AbstractThis investigation examined cross-sectional and longitudinal relations, both linear and nonlinear, of blood
pressure (BP) and its interaction with demographic and lifestyle variables to a broad spectrum of cognitive functions.
Eight hundred forty-seven participants (503 men and 344 women) from the Baltimore Longitudinal Study of Aging
completed tests of verbal and nonverbal memory, attention, perceptuo-motor speed, executive functions, and
confrontation naming, and clinical assessment of BP on 1 to 7 occasions over 11 years. Mixed-effects regression models,
adjusted for age, education, gender, alcohol consumption, smoking status, depression scores, and use of antihypertensive
medications, revealed nonlinear relations of systolic BP with longitudinal change on tests of nonverbal memory and
confrontation naming; cognitive decline was apparent among older (80 years) individuals with higher systolic BP.
Cross-sectional findings, across testing sessions, indicated moderated U- and J-shaped relations between BP and
cognitive function. Both high and low diastolic BP were associated with poorer performance on tests of executive
function and confrontation naming among less-educated persons; with tests of perceptuo-motor speed and confrontation
naming among nonmedicated (antihypertensives) individuals; and with executive function among older individuals.
Cross-sectional linear relations included higher systolic BP and poorer nonverbal memory in nondrinkers, and higher
diastolic BP and poorer working memory among less-educated individuals. Results indicate that cross-sectional and
longitudinal relations of BP to cognitive function are predominantly nonlinear and moderated by age, education, and
antihypertensive medications. Careful monitoring and treatment of both high and low BP levels may be critical to the
preservation of cognitive function. (Hypertension. 2005;45:374-379.)
Key Words: blood pressure hypertension cognitive function neuropsychology
Received August 30, 2004; first decision September 22, 2004; revision accepted January 11, 2005.
From Department of Psychology (S.R.W., P.P.G.), University of Maryland, Baltimore County, Baltimore, Md; and Laboratory of Personality and
Cognition (S.R.W., P.P.G., J.F.T., A.B.Z.), Gerontology Research Center, National Institute on Aging, Baltimore, Md.
Correspondence to Shari R. Waldstein, PhD, Department of Psychology, University of Maryland, Baltimore County, 1000 Hilltop Cir, Baltimore, MD
21250. E-mail waldstei@umbc.edu
2005 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org DOI: 10.1161/01.HYP.0000156744.44218.74
374
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Waldstein et al Blood Pressure and Cognitive Function 375
TABLE 1. Characteristics of Study Sample at First BLSA learning slope, short and long free recall), and the Benton Visual
Visit (n847) Retention Test (BVRT) (n796) evaluated nonverbal memory. Trail
Making Test Parts A and B (n847) assessed attention, perceptuo-
Variable Mean SD Minimum Maximum motor speed, visuomotor scanning, and mental flexibility (an executive
Age, y 70.6 (8.5) 39 96 function). Letter Fluency (n847) and Category Fluency (n847)
examined phonetic and semantic association fluency, respectively, and
Education, y 16.6 (2.7) 4 24
executive function. The Boston Naming Test (n847) assessed con-
Gender, % male 59 frontation naming (ie, word finding).
Race, % white 84.2
Alcohol use* 0 (2) 0 11
Blood Pressure
At each study visit, BP was measured in the morning by trained
Ever smoker, % 59 nursing staff at least 90 minutes after a light breakfast. After a
Antihypertensive 33.4 5-minute rest period, a mercury sphygmomanometer with an
medication, % appropriate-sized occluding cuff was used to measure BP once from
CES-D 6.5 (6.3) 0 45 each arm while patients sat in an upright position. Systolic BP and
diastolic BP were determined by Kortokoff phase I and phase V,
SBP, mm Hg 138.7 (20.0) 90 220 respectively. The 2 measurements were averaged for data analysis.
DBP, mm Hg 82.0 (10.9) 50 115
*1 unit of alcohol use corresponds to 1.4 drinks per week. Data presented Covariates
for alcohol use are the median and interquartile range Age and education were assessed in years. Alcohol use was quanti-
CES-D indicates Center for Epidemiological Studies Depression Scale; DBP, fied categorically according to types and numbers of drinks (one
diastolic blood pressure; SBP, systolic blood pressure. drink12 ounces beer, 4 to 5 ounces of wine, or 2 ounces of spirits)
consumed per week. Categorical ratings obtained at each visit were
added to yield a single score. Smoking status was defined as
neuropsychological test battery. The present analyses were limited to never/ever. Use of antihypertensive medications was collapsed
visits occurring on or after January 1, 1986, resulting in 928 into a single yes/no category. Depressive symptomatology was
participants (ages 39 to 96) available for potential inclusion. We examined using the Center for Epidemiological Studies Depression
excluded persons with dementia (n34;11), cerebrovascular diseases Scale (CES-D).13
including stroke (n55), and renal failure (n1) across all assess-
ment visits. Eight hundred forty-seven participants (503 men and 344
women) met study criteria. Baseline sample characteristics are Data Analyses
presented in Table 1. The total number of participants per visit is Mixed-effects regression analyses were conducted to examine cross-
listed in Table 2. Because the BLSA uses continuous enrollment sectional (collapsed across all testing sessions) and longitudinal
procedures, participants have different numbers of visits, in part, relations of BP to cognitive function. Mixed-effects models are the
because of differential start times in the project. Follow times are preferred method of analyzing data with different numbers of
also variable. Participants had an average of 2.7 (SD1.5) visits, and repeated outcome measurements that are obtained at nonuniform
the average time between visits was 2.32 (SD0.8) years. Number intervals.14,15 These analyses model change over time by computing
of follow-up visits (mean, SD, range) by 10-year increments in age rate of change for each participant based on all data for that
are as follows: 50 to 60 years (2.80, 1.79, 1 to 6); 60 to 70 years individual. The model computes rate of change for the entire group
(2.82, 1.44, 1 to 6); 70 to 80 years (2.93, 1.54, 1 to 7); 80 to 90 years and then computes each individuals deviation from the group rate.
(2.18, 1.31, 1 to 6); and 90 to 100 years (1.33, 0.71, 1 to 3). Over the Mixed-effects models evaluate the unique effects of individual
course of the investigation, 11 participants died and 7 formally predictors adjusted for all other predictors in the model, includes
withdrew from the investigation; therefore, rate of attrition was 2%. both fixed and random effects, accounts for the correlation among
Institutional Review Board approval was obtained from the Johns repeated measurements on the same participant, and is unaffected by
Hopkins Bayview Medical Center for the investigation and the randomly missing data. In the present instance, it permits analysis of
University of Maryland, Baltimore County for the current data the rate of change in cognitive performance as a function of rate of
analyses. All participants provided written informed consent. change in BP (and all relevant covariates).
To maximize the unique information provided by each neuropsycho-
Neuropsychological Tests logical test, separate models were examined for each test as a dependent
At each study visit, standard neuropsychological tests were administered measure. Separate models were constructed for systolic BP and for
by extensively trained psychometricians.12 The sample sizes that follow diastolic BP. Both linear and quadratic (squared) effects were included
each test indicate respective reductions in sample size because of in each model. Baseline age, years of education, alcohol consumption,
test-specific missing data. The Digits Forward and Backward portions of depression scores, and time interval between assessments were treated
the Wechsler Adult Intelligence ScaleRevised (n733) assessed atten- as continuous covariates, and gender, antihypertensive medications, and
tion and working memory. The California Verbal Learning Test smoking status were treated as categorical covariates. Baseline age
(n689) measured verbal learning and memory (ie, List A total, indexes cross-sectional age differences, whereas time interval (ie, years
since baseline testing for each administration of the dependent measure)
indexes longitudinal age change.
TABLE 2. Sample Size by Number of Repeat Administrations All main effects and 2-way interactions were entered into each
No. of Repeat model in addition to the 3-way interactions of baseline age, linear
Administrations No. (% of Sample) BP, and time interval, and baseline age, quadratic BP, and time
interval. A backward elimination procedure was used in which
2 595 (70.2) nonsignificant interaction terms (P0.05) were eliminated from
3 438 (51.7) each model until a final solution was reached. Significant effects of
BP on longitudinal rate of cognitive change are indicated by
4 296 (34.9)
significant interactions of BP and time interval (or the 3-way
5 106 (12.5) interaction of age, BP, and time interval). Cross-sectional relations of
6 26 (3.1) BP and cognition (mean cognitive test scores collapsed across all
testing sessions) are revealed by BP main effects or interactions of
7 3 (0.004)
BP with demographic or lifestyle covariates.
Statistical analyses were conducted using SAS versions 6.12 and either high or low BP performed more poorly than those with
8.02 (Cary, NC). Graphs were created to visualize the significant mid-range BP (a U-shaped relation). For Trail Making B, a
relations using the prototypical values of the predictors.14 In the J-shaped relation revealed that among less educated persons,
reporting of results in text, significant interaction effects were
presumed to qualify main effects and significant effects of quadratic
those with high or low BP performed more poorly than those
BP were presumed to qualify those that involved linear BP. with mid-range BP, but particularly among those with high BP.
On both tests, individuals with higher levels of education
Results performed similarly irrespective of BP level.
Significant main and interactive effects of systolic and Significant interactive effects of quadratic diastolic BP and
diastolic BP with respect to the cognitive outcomes are use of antihypertensive medication were noted for the Boston
listed in Tables 3 and 4, respectively. Longitudinal find- Naming Test and Trail Making A. For Boston Naming,
ings were as follows. First, a significant 3-way interaction individuals who were not medicated displayed poorer perfor-
of baseline age, time interval, and quadratic systolic BP mance at both high and low BP levels (as compared with
was noted for the BVRT and the Boston Naming Test. mid-range); medicated individuals performed similarly at all
Graphic depiction of predicted parameters associated with levels of BP. For Trail Making A, a J-shaped relation was
these interactions (Figure) indicates, for the BVRT, that noted such that among nonmedicated persons, those with
among younger individuals (age 60 at baseline), those with higher BP displayed poorer performance than those with
mid-range BP; those with lower BP also displayed poorer
higher systolic BP made more errors on the BVRT than
performance than those with mid-range BP, although to a
those with normal BP but improved over time (ie, practice
lesser extent than persons with high BP.
effects). In contrast, among older individuals (age 80 at
Significant interactive effects of quadratic diastolic BP and
baseline), those with higher systolic BP declined in BVRT
baseline age were identified for Letter Fluency. At younger ages,
performance over time. On the Boston Naming Test,
higher diastolic BP levels conferred a slight performance advan-
younger individuals (age 60 at baseline) with higher tage. At older ages, those with high and low diastolic BP
systolic BP performed more poorly than those with lower performed more poorly than those with mid-range BP. The
systolic BP across testing sessions. For older individuals effect was more pronounced for those with higher BP.
(age 80 at baseline), those with higher systolic BP declined Finally, results revealed 2 significant, cross-sectional, and
in performance over time. linear relations of BP to cognitive function that were not
Next, several cross-sectional findings (across all testing qualified by quadratic effects (Figure II). An interaction of
sessions) were noted. Significant linear relations of BP to systolic BP and alcohol consumption was found for the
cognitive function were almost always qualified by nonlinear BVRT. Higher systolic BP was associated with more BVRT
(ie, quadratic) effects (please see http://hyper.ahajournals.org errors among nondrinkers than individuals who reported
for Figure I depicting all quadratic associations). Specifically, drinking alcohol. An interaction of diastolic BP and education
significant nonlinear relations of diastolic BP and education for Digits Backward revealed that less-educated individuals
were found for the Boston Naming Test and Trail Making B. For with higher BP performed worse on this test than their more
Boston Naming, individuals with lower levels of education and educated counterparts.
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Waldstein et al Blood Pressure and Cognitive Function 377
Longitudinal rate of change in cognitive performance as a function of age and systolic BP for the Benton Visual Retention Test (panel 1)
and the Boston Naming Test (panel 2). Color-coding depicts relatively higher (red) and lower (blue) test scores.
implications for quality of life and daily functioning, and exacerbated in the presence of higher BP. In addition, and
therefore may be clinically meaningful. similar to previous work, we noted that higher diastolic BP
Finally, effect modification was also noted with respect to was associated with poorer performance on a test of working
linear BP. Higher levels of systolic BP were associated with memory among less educated individuals
poorer performance on a test of nonverbal memory among Younger age, higher levels of education, use of antihyper-
nondrinkers. Less alcohol consumption has previously been tensive medications, and some alcohol use may protect
associated with poorer cognitive function,20 a risk that may be against the neurobiological consequences of high BP,3 and
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Waldstein et al Blood Pressure and Cognitive Function 379
thereby cognitive performance. Relevant mechanisms include treatment can prevent cognitive decline and dementia.23 In
enhanced white matter disease, small silent infarctions, brain that regard, results of further clinical trials will be critical.
atrophy, and atherosclerosis in the large cerebral and cervicoce-
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Naming Test and Trail Making B; quadratic diastolic BP and antihypertensive medication
use for the Boston Naming Test and Trail Making A; quadratic diastolic BP and age for
Letter Fluency. Higher scores indicate worse performance on Trail Making A and B. All
Figure II: Interaction of linear systolic BP and alcohol consumption for the Benton Visual
Retention Test, and linear diastolic BP and education for Digits Backward. Results are
14.50 140
Predicted Boston Naming score
14.00 120
13.75 110
13.50 100
13.25 90
13.00 80
60 65 70 75 80 85 90 95 100 105 110 60 65 70 75 80 85 90 95 100 105 110
Diastolic blood pressure Diastolic blood pressure
15.00 48
Medication Medication
No medication No medication
14.75 47
14.50 46
Predicted Boston Naming score
14.25 45
14.00 44
13.75 43
13.50 42
13.25 41
13.00 40
60 65 70 75 80 85 90 95 100 105 110 60 65 70 75 80 85 90 95 100 105 110
Diastolic blood pressure Diastolic blood pressure
18
60 yo
70 yo
80 yo
17
Predicted Letter Fluency score
16
15
14
13
12
60 65 70 75 80 85 90 95 100 105 110
Systolic blood pressure
20 8.0
No drinking 12 years education
Moderate drinking 16 years education
18
Predicted Benton Visual Retention Test errors
7.5
16
10 6.5
8
6.0
6
4
5.5
2
0 5.0
110 120 130 140 150 160 170 180 190 200 210 60 65 70 75 80 85 90 95 100
Systolic blood pressure Diastolic blood pressure
Nonlinear Relations of Blood Pressure to Cognitive Function: The Baltimore Longitudinal
Study of Aging
Shari R. Waldstein, Paul P. Giggey, Julian F. Thayer and Alan B. Zonderman
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