Mild cognitive impairment (MCI) represents a transitional stage between normal cognitive function and dementia. In China alone, the incidence rate of MCI ranges from 9.7% to 23.3% [1], and the annual conversion rate of MCI to dementia is estimated to be 5% to 20% [2]. Hypertension is an independent and significant contributor to cognitive impairment; it increases the risk of MCI by 1.62 times. From 2007 to 2011, the prevalence of hypertension with MCI (HTMCI) was 16.5% [3]; meanwhile, a meta-analysis published in 2023 showed that the overall prevalence of HTMCI in China was 37.6% [4]. Evidence suggests that hypertension can increase the risk of cognitive-related diseases, such as Alzheimer disease (AD) and vascular dementia [5]. A meta-analysis [4] published in 2021 revealed that the combination of high blood pressure and MCI is associated with a global prevalence of up to 30%. A Lancet study reported that over the past 30 years, the number of adults aged between 30 and 79 years with high blood pressure has risen from 650 million to 1.28 billion [6]. As the prevalence of hypertension continues to rise, the number of patients experiencing both hypertension and cognitive impairment is expected to increase.

There are established pathways from hypertension to cognitive impairment, which include atherosclerosis and arteriolar sclerosis [7]. Cerebral hypoperfusion and reduced neurovascular coupling can result in brain dysfunction by depriving energy-demanding areas of oxygen and glucose, essential for cognitive processes [8]. Hypertensive amyloid production and deposition might also contribute by promoting the pathogenesis of cognitive impairment [9]. Hypertension is widely recognized as an important risk factor for cognitive impairment. However, cognitive impairment can lead to limitations in daily behavior and activities [10], subsequently affecting the drug management and nursing routines of patients with hypertension, resulting in a vicious cycle [11]. Therefore, determining ways to prevent or delay the progression of hypertension accompanied by MCI represents an urgent clinical challenge.

Microcirculation is the comorbidity pathologic basis of hypertension and cognitive dysfunction. Microcirculatory dysfunction is closely related to the occurrence and development of cognitive impairment. Studies have shown that microvascular endothelial cell abnormalities and cerebral blood flow regulation disorders can lead to local tissue hypoxia, changes in blood-brain barrier permeability, and decreased metabolic waste removal efficiency, which in turn accelerates β-amyloid deposition and tau protein hyperphosphorylation through mechanisms such as neurovascular unit disorders, enhanced oxidative stress, and neuroinflammatory activation, eventually leading to neuronal damage and decreased synaptic plasticity. So, improving microcirculation (microcirculation disturbance [MD]) is a key link in the process of prevention and cure of HTMCI, mainly reflected in the occurrence and development of hypertension [12,13]. MD-based cerebral blood flow regulation disorder and cerebral hypoperfusion are closely related to cognitive function impairment [13]; MD is the common pathophysiological basis of hypertension and cognitive impairment: they interact and influence each other through microvascular thinning degree, hemodynamics, oxidative stress level, endothelial cell function, etc [14-16].

In recent years, numerous studies have demonstrated that acupuncture exhibits significant antihypertensive effects on mild to moderate essential hypertension [17-20] and is increasingly recognized as beneficial in improving cognitive function [21-24]. However, reports on the effect of acupuncture on patients with both hypertension and cognitive impairment are lacking. Our team conducted a randomized controlled clinical trial of large-sample, multicenter acupuncture treatment of essential hypertension in the early stage and found that after 6 weeks of electroacupuncture treatment, the 24-hour average systolic blood pressure in the treatment group was significantly decreased (mean 7.2, SD 11.0 mm Hg) compared with the sham acupuncture group and the waiting treatment group, and the antihypertensive effect lasted for 6 weeks [25]. Another experiment to observe the effect of acupuncture on cognitive function in patients with poststroke cognitive impairment found that acupuncture significantly reduced the overall cognitive function of patients with poststroke cognitive impairment compared with the sham acupuncture group and the waiting treatment group and had a certain lasting effect and also reduced the incidence of dementia [26].

On the basis of the theory of MD and our previous research, this study will conduct randomized controlled experiments to explore the effect of electroacupuncture on improving cerebral microcirculation in improving cognitive function.

This is a multicenter, open-label, waiting list control randomized controlled trial. A total of 252 eligible participants will be randomly assigned in a 1:1:1 ratio to the electroacupuncture group, the sham electroacupuncture (SEA) group, and the waiting list group. The assessments of clinical outcomes will be performed at baseline, week 12, and week 24. Acupuncture treatment was administered once every other day, 3 times per week, for 12 weeks, followed by a 12-week follow-up. The flowchart and study design schedule are shown in Figures 1 and 2, respectively.

The protocol has been approved by the institutional review board of the First Affiliated Hospital of Tianjin University of traditional Chinese medicine (TCM; TYLL2023{6}051). All patients provided their written informed consent to participate in the study and authorized the publication of their data. This study was registered on April 26, 2024, with the Chinese Clinical Trial Registry (ChiCTR2400083501). Every participant will be informed of detailed information about the study before signing informed consent. The results of this trial will be published in a peer-reviewed journal. Patients and the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

We will recruit participants in the outpatient departments of 3 hospitals, including the First Teaching Hospital of Tianjin University of TCM, the TCM hospital of Sichuan Province and Hospital of Chengdu University of TCM, the Affiliated Sichuan Provincial Rehabilitation Hospital of Chengdu University of TCM, and Tianjin Medical University General Hospital. Patients with HTMCI and healthy participants who are interested and whose initial screening meets our recruitment needs will be fully informed of the entire study procedure, benefits, and risks. Clinical trial communicators will fully explain the trial to patients before the trial begins to ensure that all the patients participate voluntarily and sign an informed consent form.

The inclusion and exclusion criteria are presented in Textbox 1 [27-29].

A total of 252 eligible patients will be randomly allocated to the acupuncture group, the sham acupuncture group, and the waiting list group at a 1:1:1 ratio. An independent professional statistician, uninvolved in the trial’s implementation or subsequent statistical analysis, will generate the randomization sequence using SPSS (IBM Corp) software. Both the outcome assessor and the statistician will remain blinded to group assignments. Group assignments will be disclosed only after the completion of the statistical analysis.

All the groups receive standard treatment, including controlling blood pressure, blood glucose, blood lipid, and symptomatic treatment.

In this trial, 0.25×40 mm needles manufactured by HUATO, Suzhou, China, and the SDZ-III electroacupuncture apparatus by Suzhou Medical Appliance, Jiangsu, China, will be used. Interventions in all groups will be practiced by registered practitioners of TCM with at least 5 years of clinical experience in acupuncture. Acupuncturists will be trained in the study protocol and standardized acupuncture manipulations before study initiation.

Participants in the electroacupuncture group will receive electroacupuncture at Baihui (GV20), Shenting (GV24), Neiguan (PC6), Zusanli (ST36), Fenglong (ST40), and Taichong (LR3). Acupoints PC6, ST36, ST40, and LR3 will be applied bilaterally. All acupoints will be punctured to standardized needling depths and manipulated through lifting, thrusting, or twisting to induce the Deqi sensation. Three paired alligator clips from the electroacupuncture apparatus will be attached to GV20 and GV24, and to the homolateral ST36 and ST40, with a disperse-dense frequency (2/15 Hz) and a patient-tolerable current intensity. The precise locations and manipulations of these acupoints are depicted in Table 1 and Figure 2. This treatment will be administered over a period of 12 weeks, with sessions occurring once daily, 3 times per week.

In the SEA group, 9 nonacupoints will be selected, with their locations detailed in Table 2 and Figure 2. The selection of nonacupoints in the SEA group involves choosing points situated on nonmeridians yet proximal to the acupoints selected in the electroacupuncture group, a common approach in sham acupuncture design [30]. A shallow needling technique (approximately 5 mm depth) will be used at these nonacupoints, eschewing both reinforcing-reducing techniques and the elicitation of the Deqi sensation. The SEA device will be connected, with its connecting wires internally disconnected. The number and frequency of treatments will mirror those of the electroacupuncture group.

No acupuncture treatment will be given in the waiting list group for the first 12 weeks. Participants will be required to complete the assessments at the corresponding time points. Considering the ethical requirements, compensatory treatment will be given after 12 weeks of following up.

The specific flowchart is shown in Figure 1.

Adverse reactions, including needle-sickness, needle stagnation, needle bending, broken needle, and subcutaneous hematoma, will be closely monitored during the treatment process. Concurrently, a detailed analysis will be conducted on the correlation between all adverse events and acupuncture to rigorously evaluate the safety of acupuncture treatment. All adverse events will receive appropriate intervention, and serious adverse events will be reported to the ethics committee immediately.

Quality control will be implemented for all records of clinical trials, including case reports, needling operation lists, blood pressure monitoring forms, cognitive assessment scales, among others, with strict control of the time window for follow-up collection to ensure that the data are accurate, complete, truthful, and timely. These records shall not be omitted or arbitrarily altered.

A specialized quality control team will be established to conduct regular on-site inspections. Simultaneously, a comprehensive quality control system will be established during the implementation of the project, and we will formulate a series of standard operating procedures, including standard operating procedures for the study process, the acupuncture treatment, and the follow-up assessment. Furthermore, the Data Inspection Committee has been commissioned to regularly review and assess the data accumulated from the clinical trials, thereby evaluating the quality, efficacy, and safety of the trials.

According to the literature [52], acupuncture treatment increased the mean MoCA score by 2.83 (SD 1.13); the mean change in MoCA in the sham acupuncture group was 1.97 (1.38), waiting group, the mean change in MoCA was 0.48 (SD 1.65); the test level was α=0.01; power was 95%; and it was calculated by the PASS (version 15.0; NCSS, LLC) software to obtain a sample size of 66, considering a 20% dropout rate, 84 cases were proposed to be included in each group, and 252 participants were finally included.

Statistical analysis was performed using SPSS (version 27.0) software. All patients who completed the randomization and received the overall course of treatment were included in the efficacy analysis to ensure the integrity and comparability of the data. For different types of data, the following statistical methods will be used for analysis:

Hypertension is the leading risk factor for the global disease burden, a major cause of cardiovascular and cerebrovascular morbidity and mortality in China, and one of the most prevalent chronic diseases [53]. Microcirculation plays an important role in maintaining peripheral vascular resistance and blood pressure stability. Abnormal microvascular blood perfusion is an early manifestation of hypertension [54]. At the same time, cerebral blood flow regulation disorder and cerebral hypoperfusion have direct influence on cognitive function [13]. Therefore, MD is the common pathophysiological basis of hypertension and MCI.

Clinical findings suggest that TCD markers of cerebral flow regulation in patients with hypertension are strongly associated with cognitive ability, with poorer cognitive function associated with enhanced dynamic brain autoregulation in the middle cerebral artery [55]; The content of NO is closely related to oxidative stress response, which can activate the nuclear factor kappa-light-chain-enhancer of Activated B Cells pathway, and then cause inflammation in vivo, promote the release of proinflammatory mediators in the blood vessel wall, and accelerate the occurrence and development of hypertension and vascular complications; ET-1, as an important substance regulating vasoconstriction, can promote vascular smooth muscle cell proliferation, fibrosis, and inflammation, and has important significance in the pathophysiology of vascular endothelium [56]. All the above can further affect the microcirculation index by affecting the vascular endothelium.

Acupuncture, as a special treatment method of TCM, can regulate blood pressure by regulating the neuroendocrine system, improving metabolic activities, changing gene expression related to blood pressure, and so on [57-59]. At the same time, it has been proved that acupuncture can restore the decreased cognitive function to some extent by regulating the hypothalamic oxidative stress pathway, proinflammatory cytokine [60] and improving the brain white matter injury [61].

According to previous studies, acupuncture stimulation of LR3 and ST36 with electroacupuncture and manual acupuncture can reduce the symptoms of hypertension and subsequent cognitive dysfunction in spontaneously hypertensive rats60. The acupuncture of DU20 and ST36 can reduce blood pressure, increase microvascular dilation, reduce nerve damage, and restore cognitive dysfunction to a certain extent [62]. In addition, electroacupuncture stimulation of bilateral PC6 can affect the inflammatory pathway mediated by the regulation of AngII-TGF-β and then achieve the effect of antihypertension and improvement of spontaneously hypertensive rat cardiac fibrosis [63]. On the basis of the research results mentioned earlier, we selected GV20, GV24, PC6, ST36, ST40, and LR3 for combination therapy.

In this study, the mechanism of microcirculation is combined with modern medicine to monitor cerebral microvascular hemodynamics by TCD. Endothelium dysfunction biomarkers ET-1 and NO were used to determine the contraction and dilation of cerebral microvessels. The relationship between microcirculation and hypertension and MCI was investigated by combining clinical and experimental methods. In summary, we propose a randomized controlled trial to verify whether the improvement of electrotherapy in HTMCI is related to the regulation of microcirculation indicators by acupuncture, and to provide more clinical evidence of the effectiveness of acupuncture in reducing blood pressure and improving cognitive impairment.

This study aims to provide high-quality evidence on the efficacy and safety of electroacupuncture in patients with HTMCI. However, this protocol design also has limitations. First, it is impossible to accurately judge the causality between hypertension and cognitive impairment; thus, the reverse causality bias of MCI affecting blood pressure may occur. Second, the potential for spontaneous recovery early in cases of hypertension complicated with MCI may have confounding effects on this trial, though the waiting list group could mitigate these impacts.

This clinical trial aims to compare the efficacy of electroacupuncture versus SEA or waiting list control in the treatment of hypertension with cognitive impairment and to explore its impact on microcirculation through hemodynamic and microcirculatory indices. The results of this trial will contribute to clarifying the microcirculatory mechanisms of electroacupuncture in the treatment of hypertension with cognitive impairment, providing a solid foundation for further research on electroacupuncture therapy.