Blood pressure,cognitive dysfunction,and dementia

With the aging of the population, the incidence and prevalence of cognitive disorders are increasing. Blood pressure plays an important role in the pathogenesis or clinical progression of stroke, vascular dementia, and Alzheimer’s disease. Data from different studies reveal that the uses of antihypertensive medications decrease the risk of dementia and cognitive dysfunction. Several studies also have demonstrated a relationship between hypotension, cognitive decline, and dementia. In this review we are trying to demonstrate the relationship between blood pressure and cognitive function and also the effect of antihypertensive medications on dementia and cognitive dysfunction.     

Cognitive functions and hypertension

The prevention of cognitive disorders and dementia represents a major challenge in the coming years. Hypertension is one of the principal risk factors for cerebrovascular diseases and is also closely correlated with cognitive decline and dementia. Most longitudinal studies have shown that cognitive functioning is often inversely proportional to blood pressure values measured 15 or 20 years previously. The higher blood pressure was, the poorer cognitive function is. Data from recent therapeutic trials (SYST-EUR, PROGRESS) open the way toward the prevention of dementia (vascular or Alzheimer's type) by antihypertensive treatments. In this context, the effect of antihypertensive treatment on cognitive functions should represent one of the primary criteria of assessment in future morbidity and mortality studies in hypertensive patients.     

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.     

Prevention of dementia and cerebroprotection with antihypertensive drugs

High blood pressure is a major risk factor for stroke and is also closely correlated with cognitive decline and dementia. Indeed, most longitudinal studies showed that cognitive functioning is often inversely proportional to blood pressure values measured 15 or 20 years previously. Because of the aging of the population, the frequency of stroke and dementia will dramatically increase in the coming years. Therefore, the prevention of cerebrovascular and cognitive disorders represents a major challenge. Antihypertensive drugs have shown clinical benefits in both primary and secondary prevention of strokes. Consensus is generally that blood-pressure lowering represents the major determinant of the benefit conferred by the antihypertensive treatment for stroke prevention; however, recent studies have suggested some differences between classes of antihypertensive drugs. The results of therapeutic trials (Systolic Hypertension in Europe [Syst-Eur], Perindopril Protection Against Recurrent Stroke Study [PROGRESS]) open the way to the prevention of dementia (vascular or Alzheimer’s type) by antihypertensive treatments. These two studies suggest different mechanisms for the prevention of cognitive decline using antihypertensive drugs. In this context, reduced incidence of dementia should be the primary outcome of future trials comparing different classes of antihypertensive drugs.     

Hypertension, dementia, and antihypertensive treatment: Implications for the very elderly

A wealth of longitudinal epidemiologic evidence links high blood pressure or hypertension to cognitive decline and incident dementia. Some (but not all) studies have suggested that antihypertensive treatment is beneficial, reducing risk of decline and dementia. There are plausible mechanisms to support the possibility that hypertension may increase the risk of dementia. There is also evidence suggesting that the two dementia types thought to be most common, Alzheimer’s disease and vascular dementia, have overlapping risk factors. Seven placebo-controlled trials of antihypertensive treatment have assessed cognitive function, incident dementia, or both, with mixed outcomes. The Hypertension in the Very Elderly Trial (HYVET), despite showing reductions in mortality and stroke with active treatment, found no significant reduction of incident dementia, although the trial was stopped early. Meta-analyses used to explore this area further are inconclusive, and comparative trials are now required.     

The complex interplay of cardiovascular system and cognition: how to predict dementia in the elderly?

Prevalence of dementing illnesses is expected to grow due to aging of the population throughout the world. Vascular dementia and Alzheimer's disease share several risk factors and are nowadays considered two ends of a continuum rather than two distinct entities. Traditional cardiovascular risk markers such as diabetes, dyslipidemia, hypertension, metabolic syndrome and adiposity in mid-life are harbingers of cognitive decline, Alzheimer's disease and vascular dementia later in life. In aged populations, only diabetes has been more constantly associated with the development of cognitive dysfunction, while other risk markers have shown more mixed results. Normal aging, co-morbidities and other changes connected to cognitive decline make the interpretation of the risk markers in the elderly challenging and probably explain these contradictory findings. Control of cardiovascular risk factors has been linked to beneficial effects in terms of cognition in cross-sectional and prospective follow up studies, but the results of interventional trials have been disappointing. More research in this area is needed, specifically, placebo-controlled randomized trials in both mid-life and late-life with cognitive dysfunction as a primary endpoint.     

Hypertension and dementia

Hypertension is one of the principal risk factors for cerebrovascular diseases. Several epidemiologic studies have also indicated a positive correlation between cognitive decline or dementia and blood pressure level. Indeed, the results of most longitudinal studies show that cognitive functioning is often inversely proportional to blood pressure values measured 15 or 20 years previously. Cerebral infarcts, lacunae, and white matter changes are implicated in the pathogenesis of vascular dementia, but may also favor the development of Alzheimer’s disease. Microcirculation disorders and endothelial dysfunctions are also advanced to explain the deterioration in cognitive functions in hypertensive subjects. Data from recent therapeutic trials open the way to the prevention of dementia (vascular or Alzheimer’s type) by antihypertensive treatments and must be confirmed by other studies.     

Cognitive screening and neuropsychological assessment in early Alzheimer's disease

Cognitive screening and detailed neuropsychological assessment provide a reliable means of detecting dementia in its earliest stages, tracking the progression of cognitive decline over time, and aiding in the differential diagnosis of various dementing disorders. In addition, recent studies have shown that mild cognitive changes, and particularly declines in memory function, are evident in the "preclinical" phase of Alzheimer's disease and may help to identify elderly individuals who are likely to develop dementia in the near future. Until effective and easily obtainable biological markers for detecting the onset and progression of Alzheimer's disease are developed, neuropsychological assessment will continue to have an important role in the dementia evaluation.     

Relation of Blood Pressure to Cognitive Impairment and Dementia

Over the past decade several studies have assessed the relation of blood pressure with cognitive function and dementia. While some cross-sectional studies have shown an inverse association between blood pressure levels and cognitive performance or dementia, longitudinal studies yielded controversial results. Most studies relating blood pressure levels in mid-life with late-life risk of cognitive decline or dementia reported a harmful effect of higher blood pressure levels on cognitive function. Studies assessing the effect of late-life blood pressure levels reported that low diastolic and very high systolic levels may increase the risk. Observational studies and randomized cinical trials provide limited evidence for a protective effect of antihypertensive therapy. It seems that the older the person and the more advanced the disease process, the less harmful or even inverted the effect of blood pressure elevation on dementia risk. The reason for this may be that blood pressure declines with age-related pathology, such as vessel stiffening, weight loss, and changes in the autonomic regulation of blood flow.     

Longitudinal course of behavioral problems during Alzheimer's disease: linear versus curvilinear patterns of decline

BACKGROUND: Patients with Alzheimer's Disease (AD) are commonly assumed to experience a linear decline in behavioral functioning that parallels progressive cognitive decline. However, some researchers have suggested that specific behavioral problems either decline at different rates or improve in late dementia. METHODS: The present analyses examined 150 AD patients at an initial assessment, 61 of whom were also evaluated annually on two additional occasions. Measures of cognitive impairment and behavioral problems were obtained. RESULTS: Cross-sectional results indicated curvilinear associations between dementia severity and certain behavioral problems (forgetful behaviors, and emotional and impulsive behaviors). Longitudinal analyses further indicated trends for curvilinear rates of behavioral disturbance across time, with some problem areas showing improvement as AD progresses through the most severe stages. CONCLUSIONS: Even though Alzheimer's disease is a progressive dementia characterized by increasing cognitive deterioration, it appears to be inaccurate to expect behavioral functioning to show the same linear decline across time.     

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.     

Hypertension artérielle et démences

Prevention and treatment of dementia has turned into a major public health challenge. Several epidemiological studies have indicated a significant association between the presence of hypertension and the onset of dementia (vascular or Alzheimer's type) several years later. Cognitive disorder may be related to focal cerebral lesions of vascular origin (infarctus, lacunae) and/or chronic ischemia of the white matter (white matter lesions) related to arteriosclerosis and/or lipohyalinosis of small perforating arteries high blood pressure in mid-life to later cognitive decline and dementia. Moreover, disorders of cerebral microcirculation and endothelial dysfunction may be associated to blood brain barrier dysfunction and amyloid plaques formation leading to Alzheimer's process. Few randomized clinical trials have included a cognitive assessment and dementia as outcome in their design. They all raise some major criticisms: cognitive assessment was never the main outcome, too short follow-up to study dementia; incomplete assessment of cognition, lost of follow-up and a small proportion of subjects at risk for dementia at inclusion. However, the results of therapeutic trials (SYST-EUR, PROGRESS) open the way to the prevention of dementia (vascular or Alzheimer's type) or cognitive decline by antihypertensive treatments. A meta-analysis including randomized controlled studies, suggests a significant decrease in the risk of dementia with antihypertensive treatment compared to placebo.     

Cross-sectional and longitudinal association between antihypertensive medications and cognitive impairment in an elderly population

BACKGROUND: The effect of antihypertensive medications on cognitive function has not been well studied. The authors' objectives were to investigate the cross-sectional and longitudinal association between the use of antihypertensive medications and cognitive function and to compare different antihypertensive medication classes with regard to this association in an elderly population. METHODS: The medical records of a convenience sample of patients (n = 993 cross-sectional and 350 longitudinal; mean age, 76.8 +/- 0.3 years; 74% women; 87% White) followed at a geriatric practice were reviewed. Data abstracted included demographics, medical history (Alzheimer's disease [AD] or vascular dementia [VaD]), use of antihypertensive medications, and results of cognitive assessments (the Mini-Mental Status Examination [MMSE] and the Clock Draw Test [CDT]). RESULTS: In the cross-sectional analysis, antihypertensive use was not associated with MMSE (p >.05), CDT (p >.05), or dementia diagnosis (odds ratio for AD, 0.8; 95% confidence interval [CI], 0.6 to 1.2; odds ratio for VaD, 1.6; 95% CI, 0.6 to 4.0). In the longitudinal analysis, antihypertensive use was associated with a lower rate of cognitive decline on the MMSE (-0.8 +/- 2 points in users vs -5.8 +/- 2.5 points in nonusers; p =.007) and on the CDT (-0.3 +/- 0.8 points in users vs -2.2 +/- 0.8 points in nonusers; p =.002), and with a lower risk for the development of cognitive impairment (odds ratio, 0.56; 95% CI, 0.38 to 0.83; p =.004). The trend was similar in patients with baseline AD (p =.02). Patients taking diuretics (p =.007), angiotensin-converting enzyme inhibitors (p =.016), and beta-blockers (p =.014) had a lower rate of cognitive decline, and patients taking angiotensin receptor blockers (p =.016) had improved cognitive scores. CONCLUSIONS: Antihypertensive use, particularly diuretics, angiotensin-converting enzymes inhibitors, beta-blockers, and angiotensin receptor blockers, may be associated with a lower rate of cognitive decline in older adults, including those with AD. Until a randomized clinical trial confirms our results, findings of this observational study should be interpreted with caution.     

Cardiovascular disease and Alzheimer's disease: common links

Growing evidence supports a strong and likely causal association between cardiovascular disease (CVD), and its risk factors, with incidence of cognitive decline and Alzheimer's disease. Individuals with subclinical CVD are at higher risk for dementia and Alzheimer's. Several cardiovascular risk factors are also risk factors for dementia, including hypertension, high LDL cholesterol, low HDL cholesterol and especially diabetes. Moderate alcohol appears to be protective for both CVD and dementia. In contrast, inflammatory markers predict cardiovascular risk, but not dementia, despite biological plausibility for such a link. The substantial overlap in risk factors points to new avenues for research and prevention.     

Blood Pressure and Cognitive Outcome

Dementia, including Alzheimer’s disease, vascular dementia, and “mixed” dementia, increases with age, yet its causes, particularly of Alzheimer’s disease, are not well understood. Hypertension is an important risk factor for arteriosclerosis, particularly in the brain and kidney, and cardiovascular events, including stroke, which are risk factors for vascular dementia. Several excellent reviews have summarized the strong, consistent evidence that elevated mid-life blood pressure and hypertension are associated with higher risk of dementia and cognitive decline. However, several questions remain, including whether the relationship of blood pressure to cognitive outcomes changes with age, and whether antihypertensive medication use delays or prevents cognitive decline and dementia. The purpose of this article is to provide an update based on review of recent scientific reports and to highlight factors that might explain existing results and future research directions.     

Dietary fatty acids intake: possible role in cognitive decline and dementia

There is a recent increase in the level of interest in the possible role of dietary fatty acids in age-related cognitive decline, and cognitive impairment of both degenerative (Alzheimer's disease, AD) or vascular origin. At present, several studies suggested that an increase of saturated fatty acids (SFA) could have negative effects on cognitive functions. Furthermore, a clear reduction of risk of cognitive decline has been found in a population sample with a high intake of polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA). These findings were confirmed by studies in which high intakes of n-6 PUFA, n-3 PUFA, MUFA, and weekly fish consumption, providing large amount of n-3 PUFA, appear to be protective against the risk of AD. In our elderly population from Southern Italy, elevated unsaturated fatty acids intake (MUFA and PUFA), high levels of antioxidant compounds, and very low SFA intake could act synergistically in improving cognitive performance. Epidemiological studies on the association between diet and cognitive decline suggested a possible role of fatty acids intake in maintaining adequate cognitive functioning and possibly in preventing or delaying the onset of dementia, both of degenerative or vascular origin. Appropriate dietary measures or supplementation with specific micro- and macronutrients might open new ways for the prevention and management of cognitive decline and dementia.     

Alzheimer's disease

An estimated 24 million people worldwide have dementia, the majority of whom are thought to have Alzheimer's disease. Thus, Alzheimer's disease represents a major public health concern and has been identified as a research priority. Although there are licensed treatments that can alleviate symptoms of Alzheimer's disease, there is a pressing need to improve our understanding of pathogenesis to enable development of disease-modifying treatments. Methods for improving diagnosis are also moving forward, but a better consensus is needed for development of a panel of biological and neuroimaging biomarkers that support clinical diagnosis. There is now strong evidence of potential risk and protective factors for Alzheimer's disease, dementia, and cognitive decline, but further work is needed to understand these better and to establish whether interventions can substantially lower these risks. In this Seminar, we provide an overview of recent evidence regarding the epidemiology, pathogenesis, diagnosis, and treatment of Alzheimer's disease, and discuss potential ways to reduce the risk of developing the disease.     

Mild cognitive impairment

Mild cognitive impairment is a syndrome defined as cognitive decline greater than expected for an individual's age and education level but that does not interfere notably with activities of daily life. Prevalence in population-based epidemiological studies ranges from 3% to 19% in adults older than 65 years. Some people with mild cognitive impairment seem to remain stable or return to normal over time, but more than half progress to dementia within 5 years. Mild cognitive impairment can thus be regarded as a risk state for dementia, and its identification could lead to secondary prevention by controlling risk factors such as systolic hypertension. The amnestic subtype of mild cognitive impairment has a high risk of progression to Alzheimer's disease, and it could constitute a prodromal stage of this disorder. Other definitions and subtypes of mild cognitive impairment need to be studied as potential prodromes of Alzheimer's disease and other types of dementia.     

The rate of decline in function in Alzheimer's disease and other dementias

BACKGROUND: Functional impairment over time is a necessary condition for the diagnosis of dementia. Increasingly, it is recognized that rates of decline may not follow a linear progression. This variability may indicate that dementia in Alzheimer's disease represents disease rather than inevitable aging. In order to investigate decline in function in dementia, we developed a model of the rate of decline in functions in Alzheimer's disease and in other dementias in comparison with normal aging. METHODS: Secondary analysis of a cross-sectional, representative sample of Canadians aged 65 and older (N = 2,914) was performed. We calculated a measure identified as an impairment index, defined as the probability of the occurrences of an impairment or disability in a structured clinical examination. RESULTS: The rate of functional decline varies for different diagnostic groups and increases with severity of the disease. The distribution for the rate of decline in dementia is distinct from that in aging without cognitive impairment. In those without cognitive impairment, the distribution is exponential. Elderly persons with dementia of any type showed a log-normal distribution. CONCLUSIONS: The difference in the distributions between aging with and without dementia likely reflects fundamental differences in the processes of decline in functions in the two groups. This suggests that the declines seen in persons with dementia are distinct from normal aging. It also has implications for the testing of antidementia medications, in that modeling treatment effects based on an assumption of linear decline is likely to be flawed.     

Association of Alzheimer's disease onset with ginkgo biloba and other symptomatic cognitive treatments in a population of women aged 75 years and older from the EPIDOS study

BACKGROUND: Peripheral C4A treatment (cerebral and peripheral vasotherapeutics) and especially Ginkgo biloba extracts are prescribed for a number of symptoms, particularly memory impairment, in elderly patients. It is postulated that because of its pharmacological actions, this treatment could prevent the decline of cognitive function, but no studies have been published to date to test its efficacy in prevention of Alzheimer's disease. The potential association between use of C4A treatments, in particular EGb 761 (standardized Ginkgo biloba extracts), and dementia of the Alzheimer type was investigated. METHODS: A case-control study was nested in a cohort of 1462 community-dwelling elderly women aged over 75 years. Sixty-nine women with Alzheimer-type dementia were compared with 345 paired women whose cognitive function remained normal. This study involved women whose cognitive function was evaluated at baseline by use of Pfeiffer's test and whose medication history was taken. The onset of cognitive impairment was investigated over a 7-year follow-up period. In order to study the factors associated with the onset of dementia, the data concerning women with a score of > or = 8 on Pfeiffer's test at inclusion, indicating normal cognitive function, were analyzed. RESULTS: A multivariate analysis including potential confounding factors showed that fewer women who developed Alzheimer's dementia had been prescribed C4A treatment (including EGb 761) for at least 2 years (odds ratio = 0.31, 95% confidence interval = 0.12-0.82, p =.018). Figures for EGb 761 alone were similar but did not reach statistical significance (odds ratio = 0.38, 95% confidence interval = 0.08-1.76, p =.22). CONCLUSION: These results suggest that C4A treatment may reduce the risk of developing Alzheimer's dementia in elderly women. The potential preventive effect of C4A treatments, including EGb 761, requires further examination. To establish a causal relationship, these findings have to be confirmed with prospective studies.