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the Laboratory of Epidemiology, Demography and Biometry (M.H.F., R.P., L.J.L.), National Institute on Aging, National Institutes of Health, Bethesda, MD
General Preventive Medicine Residency Program (M.H.F.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
Institut für Medizinmanagement und Gesundheitswissenschaften (M.H.F.), Universitt Bayreuth, Germany
Pacific Health Research Institute (K.M., H.P., G.W.R., L.R.W.), Honolulu, HI
Honolulu-Asia Aging Study (K.M., H.P., G.W.R., L.R.W.), Kuakini Medical Center, Honolulu, HI
Department of Geriatric Medicine (K.M., H.P., G.W.R., L.R.W.), University of Hawaii, John A. Burns School of Medicine, Honolulu, HI
Honolulu Department of Veteran’s Affairs (G.W.R.), Honolulu, HI.
Abstract
Background and Purpose— Previous studies have shown that midlife systolic blood pressure (SBP) predicts late-life cognitive decline and incident dementia. This study explores whether this association is attributable to the pulsatile, ie, pulse pressure (PP), or the nonpulsatile component of blood pressure (BP).
Methods— Data are from the Honolulu-Asia Aging Study, a community-based study of Japanese American men. Midlife BP was measured in 1971 to 1974 and dementia assessment was conducted in late-life. The 2505 men who were dementia free in 1991 and had complete follow-up data were re-examined for incident dementia in 1994 to 1996 and 1997 to 1999. Their age ranged from 71 to 93 years. Survival analysis with age as the time scale was performed to estimate the risk (hazard ratio [HR] and 95% CI) for incident dementia associated with mid- and late-life tertiles of PP and mean arterial BP, as well as SBP and diastolic BP categories.
Results— Over a mean of 5.1 years of follow-up, 189 cases (7.5%) of incident Alzheimer disease or vascular dementia were identified. After adjustment for cerebrovascular risk factors, dementia was significantly associated with SBP (HR 1.77; 95% CI, 1.10 to 2.84, for SBP 140 mm Hg compared with SBP <120 mm Hg), but not with PP tertiles. Limiting the analysis to those never treated with antihypertensives, high levels of all 4 BP components were significantly associated with dementia. In models with 2 BP components, only SBP remained significant in both the total sample and the never-treated subgroup (HR 2.29; 95% CI, 1.23 to 4.25, for SBP 140 mm Hg in total sample), whereas PP was not significantly associated with the risk for dementia.
Conclusions— Midlife PP is not independently associated with dementia incidence. Midlife SBP is the strongest BP component predicting incident dementia.
Key Words: blood pressure dementia epidemiology
Introduction
Hypertension in midlife is a risk factor for cognitive decline and dementia.1–4 However, the potential damage on cognitive function by the different blood pressure (BP) components is less clear and has not been examined to the same extent as BP effects on cardiovascular disease (CVD) and total mortality.
High pulse pressure (PP), the difference between systolic BP (SBP) and diastolic BP (DBP), is a measure of the pulsatile component of BP and has been shown to increase the risk of CVD and total mortality.5–10 Potential physiological mechanisms of the pulsatile effects on vascular disease are currently under investigation. PP is positively correlated with arterial stiffness and therefore might be a marker for CVD.11
In many societies, both average SBP and PP increase with age, whereas average DBP decreases in older individuals.12,13 In the Framingham cohort, it has been shown that the strongest predictors for CVD change across the lifespan: from DBP to SBP and ultimately to PP.14 However, some recent studies did not show any significant additional role of PP beyond SBP alone in predicting CVD outcomes or total mortality.10,15,16
The association of midlife PP with cognitive function and dementia has not yet been examined. In the Kungsholmen Project, both low and high PP measured in late-life were found to be associated with increased incidence of dementia in women but not in men.17
Here, we examine the association of mid- and late-life PP on dementia incidence in a community-based cohort of Japanese American men.
Methods
Study Population
The Honolulu-Asia Aging Study (HAAS) began in 1991 as a continuation of the Honolulu Heart Program (HHP), a population-based cohort study of Japanese American men born between 1900 and 1919 and living on Oahu, Hawaii, when the study began in 1965.18 Participants were examined on 3 occasions between 1965 and 1974. Of 4768 survivors, 3734 (80%) participated in a fourth examination including dementia case-finding between 1991 and 1993. A further 2 examinations were subsequently carried out between 1994 and 1999, with participation rates among survivors of 84% and 90%, respectively. The study was approved by the Institutional Review Board of the Kuakini Medical Center and the Honolulu Department of Veterans Affairs, and written informed consent was given by the study participants. If subjects were unable to understand the consent form, approval was obtained from the next of kin.
Dementia Case-Finding
The multistep case-finding procedures to identify dementia cases started in 1991 and has been previously described.19,20 Briefly, the total cohort was screened with the 100-point Cognitive Abilities Screening Instrument (CASI),21 and a subset was selected to undergo further evaluation that included more detailed neuropsychologic testing, a neurologic examination, and a proxy interview. Those diagnosed with dementia received blood tests and brain imaging. Diagnoses were made in a consensus conference attended by the neurologist and 2 other study physicians with expertise in dementia. Dementia was diagnosed according to internationally accepted guidelines.22–24
BP Measurements
BP was measured at each examination taking the mean of 3 measurements made 5 minutes apart on the left arm while the subject was seated. Standard sphygmanometers and cuffs were used. DBP was recorded as the fifth phase. The analysis presented here is based on the BP measurements from examination 3 (midlife) and examination 4 (late-life). PP was defined as [SBP–DBP] and mean arterial pressure (MAP) as [DBP+ (PP)].
Confounding Variables and Covariates
We controlled for the potentially confounding effects of age and education and for cardiovascular risk factors. These included midlife alcohol consumption (none, <1 drink [13.2 g], 1 to 2 drinks, and 3 drinks/d) and smoking (never, former, current). The ankle brachial index, measured at the fourth examination, was dichotomized at 0.9; values below this point were interpreted as an indicator of generalized atherosclerosis.25 History of antihypertensive treatment was self-reported from exams 1 to 3 and obtained from the drug vials presented at examination 4. Diabetes was defined according to the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.26 Stroke and coronary heart disease history were assessed at baseline in 1965 and subsequently, via surveillance of hospital records that has been carried out through the entire follow-up period. Finally, we controlled for Apolipoprotein E (ApoE) 4 allele; participants with 1 or 2 copies of the ApoE 4 allele were considered 4 positive, and 4 negative otherwise. For all variables with missing data, a separate category within each variable was defined so that the observations remained in the analysis.
Statistical Analysis
Analytical Sample
There were 226 prevalent dementia cases identified at examination 4 and excluded from this analysis; thus, there were 3508 nondemented individuals for follow-up. Among those, 418 participants died between examination 4 and 5, 462 who declined participation, and 72 subjects with missing examination 3 BP measures. In total, there were 244 cases of incident dementia identified at exams 5 (132 cases) and 6 (112 cases), including 148 (64.2%) cases of Alzheimer disease (AD), 39 (16.0%) cases of vascular dementia (VaD), and 51 other dementia cases, including Parkinson disease and undertermined subtype. Given the heterogeneity of the other cases, we excluded them from the analysis. Therefore, the analytical sample included 2505 subjects who were not demented at examination 4, had at least 1 follow-up examination for dementia status, and had their BP measured at examination 3.
We grouped the analytical sample into tertiles of PP: <42 mm Hg, 42 to 51.5 mm Hg and >51.5 mm Hg and MAP (<94 mm Hg, 94 to 105 mm Hg and >105 mm Hg). SBP and DBP were classified according to the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7): Stage 2 (160/100 mm Hg) and stage 1 hypertension categories (140 to 159/90 to 99 mm Hg) were combined because of sample size.27 Correlations among the continuous measures of BP were estimated. Cohort characteristics were compared across the PP tertiles with age-adjusted linear models for continuous variables and logistic regression models for dichotomous outcomes. Cox-proportional hazard models using age as the time scale28 estimated the relative risk (95% CI) of incident dementia associated with each of the main BP components. Age of dementia onset was defined as the midpoint between the last examination without and the first examination with a dementia diagnosis. The proportional hazards assumption was tested based on Schoenfeld residuals.
If there was an association between PP and risk of dementia, one would expect an increasing risk with lower DBP, after adjusting for SBP. This was examined in multivariate models, adjusting for demographic and cardiovascular risk factors as described above. Because previous analyses on this cohort have shown differences in outcomes between those who were treated and not treated with antihypertensive medications,3 we conducted stratified analyses by ever (n=1066) and never (n=1439) antihypertensive treatment. We also examined whether the ApoE 4 modified the associations of interest. Finally, we examined whether there was differential survival from examination 3 to examination 4 by BP components; there was no evidence for this. The statistical analysis was performed using Stata 8 statistical software (STATA Corp).
Results
The 2505 participants were a mean age of 57.9 years at the midlife examination and 76.9 years old at first assessment of dementia, and after that were followed over a mean of 5.1 years. Compared with those who did not develop dementia, those that did were significantly older, had fewer years of schooling and consumed more alcohol in midlife (data not shown). Individuals with higher midlife PP were significantly older, had less school education, a lower CASI score, a higher BMI, and both higher SBP and higher DBP (Table 1). They were more likely to have been treated for hypertension, and more likely to have been diagnosed with diabetes, coronary heart disease (CHD), and stroke.
The various BP components were differently correlated, eg, SBP and PP had a correlation coefficient of 0.69 (Figure), and SBP and DBP of 0.58; the correlation between DBP and PP was only 0.08.
Correlation between midlife systolic blood pressure and pulse pressure (r2=0.69).
In the age-adjusted analyses of the total sample with single BP components in the model, SBP, DBP and MAP, and not PP, were significantly associated with incident dementia (Table 2). After adjusting for confounders, the association remained significant only for SBP, with a hazard ratio (HR) of 1.77 (95% CI, 1.10 to 2.84) for SBP 140 mm Hg compared with SBP <120 mm Hg. Among those who were never treated for hypertension, all 4 BP components were positively and significantly correlated with incident dementia, an association that did not significantly change after adjusting for cardiovascular confounders. For example, the HR was 2.66 (95% CI, 1.51 to 4.68) for SBP 140 mm Hg compared with SBP <120 mm Hg versus a HR of 1.81 (95% CI, 1.08 to 3.04) for the highest PP tertile compared with the lowest PP tertile (Table 2). There was no differential survival occurring before the assessment of dementia between the high PP and the high SBP group.
To test further whether there was an association between midlife PP and risk of dementia, we examined in a separate model whether there was an increasing risk for dementia with lower DBP after adjusting for SBP. Across SBP and DBP categories, highest risk was associated with higher SBP, but not lower DBP. Finally, in a separate model with 2 BP components, only midlife SBP remained significant after adjusting for PP, in both the total sample and in the subset of participants never treated for hypertension. There was no significant trend for higher or lower PP.
In models with a single BP component, results were similar for VaD and AD cases, but the relatively small number of VaD cases did not allow us to perform models with 2 BP components. Adding the baseline CASI score did not significantly change the results. There was no significant interaction between high SBP or high PP and the presence of the ApoE 4 allele. None of the analyses were significant when we performed them on late-life instead of midlife BP components.
Discussion
In this study, we examined the associations of 4 midlife BP components with incident dementia to distinguish between the pulsatile and the nonpulsatile BP effects. Midlife SBP was the best predictor, whereas midlife PP did not provide significant additional information about dementia risk beyond SBP alone. In fact, midlife DBP increased rather than decreased across PP tertiles, demonstrating that at that age, higher PP values were mainly explained by higher SBP and not lower DBP. Franklin et al have argued that only when both SBP and DBP were in the model and DBP was negatively associated with risk, would PP provide additional predictable power beyond SBP alone.29 In this study, there was no evidence for a negative association of DBP after adjustment for SBP. It is important to note that this analysis is based on midlife DBP, measured before DBP decreased because of arterial stiffness. Late-life BP were not associated with dementia outcomes at all. This may reflect changing BP levels that are associated with the dementia itself or the relatively short follow-up (average of 5.1 years) after the late-life BP assessments.
Correlations between the 4 BP components were similar to those found in the Established Populations for Epidemiologic Studies of the Elderly.30 However, when controlling for SBP in our study, a higher PP was not significantly associated with an increased risk for dementia.
It has been argued that PP is a marker of arterial stiffness and could even be a precursor of hypertension.31 The augmentation of central PP might lead to poor perfusion of the coronary vasculature during diastole, ventricular hypertrophy and dysfunction, increased ventricular oxygen consumption and ultimately myocardial infarction.5 However, it is unknown whether PP has significant direct or indirect effects on the cerebrovascular system and the brain. Secondary to brain vascular autoregulation and the distance to the aorta, it could be less affected by central pulsatile stress.
Advantages of our study are large sample size, exposure assessment in midlife, long follow-up time, and clinical dementia assessment. Several limitations should be acknowledged. First, PP was measured peripherally at the brachial artery. Especially in elderly subjects, this leads to an underestimation of central PP, which might be more closely related to vascular damage and disease.32 Our study was limited to old Japanese American men, and associations might be different in women, other ethnic groups or younger subjects. In this sample, the majority of participants had normal BP, and most individuals with severe hypertension were treated. Our analysis was limited to those individuals who survived and remained nondemented until examination 4 and continued follow-up until examination 5 or 6. Given the higher mortality of individuals with high BP leading to an increased loss to follow-up before and after the assessment of dementia, we cannot extrapolate our results to this high-risk group. However, loss of this group would lead to an underestimation of risk in our analysis, but given the nonselective survival between the high SBP and the high PP group it is unlikely to have changed the relation between SBP and PP.
Conclusion
In this study, the association of midlife PP with dementia incidence was mainly explained by the strong correlation of midlife PP and SBP; the addition of PP to SBP did not provide significant information beyond SBP alone. Late-life BP components were not associated with dementia.
Acknowledgments
This work was supported by the Intramural Research Program of the National Institutes of Health; National Institute on Aging, Grant Numbers: 1 U01 AG19349-01 and 5 R01 AG017155-04 and with resources from the Spark M. Matsunaga Veterans Affairs Medical Center, Honolulu, Hawaii.
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