Journal of the Neurological Sciences 283 (2009) 149–152

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Journal of the Neurological Sciences

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How much does hypertension affect cognition?Explained variance in cross-sectional analysis of non-demented community-dwellingindividuals in the SEARCH study

Stefan Knecht a,⁎,1, Heike Wersching a,1, Hubertus Lohmann a, Klaus Berger b, Erich Bernd Ringelstein a

a Department of Neurology, University of Muenster, Albert-Schweitzer-Strasse 33, 48149 Muenster, Germanyb Department of Epidemiology, University of Muenster, Domagkstrasse 3, 48149 Muenster, Germany

⁎ Corresponding author. Tel.: +49 251 8348195; fax:E-mail address: knecht@uni-muenster.de (S. Knecht

1 Both authors contributed equally to this work.

0022-510X/$ – see front matter © 2009 Elsevier B.V. Adoi:10.1016/j.jns.2009.02.362

a b s t r a c t

a r t i c l e i n f o

Keywords:

VascularHypertensionCognitionDementiaMicroangiopathySmall vessel

Vascular pathology impairs cognition and impaired cognition increases the risk of dementia. Hypertension isarguably the vascular risk factor that can be reverted best. Here we estimated the effect magnitude ofhypertension by determining the variance in cognition explained by systolic blood pressure (sBP) in non-demented community-dwelling individuals. We recruited 525 individuals (mean age 65, range 40–85)selected from the city registry of Muenster, Germany, measured cognitive performance with a comprehensivetest battery and assessed vascular risk based on glycosylated hemoglobin, serum cholesterol, high sensitiveC-reactive protein, body mass index, smoking pack years, and blood pressure. Including gender andeducation as well as the vascular risk factors, multiple linear regression analysis for different age groupsshowed that in midlife age groups systolic blood pressure explained up to 11% of the variance in cognitiveperformance. These findings suggest that in non-demented community-dwelling individuals hypertensionmay account for one tenth of cognitive impairment and thus for an increased risk for dementia.

© 2009 Elsevier B.V. All rights reserved.

1. Introduction

Dementia can be conceptualized as the final common pathway ofdiseases that disintegrate information processing in the brain. Theunderlying causes may differ (degenerative, vascular, or inflammatoryprocesses) and act simultaneously as well as cumulatively [1–4].Because dementia develops towards the end of life, delaying thedevelopment of dementia by 2 years might reduce the overallprevalence of dementia by 25%, if life expectancy remained thesame [5]. DeKosky and Marek proposed that a delay of 10 years wouldresult in virtual disappearance of dementia [6].

To reduce accumulation of brain damage over time, any disease-modifying intervention would have to start early—preferably beforebrain function starts to deteriorate to clinically manifest dementia [6].Not only mild cognitive impairment has been identified as a statepreceding dementia, but also cognitive performance among normalindividuals predicts progression to mild cognitive impairment [7].Therefore cognitive performance in normal individuals may even-tually become the primary focus for early interventions for preventionof dementia.

+49 45059.).

ll rights reserved.

Vascular brain disease seems particularly well suited for interven-tion because a large armamentarium for behavioral and pharmaceu-tical treatment and prevention is available. In this study, we focusedon hypertension since it is the most important and well documentedvascular risk factor that can easily be measured and controlled by avariety of established treatments. Hypertension is related to cognitivedecline in large population and patient based cohorts by way ofcardio- and cerebrovascular disease [8–15]. Recent evidence furtherindicates that the summation of hypertensive vascular brain lesions,white matter damage from small vessel disease, and typical Alzheimerpathology interact bi-directionally and jointly contribute to dementia,even when each type of lesion, on its own, would not be severeenough to cause dementia [16,17].

In a cross-sectional analysis in stroke-free community-dwellingindividuals we recently found a linear negative correlation betweensystolic blood pressure and cognition suggesting a continuum of braindamage beginning at high normal levels [18].

The effect magnitude of different hypertension grades on cognitionis largely unknown. Intervention trials examining the effect ofantihypertensive medication and cognition have provided mixedresults. Further the results from our cross-sectional study suggest thatthe relation between sBP and cognition may be age specific with therole of sBP declining with age. Thus, observational studies in late-lifeshowed that dementia was associated with low blood pressure[19,20]. In the Kungsholmen project participants with a sBP below

Table 1Characteristics of participants n=377.

Descriptive variable Mean SD Range

Age 64 6.62 44–82SBP 144 18.79 95–250BMI (kg/m2) 25 3.14 17–36Smoking (pack years) 12.6 14.85 0–70Serum cholesterol (mg/dl) 220.2 35.68 111–346Hba1c (%) 5.7 0.44 4.9–8.9hsCRP 0.27 0.43 0–4.29

%Female 54.6

150 S. Knecht et al. / Journal of the Neurological Sciences 283 (2009) 149–152

140mmHgweremore often diagnosed as demented than thosewith asBP above 140 mmHg [21,22].

Here we aimed to estimate the magnitude of the effect ofsystolic blood pressure on cognition and to determine whethereffects differ with age. For this estimation we cross-sectionallyanalyzed non-demented community-dwelling individuals exclud-ing individuals with dementia or depression.

2. Methods

The ongoing SEARCH-Health study (Systematic evaluation andalteration of risk factors for cognitive health) examines thecontribution of modifiable risk factors for cognitive aging incommunity-dwelling individuals. The research protocol has beenapproved by the local ethics committee. Participants from 40 to 85years of age are selected based only on dates of birth from thepopulation register of the city of Muenster, Germany (Table 1).They were invited to participate in the study by letter and recruitedafter giving informed consent. From a total of 2200 invited citizensso far 525 consented to participate. To reduce possible effects ofcomorbidity on the relation between blood pressure and cognitionwe restricted this analysis to non-demented and non-depressedcommunity-dwelling individuals. We therefore excluded partici-pants with scores below 25 points on the Mini-Mental StateExamination (MMSE) [23] and those with scores higher than 17 onthe Beck Depression Inventory (BDI) [24]. We further excluded

Table 2Neuropsychological tests.

Domain Test Scope

Memory Auditory Verbal Learning Test(AVLT; German version) [Helmstaedter et al. 2001]

Immediate verspanVerbal learninglearningShort and longretrievalRecognition

Digit Span (Wechsler Memory Scale-Revised(WMS-R; German Version) [Härting et al., 2000]

Immediate numWorking mem

Rey Complex Figure Test and recognition trial(RCFT) [Meyers and Meyers 1995]

Incident figuraMemory

Attention andexecutive functions

Colour–Word–Interference Test (CWIT, “StroopTest”) [Oswald and Fleischmann 1997]

Cognitive flexib

Digit Symbol Substitution Test (DSST)[Oswald and Fleischmann 1997]

Psychomotor sCognitive flexib

Trail-Making-Test (TMT) [Spreen and Strauss 2002] Cognitive speeCognitive flexibVisual search

Category and Letter Fluency [Aschenbrenner et al.,2001]

Semantic and pretrieval worki

Intellectual functions Boston Naming Test -Short form (BNT)[Morris et al., 1989; Kaplan et al., 2002]

Naming of com

RCFT-copy Constructional

participants with a history or imaging evidence of stroke, othersevere neurological conditions or intake of psychotropic medicationand patients suffering from atrial fibrillation. These exclusions left atotal of 377 community-dwelling individuals for the analyses. Allparticipants received a structured clinical face-to-face interview, aphysical examination by a trained study physician includinganthropometric measurements, blood sampling, and a comprehen-sive neuropsychological assessment.

2.1. Neuropsychological assessment

Trained technicians supervised by a clinical neuropsychologistconducted the neuropsychological assessment. The test battery wasdesigned to assess a full range of cognitive functions [25]. Tests andtheir particular neurocognitive scope are listed in Table 2.

To determine meaningful composite scores of cognitive domainswe performed a principal component analysis using the single testresults, followed by an oblique (Oblimin with Kaiser-normal-ization) rotation. The same test was not included in more thanone composite score. The resulting five factors of the principalcomponent analysis were z-transformed (mean score of 0 and astandard deviation of 1).

To obtain a measure for global cognitive performance, we usedthe sum of the single composite scores allowing for equal loadingof different cognitive domains.

2.2. Independent variables

Blood pressure was measured after a 20–40 min rest periodwhile subjects sat in an upright position. Three measurementswere taken from the left arm, one from the right arm. Bloodpressure values were then calculated from the average over the lasttwo measures of the left arm plus the measure from the right arm.Education was assessed as categorical variable (5 vs. 7 vs. 9 years ofsecondary school vs. tertiary education). Body mass index (BMI)was calculated from “body weight [kg]/(body height) [m]2”.Smoking pack years as continuous variable were calculated as “

(number of years smoking ⁎ number of cigarettes per day)/20”.Serum cholesterol, high sensitive CRP (hsCRP) and glycosylated

Test scores

bal AVLV-recall trial 1AVLT-recall trial 5

, slope of AVLT-cumulative score of recall trial 1–5

term AVLT-recall trial 6AVLT-recall trial 7AVLT-recognition trial 8

eric span WMS- digit span forwardory WMS- digit span backwardl Immediate recall

Delayed recallRecognition

ility CWIT-part 3, interference condition

peed Number of correctility symbols completedd TMT- part Aility TMT- part B

honologicalng memory

Number of correct words, letter S number of correct words, categoryanimals number of correct words, shifting categories: fruit–sport

mon objects Number of correct words

ability planing Number of points according to the scoring method

Fig. 1. Relation between age and cognitive performance in a healthy cohort of 377 community-dwelling individuals from the Muenster area in Germany. Please note that there is asteady decline of cognitive performance with age and that there is significant inter-individual variability.

151S. Knecht et al. / Journal of the Neurological Sciences 283 (2009) 149–152

hemoglobin A (HbA1c) values were analysed taking a non-fastingblood sample.

2.3. Statistical analyses

Multiple linear regression analysis models were used to testindependently the effect of age, gender, education and cardiovas-cular risk factors (systolic blood pressure, smoking pack years, BMI,serum cholesterol, hsCRP, HbA1c) on global cognitive performance.Variance was calculated as the square sum of the standardisedregression-coefficients of each covariant. The analyses were carriedout using SPSS version 15 [26].

3. Results

Global cognitive performance was found to steadily decreasewith age (Fig. 1).

Multiple regression analysis showed that 36% of variance in globalcognitive performance could be explained by identifiable factors(Table 3). These factors differed between age groups. Thus systolicblood pressure explained 8% of variance in global cognition in the agegroup 44–65 years (midlife) and b0.1% in late-life (age group 65–82 years). When dividing age by quartiles, variance explained bysystolic blood pressure was 7% for b61,11% for 61–64, b0.1% for 65–68,and b0.1% for N68 years of age.

Table 3Variance (β2) in global cognition explained by factors.

Age group Systolic bloodpressure

Education Gender Other vascular factors⁎

β β2 β β2 β β2 β2

All −0.123 0.015 0.433 0.187 0.129 0.016 0.132Midlife −0.283 0.080 0.474 0.225 0.047 0.002 0.080Late-life −0.024 b0.1 0.446 0.199 0.194 0.038 0.232

⁎age, smoking pack years, BMI, serum cholesterol, HbA1c, hsCRP.

4. Discussion

Explained variance is an indirect measure for effect magnitude.Direct measures can only be obtained from interventions. However, inthe present case explained variance provides important suggestiveevidence. First the present study showed that the effect magnitude forsystolic blood pressure on cognition amounted to one tenth ofvariance in individuals around 60 years of age. Second, effects differedmarkedly between age groups, i.e. from 11% of explained variance in61–65 to less than 0.1% in those older than 65 years of age.

The strengths of this study are the community-based design, thewide age range, the exclusion of depressed or demented individuals,the adjustment for potential confounders and the in-depth neurop-sychological testing. However, some methodological issues deservemention. First, data were obtained from cross-sectional observation.This introduces variability due to unrelated differences betweensubjects. We tried to minimize variability by setting inclusion criteriato obtain a homogenous sample and testing for confounders. Second,blood pressure in our cohort was measured only on the day ofexamination. Although we took care to have subjects rest and follow astandardized protocol, white coat hypertension is always a concern.However, if there had been a white coat effect in our cohort resultingin higher sBPmeasures, this would indicate that people can already becognitively impaired when they show high-normal sBP only understress—and presumably not outside the clinic. Further, no reliableinformation could be obtained on the history and duration of bloodpressure increase. Use of antihypertensive medication did not affectany of the correlations investigated. Missing information on durationof hypertension may have decreased the sensitivity in this study. Dataon the duration of increased sBP would have been particularly helpfulfor late-life individuals who are likely to have longer and morevariable duration of sBP increase.

Why did sBP explain less cognitive variance in late life than inmidlife? It has been suggested that in late-life because of greateratherosclerotic blood flow resistance, individuals may requireincreased sBP tomaintain cerebral perfusion pressurewhereas normal

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sBP would lead to insufficient cerebral blood supply [19,27]. Thisconcept was derived from observations in cohorts in which partici-pants up to 101 years of age were included, and in which dementiawas not an exclusion criterion [21]. Here, low blood pressure mayadditionally be the consequence rather than the cause of neurode-generation, because neurodegeneration may decrease cognition andsBP in parallel [13,28,29]. Thus, in late-life cohorts–like in our late-lifesubgroup–different and partially counterpoising factors may compli-cate the relation between sBP and cognition.

What does one tenth of variance explained by systolic bloodpressure tell us? For comparison education may be considered. In ourmodel it explained around 20% of variance in cognitive performance.Education has been found to determine age of onset of dementia [30].We assume that blood pressure will also affect latency until onset ofdementia. However, only follow-up examination can determine theexact relation between sBP and time until onset of dementia.

Intervention trials so far have included patients from a wide agerange and provided mixed results. Clinical trials showed thatantihypertensive treatment in non-demented elderly subjects with aresting systolic blood pressure of more than 160 mmHg reduced theincidence of subsequent dementia. Thus after 4 years there were onlyhalf as many cases of dementia in the treatment as compared to theplacebo group [31–33]. Conversely, other antihypertensive interven-tion studies did not reveal significant effects on cognition [34–36].However, problems were patients lost to follow-up, active medicationgiven to placebo patients as their blood pressure exceeded per-setvalues and insensitive cognitive testing [37].

We do not know if efficacy of interventions differed with age inthese trials because they were not designed accordingly. The presentevidence would suggest that antihypertensive treatment for preven-tion of cognitive decline may be most effective in midlife.

Role of the funding source

The project is supported by several public funding sources, whichhave no involvement in study design, in the collection, analysis, andinterpretation of data, in the writing of the report or in the decision tosubmit the paper for publication.

Acknowledgments

This work was supported by the BMBF-Competence NetworkMednet Atrial Fibrillation, BMBF-Research Consortium, DeutscheForschungsgemeinschaft, Volkswagen Stiftung, the European Com-mission (MRTN), and the Neuromedical Foundation Muenster. Wethank the city of Münster, Germany for supporting us in recruitingcommunity-dwelling elderly citizens.

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