Mechanisms of cognitive impairment in arterial hypertension

Abstract

Cognitive impairment in elderly patients with arterial hypertension is an urgent medical and social problem. This is especially important given the high prevalence of arterial hypertension. In this regard, the mechanisms of cognitive impairment are of growing interest in order to find new preventive and therapeutic strategies. In general, the main mechanisms determining the association between hypertension and cognitive impairment include imbalances in cerebral blood flow perfusion, immune and metabolic disorders, blood-brain barrier dysfunction, and brain structure abnormalities. Metabolic disorders, including insulin resistance in the brain, are of growing interest as mechanisms of cognitive impairment. Comorbid diseases and target organ damage, which are common in arterial hypertension, also play an important role.

Key Words: Arterial hypertension; Cognitive impairment; Blood-brain barrier; Neuroinflammation; Insulin resistance; Type 3 diabetes hypothesis

Core Tip: Arterial hypertension contributes to the development of cognitive impairment through several direct and indirect mechanisms involving hemodynamic, structural, immune, and metabolic abnormalities. There is a U-shaped relationship between blood pressure and the risk of cognitive impairment; that is, both high and low blood pressure can contribute to hemodynamic disturbances in the brain and its structural and functional impairments. Target organ damage in arterial hypertension and comorbidities, including metabolic disorders, are important for the development of cognitive impairment. In this regard, correction of risk factors and maintenance of blood pressure in the target range may be useful for the prevention of cognitive impairment.

INTRODUCTION

Arterial hypertension is one of the most widespread chronic diseases and contributes significantly to the structure of disability and mortality. The disease is often not diagnosed in a timely manner, and patients often do not pay proper attention to high blood pressure (BP) and do not receive adequate treatment, which leads to the development of numerous complications[1-3]. Arterial hypertension has multiple target organs, including the brain, kidney, and heart[4,5]. The prevalence of arterial hypertension increases with age, which is associated with increased comorbidity with other diseases characteristic of older age groups, such as diabetes mellitus and atherosclerosis, which together impair patients’ quality of life, cause cardiovascular events, and increase the risk of premature death[6-8].

Cognitive impairment in elderly patients with arterial hypertension is an unfavorable prognostic factor, as it impairs patients’ participation in the control of their disease and reduces adherence to treatment, including impaired regular intake of antihypertensive drugs. On the other hand, arterial hypertension itself is considered an important modifiable risk factor for cognitive impairment[9-12]. The results of a systematic review and meta-analysis of 209 prospective studies showed that hypertension in middle age was associated with a 1.19- to 1.55-fold increased risk of cognitive impairment, whereas taking antihypertensive drugs reduced the risk of dementia by 21%[9]. Importantly, there was a U-shaped relationship between BP and risk of cognitive impairment[13]. This is because cerebral hypoperfusion at low BP may also contribute to structural abnormalities in the brain, leading to cognitive impairment[14,15]. This is especially important in patients with atherosclerosis of the carotid and cerebral arteries, as atherosclerosis further impairs cerebral hemodynamics.

A decrease in BP for every 1 mmHg below established thresholds increased the risk of cognitive impairment by 0.7%, 1.1%, and 1.1% for systolic BP, diastolic BP, and mean arterial pressures, respectively. Conversely, exceeding thresholds by 1 mmHg increased the risk of cognitive impairment by 1.2%, 1.8%, and 2.1% for systolic BP, diastolic BP, and mean arterial pressures, respectively[14]. In addition, not only stable high BP is relevant, but also the more common variability of BP in clinical practice[16,17]. Thus, maintaining BP in the target range is an important and effective preventive strategy for complications of arterial hypertension, including the risk of cognitive impairment[18]. In this regard, the mechanisms of cognitive impairment in arterial hypertension are of clinical and research interest. In the article by Xu et al[19], nutritional indicators such as body mass index, Mini-Nutritional Assessment Scale score, hemoglobin, and albumin were found to be associated with indicators of cognitive dysfunction. In general, the current understanding of cognitive impairment in arterial hypertension is based on a complexity of causes that often act together (Figure 1).

Figure 1 Direct and indirect effects of arterial hypertension on cognitive impairment.

HEMODYNAMIC AND STRUCTURAL MECHANISMS OF COGNITIVE IMPAIRMENT IN HYPERTENSION

Disruption of the structure and function of the blood-brain barrier (BBB) is considered to be the best-known mechanism of cognitive impairment in arterial hypertension. The BBB is formed by dense intercellular connections of endothelial cells, which regulate the entry of substances from the peripheral blood flow into the brain by various mechanisms. In addition to endothelial cells, microglia, pericytes, and astrocytes participate in the regulation of the BBB and form the neurovascular complex[20-22]. In hypertension, neurovascular unit function is impaired, which impairs neurovascular coupling, leads to decreased cerebral blood flow, contribute to neuronal dysfunction and cognitive impairment[23,24]. Hypertension also leads to endothelial dysfunction, impaired autoregulation of cerebral blood flow, causes cerebral small vessel disease, which is characterized by microhemorrhages, lacunar infarcts and white matter damage, contributing to cognitive impairment[25-27]. Ischemic and hemorrhagic stroke are serious complications of hypertension and are associated with various impairments of brain function, including cognitive impairment[28,29]. Small lacunar strokes often have no motor or sensory impairment, but manifest cognitive deficits, forming the clinic of vascular dementia[30,31]. Thus, hemodynamic abnormalities caused by high BP values can disrupt normal histologic and anatomic structures in the brain, which impairs their function. Macrovascular pathologies and microvascular abnormalities leading to structural changes in the brain are closely associated with accelerated cognitive decline and are increasingly recognized as a key factor in the pathogenesis of vascular cognitive impairment and dementia, as well as Alzheimer’s disease (AD)[32].

IMMUNE MECHANISMS OF COGNITIVE IMPAIRMENT IN HYPERTENSION

High BP can impair the function of the BBB, promoting the entry of substances and cells into the brain, which activates many different mechanisms including inflammation and oxidative stress and causes further vascular damage[33]. Infiltration of monocytes and their subsequent differentiation into macrophages promotes microglia activation. Microglia perform immune functions in the brain and, when activated, can produce reactive oxygen species and cytokines that contribute to neuroinflammation and further increase BP. The systemic and neurovascular inflammation that develops in hypertension further damages the BBB and neurovascular unit, contributing to cognitive impairment[34,35]. Chronic activation of renin angiotensin system plays an important role in neuroinflammation.

Under normal conditions, angiotensin II (Ang II) circulating in the bloodstream does not cross the BBB due to its hydrophilic nature. However, elevated blood levels of Ang II in hypertension and impaired BBB integrity promote Ang II entry into the brain, where it contributes to increased sympathetic activity and the development of neurogenic hypertension. Ang II also activates perivascular macrophages that produce superoxide, leading to BBB disruption and cognitive impairment[24,36]. Ang II and prorenin have been found to increase the production of reactive oxygen species and proinflammatory cytokines (interleukin-1 beta [IL-1β], IL-6, tumor necrosis factor alpha) while decreasing IL-10 production in the paraventricular nucleus of the hypothalamus and rostral ventral lateral medulla[37]. Proinflammatory cytokines can impair synaptic plasticity and neuronal communication and disrupt neurogenesis in the hippocampus, which is critical for learning and memory. In addition, neuroinflammation can lead to the loss of synaptic proteins such as postsynaptic density protein-95 and synaptophysin, which are essential for synaptic plasticity and cognitive function[38,39]. Intravenous administration of minocycline, a microglia inhibitor in experiment in rats with hypertension, results in a decrease in BP induced by Ang II administration, and deletion of microglia in transgenic mice with Ang II-induced hypertension results in decreased levels of tumor necrosis factor α and IL-1β and decreased BP[40,41].

Thus, immune mechanisms play an important role in the development of cognitive disorders in arterial hypertension and are a promising topic for further research. It is also relevant to study the relationship of systemic inflammation, which is often found in various chronic diseases and in older individuals with cognitive impairment[42,43]. Chronic systemic inflammation and oxidative stress, for example, are often found in patients with chronic obstructive pulmonary disease, and cognitive impairment is a serious prognostically significant problem in these patients[44-48].

METABOLIC MECHANISMS OF COGNITIVE IMPAIRMENT IN HYPERTENSION

Metabolic disorders including atherosclerosis, obesity, insulin resistance, and diabetes mellitus are common among patients with arterial hypertension, with arterial hypertension contributing to their progression[7]. Studies demonstrate a different association of body mass index (BMI) with cognitive impairment. Each 1 kg/m² increase in BMI in obese older adults was associated with a 3% increase in the prevalence of cognitive impairment, regardless of comorbidities such as hypertension or diabetes[49]. Low BMI also increased the risk of cognitive impairment, whereas a BMI between 23.2 kg/m² and 27.8 kg/m² was associated with a reduced risk of cognitive impairment[50]. A study by Xu et al[19] found that the worse the nutritional status of elderly hypertensive patients, the higher the risk of cognitive impairment. These findings increase interest in the relationship between metabolic factors and cognitive function. The association of atherosclerosis with cerebral circulatory disorders is well known and are the subject of extensive research.

The role of insulin and insulin resistance on cognitive function is of growing interest. Glucose is the main source of energy for the central nervous system (CNS) and is essential for its normal function. However, unlike peripheral tissues, glucose supply to the CNS does not depend on insulin. Glucose transport into the CNS is accomplished by glucose transporter 1 by facilitated diffusion, because the level of glucose in the brain intercellular fluid and cerebrospinal fluid is much lower than in the blood. Insulin has no effect on both glucose transport across the BBB and virtually no effect on glucose utilization by CNS cells, but rather performs neuroprotective functions in the brain, which has deep evolutionary roots[51]. Notably, insulin itself also penetrates the CNS through the BBB (the possibility of insulin synthesis in the brain itself has also been discussed[52]) and in the brain supports neuronal growth, repair, and synaptic viability, and protects against oxidative stress, amyloid-β (Aβ) toxicity, and brain ischemia[53]. Insulin acts as a neuromodulator by affecting the metabolism of neurotransmitters, including dopamine, and modulating the release and uptake of catecholamines and gamma-aminobutyric acid[53-55]. Insulin is critical for cognitive functions, particularly memory formation and storage. It enhances synaptic plasticity, which is essential for learning and memory processes[53-55]. Insulin in the brain acts through two major signaling pathways: The phosphoinositide-3-kinase/Akt pathway, which is responsible for metabolic effects, and the mitogen-activated protein kinase pathway, which affects growth, survival, and gene expression[55]. Insulin and insulin-like growth factor-1 (IGF-1) are linked by some evolutionary and functional relationships in the brain. Insulin and IGF-1 receptors are expressed in all cell types of the CNS[51]. IGF-1 deficiency in hypertensive mice leads to decreased microvascular density, increased neuroinflammation, and impaired cognitive function, underscoring the role of IGF-1 in maintaining brain microvascular health[56,57]. On the other hand, insulin sensitivity index is potentially associated with increased risk of lacunes, severe age-related white matter changes[58]. Thus, insulin and IGF-1 have functions that are important for neuronal survival and maintenance of CNS integrity[59].

Insulin resistance in the brain is considered a cause of the development of AD and is known as type 3 diabetes mellitus, although the term is not universally accepted or used as a diagnostic category, but rather a theoretical concept[60-62]. According to the “type 3 diabetes” hypothesis, AD is proposed to be a form of brain-specific insulin resistance characterized by impaired insulin signaling in brain cells. Insulin resistance in the brain of Alzheimer’s patients is also associated with resistance to IGF-1[63-67]. Brain cell resistance to insulin, oxidative stress and neuroinflammation are thought to contribute to the accumulation of Aβ peptides through several mechanisms. Insulin can activate the extracellular excretion of Aβ and inhibit its intracellular accumulation by activating the cleavage of Aβ by the insulin-degrading enzyme (IDE). IDE regulates the levels of insulin, Aβ protein, and the Aβ precursor protein intracellular domain in vivo[68]. Insulin resistance causes IDE sequestration, thereby reducing Aβ clearance and promoting its aggregation[59,69]. Insulin resistance stimulates the mitogen-activated protein kinase signaling pathway and increases beta-secretase 1 expression, which ultimately leads to abnormal accumulation of Aβ peptides, as beta-secretase 1 is involved in Aβ formation. Insulin resistance also causes decreased activation of the phosphoinositide-3-kinase/Akt signaling pathway and then dephosphorylation and activation of glycogen synthase kinase-3β, which is one of the kinases involved in tau protein phosphorylation. In addition, insulin resistance leads to inhibition of protein phosphatase 2A, which leads to hyperphosphorylation of tau protein and accumulation of neurofibrillary tubules[69].

Thus, insulin and insulin resistance in the brain may have a complex effect on cognitive function. However, insulin resistance in the brain and peripheral tissues (in type 2 diabetes mellitus) are not necessarily related and may occur independently of each other. Furthermore, the functions of insulin in the brain and peripheral tissues differ, which has implications for understanding its role for cognitive function[70-73]. It should be noted that there is ongoing debate as to whether insulin resistance is a cause or consequence of abnormal Aβ expression and protein processing. In this regard, the hypothesis of type 3 diabetes mellitus as a mechanism of AD needs new research. Thus, metabolic abnormalities in arterial hypertension are a frequent phenomenon, especially among elderly patients. The contribution of metabolic abnormalities for cognitive function is still underestimated properly and is a promising topic of study to improve existing therapeutic approaches. In addition, metabolic and inflammatory mechanisms are often combined, which is of clinical importance[74,75].

INDIRECT EFFECTS OF HYPERTENSION ON COGNITIVE IMPAIRMENT THROUGH TARGET ORGANS

It should be noted that hypertension may not only act directly through the mechanisms described above, but may also cause target organ damage that also increases the risk of cognitive impairment. Arterial hypertension contributes to the development of chronic kidney disease through several known mechanisms. Low renal function in elderly patients is associated with poorer cognitive function[76,77]. Moreover, in the early stages, chronic kidney disease has a negligible impact on cognitive abilities. At the same time, cognitive abilities are preserved until kidney function deteriorates significantly[78]. The prevalence of cognitive impairment is particularly high in patients on dialysis[79]. Arterial hypertension increases the likelihood of atrial fibrillation (AF), which is associated with structural remodeling of the heart[80]. Early onset of arterial hypertension has been associated with an increased risk of AF and earlier onset of AF[81]. In patients with hypertension, drug treatment can control structural cardiac remodeling and delay or prevent the onset of AF[82]. In turn, AF increases the risk of cognitive impairment and vascular dementia, which is largely mediated by the risk of thromboembolism[83].

Arterial hypertension is also an important cause of chronic heart failure (CHF), which develops as a final outcome of cardiac remodeling[84,85]. CHF is an important cause of reduced quality of life in patients and premature death. CHF is associated with impaired cognitive function through several known mechanisms[86,87]. It has been shown that approximately 62% of patients with CHF did not comply with physician orders due to cognitive impairment. Patients with CHF who did not comply with physician's orders had frontal cognitive impairment (58%), memory impairment (40%), and mixed forms (21%)[88]. Decompensation of CHF further impairs cognitive function[89]. Thus, arterial hypertension may contribute to the development of various diseases due to target organ damage, which may also be a cause of cognitive impairment.

CONCLUSION

Thus, arterial hypertension is characterized by an increased risk of cognitive impairment, which is based on multiple overlapping mechanisms. A better understanding of hemodynamic, immune and metabolic (including nutritional) causes of cognitive impairment can be used to improve their prognosis, diagnosis and treatment. It is important to note that many aspects of cognitive impairment in arterial hypertension are still unclear and are promising areas for future research. The question of the choice of drugs for antihypertensive therapy remains unresolved, as it is assumed that drugs with different mechanisms of action may have different effects on the prevention of cognitive impairment. For example, angiotensin II receptor blockers may act pathogenetically, whereas in other studies there was no unequivocal answer that any drugs have an advantage in the prevention of dementia[90-92]. It should be noted that the limitations of studies evaluating the efficacy of antihypertensive pharmacotherapy for the prevention of cognitive impairment are the duration of studies, the complexity of modeling clinical conditions, including consideration of associated risk factors and diseases. In addition, the BP numbers themselves remain a matter of debate, which should be aimed for in different age groups, taking into account various diseases such as carotid and cerebral atherosclerosis[18,93,94]. The discussions are also related to the negative impact of cerebral hypoperfusion at low BP on cognitive function and, in general, on prognosis. In the Leiden 85+ study, it was shown that lower systolic BP in older adults taking antihypertensive medications was associated with higher mortality and more rapid cognitive decline[95]. Orthostatic hypotension is common in the elderly and is associated with cognitive decline[96].

The metabolic characteristics of cognitive impairment are also of interest. Obesity, insulin resistance and diabetes mellitus represent one side of a broad spectrum of metabolic disorders. Complex problems such as sarcopenic obesity, which includes a combination of obesity and decreased skeletal muscle mass and strength, are of growing interest. Sarcopenic obesity is independently associated with moderate cognitive impairment and dementia in elderly patients[97-99]. Sarcopenic obesity has been found to be associated with hypertension, diabetes, and impaired lipid metabolism[100,101]. Obesity and sarcopenic obesity, for example, increase the risk of hypertension[102]. A correlation has been found between sarcopenia, sarcopenic obesity and arterial stiffness in the elderly[103]. Cachexia is another complex metabolic process that is common in comorbid elderly patients, also associated with progressive dementia[104]. Disorders of skeletal muscle structure and function is one of the mechanisms linking sarcopenia and cachexia to cognitive impairment. Skeletal muscle is a metabolically active organ that consumes a significant portion of glucose and produces various immune and metabolic factors such as myokines, microRNAs, and IGF-1. It has been suggested that myokines can penetrate the BBB by acting on brain cells, such as increasing the local expression of neurotrophins such as brain-derived neurotrophic factor[105,106]. The myokine irisin, which is produced by skeletal muscles during exercise, is considered to be one of the links between skeletal muscle function and cognitive function of the brain[107,108]. These data suggest the important role of adequate physical muscle activity, which may be impaired with age, obesity, sarcopenia, and high and low BP. Therefore, for patients with loss of function but preserved activities of daily living, a more detailed geriatric assessment is required to explore the risks and benefits of antihypertensive therapy[18].

There is also growing interest in the gut-brain axis, which suggests a link between the gut microbiota and brain function, including cognitive impairment. The gut microbiota under normal conditions produces a large number of bioactive substances, such as short-chain fatty acids, which enter the systemic bloodstream and exert complex effects on various organs[109]. Alterations in the composition of the gut microbiota are associated with cognitive impairment[110,111]. In this regard, the gut microbiota may be a potential biomarker of cognitive impairment and a potential therapeutic target[112-114]. Of interest are the data on how age, the presence of various diseases, and the intake of various medications affect the composition and function of the gut microbiota. Thus, cognitive function has a complex regulation, with many different overlapping mechanisms involved in its maintenance. A better understanding of these mechanisms will improve approaches to the diagnosis, prevention, and treatment of cognitive disorders.