In 288 men and women from general population in a cross-sectional survey, all neuropsychological tests were negatively associated with age; memory and executive function were also positively related with education. The hypertensives (HT) were less efficient than the normotensives (NT) in the test of memory with interference at 10 sec (MI-10) (−33%,
Dementia represents a considerable public health issue in developed countries due to progressive increase of affected individuals occurring with rapid ageing of population [
The right approach to this problem is to place emphasis on preventive strategies to identify and counterbalance the risk factors at a population level.
Although hypoperfusion and neurodegeneration have emerged as possible underlying mechanisms, the pathophysiology of the relationship between high BP and low cognition remains unclear. Not only this, but also the BP levels that should be targeted to achieve optimal perfusion while preventing cognitive decline are still being debated [
The aim of the present study is to investigate the relationships of the different components of BP with cognitive function and cognitive reserve in a representative sample of general population and to identify the domains most affected.
All men and women aged ≥50 years living in two Italian towns were invited by letter for a screening; 1,377 (76%) agreed with the study protocol, gave informed consent, and were recruited and regularly followed up; 288 randomly selected subjects (164 men and 124 women) underwent the neuropsychological tests described below and were considered for the analysis of data in the present work. Their general characteristics did not differ significantly from those of the remaining part of the sample (data not shown). The protocol of the LEOGRA study was extensively described elsewhere [
General characteristics of the study cohort.
Body mass index (kg/m2) | |
Obesity (%) | 18 |
Left ventricular mass index (kg/m2) | |
Left ventricular hypertrophy (%) | 54.2 |
Systolic blood pressure (mmHg) | |
Diastolic blood pressure (mmHg) | |
Heart rate (bpm) | |
Pulse pressure (mmHg) | |
History of coronary events (%) | 7.3 |
History of cerebrovascular events (%) | 3.2 |
Haematocrit (%) | |
Sedimentation rate (mm/h) | |
Blood glucose (mg/dL) | |
Diabetes (%) | 18 |
Serum uric acid (mg/dL) | |
Low-density-lipoprotein cholesterol (mg/dL) | |
High-density-lipoprotein cholesterol (mg/dL) | |
Serum triglycerides (mg/dL) | |
Circulating cortisol ( | |
Circulating T3 (ng/dL) | |
Circulating T4 ( | |
Plasma TSH (mlU/L) | |
Circulating insulin ( | |
HOMA-R | |
Apolipoprotein B/A ratio | |
Current smokers (%) | 10.4 |
Cigarettes/day in smokers |
Mean ± standard deviation is provided for continuous variables, percent values for categorical variables. HOMA-R: homeostasis model assessment index; TSH: thyrotropin.
Cognitive assessment was performed by means of mini-mental state examination (MMSE) [
Short-term memory was studied by means of digit span [
The entire battery of tests was administered in a single session which took approximately two hours to complete. The digit span [
The results of the neuropsychological battery were compared to the normative sample for Italian subjects aged ≥50 years [
Cognitive reserve index (CRI)—the ability to optimize and maximize performance through recruitment of brain networks and/or compensation by alternative cognitive strategies—was also measured through a validated questionnaire [
The label of arterial hypertension [
Left ventricular hypertrophy required a left ventricular mass index ≥125 g/m2 in men or ≥110 g/m2 in women [
Subjects were labelled as diabetic when having fasting blood glucose repeatedly ≥126 mg/dL, blood glucose ≥140 mg/dL two hours after 75 g oral glucose, blood glucose ≥200 mg/dL at casual measurement, or current antidiabetic treatment confirmed by general practitioner [
History was positive for coronary artery disease when the Minnesota code was 1.2, 1.2, or 1.3 if absent 6.4.1, or 4.1 or 4.4 if absent 6.4.1, 7.1.1, and 7.2.1, or 5.1, 5.2, 5.3, or 5.4 if absent 6.4.1, 7.7.1, 7.2.1, and 7.4, or akinesia or dyskinesia were present at echocardiogram, or in the presence of positive myocardial scintigraphy or stress test, or of positive history of myocardial infarction or angina pectoris confirmed by hospital files, or in chronic appropriate antianginal treatment, or in the presence of hospital discharge with diagnosis-related group 410–414.
History was positive for cerebrovascular disease when in the presence of neurological signs, on positive history of stroke or transient ischaemic attack, or positive TC or MR or on hospital discharge with DRG 430–438.
Education was defined as years of schooling. MMSE was defined as low when scoring <24, MI-10, and CLOX when below the first tertile.
Continuous variables were expressed as mean and standard deviation and compared with analysis of variance and the post hoc Bonferroni’s correction. Categorical variables were expressed as percent rates and compared with the Pearson’s
The label of “hypertension” was first used to stratify subjects, and the two categories (normotensive, hypertensive) were compared. The systolic and diastolic BP components were then used as independent variables in multivariate regression analyses having the test scores as dependent. Finally, as a unitary representation of the systolic and diastolic components [
Gender, age, BMI, historical cerebrovascular, and coronary events, education, arterial hypertension, diabetes, and antihypertensive treatment were used as covariables in multivariate analysis.
Finally, the joint distribution of mean systolic and diastolic BP was evaluated by BP vector analysis (mean vector with 95% confidence intervals) in subjects having normal or impaired test performance. This method has been described elsewhere [
The investigation met the principles outlined in the Declaration of Helsinki and institutional guidelines and was approved by the Local Ethics Committee. Before the study and after consulting his/her own general practitioner, each subject accepted and signed an informed consent.
The cohort characteristics are shown in Table
No significant difference was detected between men and women. Consequently, the subsequent analysis was irrespective of gender.
The scores of neuropsychological tests were not different from those expected for a normal group of reference persons of the same age [
Multiple regressions of the neuropsychological tests with age and education.
Tests | Age (years) | Education (years) | ||
Mini-mental state examination | −0.14 (0.03) | <0.0001 | −0.01 (0.09) | 0.9 (NS) |
Digit span | −0.03 (0.01) | <0.001 | 0.06 (0.03) | 0.06 (NS) |
Immediate prose memory | −0.19 (0.03) | <0.0001 | 0.38 (0.11) | <0.001 |
Delayed prose memory | −0.24 (0.04) | <0.0001 | 0.41 (0.13) | <0.001 |
Memory with interference at 10 sec | −0.08 (0.02) | <0.0001 | 0.20 (0.17) | <0.005 |
Memory with interference at 30 sec | −0.07 (0.02) | <0.0001 | 0.32 (0.06) | <0.0001 |
Phonemic verbal fluency | −0.12 (0.03) | <0.0001 | 0.28 (0.09) | <0.005 |
Trail making test A | 0.93 (0.30) | <0.005 | −2.78 (0.99) | <0.01 |
Trail making test B | 2.45 (0.62) | <0.0001 | −3.32 (2.04) | 0.1 (NS) |
Overlapping figure | −0.34 (0.06) | <0.0001 | 0.32 (0.20) | 0.09 (NS) |
Clock drawing test | −0.07 (0.03) | <0.01 | 0.27 (0.08) | <0.005 |
4After stratifying subjects according to the ESH/WHO label of hypertension [
Cognitive tests scores by blood pressure value adjusted for age and education.
Tests | Whole cohort ( | Normotensive subjects ( | Hypertensives subjects ( | ||
---|---|---|---|---|---|
Mini-mental state examination | <0.005 | <0.05 | |||
Digit span | 0.04 | 0.3 (NS) | |||
Immediate prose memory | 0.03 | 0.7 (NS) | |||
Delayed prose memory | <0.01 | 0.9 (NS) | |||
Memory with interference at 10 sec | <0.0001 | <0.05 | |||
Memory with interference at 30 sec | <0.005 | 0.2 (NS) | |||
Trail making test A | 0.3 (NS) | 0.6 (NS) | |||
Trail making test B | <0.01 | 0.2 (NS) | |||
Phonemic verbal fluency | 0.03 | 0.9 (NS) | |||
Overlapping figure | <0.001 | 0.2 (NS) | |||
Clock drawing test | <0.0001 | <0.01 | |||
Cognitive reserve index | 0.03 | <0.05 |
95% confidence intervals in brackets; NS: nonsignificant difference.
In multiple regression analysis adjusted for age and education, both systolic BP and PP resulted to be independent predictors of MMSE, with MI-10 and CLOX, while the diastolic component taken alone did not (Table
Regression of the test scores with the systolic and diastolic components of blood pressure.
Systolic blood pressure | Diastolic blood pressure | Pulse pressure | ||||
Mini-mental state examination | 0.97 | 0.02 | 0.97 | 0.2 (NS) | 0.97 | 0.02 |
Digit span | 0.99 | 0.06 (NS) | 0.99 | 0.5 (NS) | 0.99 | 0.06 |
Immediate prose memory | 0.99 | 0.6 (NS) | 1.00 | 0.9 (NS) | 0.99 | 0.5 (NS) |
Delayed prose memory | 0.99 | 0.6 (NS) | 1.05 | 0.2 (NS) | 0.97 | 0.1 (NS) |
Memory with interference at 10 sec | 0.98 | <0.005 | 0.97 | 0.1 (NS) | 0.97 | <0.01 |
Memory with interference at 30 sec | 0.99 | 0.2 (NS) | 0.98 | 0.3 (NS) | 0.99 | 0.3 (NS) |
Trail making test A | 0.95 | 0.7 (NS) | 0.99 | 0.1 (NS) | 1.16 | 0.4 (NS) |
Trail making test B | 1.31 | 0.5 (NS) | 2.18 | 0.3 (NS) | 1.09 | 0.8 (NS) |
Phonemic verbal fluency | 0.98 | 0.1 (NS) | 1.00 | 0.9 (NS) | 0.97 | 0.06 (NS) |
Overlapping figures | 0.99 | 0.5 (NS) | 1.01 | 0.8 (NS) | 0.97 | 0.4 (NS) |
Clock drawing test | 0.96 | <0.001 | 0.99 | 0.8 (NS) | 0.95 | <0.0001 |
Cognitive reserve index | 0.94 | 0.2 (NS) | 1.09 | 0.4 (NS) | 0.82 | <0.001 |
95% confidence intervals in brackets;
When systolic and diastolic BPs were analyzed together with bivariate vector analysis, the 95% confidence ellipses of the mean of the pair of variables “systolic BP; diastolic BP” obtained from subjects showing low MMSE, MI-10 and CLOX did not overlap (
Vector analysis of the pair of variables “systolic blood pressure; diastolic blood pressure.” The points and the 95% confidence ellipses represent the mean values of systolic and diastolic pressure among subjects with normal (●) and low
CRI was 6% lower in the hypertensives than in the normotensives (Table
Vector analysis of the pair of variables “systolic blood pressure; diastolic blood pressure.” The points and the 95% confidence ellipses represent the mean values of systolic and diastolic pressure among subjects with cognitive reserve index ≥94 (●) and <94
High BP is known to be a risk factor for cognitive decline, and many studies demonstrated a relationship between BP levels and cognitive impairment [
The reasons of the association between arterial hypertension and impaired cognition are not completely understood, even though knowledge in this field is increasing. It is established that high BP causes directly or indirectly cerebral vascular damage (mainly
In our experience, the cognitive reserve was 6% lower in hypertensive than in normotensive subjects. The idea of a reserve against brain damage comes from the observation that the relationship between brain damage degree and clinical manifestation is not linear [
In conclusion, our study contributes to the belief that a link exists between BP and cognition, higher values of systolic BP being associated to impaired cognitive function. Although high BP is not sufficient
This study is novel in that it highlights the accessory role of diastolic in addition to systolic BP in modulating cognitive functions at a population level. Not only this, but also it clarifies that the cognitive decline accompanying high BP is not indiscriminate, but limited to memory and executive functions. Finally, it introduces in the estimation of cognitive decline an innovative concept, that of CRI, that seems to be particularly affected by pulse pressure.
For readers less familiar with multivariate analysis, we report the basic definitions of multivariate confidence intervals as well as formulae for their calculations in the particular case of the assumption of the bivariate normal distribution for blood pressure vector (BP = SBP on
Both approximate and exact methods are available for calculations of confidence ellipses of a bivariate normal distribution. Our modified version of the exact methods utilizes common statistics of the simple linear correlation analysis. Given
The authors declare no conflict of interests.