The relationship between the status of hypertension and lifestyle risk factors in middle-aged and elderly patients with mild cognitive impairment: a case-control study

Abstract

BACKGROUND

In epidemiological studies, hypertension is related to the difference in the incidence of cognitive impairment, but the evidence is currently inconsistent regarding the association of disease duration, treatment, control, and life risk factors with mild cognitive impairment (MCI) in patients with hypertension.

METHODS

We selected 572 patients with hypertension treated in six medical centers in Nanjing from 2017 to 2020. The cognitive function of participants was assessed using MoCA. Potential risk factors were investigated by a structured questionnaire. Risk factors associated with the conversion of MCI occurring in hypertension were analyzed using multifactorial regression analysis.

RESULTS

MCI was observed in 256 of 572 individuals. MCI was more likely with increasing age (OR=1.15, 95%CI 1.10-1.20), and high education was better at preventing MCI (OR=0.47, 95%CI 0.32-0.71) among baseline clinical characteristics. Risk factors independently associated with MCI were diabetes (OR=2.40, 95%CI 1.53-3.76), Hyperlipidemia (OR=1.49, 95%=1.01-2.16), high salt diet (OR=2.27, 95%CI 1.34-3.84), and physical activity:༞2h/week (OR=0.65, 95%0.44-0.94). Controlling blood pressure to target values helped prevent MCI(OR=0.44, 95%CI 0.30-0.65), and these results were similar when stratified by age.

CONCLUSION

Our results suggest that it is necessary to popularize hypertension knowledge and a healthy lifestyle, and optimize treatment to achieve the goal of preventing cognitive decline in the middle-aged and elderly.

Background

With the rapid development of China's economy, the aging population in eastern China has also arrived, and the prevalence of hypertension continues to rise. According to the latest survey, the current number of patients with hypertension over 18 years old in China is about 240 million.^[1] It has become one of China’s major public health problems.

Hypertension can cause not only serious complications such as stroke, heart failure, cardiovascular events but also an important risk factor for cognitive impairment.^[2]According to a national epidemiological survey in China, hypertension increases the risk of dementia and MCI by 1.86 and 1.62 times, respectively.^[3] According to its severity, cognitive impairment is often classified into mild cognitive impairment (MCI) and dementia. Evidence has demonstrated that individuals with MCI are at a higher risk of progressing to dementia, particularly in the elderly population.^[4] Cognitive dysfunction can seriously affect the patient's ability to live and socialize while increasing the burden on the patient's economy, family, and society.^[5] In the past few decades, the prevalence of dementia in China has been increasing rapidly.^[3] Therefore, there is an urgent need to identify people at high risk of MCI for early identification and early intervention to prevent these people from progressing to dementia. Moreover, an optimal treatment approach must be developed to prevent the expected social and disease burden.

The current study aims to investigate the cognitive function of hypertensive patients aged between 50 and 75 years old in various regions of Nanjing, China, and their risk factors for developing MCI, to determine whether treatment of hypertension has an effect on cognitive impairment, and to provide a basis for early prevention and delaying the onset of dementia. The findings from this study will provide health professionals with useful information on risk management and measures to reduce cognitive impairment in patients with hypertension.

Methods

Study population

Data for this study were collected from patients who, age between 50 and 75 years old, were diagnosed with hypertension in the Affiliated Hospital of Nanjing University of Chinese Medicine, Zhimaying Community Health Service Center, Zhonghuamen Community Health Service Center, Confucius Temple Community Health Service Center, and Chaotiangong Community Health Service Center from May 2017 to October 2020. In this study, patients with non-essential hypertension, severe visual and hearing impairment, Alzheimer's disease, or other causes of dementia, heart failure, and stroke were excluded. The screen flow chart of the study sample is shown in Fig.1. The study was approved by the Ethics Committee of the Affiliated Hospital of Nanjing University of Chinese Medicine (2018NL-080-03), and written informed consent was obtained from the patients or their families. 

Data collection

Each participant completed a standardized questionnaire through a face-to-face interview. Data were collected on the participants’ demographic characteristics (age, gender, occupation, education, BMI), medical histories (history of hypertension, diabetes mellitus, white matter hyperintensity, coronary artery disease, hyperlipidemia, and treatment data), and lifestyles (dietary preferences, smoke, drinking alcohol, physical activity, hobbies, sleep duration). The BMI of all patients was classified into four categories according to Chinese adult standards: underweight (BMI < 18.5), normal weight (18.5 ≤ BMI < 24.0), overweight (24.0 ≤ BMI < 28.0), or obesity (BMI ≥ 28.0).^[6]

Neuropsychological and MRI assessment

Trained neurologists evaluated each participant’s cognitive function with the Chinese version of the Montreal Cognitive Assessment (MoCA-Chinese Beijing version) scale, which is a commonly used measurement in China.^[7] For the diagnosis of MCI, the patient should complain of cognitive decline, which was confirmed by others and met the 2011 NIA-AA requirements for the diagnosis of MCI.^[8]It included the following four points: there was altered cognitive function; the cognitive impairment involved one or more cognitive domains; functional independence was maintained; it was not sufficient for a diagnosis of dementia, and the ability to perform daily living was not affected.

The sensitivity of MoCA to detect MCI is higher than that of Mini-Mental Status Exam (MMSE).^[9] Mild cognitive impairment was defined as 18≤MoCA <26.^{[10] [11]}Those with no more than 6-year education add 1 point to the total score.^[12] All subjects underwent MRI on a device with a 1.5-T magnet. MRI was used to estimate the severity of WMH and stroke. All hypertension patients were divided into the MCI group and the non-MCI group.

Statistical analysis

Continuous variables were expressed as the mean ± standard deviation if they followed a normal distribution; otherwise, they were expressed as the median (interquartile range). Categorical variables were expressed as frequencies (percentages). As appropriate one-way analysis of variance or the Kruskal–Wallis test was used to compare continuous variables. Categorical variables were compared using χ² test or Fisher’s exact test, as appropriate. Univariate analysis was performed with the Student's t-test, Mann-Whitney U-test, or Chi-square test. Variables with P<0.05 in univariate analysis were then included in the forward stepwise logistic regression model.

There were some missing values in the data survey of this study, and the following methods were used to deal with the missing values: the questionnaires with vacancy rate ≥ 5% were invalidated; the questionnaires with vacancy rate < 5% were filled with the mean value.

Results

Description of the population

A total of 572 patients (307 males and 265 females) with essential hypertension were included in the present study. The total mean MoCA score was 25.03 ± 3.72 (median 26), and 44.76% (n= 256) of the study participants scored below the recommended cut-off for MCI or dementia (<26 points). The distribution of the MoCA score is shown in Fig.2. Baseline characteristics of the two groups are shown in Table 1. The mean age of the participants was 61.31±4.74 years, ranging from 50 to 75 years, and 49.48% of them (n=283) were workers by occupation. Compared with the non-MCI group, patients in the MCI group were older, and had a lower level of education, higher weight.

Analysis of risk factors for MCI

According to univariate analysis (Table 2), age, education, BMI, cigarette smoking, physical activity, sleep duration, food preferences, WMH, diabetes mellitus, hyperlipidemia, regular medication, controlled hypertensives, and hypertension grade (grade Ⅲ) were significantly different between MCI group and non MCI group (P<0.05). To reduce the effect of confounding factors, we further performed a multivariable analysis with the occurrence of MCI or not as the dependent variable (occurrence =1, not occurrence =0). And the variables with P<0.05 in univariate analysis as the independent variables were included. Logistic stepwise regression the analysis showed that age (OR: 1.15, 95%CI: 1.10-1.20), education (OR: 0.47, 95%CI: 0.32-0.71), physical activity (OR: 0.65, 95%CI: 0.44-0.94), food preferences (OR: 2.27, 95%CI: 1.34-3.84), diabetes mellitus (OR: 2.40, 95%CI: 1.53-3.76), hyperlipidemia (OR: 1.49, 95%CI: 1.01-2.16), controlled hypertensives  (OR: 0.44, 95%CI: 0.30-0.65), and hypertension grade (OR: 6.13, 95%CI: 1.47-25.52) were independent risk factors for MCI in hypertensive patients with adjustment for other covariates with P < 0.05 in the univariable analysis.

The probability test outcome variable for predicting MCI was generated based on a multivariable logistic regression data model, and it was plotted as a ROC curve to predict MCI outcomes. The area under the ROC curve was 0.772, which was between 0.7 and 0.9, indicating that the model had a good predictive value. And the P-value <0.001, 95% CI: 0.734-0.810. 

Relationship between the current treatment status of hypertension and MCI

Table 3 shows the associations of risk factors between the duration, regular antihypertensive medication, hypertension control, and the prevalence of MCI by gender. After adjusting for age, education, physical activity, food preferences, diabetes mellitus, hyperlipidemia, controlled hypertensives, and hypertension grade. We found that the duration of hypertension and the regular use of anti-hypertensive drugs did not significantly change the prevalence of MCI both in males and female. However, the difference between the controlled hypertensive patients who achieved their treatment goal was significant. In the male and female hypertensive patients, the adjusted OR (95% CI) of having MCI in those participants were 0.47 (0.28-0.79) and 0.40 (0.22-0.73). 

Table 4 shows the adjusted variables between the duration, regular antihypertensive medication, and control of hypertension, and the prevalence of MCI by age. We found that the older the group, the lower the percentage of them who were taking antihypertensive medications regularly and having their blood pressure controlled. However, there were no statistically significant differences. In the 58-65 age group (n=351), the adjusted OR (95% CI) of having MCI was 0.40 (0.25-0.66) in those controlled hypertensives compared with those uncontrolled individuals. However, among the regular use of antihypertensive medication patients, there was no difference in the prevalence of MCI between the patients who did not take medication regularly. Also, the differences were not significant between 50–57 years and ⩾65 years.

Discussion

This study is a population-based case-control study with a strict training process and quality assurance programs. The risk of developing MCI in hypertensive patients in this study appears to be influenced by various factors. And after adjusting for confounding factors, we found that controlling patients' hypertension to target levels (no matter the type of hypertensive drugs used) reduced the incidence of MCI, particularly in the younger elderly population in an urban community in Nanjing China.

Research on hypertension and cognitive impairment first began in the 1960s with the study of pilots.^[13] Until now, there has been controversy about studying the effects of hypertension on cognitive impairment in the middle-aged and elderly population. Several observational studies have found that chronic hypertension, especially high SBP in middle age (40-65 years), was associated with an increased risk of cognitive impairment or dementia in later life.^{[2, 14, 15]} However, studies on the relationship between blood pressure levels and cognitive decline and dementia at older ages have reached inconsistent conclusions. An observational study in Italy has shown that hypertension in the elderly was not related to cognitive impairment.^[16] Some studies have even suggested that higher blood pressure levels are associated with better cognitive function scores.^[17] In the present study, MCI occurred in about 44.8% of hypertensive patients, and we found no significant difference in the prevalence of MCI between 50-57, 58-65, and >65 age groups. However, the prevalence of MCI among adults aged ≥60 years in China was 15.5% in 2020,^[3] significantly lower than that of hypertensive patients in this study. Our findings suggest an effect of hypertension on the onset of MCI in middle-aged and older adults, and grade 3 hypertension was more likely to have cognitive impairment than grade 1 hypertension. But the further expansion of the sample size is needed to confirm the findings.

Currently recognized research concluded that structural changes in the cerebral vasculature secondary to long-term hypertension, with endothelial damage, leading to altered cerebral perfusion was thought to be the main biological pathway linking hypertension to cognitive impairment.^{[18] [19]}Therefore, antihypertensive treatment is crucial. There is controversy about whether lowering blood pressure helps prevent cognitive impairment in patients with hypertension. This year, a cohort study in Brazil showed that effective treatment of hypertension at any age could prevent or slow cognitive decline. ^[20] In 2020, a meta-analysis that included six prospective studies (containing 31,090 participants) showed that receiving antihypertensive therapy reduced the risk of cognitive impairment by 12% and the risk of Alzheimer's disease by 16% compared with not receiving antihypertensive therapy, and this effect was independent of the type of antihypertensive drugs.^[21] Also, there was meta-analyze that held the opposite view. Chang et al. evaluated the association between antihypertensive medication use and the risk of cognitive decline but showed that antihypertensive treatment did not decrease the risk of cognitive decline.^[22]

The present study found that the two key ORs for the prevention of MCI (patients on regular hypertension medication compared with that not on regular hypertension medication and patients with controlled hypertension compared with those uncontrolled hypertension) were similar in the univariate analysis. However, in multivariate regression analysis, we found that the prevalence of MCI was significantly lower in patients with hypertension who reached the treatment target than in those who did not, although they were taking antihypertensive drugs regularly. The results suggest that hypertension treatment has a protective effect on MCI, but treatment targets (blood pressure level) need to be met, and this effect was not statistically significant across different classes of antihypertensive agents (ACEI, ARB, β-blockers, CCB, and else).

In addition, many complex factors may be involved in the poorer cognitive performance of hypertensive patients. Hypertension was always accompanied by other risk factors, such as diabetes and hyperlipidemia. Diabetes can lead to abnormal cerebral angiogenesis and increased capillary density in the central nervous system. This change would accelerate the damage and leakage of blood vessels in the process of neurodegeneration.^[23] Ryuno and his colleagues found that hypertension combined with diabetes was more likely to have future cognitive decline than hypertension or diabetes alone,^[24]which is similar to the results of the current study. Hyperlipidemia can cause chronic inflammation of the nervous system, damage nerve cells and impair the function of vascular endothelial cells, and affect the brain's cognitive function.^[25] The prevalence of MCI in patients with hyperlipidemia was 1.49 times higher than in patients without hyperlipidemia in the current study. But research on the relationship between blood lipids and MCI is still divided, with some researchers suggesting that elevated blood lipids have beneficial effects on cognitive function in the elderly population.^{[26, 27]} Future studies should focus on the interaction of multiple risk factors with a more extended follow-up period.

In terms of personal life, we also identified factors associated with the development of MCI in patients with hypertension in the current study. For instance, education, dietary preferences, and physical exercise. A study by Langa et al. found that as education levels increased, the prevalence of cognitive impairment among those aged 70 and older decreased from 12.2% in 1993 to 8.7% in 2002.^[28] This study suggests that the cognitive reserve generated by early education and cognitive stimulation can prevent MC that the cognitive reserve generated by early education and cognitive stimulation can prevent MCI. Therefore, further strengthening children’s education will help reduce the burden of dementia and cognitive impairment. The salt intake of Chinese residents is one of the highest globally. The average daily intake of salt for adults has been above 10 grams for the past 40 years, more than twice the recommended amount.^[29] Excessive salt intake can directly cause hypertension, which could lead to cognitive decline,^[30] and reduces blood flow to the brain and lead to dementia.^[31] Khater et al. ^[32] confirmed that good dietary status maintains good cognitive health, the Mediterranean dietary pattern has been shown to have a cognitive protective effect, ^[33] but the further research evidence is needed for its use in patients with hypertension. Whether physical exercise affects cognitive impairment in hypertensive patients has not been confirmed by authoritative studies. However, a meta-analysis demonstrated that maintaining physical activity in hypertensive patients helped improve cognitive function scores^[34], and brisk walking for 40 minutes three times per week reduces brain atrophy and improves memory and other cognitive functions.^[35] More research is needed in the future to individualize the type, frequency, and duration of physical exercise.

There are limitations to this study. First, there may be recall bias in the collection of patients data (e.g., disease histories), as each piece of information was self-reported by the patient. To avoid such problems, we asked participants to bring historical medical paperwork and let their relatives join in the conversation if possible. Second, changes in MoCA scores over time were not studied. If differences in MoCA were not related to hypertension, the ability to identify specific risk factors (e.g., treatment for hypertension) would be reduced. Third, specific dietary and blood pressure variances were not collected from participants. The factors may be essential covariates in the analysis of the study. Fourth, the relationship between hypertension and cognitive function is complicated, which the middle-aged and elderly often have an exceptionally high number of risk factors, such as coronary heart disease, depression, and insomnia. And although we adjusted for confounding variables in our analysis, we cannot guarantee the effect of other undetected covariates on the current study results. Fifth, the present study may have been subject to misclassification bias. Some patients may not have taken their antihypertensive medication on the morning of the study because some participants may have been required to fast on the day of the blood test. Their blood pressure may have been elevated on the study day, so the investigators would have misclassified them as patients with irregular medication or uncontrolled hypertension. Finally, Nanjing is a developed area in eastern China and the study results may not be generalizable to less economically developed areas in northwestern China. Further prospective studies with large nationwide sample sizes are needed to explore practical measures to prevent and treat MCI in China's middle-aged and elderly hypertensive population.

Conclusion

This study shows that patients with hypertension who regularly take hypertensive drugs and control their blood pressure to achieve treatment goals have an important role in preventing MCI. And educational level, physical exercise, salty diet, diabetes, and hyperlipidemia are related to cognitive function in hypertensive patients, but it still needs to be confirmed in a larger sample size. Our results suggest that it is necessary to popularize hypertension knowledge and a healthy lifestyle, and optimize treatment to achieve the goal of preventing cognitive decline in the middle-aged and elderly.

Abbreviations

MCI: mild cognitive impairment; SD: standard deviation; IQR: interquartile range; BMI: body mass index; WMH: white matter hyperintensities; DOH: duration of hypertension; CCB: calcium Channel Blockers, ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; BB: Beta-receptor blocker.

Declarations

Acknowledge

This study was supported by the National Natural Science Foundation of China (81673759) and the Social Science and Technology Development Program of Jiangsu Province (BE2017769).

Author contributions

XY and CC helped design the study and analyzed the data. XY, TM, JL, JD and HL helped with the data collection and field operations. The manuscript was drafted by XY. All authors contributed to the critical review and final approval of the submitted manuscript.

Availability of data and materials 

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Ethics approval and consent to participate

The study was approved by the Ethics Committee of the Affiliated Hospital of Nanjing University of Chinese Medicine (2018NL-080-03). All of the included patients signed written informed consent forms.

Consent for publication 

Not Applicable.

Competing interests

None

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Tables

Table1. Baseline characteristics according to mild cognitive impairment groups

Abbreviation: SD=standard deviation; IQR=interquartile range; BMI= body mass index; WMH=white matter hyperintensities; DOH=duration of hypertension; CCB=calcium Channel Blockers, ACEI=angiotensin-converting enzyme inhibitor;  ARB=angiotensin receptor blocker; BB=Beta-receptor blocker.

*Adjusted with P < 0.05 in the univariable analysis age, education, BMI, physical activity, cigarette smoking, drinking alcohol, sleep duration, food preferences, WMH, diabetes mellitus, hyperlipidemia, regular medication, controlled hypertensives and hypertension grade.

*Adjusted for age, education, physical activity, food preferences, diabetes mellitus, hyperlipidemia, controlled hypertensives and hypertension grade.

*Adjusted for age, education, physical activity, food preferences, diabetes mellitus, hyperlipidemia, controlled hypertensives and hypertension grade.