Hypertension, Brain Damage and Cognitive Decline

Loss of cognitive function is one the most devastating manifestations of ageing and vascular disease. Cognitive decline is rapidly becoming an important cause of disability worldwide and contributes significantly to increased mortality. There is growing evidence that hypertension is the most important modifiable vascular risk factor for development and progression of both cognitive decline and dementia. High blood pressure contributes to cerebral small and large vessel disease resulting in brain damage and dementia. A decline in cerebrovascular reserve capacity and emerging degenerative vascular wall changes underlie complete and incomplete brain infarcts, haemorrhages and white matter hyperintensities. This review discusses the complexity of factors linking hypertension to brain functional and structural changes, and to cognitive decline and dementia. The evidence for possible clinical markers useful for prevention of decreased cognitive ability, as well as recent data on vascular mechanism in the pathogenesis of cognitive decline, and the role of antihypertensive therapies in long-term prevention of late-life cognitive decline will be reviewed.     

Arterial Hypertension and Brain Damage—Evidence from Animal Models (Review)

Hypertension is an important risk factor for cerebrovascular disease including stroke and has also a role in the development of vascular cognitive impairment (VCI) and vascular dementia (VaD). Research on pathophysiology and treatment of hypertensive brain damage may benefit from the availability of animal models. This paper has reviewed the main animal models of hypertension in which brain damage is documented. Spontaneously hypertensive rats (SHR) represent the animal model more largely used. In these rats cerebrovascular changes, brain atrophy, loss of nerve cells in cerebrocortical areas, and glial reaction were documented. Several changes observed in SHR are similar to those found by in vivo imaging studies in essential hypertensives. It is documented that brain gets benefit from lowering abnormally elevated blood pressure and that reduction of hypertension protects brain from stroke and probably reduces the incidence of VaD. The influence of anti‐hypertensive treatment on brain structure and function in animal models of hypertension is reviewed. Among classes of drugs investigated, dihydropyridine‐type Ca²⁺ antagonists were those with a most documented protective effect on hypertensive brain damage. Limits and perspectives in the use of animal models for assessing brain damage caused by hypertension and protection from it are discussed.     

Arterial hypertension and brain damage--evidence from animal models (review)

Hypertension is an important risk factor for cerebrovascular disease including stroke and has also a role in the development of vascular cognitive impairment (VCI) and vascular dementia (VaD). Research on pathophysiology and treatment of hypertensive brain damage may benefit from the availability of animal models. This paper has reviewed the main animal models of hypertension in which brain damage is documented. Spontaneously hypertensive rats (SHR) represent the animal model more largely used. In these rats cerebrovascular changes, brain atrophy, loss of nerve cells in cerebrocortical areas, and glial reaction were documented. Several changes observed in SHR are similar to those found by in vivo imaging studies in essential hypertensives. It is documented that brain gets benefit from lowering abnormally elevated blood pressure and that reduction of hypertension protects brain from stroke and probably reduces the incidence of VaD. The influence of anti-hypertensive treatment on brain structure and function in animal models of hypertension is reviewed. Among classes of drugs investigated, dihydropyridine-type Ca2+ antagonists were those with a most documented protective effect on hypertensive brain damage. Limits and perspectives in the use of animal models for assessing brain damage caused by hypertension and protection from it are discussed.     

Vascular Dementia: Distinguishing Characteristics, Treatment, and Prevention

Vascular dementia (VaD) is the second-most-common cause of dementia in the elderly, after Alzheimer's disease (AD). VaD is defined as loss of cognitive function resulting from ischemic, hypoperfusive, or hemorrhagic brain lesions due to cerebrovascular disease or cardiovascular pathology. Diagnosis requires the following criteria: cognitive loss, often predominantly subcortical; vascular brain lesions demonstrated by imaging; a temporal link between stroke and dementia; and exclusion of other causes of dementia. Poststroke VaD may be caused by large-vessel disease with multiple strokes (multiinfarct dementia) or by a single stroke (strategic stroke VaD). A common form is subcortical ischemic VaD caused by small-vessel occlusions with multiple lacunas and by hypoperfusive lesions resulting from stenosis of medullary arterioles, as in Binswanger's disease. Unlike with AD, in VaD, executive dysfunction is commonly seen, but memory impairment is mild or may not even be present. The cholinesterase inhibitors used for AD are also useful in VaD. Prevention strategies should focus on reduction of stroke and cardiovascular disease, with attention to control of risk factors such as hypertension, diabetes mellitus, hypercholesterolemia, and hyperhomocysteinemia.     

Hypertension as a risk factor of dementia and cognitive decline in the elderly

Management of dementia and cognitive decline is a major issue in geriatrics. Since the average age of society is advancing and patients of dementia are increasing, it is important to remove risk factors of dementia and cognitive decline in order to maintain quality of life in the elderly and to save cost of medicine and care. While hypertension has been known to be a risk factor of cerebrovascular events and vascular dementia, recent studies show that midlife hypertension is also a risk factor of cognitive decline and Alzheimer's disease in late life. Clinical trials and retrospective observation studies also show that treatment of hypertension decreases the risk of Alzheimer's disease. These issues are also related with the consideration of vascular factors in Alzheimer's disease. The white matter lesion as a consequence of hypertension and its meaning in Alzheimer's disease are also discussed.     

Arterial hypertension: a cause of cognitive impairment and of vascular dementia

Arterial hypertension is a well-documented modifiable risk factor for cerebrovascular disease and for both cerebral infarction and intracerebral hemorrhage. Recent studies indicate a relationship between high blood pressure in midlife and dementia in late life and suggest that arterial hypertension may represent a cause of vascular dementia (VaD). This paper has reviewed the main evidence of a link between arterial hypertension and vascular cognitive impairment or VaD. Brain lesions induced by hypertension, diagnostic procedures for early diagnosis of vascular cognitive impairment in at risk subjects and the need to include cognitive assessment in patient's general visits in hypertension units are discussed.     

Are antihypertensive agents protective against dementia? A review of clinical and preclinical data

In the United States, the size of the population of persons aged 65 years or older is expected to double within the next 30 years, resulting in a marked increase in the prevalence of dementia. Hypertension is a risk factor for cognitive impairment and dementia in addition to cerebrovascular morbidity and mortality. The evidence for a connection between high blood pressure in midlife and dementia in late life comes from numerous longitudinal studies. A placebo-controlled, double-blind, randomized trial involving 2,418 patients aged 60 years or older with isolated systolic hypertension demonstrated that active treatment based on the dihydropyridine calcium antagonist nitrendipine with the addition of enalapril, hydrochlorothiazide, or both if needed to control systolic blood pressure to <150 mmHg, significantly reduced not only stroke and cardiovascular complications but also the incidence of vascular dementia and Alzheimer's disease. Several trials of antihypertensive treatment are ongoing to confirm this important finding. The newer dihydropyridine calcium antagonists lacidipine and lercanidipine are effective and well tolerated in the treatment of hypertension. In animal models, these newer agents also have been shown to prevent the progression of hypertensive microvascular damage. Their neuroprotective effects offer possible unique advantages in the management of hypertension.     

Arterial hypertension and cognitive dysfunction in physiologic and pathologic aging of the brain

Arterial hypertension is the most important modifiable cerebrovascular risk factor; its relationship with cerebrovascular disease is continuous, consistent, and independent. Different and probably converging pathophysiologic mechanisms explain the role of arterial hypertension in causing cognitive dysfunction in pathologic aging of the brain, specifically, vascular dementia and Alzheimer's disease.     

Controlled hypertension induces cerebrovascular and gene alterations in Cyp1a1-Ren2 transgenic rats

Hypertension is a major risk factor for small vessel disease and dementia, but the pathogenic mechanisms are not fully known. This study aimed to assess cerebrovascular alterations in response to different durations (4 or 6 months) of controlled hypertension in an inducible transgenic rat model of hypertension (Cyp1a1-Ren2) as compared with normotensive litter mate controls. After 6 months of hypertension as compared with controls, a significant reduction in vascular width was paralleled by an increase in the protein levels of claudin-5, an endothelial tight junction protein. Notably, vascular alterations were associated with increased microglia, and these changes were preceded by increased eNOS expression. Investigation of global gene expression by microarray analysis indicated alterations in predominantly growth factor related genes. Herein, we show that modest, sustained levels of hypertension are sufficient to cause cerebrovascular alterations accompanied by endothelial and inflammatory changes. These changes are paralleled by alterations in growth factor expression suggestive of a mechanistic role.     

Arterial hypertension and cognitive deficit

Cognitive impairment and dementia are more and more common in the elderly. The first begins, it advances silently and it leads to dementia in few years. Arterial hypertension represents the most important cerebrovascular risk factor after age. In numerous studies an inverse relationship between blood pressure values and cognitive performance emerges: it is possible that arterial hypertension plays a role in the pathogenesis of cognitive decline. Even in asymptomatic subjects the magnetic resonance signs of cerebral damage accompany cognitive impairment development. Antihypertensive therapy influence on cognitive function represents a subject of actual interest. The most studied drugs are calcium antagonists and ACE-inhibitors; they seem to have a protective effect on cognitive impairment, with regard to diuretics and beta-blockers. It would be important to study hypertensive patients, above all young asymptomatic hypertensives, even about cognitive functions, to prevent and consider cognitive decline and effective organ damage.     

Epidemiology of vascular dementia.

Although epidemiological studies are limited by diagnostic uncertainties, they suggest that stroke increases the risk of dementia. The mortality rate is higher in vascular dementia (VaD) than in Alzheimer's disease (AD). Community-based studies have provided several consistent findings: (i) age dependence with prevalence rates doubling every 5 years, (ii) a higher frequency in men and (iii) nation-to-nation differences. The prevalence of VaD ranges from 2.2% in 70- to 79-year-old women, to 16.3% in men >80 years. One sixth of acute stroke patients have preexisting dementia. The incidence of VaD has been studied much less extensively than that of AD, and substantial variations in the incidence rates have been observed: annual incidence rates (per 100,000) range from 20 to 40 between 60 and 69 years of age and from 200 to 700 over 80. The incidence rate of VaD declined over the last 2 decades, probably as a consequence of effective stroke prevention. It is generally assumed that risk factors for VaD are those of stroke, with arterial hypertension as leading factor, followed by atherosclerotic disease, low education level, alcohol abuse and heart disease. Stroke characteristics, such as lacunar infarction and left-sided hemispheric lesions, are major determinants of VaD. The cerebrovascular lesions are likely to be the only cause of dementia in strategic infarcts, in lacunar state, in hereditary cystatin C amyloid angiopathy and in CADASIL. However, white matter changes, and associated Alzheimer pathology, which are both frequent in this age category, may also contribute to the cognitive decline.     

Hypertension and Dementia: A comprehensive review from the HOPE Asia Network

Approximately 365 million people in Asia were classified as elderly in 2017. This number is rising and expected to reach approximately 520 million by 2030. The risk of hypertension and cognitive impairment/dementia increases with age. Recent data also show that the prevalence of hypertension and age‐related dementia are rising in Asian countries. Moreover, not many people in Asian countries are aware of the relationship between hypertension and cognitive impairment/dementia. Furthermore, hypertension control is poorer in Asia than in developed countries. Hypertension is known to be a major risk factor for damage to target organs, including the brain. Decreased cognitive function can indicate the presence of target organ damage in the brain. Twenty‐four‐hour blood pressure profiles and blood pressure variability have been associated with cognitive impairment and/or silent cerebral diseases, such as silent cerebral infarction or white matter lesions, which are predisposing conditions for cognitive impairment and dementia. Hypertension that occurs in midlife also affects the incidence of cognitive impairments in later life. Managing and controlling blood pressure could preserve cognitive functions, such as by reducing the risk of vascular dementia and by reducing the global burden of stroke, which also affects cognitive function.     

H型高血压与血管性痴呆

脑血管病是我国首位死亡原因。我国脑卒中年死亡人数200多万,在导致脑卒中发生的可控因素中,高血压和同型半胱氨酸升高位居前列,二者在导致脑卒中的发生上具有协同作用,而缺血性脑卒中是导致血管性痴呆的重要病因。我国学者将伴有同型半胱氨酸升高的高血压定义为＂H型高血压＂。我国原发性高血压患者中约有75%为H型高血压。血管性痴呆是指由各类脑血管病所致的痴呆综合征,是继阿尔茨海默病之后第二常见的痴呆。高血压和高同型半胱氨酸血症可引起认知功能障碍,进而导致血管性痴呆的发生,且待患者达血管性痴呆的诊断标准时,常已错过重要的早期干预治疗阶段,故在认知功能明显损害之前就发现并进行干预是非常重要的。现对H型高血压和血管性痴呆的关系做一综述。     

Cerebral white matter lesions in essential hypertension

The pathogenesis and clinical significance of cerebral white matter lesions (WML) remain controversial. Most studies have shown that age, hypertension, diabetes mellitus, and a history of stroke or heart disease are the most important factors related to the presence of cerebral WML. Moreover, some studies suggest that the presence of WML are closely related to cerebrovascular disease and cognitive impairment in elderly patients with vascular risk factors, particularly hypertension. In this review, different points of view about cerebral WML are discussed, with special focus on the presence of WML in essential hypertension. Some authors suggest that the presence of WML in hypertensive patients could be considered an early marker of brain damage.     

Essential hypertension

Essential hypertension can be defined as a rise in blood pressure of unknown cause that increases risk for cerebral, cardiac, and renal events. In industrialised countries, the risk of becoming hypertensive (blood pressure >140/90 mm Hg) during a lifetime exceeds 90%. Essential hypertension usually clusters with other cardiovascular risk factors such as ageing, being overweight, insulin resistance, diabetes, and hyperlipidaemia. Subtle target-organ damage such as left-ventricular hypertrophy, microalbuminuria, and cognitive dysfunction takes place early in the course of hypertensive cardiovascular disease, although catastrophic events such as stroke, heart attack, renal failure, and dementia usually happen after long periods of uncontrolled hypertension only. All antihypertensive drugs lower blood pressure (by definition) and this decline is the best determinant of cardiovascular risk reduction. However, differences between drugs exist with respect to reduction of target-organ disease and prevention of major cardiovascular events. Most hypertensive patients need two or more drugs for blood-pressure control and concomitant statin treatment for risk factor reduction. Despite the availability of effective and safe antihypertensive drugs, hypertension and its concomitant risk factors remain uncontrolled in most patients.     

Potential for antihypertensive treatment with an AT(1)-receptor blocker to reduce dementia in the elderly

Hypertension is an established risk factor for stroke and other cerebrovascular disorders. Both stroke and small lacunar infarcts or white matter lesions can cause cognitive impairment and dementia, and there is evidence that vascular risk factors play a major role in the development of both Alzheimer's disease and vascular dementia. Several large epidemiological studies have shown that raised blood pressure in midlife is a strong risk factor for dementia later in life; however, blood pressure often decreases following the development of dementia. The cognitive function hypothesis proposes that elevated blood pressure increases the risk of decline of cognitive function, and that this can be reversed by active lowering of blood pressure. Evidence in support of this hypothesis comes from the Syst-Eur Dementia project, and from a number of smaller studies. SCOPE (Study on Cognition and Prognosis in the Elderly) is a large prospective study involving almost 5000 elderly patients (age 70-89 years), who are randomised to receive candesartan cilexetil, 8-16 mg, or placebo. Candesartan was chosen for this study because it is effective and well tolerated in elderly patients. SCOPE should provide important information on the long-term effects of AT(1)-receptor blocker treatment with candesartan on morbidity-including effects on cognitive function-and cardiovascular mortality in elderly hypertensive patients.     

Is dementia a disease?

BACKGROUND: It is customary for many neurologists to think that dementia is a disease. This view is based on the following reasons: (1) a brain disease is the cause of cognitive impairment; (2) therefore, such cognitive impairment is substituted for the disease, becoming dementia, which is then also regarded as a mental disease. OBJECTIVE: In this brief article, I take exception to such a view, contrary to the common belief in the medical field, on the ground that senile plaques and/or neurofibrillary tangles or any other factors cause neuronal apoptosis but they do not cause dementia directly. METHODS: Literature on dementia and aphasia are critically and briefly reviewed to get the historical perspective that it is the progressive neuronal losses, losing brain functions as a result, that cause dementia; that is, brain diseases cause neuronal losses which then result in the decrease of brain functions, thereby leading to dementia. RESULTS: There is no direct cause-effect relationship between brain disease, be it caused by vascular factors or not, and dementia which is the consequence or sequela of neuronal losses. CONCLUSIONS: It is concluded that dementia is not a disease and yet it occurs not only in Parkinson's disease, Alzheimer's disease (AD), Huntington's disease and Pick's disease, but also in any other neurodegenerative disease, e.g., spinocerebellar ataxia, or vascular disease, e.g., Binswanger's disease, as part of the process of aging; in fact, AD is now regarded by some as a vascular disorder with neurodegenerative consequence, rather than a neurodegenerative disorder with vascular consequence. But vascular disorder is misleading if AD includes both neurofibrillary tangles and senile plaques; on the other hand, AD cannot be a vascular disorder if it includes only neurofibrillary tangles, as it should. Dementia, in this context, is re-defined as the differential manifestation of deteriorating brain functions over time as a part of aging due to cell deaths in the brain caused by any neurodegenerative disease. Its prominent symptoms are language disorders which must be distinguished from aphasias. It is also suggested that in fairness to Fischer, senile plaques be designated as Fischer's disease separate from neurofibrillary tangles for which AD was originally named as an eponym.     

Diabetes,Alzheimer's disease and apolipoprotein genotype

Non-insulin dependent diabetes mellitus (NIDDM) has been associated with a number of physiological consequences including neuropathy, retinopathy and incidence of vascular disease. Recently, several authors reviewed studies that suggested that NIDDM is associated with cognitive impairments leading to a higher incidence of dementia and Alzheimer's disease. The current diagnostic practices that typically exclude from an AD diagnostic any patients with suspected vascular dementia, makes it very hard to resolve this issue and likely result in an underestimation of the number of people with Alzheimer's disease and diabetes. When people with cerebrovascular disease are included, diabetes is associated with an increased risk for Alzheimer's disease. Studies that have examined peripheral glucoregulation in Alzheimer's disease are not consistent but some show small to moderate impairments in insulin sensitivity. One recent study suggest that in people that have both diabetes and an ApoE4 allele, the risk of developing Alzheimer's disease is more than double the risk of people with an ApoE4 allele without diabetes. Although diabetes does not produce any of the usual brain pathology associated with Alzheimer's disease, one study has shown that diabetes dramatically increases the amyloid deposition and neurofibrillary tangles in people with the ApoE4 genotype. Taken together, the data available suggest that diabetes is probably a risk factor for Alzheimer's disease mainly through the cerebrovascular disease diabetes causes. In people with other risk factors such as ApoE4 allele, diabetes appears to lead to a more dramatic increase in Alzheimer's disease pathology.     

Cognition and Hemodynamics

The relationship between cerebral hemodynamics and cognitive performance has increasingly become recognized as a major challenge in clinical practice for older adults. Both diabetes and hypertension worsen brain perfusion and are major risk factors for cerebrovascular disease, stroke, and dementia. Cerebrovascular reserve has emerged as a potential biomarker for monitoring pressure–perfusion–cognition relationships. Endothelial dysfunction and inflammation, microvascular disease, and mascrovascular disease affect cerebral hemodynamics and play an important role in pathohysiology and severity of multiple medical conditions, presenting as cognitive decline in the old age. Therefore, the identification of cerebrovascular vascular reactivity as a new therapeutic target is needed for prevention of cognitive decline late in life.     

Pr?vention der vaskul?ren Demenz

During recent years, increasing knowledge has been obtained from clinical studies about the impact that vascular factors have on cognitive function and dementia. Due to demographic reasons and still insufficient control of all vascular risk factors, dementia and associated problems are of increasing importance and will have impact on economical and social development in most countries. The incidence of cognitive impairment and dementia will increase exponentially. As long as no causal therapy for dementia exists, diagnosis and control of risk factors for dementia will need much more attention. Hypertension is not only the most important risk factor for stroke that often leads to dementia but also for silent brain infarcts, which are also associated with onset of dementia. Uncontrolled hypertension is associated with cognitive impairment and sufficient control of hypertension in middle-aged patients can reduce the risk of dementia in older ages. Nevertheless, treatment of all other risk factors (e.g., diabetes mellitus, hyperlipidemia, atrial fibrillation) is important to reduce the onset of not only vascular but also Alzheimer dementia.