Association between H-type hypertension and Cognitive impairment in Kailuan community of China: A cross-sectional study.

Background Hypertension (HTN) and hyperhomocysteinemia (HHcy) have been reported to be independent predictors of cognitive impairment. However, the conclusions were inconsistent and few studies had reported the combination prediction of HTN and HHcy for cognitive impairment. Our study aimed to evaluate the association between H-type HTN, HTN and HHcy and the risk of cognitive impairment. We used a cross-sectional study- participants aged over 40 years, which were selected from Kailuan communities in China. Cognitive impairment was determined by MMSE scale (MMSE<24). Multivariable logistic regression was used to analyze the association of H-type HTN and cognitive impairment, and we also made stratification analysis by age of participants. A total of 3454 participants were included in our study, and ≥65 years old was 16.79%; the gender of male was 56.77%. The prevalence of cognitive impairment in the H-type HTN (HTN+/HHcy+) group (10.74%) was significantly higher than other three groups (2.92%, 6.42%, 5.86%, respectively). The logistic regression results showed that participants with H-type HTN was positively associated with cognitive impairment risk (OR = 2.57, 95% CI: 1.38-4.80). Similar results were observed in participants stratified by age (65 years) (<65 years old: OR =2.01, 95% CI: 0.87- 4.67 ; ≥65 years old: OR=3.63, 95% CI: 1.32-10.01). Our finding indicated that H-type HTN was positively associated with the risk of cognitive impairment, especially in ≥ 65 years old. H-type HTN could be the major intervention measures to decrease the incidence of cognitive impairment as well as the stroke in Health Practice Management.


Introduction
Cognitive impairment, especially dementia, is common in the elderly and seriously affects the quality of life [1]. Dementia is the most serious expression of cognitive impairment characterized by progressive functional decline in one or more cognitive domains. The prevalence of dementia has measurements for blood pressure and the levels of tHcy: 16.79% of subjects were elderly(≥ 65 years old) and mean age was 53 years (range: 40-89 years). The prevalence of cognitive impairment, Htype HTN, HTN and HHcy were 4.81%, 7.82%, 17.28% and 39.95%, respectively. The characteristic of the participants in our study are summarized in the Table 1. Significant differences were found in age, gender, education level, physical activity, current smoking, drinking, dyslipidemia, diabetes, BMI and LDL-C during different groups ( all P 0.05). There were no significant differences in mean or standard deviation or proportion between different groups for marital status, income, TC and HDL-C ( all P 0.05).
The proportion of cognitive impairment in the H-type HTN (HTN+/HHcy+) group (10.74%) was higher than other three groups (2.92%, 6.42% and 5.86%, respectively), and the difference had statistical significance (P 0.05) (Fig. 2). The prevalence of cognitive impairment in patients with H-type HTN over 65 years old was 22.95%, which was much higher than other characteristic populations (P 0.001).
Associations between HTN, HHcy and cognitive impairment.
Association between H-type HTN and cognitive impairment risk.
Subgroup analysis of the association of H-type HTN and the risk of cognitive impairment risk.
Age with H-Type HTN was significantly association with cognitive impairment (Fig. 5, P for interaction < 0.001). Stratified analyses showed that the risk of cognitive impairment is higher in elderly H-type hypertensive patients over 65 years old (OR = 3.63, 95% CI: 1.32-10.01). The adjusted OR and 95% CI for cognitive impairment with H-type HTN among participants younger than 65 were 2.01 (0.87-4.67).
Similar results were not observed in the different gender of participant. The adjusted ORs and 95% CIs for cognitive impairment with H-type HTN in different gender were 2.44 (1.19-5.03) and 3.14 (0.86-11.42), respectively.

Discussion
Our study found that H-type HTN was positively associated with the risk of cognitive impairment, in Kailuan community study which was based on the APCP cohort study, especially the participants aged ≥ 65 years. In addition, HTN but not isolated HHcy could be an independent risk factors for cognitive impairment.
Previous studies reported that HTN or HHcy were significantly associated with cognitive impairment [26,27]. To our knowledge, few studies explored the association between H-type HTN and cognitive function. Significant associations have been confirmed between H-type HTN and cardiovascular and cerebrovascular diseases, such as carotid atherosclerotic plaques and stroke [28,29]. In the present study, we explored the combined association of HTN or HHcy and the risk of cognitive impairment.
Our results showed that the ORs of cognitive impairment were increased with the combination of HTN and HHcy develops into H-type HTN. The risk for cognitive impairment in subjects with H-type HTN were 2.6 and 1.4 times with healthy and isolated HTN. Participants were further stratified by gender and age of 65 years (< 65 years old and ≥ 65 years old). We found that older people over the age of 65 had a higher risk of cognitive impairment. Findings of our study provide the evidence that H-type HTN, the combination of HTN and HHcy, could predict cognitive impairment and may be an independent of other risk factors.
Although there is an agreement that the implication of HTN on the risk of cerebrovascular injury, whether HTN is really harmful to cognitive function remains controversial [14,26,30]. When our study was based on a population with non-HTN and non-HHcy and a population without HTN alone, the conclusions were consistent that the damaging effects of HTN on cognition. In addition, HHcy has been reported to contribute to the progression of cognitive impaiment [27]. In our study, the same conclusion was obtained when the non-HHcy population as a reference. However, non-HTN with non-HHcy as reference, we found that isolated HHcy was no significant effect on cognitive impairment.
The predictive role of HTN for cognitive impairment has been widely proven, chronic conditions of HTN lead to deterioration of cognitive impairment in the test that assesses hippocampal functions.
HTN could cause damage to the hippocampal and produces typical features such as hypoperfusion, brain amyloid deposition and neuroinflammation. Although the association between HHcy and cognitive impairment is controversial, there have been studies demonstrating the potential mechanisms by which Hcy may induce cerebral arteriosclerosis and catalyze the development of cognitive impairment, such as increased oxidative stress of body tissue, alterations of lipid metabolism, and impaired endothelial function, increase the adhesion of platelets as well as induces the thrombosis [31,32]. Cerebral arteriosclerosis could induces cerebral infarcts or hemorrhage of varying size and type, attributing to development of cognitive impairment [33]. In addition, the synergistic effects of HTN and HHcy may be explained by the fact that HHcy activates the angiotensin-converting enzyme by inhibiting the production of endogenous hydrogen sulfide to lead to or aggravate HTN [34,35]. Therefore, when HTN and HHcy are combined, the effects on cognitive impairment may be increased.
In our study, we supplement epidemiological evidence that H-type HTN was an independent risk factor and provides predictive values for cognitive impairment among the elderly. Most of the previous studies analyzed the association between H-type hypertension for cerebrovascular diseases, such as carotid intima-media thickness. To the best of our knowledge, our study was the first community-based and large sample size to assess the potential relationship between H-type hypertension and cognitive impairment.
Despite the large sample size of our study, several limitations should be noted. First, we measured the Hcy concentration but not the Hcy activity in 2012 participant, which might produce a positive bias to evaluate the effect of Hcy. Second, the study was performed based on the participants in China who were 40 years old or older. Therefore, it may be not generalizable for young people who were under the 40 years old. Finally, in this cross-sectional study, we cannot make causal inferences and get more convincing results.

Conclusion
In summary, our study has provided the evidence for the role of H-type HTN and discussed controversies in relation to HTN or HHcy of cognitive impairment. Our findings indicated that H-type HTN might be a useful marker for cognitive impairment risk assessment especially in elder over 65. Htype HTN could be the major intervention measures to decrease the incidence of cognitive impairment as well as the stroke in Health Practice Management.    The proportion of participants with cognitive impairment between genders in the study groups. *HTN+, hypertension; HTN-, without hypertension; HHcy+, homocysteinemia; HHcy-, without homocysteinemia.  Association of H-type hypertension and cognitive impairment. *HTN+, hypertension; HTN-, without hypertension; HHcy+, homocysteinemia; HHcy-, without homocysteinemia; Hypertension was defined as systolic pressure >140 mmHg or diastolic pressure >90 mmHg. Homocysteinemia was defined as the level of plasma homocysteine > 15µmol/L.

Figure 5
Association of H-type hypertension and cognitive impairment between different ages and genders in our study. *adjusted for age, sex, education, current smoking, alcohol consumption, physical activity, hyperlipidemia, diabetes mellitus, and BMI. **P for interaction <0.001.

Supplementary Files
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