0.231) (-0.113, 0.102) (-0.062, 0.169) -0.052 0.092 -0.073 0.010 (-0.276, 0.172) (-0.129, 0.313) (-0.222, 0.076) (-0.150, 0.170) -0.113 -0.084 -0.086 0.010 (-0.301, 0.075) (-0.269, 0.101) (-0.211, 0.039) (-0.125, 0.145) 0.056 0.023 -0.036 0.024 (-0.150, 0.262) (-0.180, 0.226) (-0.173, 0.100) (-0.123, 0.172) 0.168 0.134 -0.024 0.079 (0.023, 0.313) (-0.009, 0.276) (-0.120, 0.072) (-0.025, 0.182) 0.38 0.18 Alpha Blockers 0.64 0.18 Central Agonists 0.01 0.03 0.17 Global Cognitive Change Verbal Memory Change Executive Function Change 0.32 Calcium Channel Blockers 0.60 0.82 0.60 Combined Alpha/Beta Blockers 0.60 0.51 0.18 ACE Inhibitors 0.50 0.37 0.92 Visual Memory Change 0.32 0.16 0.55 0.36 0.91 0.88 0.75 0.14 *All regression models were adjusted for baseline cognitive score, age, race, gender, trial, and SBP. The β coefficient unit is defined as change in cognitive score per 1 mmHg increase in blood pressure Diuretics 0.02 0.07 0.63 ARBs 0.65 0.41 0.33 Beta Blockers 0.24 ! 30! Table 6. Adjusted association between antihypertensive medication and cognitive change, not including SBP* β (95% CI) P-value β (95% CI) P-value β (95% CI) P-value β (95% CI) P-value 0.290 0.391 0.090 0.207 (-0.287, 0.867) (-0.177, 0.958) (-0.293, 0.473) (-0.202, 0.615) 0.779 0.638 0.267 0.283 (0.192, 1.365) (0.062, 1.214) (-0.122, 0.657) (-0.133, 0.699) 0.126 0.182 0.284 0.116 (-0.516, 0.768) (-0.448, 0.813) (-0.142, 0.709) (-0.339, 0.570) 0.007 0.043 -0.010 0.030 (-0.150, 0.164) (-0.112, 0.197) (-0.115, 0.094) (-0.083, 0.143) -0.106 0.056 -0.076 -0.018 (-0.326, 0.114) (-0.160, 0.272) (-0.222, 0.069) (-0.175, 0.138) -0.151 -0.105 -0.088 -0.010 (-0.336, 0.035) (-0.287, 0.078) (-0.211, 0.035) (-0.143, 0.123) 0.018 0.001 -0.040 0.005 (-0.187, 0.222) (-0.200, 0.202) (-0.175, 0.096) (-0.141, 0.151) 0.111 0.098 -0.027 0.052 (-0.029, 0.251) (-0.040, 0.236) (-0.120, 0.066) (-0.049, 0.152) Global Cognitive Change Verbal Memory Change Executive Function Change Alpha Blockers 0.32 0.18 0.64 Central Agonists 0.01 0.03 0.18 Combined Alpha/Beta Blockers 0.70 0.57 0.19 ACE Inhibitors 0.93 0.59 0.85 ARBs 0.34 0.61 0.30 0.56 Beta Blockers 0.11 0.26 0.16 Calcium Channel Blockers 0.86 0.99 0.56 Visual Memory Change 0.32 0.18 0.62 0.61 0.82 0.88 0.95 0.31 *All regression models were adjusted for baseline cognitive score, age, race, gender, trial, and SBP. The β coefficient unit is defined as change in cognitive score per 1 mmHg increase in blood pressure Diuretics 0.12 0.16 ! 31! FIGURES *" *" #1.5" #1" #0.5" 0" 0.5" 1" 1.5" 2" 2.5" 3" Alpha& Blockers& Central& Agonists& Combined& Alpha/Beta& Blockers& ACE& Inhibitors& ARBs& Beta& Blockers& Calcium& Channel& Blockers& Diure<cs& Beta&Coefficient& An<hypertensive&Medica<on& <65"Years" of"Age" Ages"65" and"Older" Figure&1a.&Change"in"Global"Cogni>on:"Interac>on"of"An>hypertensive"medica>on"and" Age"Group."The"star"symbol"(*)"denotes"sta>s>cally"significant"interac>on"between" an>hypertensive"medica>on"and"age"group"(p<0.05)."The"lines"indicate"the"95%" confidence"interval." " ! 32! !1.5% !1% !0.5% 0% 0.5% 1% 1.5% 2% 2.5% Alpha% Blockers% Central% Agonists% Combined% Alpha/Beta% Blockers% ACE% Inhibitors% ARBs% Beta%Blockers%Calcium% Channel% Blockers% DiureBcs% Beta%Coefficient% An-hypertensive%Medica-on% <65%Years% of%Age% Ages%65% and%Older% Figure%1b.%Change%in%Verbal%CogniBon:%InteracBon%of%AnBhypertensive%medicaBon%and% Age%Group.%The%star%symbol%(*)%denotes%staBsBcally%significant%interacBon%between% anBhypertensive%medicaBon%and%age%group%(p<0.05).%The%lines%indicate%the%95%% confidence%interval.% % ! 33! !1.5% !1% !0.5% 0% 0.5% 1% 1.5% Alpha% Blockers% Central% Agonists% Combined% Alpha/Beta% Blockers% ACE% Inhibitors% ARBs% Beta%Blockers%Calcium% Channel% Blockers% DiureAcs% Beta%Coefficient% An-hypertensive%Medica-on% <65%Years% of%Age% Ages%65% and%Older% Figure%1c.%Change%in%ExecuAve%CogniAon:%InteracAon%of%AnAhypertensive%medicaAon%and% Age%Group.%The%star%symbol%(*)%denotes%staAsAcally%significant%interacAon%between% anAhypertensive%medicaAon%and%age%group%(p<0.05).%The%lines%indicate%the%95%% confidence%interval.% ! 34! ! !1.5% !1% !0.5% 0% 0.5% 1% 1.5% 2% Alpha% Blockers% Central% Agonists% Combined% Alpha/Beta% Blockers% ACE% Inhibitors% ARBs% Beta%Blockers%Calcium% Channel% Blockers% DiureBcs% Beta%Coefficient% An-hypertensive%Medica-on% <65%Years% of%Age% Ages%65% and%Older% Figure%1d.%Change%in%Visual%Memory:%InteracBon%of%AnBhypertensive%medicaBon%and%Age% Group.%The%star%symbol%(*)%denotes%staBsBcally%significant%interacBon%between% anBhypertensive%medicaBon%and%age%group%(p<0.05).%The%lines%indicate%the%95%% confidence%interval.%

Abstract (if available)

Abstract Background: Hypertension has been previously linked to cognitive decline in some populations. Based on this association, antihypertensive medications have been hypothesized to reduce cognitive decline. We evaluated the relationship of blood pressure and antihypertensive medications to cognitive change using data from three clinical trials conducted in the Atherosclerosis Research Unit at the University of Southern California: B-Vitamin Atherosclerosis Intervention Trial (BVAIT), Women’s Isoflavone Soy Health (WISH), and Early Versus Late Intervention Trial with Estradiol (ELITE). ❧ Methods: A total of 1334 patients (1057 postmenopausal women, 277 men), with an average (SD) age of 60.6 (8.0) were included in the secondary analysis of the three clinical trials. The dataset was analyzed using multiple linear regression, adjusting for age, baseline cognitive score, race, gender, and trial. Cognitive change scores (endpoint minus baseline) were calculated after 2.5 years of follow-up for global cognition, verbal memory, executive function, and visual memory. Different regression models were used to assess the association of these changes in cognition with systolic blood pressure (mean and SD measured over the trial), diastolic blood pressure (mean and SD), and pulse pressure. In the regression models evaluating the association of antihypertensive medication and changes in cognition, two separate analyses were performed, one with mean systolic blood pressure as a model covariate, and the other excluding systolic blood pressure. ❧ Results: Higher levels of systolic blood pressure and pulse pressure were statistically significantly associated with a decline in global cognition (p=0.013 and p=0.004, respectively). Pulse pressure was also significantly negatively associated with changes in verbal memory and visual memory (p=0.04 and p=0.03, respectively). In the models including SBP, diuretic use was significantly positively associated with change in global cognition (p=0.02)

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Asset Metadata

Creator Ye, Victor Mao (author)

Core Title Relationship of blood pressure and antihypertensive medications to cognitive change in the BVAIT, WISH, and ELITE clinical trials

School Keck School of Medicine

Degree Master of Science

Degree Program Applied Biostatistics and Epidemiology

Publication Date 07/17/2015

Defense Date 07/16/2015

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag antihypertensive medications,blood pressure,clinical trial,cognitive function,linear regression,OAI-PMH Harvest

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Mack, Wendy Jean (committee chair), Hodis, Howard (committee member), Karim, Roksana (committee member)

Creator Email victormye@gmail.com,vye@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c3-597305

Unique identifier UC11301292

Identifier etd-YeVictorMa-3628.pdf (filename),usctheses-c3-597305 (legacy record id)

Legacy Identifier etd-YeVictorMa-3628.pdf

Dmrecord 597305

Document Type Thesis

Format application/pdf (imt)

Rights Ye, Victor Mao

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA