Authors:
Moatassem S. Amer MD,
Shereen M. Mousa MD,
Ahmed S. Mohammedin MS

Geriatrics & Gerontology Department, Faculty of Medicine,
Ain Shams University

Corresponding Author:
Prof. Moatassem S. Amer MD (Internal Medicine)
Professor of Geriatric Medicine & Internal Medicine
Address: Geriatrics & Gerontology Department, Faculty of Medicine, Ain Shams University, Abbassyia, 11566, Cairo, Egypt
Tel: +20123100373
Fax: +2024826726
Email: motassem.amer@yahoo.com

Contributing Author:
Dr Shereen M. Mousa, MD (Geriatrics)
Lecturer of Geriatric Medicine
Address: Geriatrics & Gerontology Department, Faculty of Medicine, Ain Shams University, Abbassyia, 11566, Cairo, Egypt
Tel: +20165659458
Fax: +2024826726
Email: sonata_s_h_m@yahoo.com

Alternate Corresponding Author:
Dr Ahmed S. Mohammedin, M.Sc (Geriatrics)
Assistant Lecturer of Geriatric Medicine
Address: Geriatrics & Gerontology Department, Faculty of Medicine, Ain Shams University, Abbassyia, 11566, Cairo, Egypt
Tel: +20102412579
Fax: +2024826726
Email: ashashyou@yahoo.com

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

INTRODUCTION
Cognitive functions are defined as the ability to think and understand the world, and are divided into: Attention (the ability to focus and sustain thought and perception); Orientation to time and place; Memory, which involves learning (registration) or recalling what has been learned; Language function; Praxis (the ability to perform learned motor tasks) and Executive functions(1). Executive function is defined as the ability to plan, initiate, sequence, monitor, and inhibit complex behavior(2). Another simple definition of Executive functions is the ability to plan one's behaviour to achieve a goal (3). The relationship between hypertension (HTN) and cognitive/executive functions is of growing interest because of the high prevalence of both hypertension and cognitive/executive functions decline in the elderly. In Egypt the prevalence of HTN in the population was 26.3% in 1998. The prevalence rate was 59.4% in the 65-74 years age group. HTN prevalence increased progressively with age, with the exception of the oldest age group >75 years. HTN highest prevalence rate was in greater in the Cairo area (31.0%), and only one third (37.5%) of all hypertensive individuals were aware of their disease with an estimated number of hypertensive individuals receiving pharmacological treatment in Egypt of 23.9% and an estimated percentage of hypertensive individuals whose blood pressure (BP) was under control, of 8% (4). In a study conducted in seven geriatric centers of the Egyptian ministry of health and population, it was found that hypertension is the major health problem of the elderly in Egypt (5). With the increase in life expectancy in Egypt (71.8 year in 2008) (6) Egypt is expected to have more elderly with hypertension in the future.

The deleterious effect of HTN on white matter and brain volume was reported by Raz et al., (7) who reported that these effects are not global, and they appear to be confined to the frontal regions of the brain and more specifically to the prefrontal cortex and the underlying white matter leading to cognitive changes that suggest isolated vulnerability of some executive functions to HTN. However other studies denied any effect of HTN on cognitive/executive functions.(8)

Failure of identification of medically ill patients with executive impairments has important clinical consequences, as regards medication adherence, preservation of autonomy, relapse prevention, post discharge placement, and potentiality for rehabilitation.(2). Thus our aim was to study the relationship between HTN and cognitive/executive functions in elderly Egyptians.

MATERIALS AND METHODS
Participants and study design
A case-control study was conducted at Ain Shams University Hospital's outpatient clinics on a sample of 120 subjects (79 male and 41 female) with a mean age of (65.2 ±4.92) years were eligible for the study. Eligible cases were elderly aged >60 years who were known hypertensives. Eligible controls were elderly aged >60 years who were non-hypertensives. History and clinical examination was done to all subjects to exclude conditions that affected cognitive/executive functions as neuropsychiatric disorders, cardiovascular diseases, alcoholism, drug abuse, cognitive impairment or delirium.

Measurements
Blood pressure (BP) measurement was performed according to the Seventh Report of the Joint National Committee of Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII).(9) At least two measurements were made. Systolic Blood Pressure (SBP) was defined as the point at which the first of two or more sounds is heard, and Diastolic Blood Pressure (DBP) as the point before the disappearance of sounds. Pulse pressure (PP) was calculated by subtracting the DBP from the SBP, while Mean Arterial Pressure (MAP) was calculated by summation of DBP and one third of the pulse pressure.(10)

Cognitive/executive functions were tested by a battery of tests that included:
MMSE Arabic version(11), Block design test (BD), of the Wechsler adult intelligence scale-revised version (WAIS-R) Arabic version(12), Digit span subtest-forward (DSF) of the WAIS-R Arabic version(12), Digit span subtest-Backward (DSB) Arabic version(12), Letter verbal fluency test (LVF) (13), Animal (Category) verbal fluency test (AVF) (14), Contrasting program test (CP) (15)

Statistical Analysis
Description of all data in the form of mean (M) and standard deviation (SD) for quantitative variables was done. Frequency and percentage was done for qualitative variables. Comparison between quantitative variables was done using t-test to compare two groups and ANOVA (analysis of variance) to compare more than two groups. Post Hoc test was done to detect the least significant difference. Comparison of qualitative variables was done using the Chi-square test.

ETHICS
This study had the approval of the ethics committee of the Ain Shams Faculty of medicine. All subjects consented (orally or written) to participation in the study

RESULTS

*SD = Standard deviation.
† ADL = Activities of daily living.
‡IADL = Instrumental activities of daily living.
§ MMSE = Mini Mental Status Examination.
BD = Block Design.
# DSF = Digit Span Forward.
** DSB = Digit Span Backward.
†† LVF = Letter Verbal Fluency.
‡‡ AVF = Animal Verbal Fluency.
§§ CP = Contrasting program

Table 1: Description and demography of cases and controls and mean scores of cognitive/executive tests; MMSE, BD, DSF, DSB, LVF, AVF, and CP

* SBP = Systolic Blood Pressure.
† SD = Standard deviation.
‡DBP = Diastolic Blood Pressure.
§MAP = Mean Arterial Pressure.
PP = Pulse Pressure.
# MMSE = Mini Mental Status Examination.
** BD = Block Design.
†† DSF = Digit Span Forward.
‡‡ DSB = Digit Span Backward.
§§ LVF = Letter Verbal Fluency.
AVF = Animal Verbal Fluency.
# CP = Contrasting program

Table 2: Comparison between controlled, uncontrolled hypertensive, and non hypertensive subjects as regards their mean SBP, DBP, MAP, PP, and the mean scores of the following tests; MMSE, BD, DSF, DSB, LVF, AVF, and CP

There was no statistically significant difference between cases and controls as regards age, gender, educational level, and the performance in the Activity of Daily Living (ADL) and the Instrumental Activity of Daily Living (IADL) (P > 0.05) (Table 1), thus the effect of HTN on cognitive/executive functions was easily studied between the two groups independently of those variables. Results revealed that cognitive/executive performance did not show statistically significant difference between the two groups (P > 0.05) in all cognitive/executive tests (Table 1). As regards the results of hypertensive subjects, they did not perform worse than the non hypertensive (Table 2). The uncontrolled subjects performed much worse than the controlled subjectss with a statistically significant difference. The studied population was divided into 3 groups: the controlled hypertensive, the uncontrolled hypertensive, and the non hypertensive group. The comparison between the 3 groups revealed that the controlled hypertensive subjects had better scores in MMSE (P < 0.001), DSF (P < 0.001), DSB (P = 0.024), LVF (P = 0.012), and CP (P < 0.001) than the uncontrolled and the non hypertensive (Table 2).

* SBP = Systolic Blood Pressure.
† SD = Standard deviation.
‡DBP = Diastolic Blood Pressure.
§MAP = Mean Arterial Pressure.
PP = Pulse Pressure.
# MMSE = Mini Mental Status Examination.
** BD = Block Design.
†† DSF = Digit Span Forward.
‡‡ DSB = Digit Span Backward.
§§ LVF = Letter Verbal Fluency.
AVF = Animal Verbal Fluency.
# CP = Contrasting program

Table 3: Comparison of subjects as regard BP control, treatment category, education, blood pressure variables and cognitive executive test

When comparing BP control, education treatment category and cognitive /executive tests by ANOVA, BP control showed a statistically significant relation with all tests: MMSE (P < 0.001), BD (P < 0.001) DSF (P= 0.018), DSB (P < 0.001), LVF (P = 0.01), CP (P = 0.001) except AVF (P = 0.09). Treatment category showed significant relation with only BD (P =0.005), DSF (P =0.042) and CP (P =0.012); Education showed a statistically significant relation with all cognitive/executive tests: BD (P = 0.001), DSB (P = 0.006), LVF (P < 0.001), CP (P = 0.05), AVF (P < 0.001) except MMSE (P = 0.12) and DSF (P=0.592) (Table 3).

DISCUSSION
HTN is the major health problem of elderly in Egypt.(5) The association between HTN and the decline in the Cognitive/executive functions was reported by several studies.(16,17) On the other hand Posner et al.,(18) reported that HTN is not associated with changes in memory, language or general cognitive functions over time. The mechanisms underlying HTN-related cognitive changes are complex and are not yet fully understood.(19) so the purpose of the study was to assess the relationship between HTN and cognitive/executive functions in elderly. According to the Research Committee of the American neuropsychiatric association, there is no established golden test for executive control function (ECF). This may be due to three reasons. Firstly, the frontal lobe represents so much of the brain's weight and surface area; it seems unlikely that any one measure could assess its functions comprehensively. Secondly, the frontal system has many subcortical connections which are also relevant to ECF. Finally, the ECF has an intimate relationship with other cognitive functions. So, we are searching for an executive battery, not an executive measure,(20) This statement explains the diversity in literature discussing the effect of HTN on cognitive/executive functions. This could be due to the use of different cognitive/executive tests, so we selected a battery of the cognitive/executive tests: MMSE, BD, DSF, DSB, LVF, AVF, and CP.

Results revealed no statistically significant difference between hypertensive and non hypertensive subjects as regards cognitive/executive performance, but comparing the studied population as 3 groups (controlled hypertensives, uncontrolled hypertensives, and non hypertensives) revealed that the controlled groups had better scores even than the normal subjects. This finding raises the question of why did the controlled hypertensive patients perform better? There may be several possibilities. One of these is; they had the ideal BP measurements for the best cognitive/executive performance which in our study were 127.5±8.44 for SBP, 75.71±6.34 for DBP, 101.42±6.78 for MAP, and 51.78±7.72 for PP. But in fact these readings did not differ significantly from that of the uncontrolled; 160.47±8.64 for SBP, 89.22±7.84 for DBP, 125.15±6.65 for MAP, and 71.25±10.39 for PP; or the non hypertensive ones; 118±11.6 for SPB, 71.66±7.63 for DBP, 94.58±9.21 for MAP, and 46.5±7.98 for PP; thus this may be individualized; each person may have his ideal BP measurements for better cognitive/executive performance.

Another important possibility may be the effect of the drugs used for BP control. ACE inhibitors were the most antihypertensive drugs used by the controlled patients (21 of the cases groups); who had the best cognitive/executive performance. Literature shows that antihypertensive that cross the blood brain barrier and affect the renin-angiotensin-aldosterone system (such as Captopril and Perindopril) control BP and provide protection against cognitive decline.(21) Also ACE inhibitors were found to be independently associated with the stability of cognitive function and were a protective factor for cognitive deterioration.(22) The relationship between different BP components of subjects and cognitive/executive tests showed that high SBP or MAP or PP was associated with worse performance in almost all tests. The DBP did not show such direct relation, but it may have an indirect effect through the MAP or PP. The specific cognitive functions affected by high blood pressure have not yet been thoroughly or unequivocally determined; however, high blood pressure is consistently related to deficits in attention(23), learning and memory(24), some visuospatial functions(25), and abstract reasoning and other executive functions.(26, 27) Another factor that might have influenced the performance of hypertensive subjects was the educational level. A highly statistical significant relation was found between having lower level of education (illiterate, below high school) and the worse performance in the following tests MMSE, BD, DSB, LVF, AVF, and CP. Waldstein et al.,(28) assessed attention, working memory, and executive function on 847 participants (503 men and 344 women), by using DSF test, DSB test and Category Fluency test, she reported that less-educated elderly, and non-medicated (with anti-hypertensive drugs), cases were most vulnerable to negative effects of hypertension on the selected cognitive/executive tests. She also states that higher levels of education and use of antihypertensive medications may protect against the neurobiological consequences of hypertension. Regarding the relationship between education and cognitive/executive tests(29) she concluded that a limited formal education is associated with less cognitive function. Also(30) found that in elderly Egyptians lack of education in early life enhanced later cognitive decline. In Egypt the percentage of elderly above 65 years who have completed secondary education was 7.5% in males and 2.8 % in females in 2005.(6)

Education has a marked effect on neuropsychological test performance.(31) For example, the cutoff for "normal" performance on the Mini-Mental State Examination may vary by as much as eight points depending on the individual's educational level.(32) Education specific normative data are not available for most tests, and interpretation of test results in individuals with unusually high or low levels of education must be done with caution. (31)

In conclusion our study revealed that HTN per se may not add to the burden of cognitive/executive dysfunction when compared to non hypertension but the risk lies in having high uncontrolled BP measurements. The conclusion that each individual might have an individualized BP measurement at which he/she performs better needs further assessment and studying. Finally the use of ACE inhibitors by hypertensive patients may have a beneficial effect on cognitive/executive functions but can this be applied on normal individuals? This needs still further investigation.

ACKNOWLEDGMENT
The authors wish to thank study participants and staff of Ain Shams University hospital for their patience and help that made this study possible.
This study was supported by Ain Shams University Faculty of medicine.


REFERENCES
[1] Beers M and Berkow R (2000), eds. The Merck Manual of Geriatrics. 3rd ed.
Whitehouse Station, NJ: Merck Research Laboratories
[2] Schillerstrom JE, Horton MS, Royall DR. (2005): The impact of medical illness on executive function: Psychogeriatrics; 46: 508-16..
[3] Rose J and Colombo M (2005): Neural Correlates of Executive Control in the
Avian Brain PLoS Biol; 3(6): e190..
[4] Ibrahim M, (2001): Manual of hypertension. Egyptian Hypertension Society, Cairo.
[5] Badr S, Mansour E, Salah M, Mohammed M (2005). Geriatric health problems among attendants of the upgraded ministry of health and population geriatric health care centers. Reports of Egyptian ministry of health and population, 2005.
[6] Kinsella K and Wan H (2009): An Aging World: 2008. U.S. Census
Bureau, International Population Reports, P95/09-1, U.S. Government Printing Office, Washington, DC. Pp 34, 105
[7] Raz N, Rodrigue K, Acker J. Hypertension and the Brain: Vulnerability of the
Prefrontal Regions and Executive Functions. Behav Neurosci.2003; 117, 1169- 80.
[8] Morris MC, Scherr PA, Hebert LE, Glynn RJ, Bennett DA, Evans DA. Association of Incident Alzheimer Disease and Blood Pressure Measured From 13 Years Before to 2 Years After Diagnosis in a Large Community Study. Arch Neurol. 2001; 58:1640-6.
[9] Chobanian A; Bakris G .; Black H; Cushman W; Green L; Izzo, Jr J; Jones D; Materson B; Oparil S; Wright, Jr J; Roccella E; the National High Blood Pressure Education Program Coordinating Committee. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003; 42: 1206-52.
[10] Ganong W. Review of medical physiology. Lange medical publications. 21st ed
California,1998.
[11] El-Okl M. Prevalence of Alzheimer dementia and other causes of dementia in Egyptian elderly. MD thesis, Geriatrics Department, Ain Shams University library.2002.
[12] Melika L. Wechsler Intelligence Scale for adults and adolescents. El-Nahda Egyptian library, Cairo 1991; 91:92-97-101.
[13] Gladsjo JA, Schuman CC, Evans JD, Peavy GM, Miller SW, Heaton RK Norms for letter and category fluency: demographic corrections for age, education, and ethnicity.
Assessment.1999;6:147-78.
[14] Morris JC, Heyman A, Mohs RC, Hughes JP, van Belle G, Fillenbaum G, Mellits ED, Clark C The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part I: clinical and neuropsychological assessment of Alzheimer's disease. Neurology.1989; 39:1159-65.
[15] Stewart J. The frontal/subcortical dementias: Common dementing illnesses associated with prominent and disturbing behavioral changes. Geriatrics.2006; 61:23-7.
[16] Tzourio C, Dufouil C, Ducimetière P, Alpérovitch A cognitive decline in individuals with high blood pressure, A longitudinal study in the elderly: EVA Study Group. Epidemiology of Vascular Aging. Neurology.1999; 53: 1948-52.