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Hypertension and Cognitive Impairment: Kahrizak Elderly Study
International Journal of Gerontology 5 (2011) 212e216
Contents lists available at SciVerse ScienceDirect
International Journal of Gerontology journal homepage: www.ijge-online.com
Original Article
Hypertension and Cognitive Impairment: Kahrizak Elderly Studyq Farshad Sharifi 1, 2, Mona Hedayat 3, Hossein Fakhrzadeh 1 *, Mohammad Jafar Mahmoudi 3, Maryam Ghaderpanahi 1, Mojde Mirarefin 1, Yaser Tajalizadekhoob 1, Zohre Badamchizade 4, Bagher Larijani 4 1
Elderly Health Research Center, Endocrinology and Metabolism Research Institute,Tehran University of Medical Sciences, 2 Research and Education Affairs, Kahrizak Charity Foundation, 3 Division of Cardiology, Department of Internal Medicine, School of Medicine, Tehran University of Medical Sciences, 4 Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran
a r t i c l e i n f o
s u m m a r y
Article history: Received 23 August 2010 Received in revised form 3 March 2011 Accepted 9 March 2011 Available online 5 January 2012
Background: Dementia is a major cause of cognitive impairment in the elderly. Numerous studies have investigated the association between hypertension and cognitive disorders in elderly persons, with inconsistent results. The goal of the study was to investigate the association between hypertension at baseline and cognitive impairment after 24 months’ follow-up in the elderly residents of the Kahrizak Charity Foundation (KCF) in Iran. Methods: There were 211 elderly residents of KCF aged 65 years or older with a Mini Mental State Examination (MMSE) score greater than 10. The MMSE score was assessed at the end of the study. Blood pressure was measured in all of the participants at the beginning of study. Data were compared between hypertensive and normotensive patients. Results: A total of 63.5% of patients had impaired cognition (61% and 63.9% in normotensive and hypertensive patients, respectively). Cross sectional analysis of baseline data in a multiple regression model has revealed that diastolic high blood pressure was a risk factor for cognitive impairment even after adjustment for confounding factors (odds ratio: 2.42, 95% CI: 1.01-5.78). In the cohort follow-up analysis, the relative risk of cognitive impairment for patients aged 75 years or older with final diagnosis of hypertension was 0.72 (0.57e0.92). The relative risk of patients with systolic high blood pressure and history of hypertension was 19% and 10%, respectively, which was lower than normotensive group but such differences were not significant. Conclusions: High systolic blood pressure in very old persons may have a preventive effect on development and progression of cognitive impairment. However, diastolic high blood pressure perhaps may be a risk factor for cognitive impairment in elderly persons. Copyright Ó 2011, Taiwan Society of Geriatric Emergency & Critical Care Medicine. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: cognitive impairment, diastolic high blood pressure, elderly, systolic high blood pressure
1. Introduction Dementia is one of the most disabling neurologic disorders of aging populations. It is a progressive disorder characterized by impairment of memory and at least one of the intellectual functions of the brain severe enough to interfere with daily activities and independence1. The burden of the disease tends to increase in parallel with increased life expectancy, and by 2040 it will account for 81.1 million cases worldwide2. Symptomatic therapy currently q All contributing authors declare no conflict of interest. * Correspondence to: Dr Hossein Fakhrzadeh, Elderly Health Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, 5th floor, Dr Shareeati Hospital, North Karegar Avenue, Tehran, Iran. E-mail address: [email protected] (H. Fakhrzadeh).
is the mainstay of disease management and no curative strategies are available. The progressive and irreversible nature of the disease sheds light on the importance of identification and primary prevention of risk factors3,4. Alzheimer disease (AD) and vascular dementia (VaD) contribute to approximately 60% and 26%, respectively, of all dementia syndromes5. Numerous longitudinal and cross-sectional studies have demonstrated the association between cardiovascular disease (CVD) risk factors, i.e., diabetes mellitus, hypertension, dyslipidemia, obesity, and smoking, with AD and VaD as the leading causes of dementia6e10. Therefore, by taking appropriate measures aimed at prevention, early detection, and treatment of CVD risk factors, cognitive decline will no longer be an inevitable component of aging. Hypertension is a common disorder among elderly adults and its prevalence tends to rise as the population ages. Hypertension is
1873-9598/$ e see front matter Copyright Ó 2011, Taiwan Society of Geriatric Emergency & Critical Care Medicine. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.ijge.2011.12.001
Hypertension and Cognitive Impairment
diagnosed in approximately 65% of adults 65 years and older11. VaD is a heterogeneous disorder including multi-infarct dementia, strategic infarct dementia, and subcortical ischemic dementia12. The common features among these clinical syndromes are atherothrombosis or cardiogenic embolism in large- and medium-sized vessels and hypertensive/arteriosclerotic angiopathy in small vessels4,12. AD traditionally has been regarded as a primary neurodegenerative disorder. However, the role of vasculopathy and the contribution of vascular risk factors to the development of AD have received much attention in recent years13e15. Therefore, regardless of the underlying etiologies, controlling blood pressure as a pharmacologically modifiable risk factor might prevent dementia or slow the progression of cognitive decline. Some epidemiologic studies have addressed the relationship between blood pressure, cognitive function, and dementia. However, marked discrepancies exist between the results of crosssectional and longitudinal studies. Furthermore, apparent inconsistencies exist in the results of similarly designed population-based observational studies. Positive correlation, negative correlation, U-shaped correlation, J-shaped correlation, and no association between blood pressure and cognition has been reported7,8,10. The goal of the current study is to investigate the association between blood pressure at the beginning of the study and cognitive impairment after 24 months in elderly patients. 2. Materials and methods 2.1. Participants All participants were 65 years or older and lived in KCF. Patients with end-stage liver, cardiac, and renal diseases, Parkinson disease, and severe dementia (defined as obtaining scores 10 on the MiniMental State Examination [MMSE])16 were excluded. Informed consent was obtained from all participants and also their firstdegree relatives if their MMSE score was less than 22. The study protocol was approved by the ethics committee (PM184/10/0123 K, this Code represent the Persian calendar day with related official numbers) in the Endocrinology and Metabolism Research Center of Tehran University of Medical Sciences. 2.2. Data collection 2.2.1. Demographic and medical information Demographic characteristics including age, sex, education level, and smoking status and previous medical diagnosis including the history of diabetes mellitus, hypertension, cardiovascular disease (CVD), and stroke were obtained from participants’ medical records. 2.2.2. Medical examination At the beginning of the study, blood pressure, height, and weight were measured by trained nurses or research assistants. Blood pressure measurements were performed by a tonometer automatic sphygmomanometer (Omron 7, Tokyo, Japan) which was calibrated by a mercury sphygmomanometer after every 100 measurements, according to the guidelines of The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) with the participant in a recumbent position after 5 minutes of rest; the average of three measurements was recorded. Participants were advised to avoid alcohol, cigarette smoking, caffeinated beverages, and exercise for at least 30 minutes before blood pressure measurement. An average of three measurements was recorded at 3-day intervals during 1 week. A history of hypertension was assumed for any participant who was under treatment with antihypertensive drugs or if he or she
213
had a history of hypertension in his or her medical documents. With this guideline, the systolic high blood pressure was defined as systolic blood pressure was 140 mmHg; diastolic high blood pressure was defined as diastolic blood pressure 90 mmHg; a final diagnosis of hypertension was assumed if either systolic or diastolic high blood pressure or a history of hypertension existed. The accuracy of height and weight measurements was 0.5 cm and 0.1 kg, respectively. The body mass index (BMI) was calculated as weight (kg) divided by height squared (m2). 2.2.3. Laboratory tests Twelve-hour overnight fasting blood samples were collected to determine serum glucose. Serum fasting glucose was measured by an enzymatic colorimetric technique in the fasting condition (ParsAzmun Kits, Tehran, Iran). In study participants, diabetes was defined according to American Diabetes Association criteria as diagnosis of the condition in the participants’ medical records and/ or current use of hypoglycemic drugs and insulin and/or fasting serum glucose 126 mg/dL. 2.2.4. Neuropsychologic tests At baseline and at the end of the study, the Persian-adapted MMSE questionnaire was used to assess cognitive status. MMSE was assessed twice in 2 days during a week; the mean MMSE score was calculated for each participant. The Persian standardized version of MMSE was administered16. This consists of 11 questions assessing a broad range of cognitive functions including orientation, recall, attention, calculation, language manipulation, and constructional praxis17. Patients’ mental status on MMSE was interpreted as normal or impaired based on age- and education-specific norms18. Depression was evaluated by the 15-item Persian adapted Geriatric Depression Scale (GDS) questionnaire19,20. Both MMSE and GDS were implemented by one trained clinical psychologist. 2.3. Follow-up protocol All the participants were on low-salt and relative low-fat diet regimens. Meal plan was similar in all of them due to residency in a nursing home. Blood pressure was measured three times every 6 months based on the JNC 7 protocol using an automatic sphygmomanometer (Omron 7, Japan) that was calibrated by a mercury sphygmomanometer. MMSE, GDS, and fasting blood samples for the routine laboratory tests were obtained from participants at the start of the study and every year thereafter. Weight and height also were measured yearly. 2.3.1. Diagnosis High systolic blood pressure was defined as systolic blood pressure 140 mm Hg. High diastolic blood pressure was defined as diastolic blood pressure 90 mm Hg in three separate blood pressure measurements at baseline. If there was either a history of hypertension in the patients’ medical records or a history of antihypertensive medication use, this was considered as having a history of hypertension. A final diagnosis of hypertension was considered if there was a history of hypertension, use of antihypertensive medication, or a baseline systolic blood pressure of 140 mmHg or diastolic blood pressure of 90 mmHg in three separate measurements. 2.4. Statistical analyses SPSS version 18(Chicago, IBM) and STAT SE8 (Texas, StataCorp Lp) were used for all analyses. Normally distributed continuous variables were expressed as mean standard deviation and were compared using the Student t test. Categorical data were expressed
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F. Sharifi et al.
Table 1 Characteristics of study subjects.
Age Female (%) BMI Education (illiterate) (%) Smoker (%) Diabetes (%) Cardiovascular disease (%) Stroke (%) GDS score MMSE score
Table 3 Association of systolic/diastolic high blood pressure, history, and final diagnosis of hypertension at baseline with cognitive impairment in cross-sectional analysis.
Normotensive (n ¼ 44)
Hypertensive (n ¼ 166)
p
76.007.70 40 25.015.34 71.7 10 8.3 16.7 13.3 10.59 6.98 19.07 5.02
78.62 7.43 50 24.75 5.53 57 12.8 13.7 47.49 12.2 12.73 6.72 19.58 5.03
0.04* 0.007* 0.78 0.03* 0.55 0.00* 0.00* 0.81 0.06 0.55
Adjusteda
Unadjusted
*p < 0.05. BMI ¼ body mass index; GDS ¼ Geriatric Depression Scale; MMSE ¼ Mini-Mental State Examination.
as percentages and were compared using the c2 test. A p value < 0.05 was considered statistically significant. Comparisons of the means of blood pressure between impaired and normal cognitive groups were performed using the Student t test. A logistic regression model was used to study the association between cognitive impairment (dependent variable) and systolic/diastolic high blood pressure, history, and final diagnosis of hypertension (independent variables) at baseline. The results were expressed as odds ratio and confidence interval. In cohort analysis, the relative risk was calculated; the existence of high systolic and diastolic blood pressure and hypertension at the onset of the study was identified as an exposed variable. Sensitive analysis was done to assess the effect of lost to follow-up on study findings.
Systolic high blood pressure Diastolic high blood pressure History of hypertension Final diagnosis of hypertension
OR
CI
OR
CI
0.92 2.52b 0.87 0.89
0.48e1.78 1.06e5.95 0.47e1.61 0.41e1.90
0.93 2.42b 0.88 0.90
0.47e1.82 1.01e5.78 0.47e1.64 0.42e1.92
CI ¼ confidence interval; OR ¼ odds ratio. a Adjusted according to age, sex, body mass index, smoking, history of stroke, and cardiovascular disease by forward condition method. b Significant at p < 0.05; in multiple logistic regression model.
3.4. Cross-sectional analysis Cognitive function showed no significant association with systolic high blood pressure, history, or final diagnosis of hypertension (categorized variable). However, diastolic high blood pressure was a risk factor for cognitive impairment (odds ratio 2.42, p < 0.05) after adjustment for sex, BMI, smoking, history of stroke, and cardiovascular disease. The results are summarized in Table 3. 3.5. Risk analysis
3. Results
Cognitive impairment relative risk has been calculated for the following variables: systolic and diastolic high blood pressure, history of hypertension, and final diagnosis of hypertension. In addition, these values were estimated in those younger than 75 years and in those 75 years and older (Tables 4e6). The relative risk of cognitive impairment for final diagnosis of hypertension is significantly lower than 1 (0.72) in the second group (p < 0.05).
3.1. Demographic and medical characteristics
3.6. Loss analysis
The clinical characteristics of the participants are shown in Table 1. A total of 211 cases were included; 85 were males with a mean age of 76.64 6.99 years and 126 were females with a mean age of 79.06 7.76 years. Smoking status, BMI, history of stroke, and GDS and MMSE scores were similar between hypertensive and normotensive groups. However, there were significant differences between the two groups with regard to age, sex, educational level, diagnosed diabetes mellitus, and history of CVD (Table 1).
Fifty-three participants who were enrolled in this study died; two others left the institute and were lost to follow-up. The mean blood pressure of the participants who died was not significantly different from that of the living participants. In addition, there were no significant differences between the MMSE scores of persons who died and living participants (Table 7). In addition, sensitive analysis was performed with two assumptions. First, all of the participants who died or were lost to follow-up were assumed to be in the impaired cognition group, and the relative risk of impaired cognition for final diagnosis of hypertension was calculated to be 0.89 (0.95% confidence interval 0.75e1.06). Second, we assumed that the mental status of participants who died or were lost to follow-up did not change during the follow-up period, and the relative risk of impaired cognition for final diagnosis of hypertension was calculated to be 0.85 (0.95% confidence interval 0.68e1.06).
3.2. Cognitive function Accordingly, 61.5% of participants had impaired cognition. There was no significant difference between impaired cognition in hypertensive and normotensive groups (61% and 63.9%, respectively). 3.3. Blood pressure and cognitive function
4. Discussion Systolic, diastolic, and mean blood pressures were higher in impaired cognitive groups than normal cognitive groups. However, the differences were not significant (p > 0.05) (Table 2). Table 2 Mean values of systolic, diastolic, and mean blood pressures between subjects with normal and impaired cognition. Cognition
Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Mean blood pressure (mmHg) SD ¼ standard deviation.
In this study we assessed the relation of cognitive impairment, which was defined based on the MMSE cutoff point, with hypertension in a cohort follow-up study. The MMSE cutoff point was calculated based on age and education-specific norms. At baseline Table 4 Relative risk of cognitive impairment for hypertension components exposure.
Normal Mean SD
Impaired Mean SD
p
Exposed variable
Relative risk
95% CI of RR
p
132.24 23.6 75.44 12.63 94.64 15.21
135.55 27.68 77.13 15.62 96.52 18.36
0.49 0.51 0.55
History of hypertension Systolic high blood pressure Diastolic high blood pressure Final diagnosis of hypertension
0.90 0.81 1.12 0.80
0.71e1.15 0.61e1.06 0.86e1.46 0.63e1.01
0.16 0.09 0.53 0.07
CI ¼ confidence interval; RR ¼ relative risk.
Hypertension and Cognitive Impairment
215
Table 5 Relative risk of cognitive impairment for hypertension components exposure in patients younger than 75 years. Exposed variable
RR
95% CI of RR
p
History of hypertension Systolic high blood pressure Diastolic high blood pressure Final diagnosis of hypertension
0.78 0.89 1.15 0.81
0.49e1.22 0.55e1.44 0.71e1.86 0.53e1.24
0.81 0.79 0.65 0.78
CI ¼ confidence interval; RR ¼ relative risk.
there were differences between hypertensive and normotensive participant groups in terms of mean age, sex, education level, CVD, and diabetes. Some of these differences, such as sex and education level, were randomized and some others such as CVD may be ascribed to complications of hypertension. This finding is obvious because of the higher prevalence of CVD in hypertensive compared with normotensive participants. In cross-sectional analysis of baseline data, diastolic high blood pressure was a strong risk factor for cognitive impairment even after adjustment for sex, age, BMI, smoking, history of stroke, and CVD. In cohort analysis after 24 months, the relative risk of diastolic high blood pressure was more than 1 but it was not significant. This finding may indicate that diastolic blood pressure of 90 mmHg or greater in elderly patients is a risk factor for cognitive impairment. The same results were reported in a recent cross sectional analysis21. The relative risk of cognitive impairment in patients with hypertension, systolic high blood pressure, and history of hypertension were respectively 20%, 19% and 10% lower than normotensive subjects. However, these findings were not statistically significant with a 95% confidence interval. Nevertheless, in those 75 years or older, there was a 28% and 24% lower relative risk for final diagnosis of hypertension and systolic high blood pressure respectively than normotensive ones. Perhaps this finding indicated that a final diagnosis of hypertension (hypertension history or presence of systolic or diastolic high blood pressure), which was defined as hypertension history and the presence of systolic and diastolic high blood pressure, had a preventive effect on the development or progression of cognitive impairment in older persons. This discrepancy between the effect of high systolic and diastolic blood pressure on cognitive impairment can probably be explained by the effect of systolic blood pressure on brain tissue perfusion, but apparently the diastolic blood pressure does not have a similar effect22. Guo et al23, in a population-based study with 1736 participants, have reported that those older than 75 years with increasing systolic blood pressure tend to have a lower risk of cognitive impairment, and this effect was retained in a level of 180 mmHg systolic blood pressure. However, diastolic blood pressure 95 mmHg was a risk factor for cognitive impairment. Some studies have revealed a positive correlation between elevated blood pressure and cognitive impairment/dementia, including the large-scale Atherosclerosis Risk in Communities study, which used systolic blood pressure of at least 160 mmHg to Table 6 Relative risk of cognitive impairment for hypertension components exposure in patients 75 years or older. Exposed variable
RR
95% CI of RR
p
History of Hypertension Systolic high blood pressure Diastolic high blood pressure Final Diagnosis of hypertension
0.95 0.76 1.11 0.72*
0.71e1.27 0.54e1.05 0.81e1.51 0.57e0.92
0.48 0.15 0.78 0.04
* p < 0.05. CI ¼ confidence interval; RR ¼ relative risk.
Table 7 Comparison of exposure and outcome variable in alive, dead, and discharged groups (ANOVA).
Systolic blood pressure Diastolic blood pressure History of hypertension Final diagnosis of hypertension MMSE score
Alive group n ¼ 155
Dead group n ¼ 53
Discharged group n¼2
p
134.72 25.76 77.06 14.80 57.7% 76.9%
139.07 22.86 78.73 13.68 67.9% 84.9%
135 10 75 5 50% 100%
0.53 0.73 0.22 0.36
19.73 4.95
18.89 5.63
23.5 3.53
0.38
ANOVA ¼ analysis of variance; MMSE ¼ Mini-Mental State Examination.
define hypertension24. However, impaired cognition has been reported with moderately increased blood pressure in the absence of clinically evident target organ damage25. As mentioned previously, vascular risk factors contribute to the development and progression of VaD and AD6e10. Extensive review of the literature, including both cross-sectional and longitudinal studies, in addition to the results of clinical trials evaluating the effect of antihypertensive medications, provided sufficient valid evidence to formulate a plausible hypothesis. It has been postulated that long-standing hypertension beginning in midlife is implicated in the development of late-life cognitive impairment and dementia. On the contrary, elderly patients with hypertension are less prone to the development of cognitive impairment and dementia. This seemingly paradoxic effect is partly due to the protective role of elevated blood pressure in cerebral perfusion in elderly patients with stiffer arteries and the progressive decline in blood pressure as a consequence of established dementia7,8,10. In the clinical setting, restricted control of hypertension might not have a beneficial effect on cognitive decline in elderly patients. Therefore, in the analysis of cognitive impairment prevention, overemphasis on blood pressure control may not have any implication. Some limitations of the current study deserve mention. First, the inadequate number of participants was a major limitation to make further conclusions, especially because we could not categorize the participants in more than four categories for age and level of blood pressure. Second, assessment of mental status by using one instrument was another limitation of this study. Although the MMSE is the most commonly used instrument for screening of cognitive status in elderly patients26, it was better to use two instruments instead of one. Using an instrument that was less dependent on education level of the participants was desirable. The strengths of our study were rigid control of background factors such as similarity of diet regimen in all of the participants and few patients lost to follow-up. Acknowledgments This study has been funded by the Endocrinology and Metabolism Research Center affiliated with Tehran University of Medical Sciences. The authors are grateful to Ms. Neda Nazari for cooperation with execution of this study. References 1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. Washington, DC; 2000. 2. Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a delphi consensus study. Lancet. 2005;352:1347e1351. 3. Patterson C, Feightner JW, Garcia A, et al. Diagnosis and treatment of dementia: 1.Risk assessment and primary prevention of Alzheimer disease. CMAJ. 2008;178:548e559.
216 4. Sorrentino G, Migliaccio R, Bonavita V. Treatment of vascular dementia: the route of prevention. Eur Neurol. 2008;60:217e223. 5. Kalaria RN, Maestre GE, Arizaga R, et al. Alzheimer’s disease and vascular dementia in developing countries: prevalence, management, and risk factors. Lancet Neurol. 2008;7:812e826. 6. Fillit H, Nash DT, Rundek T, et al. Cardiovascular risk factors and dementia. Am J Geriatr Pharmacothe. 2008;6:100e118. 7. Duron E, Hanon O. Vascular risk factors, cognitive decline, and dementia. Vasc Health Risk Manag. 2008;4:363e381. 8. Kloppenborg RP, van den Berg E, Kappelle LJ, et al. Diabetes and other vascular risk factors for dementia: which factor matters most? A systematic review. Eur J Pharmacol. 2008;585:97e108. 9. Gorelick PB. Risk factors for vascular dementia and Alzheimer disease. Stroke. 2004;35:2620e2622. 10. Qui Ch, Winblad B, Fratiglioni L. The age-dependent relation of blood pressure to cognitive function and dementia. Lancet Neurol. 2005;4:487e499. 11. Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217e223. 12. Cherubini A, Lowenthal DT, Paran E, et al. Hypertension and cognitive function in the elderly. Am J Ther. 2007;14:533e554. 13. De La Torre JC. Alzheimer’s disease as a vascular disorder: nosological evidence. Stroke. 2002;33:1152e1162. 14. De La Torre JC. Is Alzheimer’s disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. Lancet Neurol. 2004;3:184e190. 15. Launer LJ. Demonstrating the case that AD is a vascular disease: epidemiologic evidence. Aging Res Rev. 2002;1:61e77. 16. Frughan M, Jafari Z, Peymaneh S, et al. Adapting mini mental state exam of old ages dwelling in Tehran, 2006. J Tazeh-hay-e Oloum Shenaakhti. 2008;10:29e37 [In Persian]. 17. Folstein MF, Folstein SE, McHugh PR. Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189e198.
F. Sharifi et al. 18. Crum RM, Anthony JC, Bassett SS, et al. Population-based norms for the mini-mental state examination by age and educational level. JAMA. 1993;269: 2386e2391. 19. Sheikh JL, Yesavage JA. Geriatric Depression scale (GDS): recent evidence and development of a shorter version. Clin Gerontol. 1986;5:165e173. 20. Malakouti SK, Fatollahi P, Mirabzadeh A, et al. Reliability, validity and factor structure of the GDS-15 in Iranian elderly. Int J Geriatr Psychiatry. 2006;21: 588e593. 21. Tsivgoulis G, Alexandrov AV, Wadley VG, et al. Association of higher diastolic blood pressure levels with cognitive impairment. Neurology. 2009;73: 589e595. 22. Duschek S, Schandry R. Reduced brain perfusion and cognitive performance due to constitutional hypotension. Clin Auton Res. 2007;17:69e76. 23. Guo Z, Fratiglioni L, Winblad B, et al. Blood pressure and performance on the mini-mental state examination in the very old: cross-sectional and longitudinal data from the Kungsholmen project. Am J Epidemiol. 1997;145: 1106e1113. 24. Cerhan JR, Folsom AR, Mortimer JA, et al. Correlates of cognitive function in middle-aged adults. Gerontology. 1998;44:95e105. 25. Harrington F, Saxby BK, McKeith IG, et al. Cognitive performance in hypertensive and normotensive older subjects. Hypertension. 2000;36:1076e1082. 26. Brodaty H, Low LF, Gibson L, Burns K. What is the best dementia screening instrument for general practitioners to use? Am J Geriatr Psychiatry. 2006;14:391e400.
Further reading 1. Jones DW, Hall JE. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure and evidence from new hypertension trials. Hypertension. 2004;43:1e3.
Contents lists available at SciVerse ScienceDirect
International Journal of Gerontology journal homepage: www.ijge-online.com
Original Article
Hypertension and Cognitive Impairment: Kahrizak Elderly Studyq Farshad Sharifi 1, 2, Mona Hedayat 3, Hossein Fakhrzadeh 1 *, Mohammad Jafar Mahmoudi 3, Maryam Ghaderpanahi 1, Mojde Mirarefin 1, Yaser Tajalizadekhoob 1, Zohre Badamchizade 4, Bagher Larijani 4 1
Elderly Health Research Center, Endocrinology and Metabolism Research Institute,Tehran University of Medical Sciences, 2 Research and Education Affairs, Kahrizak Charity Foundation, 3 Division of Cardiology, Department of Internal Medicine, School of Medicine, Tehran University of Medical Sciences, 4 Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran
a r t i c l e i n f o
s u m m a r y
Article history: Received 23 August 2010 Received in revised form 3 March 2011 Accepted 9 March 2011 Available online 5 January 2012
Background: Dementia is a major cause of cognitive impairment in the elderly. Numerous studies have investigated the association between hypertension and cognitive disorders in elderly persons, with inconsistent results. The goal of the study was to investigate the association between hypertension at baseline and cognitive impairment after 24 months’ follow-up in the elderly residents of the Kahrizak Charity Foundation (KCF) in Iran. Methods: There were 211 elderly residents of KCF aged 65 years or older with a Mini Mental State Examination (MMSE) score greater than 10. The MMSE score was assessed at the end of the study. Blood pressure was measured in all of the participants at the beginning of study. Data were compared between hypertensive and normotensive patients. Results: A total of 63.5% of patients had impaired cognition (61% and 63.9% in normotensive and hypertensive patients, respectively). Cross sectional analysis of baseline data in a multiple regression model has revealed that diastolic high blood pressure was a risk factor for cognitive impairment even after adjustment for confounding factors (odds ratio: 2.42, 95% CI: 1.01-5.78). In the cohort follow-up analysis, the relative risk of cognitive impairment for patients aged 75 years or older with final diagnosis of hypertension was 0.72 (0.57e0.92). The relative risk of patients with systolic high blood pressure and history of hypertension was 19% and 10%, respectively, which was lower than normotensive group but such differences were not significant. Conclusions: High systolic blood pressure in very old persons may have a preventive effect on development and progression of cognitive impairment. However, diastolic high blood pressure perhaps may be a risk factor for cognitive impairment in elderly persons. Copyright Ó 2011, Taiwan Society of Geriatric Emergency & Critical Care Medicine. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: cognitive impairment, diastolic high blood pressure, elderly, systolic high blood pressure
1. Introduction Dementia is one of the most disabling neurologic disorders of aging populations. It is a progressive disorder characterized by impairment of memory and at least one of the intellectual functions of the brain severe enough to interfere with daily activities and independence1. The burden of the disease tends to increase in parallel with increased life expectancy, and by 2040 it will account for 81.1 million cases worldwide2. Symptomatic therapy currently q All contributing authors declare no conflict of interest. * Correspondence to: Dr Hossein Fakhrzadeh, Elderly Health Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, 5th floor, Dr Shareeati Hospital, North Karegar Avenue, Tehran, Iran. E-mail address: [email protected] (H. Fakhrzadeh).
is the mainstay of disease management and no curative strategies are available. The progressive and irreversible nature of the disease sheds light on the importance of identification and primary prevention of risk factors3,4. Alzheimer disease (AD) and vascular dementia (VaD) contribute to approximately 60% and 26%, respectively, of all dementia syndromes5. Numerous longitudinal and cross-sectional studies have demonstrated the association between cardiovascular disease (CVD) risk factors, i.e., diabetes mellitus, hypertension, dyslipidemia, obesity, and smoking, with AD and VaD as the leading causes of dementia6e10. Therefore, by taking appropriate measures aimed at prevention, early detection, and treatment of CVD risk factors, cognitive decline will no longer be an inevitable component of aging. Hypertension is a common disorder among elderly adults and its prevalence tends to rise as the population ages. Hypertension is
1873-9598/$ e see front matter Copyright Ó 2011, Taiwan Society of Geriatric Emergency & Critical Care Medicine. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.ijge.2011.12.001
Hypertension and Cognitive Impairment
diagnosed in approximately 65% of adults 65 years and older11. VaD is a heterogeneous disorder including multi-infarct dementia, strategic infarct dementia, and subcortical ischemic dementia12. The common features among these clinical syndromes are atherothrombosis or cardiogenic embolism in large- and medium-sized vessels and hypertensive/arteriosclerotic angiopathy in small vessels4,12. AD traditionally has been regarded as a primary neurodegenerative disorder. However, the role of vasculopathy and the contribution of vascular risk factors to the development of AD have received much attention in recent years13e15. Therefore, regardless of the underlying etiologies, controlling blood pressure as a pharmacologically modifiable risk factor might prevent dementia or slow the progression of cognitive decline. Some epidemiologic studies have addressed the relationship between blood pressure, cognitive function, and dementia. However, marked discrepancies exist between the results of crosssectional and longitudinal studies. Furthermore, apparent inconsistencies exist in the results of similarly designed population-based observational studies. Positive correlation, negative correlation, U-shaped correlation, J-shaped correlation, and no association between blood pressure and cognition has been reported7,8,10. The goal of the current study is to investigate the association between blood pressure at the beginning of the study and cognitive impairment after 24 months in elderly patients. 2. Materials and methods 2.1. Participants All participants were 65 years or older and lived in KCF. Patients with end-stage liver, cardiac, and renal diseases, Parkinson disease, and severe dementia (defined as obtaining scores 10 on the MiniMental State Examination [MMSE])16 were excluded. Informed consent was obtained from all participants and also their firstdegree relatives if their MMSE score was less than 22. The study protocol was approved by the ethics committee (PM184/10/0123 K, this Code represent the Persian calendar day with related official numbers) in the Endocrinology and Metabolism Research Center of Tehran University of Medical Sciences. 2.2. Data collection 2.2.1. Demographic and medical information Demographic characteristics including age, sex, education level, and smoking status and previous medical diagnosis including the history of diabetes mellitus, hypertension, cardiovascular disease (CVD), and stroke were obtained from participants’ medical records. 2.2.2. Medical examination At the beginning of the study, blood pressure, height, and weight were measured by trained nurses or research assistants. Blood pressure measurements were performed by a tonometer automatic sphygmomanometer (Omron 7, Tokyo, Japan) which was calibrated by a mercury sphygmomanometer after every 100 measurements, according to the guidelines of The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) with the participant in a recumbent position after 5 minutes of rest; the average of three measurements was recorded. Participants were advised to avoid alcohol, cigarette smoking, caffeinated beverages, and exercise for at least 30 minutes before blood pressure measurement. An average of three measurements was recorded at 3-day intervals during 1 week. A history of hypertension was assumed for any participant who was under treatment with antihypertensive drugs or if he or she
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had a history of hypertension in his or her medical documents. With this guideline, the systolic high blood pressure was defined as systolic blood pressure was 140 mmHg; diastolic high blood pressure was defined as diastolic blood pressure 90 mmHg; a final diagnosis of hypertension was assumed if either systolic or diastolic high blood pressure or a history of hypertension existed. The accuracy of height and weight measurements was 0.5 cm and 0.1 kg, respectively. The body mass index (BMI) was calculated as weight (kg) divided by height squared (m2). 2.2.3. Laboratory tests Twelve-hour overnight fasting blood samples were collected to determine serum glucose. Serum fasting glucose was measured by an enzymatic colorimetric technique in the fasting condition (ParsAzmun Kits, Tehran, Iran). In study participants, diabetes was defined according to American Diabetes Association criteria as diagnosis of the condition in the participants’ medical records and/ or current use of hypoglycemic drugs and insulin and/or fasting serum glucose 126 mg/dL. 2.2.4. Neuropsychologic tests At baseline and at the end of the study, the Persian-adapted MMSE questionnaire was used to assess cognitive status. MMSE was assessed twice in 2 days during a week; the mean MMSE score was calculated for each participant. The Persian standardized version of MMSE was administered16. This consists of 11 questions assessing a broad range of cognitive functions including orientation, recall, attention, calculation, language manipulation, and constructional praxis17. Patients’ mental status on MMSE was interpreted as normal or impaired based on age- and education-specific norms18. Depression was evaluated by the 15-item Persian adapted Geriatric Depression Scale (GDS) questionnaire19,20. Both MMSE and GDS were implemented by one trained clinical psychologist. 2.3. Follow-up protocol All the participants were on low-salt and relative low-fat diet regimens. Meal plan was similar in all of them due to residency in a nursing home. Blood pressure was measured three times every 6 months based on the JNC 7 protocol using an automatic sphygmomanometer (Omron 7, Japan) that was calibrated by a mercury sphygmomanometer. MMSE, GDS, and fasting blood samples for the routine laboratory tests were obtained from participants at the start of the study and every year thereafter. Weight and height also were measured yearly. 2.3.1. Diagnosis High systolic blood pressure was defined as systolic blood pressure 140 mm Hg. High diastolic blood pressure was defined as diastolic blood pressure 90 mm Hg in three separate blood pressure measurements at baseline. If there was either a history of hypertension in the patients’ medical records or a history of antihypertensive medication use, this was considered as having a history of hypertension. A final diagnosis of hypertension was considered if there was a history of hypertension, use of antihypertensive medication, or a baseline systolic blood pressure of 140 mmHg or diastolic blood pressure of 90 mmHg in three separate measurements. 2.4. Statistical analyses SPSS version 18(Chicago, IBM) and STAT SE8 (Texas, StataCorp Lp) were used for all analyses. Normally distributed continuous variables were expressed as mean standard deviation and were compared using the Student t test. Categorical data were expressed
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Table 1 Characteristics of study subjects.
Age Female (%) BMI Education (illiterate) (%) Smoker (%) Diabetes (%) Cardiovascular disease (%) Stroke (%) GDS score MMSE score
Table 3 Association of systolic/diastolic high blood pressure, history, and final diagnosis of hypertension at baseline with cognitive impairment in cross-sectional analysis.
Normotensive (n ¼ 44)
Hypertensive (n ¼ 166)
p
76.007.70 40 25.015.34 71.7 10 8.3 16.7 13.3 10.59 6.98 19.07 5.02
78.62 7.43 50 24.75 5.53 57 12.8 13.7 47.49 12.2 12.73 6.72 19.58 5.03
0.04* 0.007* 0.78 0.03* 0.55 0.00* 0.00* 0.81 0.06 0.55
Adjusteda
Unadjusted
*p < 0.05. BMI ¼ body mass index; GDS ¼ Geriatric Depression Scale; MMSE ¼ Mini-Mental State Examination.
as percentages and were compared using the c2 test. A p value < 0.05 was considered statistically significant. Comparisons of the means of blood pressure between impaired and normal cognitive groups were performed using the Student t test. A logistic regression model was used to study the association between cognitive impairment (dependent variable) and systolic/diastolic high blood pressure, history, and final diagnosis of hypertension (independent variables) at baseline. The results were expressed as odds ratio and confidence interval. In cohort analysis, the relative risk was calculated; the existence of high systolic and diastolic blood pressure and hypertension at the onset of the study was identified as an exposed variable. Sensitive analysis was done to assess the effect of lost to follow-up on study findings.
Systolic high blood pressure Diastolic high blood pressure History of hypertension Final diagnosis of hypertension
OR
CI
OR
CI
0.92 2.52b 0.87 0.89
0.48e1.78 1.06e5.95 0.47e1.61 0.41e1.90
0.93 2.42b 0.88 0.90
0.47e1.82 1.01e5.78 0.47e1.64 0.42e1.92
CI ¼ confidence interval; OR ¼ odds ratio. a Adjusted according to age, sex, body mass index, smoking, history of stroke, and cardiovascular disease by forward condition method. b Significant at p < 0.05; in multiple logistic regression model.
3.4. Cross-sectional analysis Cognitive function showed no significant association with systolic high blood pressure, history, or final diagnosis of hypertension (categorized variable). However, diastolic high blood pressure was a risk factor for cognitive impairment (odds ratio 2.42, p < 0.05) after adjustment for sex, BMI, smoking, history of stroke, and cardiovascular disease. The results are summarized in Table 3. 3.5. Risk analysis
3. Results
Cognitive impairment relative risk has been calculated for the following variables: systolic and diastolic high blood pressure, history of hypertension, and final diagnosis of hypertension. In addition, these values were estimated in those younger than 75 years and in those 75 years and older (Tables 4e6). The relative risk of cognitive impairment for final diagnosis of hypertension is significantly lower than 1 (0.72) in the second group (p < 0.05).
3.1. Demographic and medical characteristics
3.6. Loss analysis
The clinical characteristics of the participants are shown in Table 1. A total of 211 cases were included; 85 were males with a mean age of 76.64 6.99 years and 126 were females with a mean age of 79.06 7.76 years. Smoking status, BMI, history of stroke, and GDS and MMSE scores were similar between hypertensive and normotensive groups. However, there were significant differences between the two groups with regard to age, sex, educational level, diagnosed diabetes mellitus, and history of CVD (Table 1).
Fifty-three participants who were enrolled in this study died; two others left the institute and were lost to follow-up. The mean blood pressure of the participants who died was not significantly different from that of the living participants. In addition, there were no significant differences between the MMSE scores of persons who died and living participants (Table 7). In addition, sensitive analysis was performed with two assumptions. First, all of the participants who died or were lost to follow-up were assumed to be in the impaired cognition group, and the relative risk of impaired cognition for final diagnosis of hypertension was calculated to be 0.89 (0.95% confidence interval 0.75e1.06). Second, we assumed that the mental status of participants who died or were lost to follow-up did not change during the follow-up period, and the relative risk of impaired cognition for final diagnosis of hypertension was calculated to be 0.85 (0.95% confidence interval 0.68e1.06).
3.2. Cognitive function Accordingly, 61.5% of participants had impaired cognition. There was no significant difference between impaired cognition in hypertensive and normotensive groups (61% and 63.9%, respectively). 3.3. Blood pressure and cognitive function
4. Discussion Systolic, diastolic, and mean blood pressures were higher in impaired cognitive groups than normal cognitive groups. However, the differences were not significant (p > 0.05) (Table 2). Table 2 Mean values of systolic, diastolic, and mean blood pressures between subjects with normal and impaired cognition. Cognition
Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Mean blood pressure (mmHg) SD ¼ standard deviation.
In this study we assessed the relation of cognitive impairment, which was defined based on the MMSE cutoff point, with hypertension in a cohort follow-up study. The MMSE cutoff point was calculated based on age and education-specific norms. At baseline Table 4 Relative risk of cognitive impairment for hypertension components exposure.
Normal Mean SD
Impaired Mean SD
p
Exposed variable
Relative risk
95% CI of RR
p
132.24 23.6 75.44 12.63 94.64 15.21
135.55 27.68 77.13 15.62 96.52 18.36
0.49 0.51 0.55
History of hypertension Systolic high blood pressure Diastolic high blood pressure Final diagnosis of hypertension
0.90 0.81 1.12 0.80
0.71e1.15 0.61e1.06 0.86e1.46 0.63e1.01
0.16 0.09 0.53 0.07
CI ¼ confidence interval; RR ¼ relative risk.
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Table 5 Relative risk of cognitive impairment for hypertension components exposure in patients younger than 75 years. Exposed variable
RR
95% CI of RR
p
History of hypertension Systolic high blood pressure Diastolic high blood pressure Final diagnosis of hypertension
0.78 0.89 1.15 0.81
0.49e1.22 0.55e1.44 0.71e1.86 0.53e1.24
0.81 0.79 0.65 0.78
CI ¼ confidence interval; RR ¼ relative risk.
there were differences between hypertensive and normotensive participant groups in terms of mean age, sex, education level, CVD, and diabetes. Some of these differences, such as sex and education level, were randomized and some others such as CVD may be ascribed to complications of hypertension. This finding is obvious because of the higher prevalence of CVD in hypertensive compared with normotensive participants. In cross-sectional analysis of baseline data, diastolic high blood pressure was a strong risk factor for cognitive impairment even after adjustment for sex, age, BMI, smoking, history of stroke, and CVD. In cohort analysis after 24 months, the relative risk of diastolic high blood pressure was more than 1 but it was not significant. This finding may indicate that diastolic blood pressure of 90 mmHg or greater in elderly patients is a risk factor for cognitive impairment. The same results were reported in a recent cross sectional analysis21. The relative risk of cognitive impairment in patients with hypertension, systolic high blood pressure, and history of hypertension were respectively 20%, 19% and 10% lower than normotensive subjects. However, these findings were not statistically significant with a 95% confidence interval. Nevertheless, in those 75 years or older, there was a 28% and 24% lower relative risk for final diagnosis of hypertension and systolic high blood pressure respectively than normotensive ones. Perhaps this finding indicated that a final diagnosis of hypertension (hypertension history or presence of systolic or diastolic high blood pressure), which was defined as hypertension history and the presence of systolic and diastolic high blood pressure, had a preventive effect on the development or progression of cognitive impairment in older persons. This discrepancy between the effect of high systolic and diastolic blood pressure on cognitive impairment can probably be explained by the effect of systolic blood pressure on brain tissue perfusion, but apparently the diastolic blood pressure does not have a similar effect22. Guo et al23, in a population-based study with 1736 participants, have reported that those older than 75 years with increasing systolic blood pressure tend to have a lower risk of cognitive impairment, and this effect was retained in a level of 180 mmHg systolic blood pressure. However, diastolic blood pressure 95 mmHg was a risk factor for cognitive impairment. Some studies have revealed a positive correlation between elevated blood pressure and cognitive impairment/dementia, including the large-scale Atherosclerosis Risk in Communities study, which used systolic blood pressure of at least 160 mmHg to Table 6 Relative risk of cognitive impairment for hypertension components exposure in patients 75 years or older. Exposed variable
RR
95% CI of RR
p
History of Hypertension Systolic high blood pressure Diastolic high blood pressure Final Diagnosis of hypertension
0.95 0.76 1.11 0.72*
0.71e1.27 0.54e1.05 0.81e1.51 0.57e0.92
0.48 0.15 0.78 0.04
* p < 0.05. CI ¼ confidence interval; RR ¼ relative risk.
Table 7 Comparison of exposure and outcome variable in alive, dead, and discharged groups (ANOVA).
Systolic blood pressure Diastolic blood pressure History of hypertension Final diagnosis of hypertension MMSE score
Alive group n ¼ 155
Dead group n ¼ 53
Discharged group n¼2
p
134.72 25.76 77.06 14.80 57.7% 76.9%
139.07 22.86 78.73 13.68 67.9% 84.9%
135 10 75 5 50% 100%
0.53 0.73 0.22 0.36
19.73 4.95
18.89 5.63
23.5 3.53
0.38
ANOVA ¼ analysis of variance; MMSE ¼ Mini-Mental State Examination.
define hypertension24. However, impaired cognition has been reported with moderately increased blood pressure in the absence of clinically evident target organ damage25. As mentioned previously, vascular risk factors contribute to the development and progression of VaD and AD6e10. Extensive review of the literature, including both cross-sectional and longitudinal studies, in addition to the results of clinical trials evaluating the effect of antihypertensive medications, provided sufficient valid evidence to formulate a plausible hypothesis. It has been postulated that long-standing hypertension beginning in midlife is implicated in the development of late-life cognitive impairment and dementia. On the contrary, elderly patients with hypertension are less prone to the development of cognitive impairment and dementia. This seemingly paradoxic effect is partly due to the protective role of elevated blood pressure in cerebral perfusion in elderly patients with stiffer arteries and the progressive decline in blood pressure as a consequence of established dementia7,8,10. In the clinical setting, restricted control of hypertension might not have a beneficial effect on cognitive decline in elderly patients. Therefore, in the analysis of cognitive impairment prevention, overemphasis on blood pressure control may not have any implication. Some limitations of the current study deserve mention. First, the inadequate number of participants was a major limitation to make further conclusions, especially because we could not categorize the participants in more than four categories for age and level of blood pressure. Second, assessment of mental status by using one instrument was another limitation of this study. Although the MMSE is the most commonly used instrument for screening of cognitive status in elderly patients26, it was better to use two instruments instead of one. Using an instrument that was less dependent on education level of the participants was desirable. The strengths of our study were rigid control of background factors such as similarity of diet regimen in all of the participants and few patients lost to follow-up. Acknowledgments This study has been funded by the Endocrinology and Metabolism Research Center affiliated with Tehran University of Medical Sciences. The authors are grateful to Ms. Neda Nazari for cooperation with execution of this study. References 1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. Washington, DC; 2000. 2. Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a delphi consensus study. Lancet. 2005;352:1347e1351. 3. Patterson C, Feightner JW, Garcia A, et al. Diagnosis and treatment of dementia: 1.Risk assessment and primary prevention of Alzheimer disease. CMAJ. 2008;178:548e559.
216 4. Sorrentino G, Migliaccio R, Bonavita V. Treatment of vascular dementia: the route of prevention. Eur Neurol. 2008;60:217e223. 5. Kalaria RN, Maestre GE, Arizaga R, et al. Alzheimer’s disease and vascular dementia in developing countries: prevalence, management, and risk factors. Lancet Neurol. 2008;7:812e826. 6. Fillit H, Nash DT, Rundek T, et al. Cardiovascular risk factors and dementia. Am J Geriatr Pharmacothe. 2008;6:100e118. 7. Duron E, Hanon O. Vascular risk factors, cognitive decline, and dementia. Vasc Health Risk Manag. 2008;4:363e381. 8. Kloppenborg RP, van den Berg E, Kappelle LJ, et al. Diabetes and other vascular risk factors for dementia: which factor matters most? A systematic review. Eur J Pharmacol. 2008;585:97e108. 9. Gorelick PB. Risk factors for vascular dementia and Alzheimer disease. Stroke. 2004;35:2620e2622. 10. Qui Ch, Winblad B, Fratiglioni L. The age-dependent relation of blood pressure to cognitive function and dementia. Lancet Neurol. 2005;4:487e499. 11. Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217e223. 12. Cherubini A, Lowenthal DT, Paran E, et al. Hypertension and cognitive function in the elderly. Am J Ther. 2007;14:533e554. 13. De La Torre JC. Alzheimer’s disease as a vascular disorder: nosological evidence. Stroke. 2002;33:1152e1162. 14. De La Torre JC. Is Alzheimer’s disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. Lancet Neurol. 2004;3:184e190. 15. Launer LJ. Demonstrating the case that AD is a vascular disease: epidemiologic evidence. Aging Res Rev. 2002;1:61e77. 16. Frughan M, Jafari Z, Peymaneh S, et al. Adapting mini mental state exam of old ages dwelling in Tehran, 2006. J Tazeh-hay-e Oloum Shenaakhti. 2008;10:29e37 [In Persian]. 17. Folstein MF, Folstein SE, McHugh PR. Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189e198.
F. Sharifi et al. 18. Crum RM, Anthony JC, Bassett SS, et al. Population-based norms for the mini-mental state examination by age and educational level. JAMA. 1993;269: 2386e2391. 19. Sheikh JL, Yesavage JA. Geriatric Depression scale (GDS): recent evidence and development of a shorter version. Clin Gerontol. 1986;5:165e173. 20. Malakouti SK, Fatollahi P, Mirabzadeh A, et al. Reliability, validity and factor structure of the GDS-15 in Iranian elderly. Int J Geriatr Psychiatry. 2006;21: 588e593. 21. Tsivgoulis G, Alexandrov AV, Wadley VG, et al. Association of higher diastolic blood pressure levels with cognitive impairment. Neurology. 2009;73: 589e595. 22. Duschek S, Schandry R. Reduced brain perfusion and cognitive performance due to constitutional hypotension. Clin Auton Res. 2007;17:69e76. 23. Guo Z, Fratiglioni L, Winblad B, et al. Blood pressure and performance on the mini-mental state examination in the very old: cross-sectional and longitudinal data from the Kungsholmen project. Am J Epidemiol. 1997;145: 1106e1113. 24. Cerhan JR, Folsom AR, Mortimer JA, et al. Correlates of cognitive function in middle-aged adults. Gerontology. 1998;44:95e105. 25. Harrington F, Saxby BK, McKeith IG, et al. Cognitive performance in hypertensive and normotensive older subjects. Hypertension. 2000;36:1076e1082. 26. Brodaty H, Low LF, Gibson L, Burns K. What is the best dementia screening instrument for general practitioners to use? Am J Geriatr Psychiatry. 2006;14:391e400.
Further reading 1. Jones DW, Hall JE. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure and evidence from new hypertension trials. Hypertension. 2004;43:1e3.