Vascular cognitive deterioration and stroke

Vascular cognitive impairment, the recent modification of the terminology related to vascular burden of the brain, reflects the all-encompassing effects of vascular disease or lesions on cognition. It incorporates the complex interactions between vascular aetiologies, risk factors and cellular changes within the brain and cognition. The concept covers the frequent poststroke cognitive impairment and dementia, as well as cerebrovascular disease (CVD) as the second most common factor related to dementia. CVD as well as vascular risk factors including arterial hypertension, history of high cholesterol, diabetes or forms of heart disease are independently associated with an increased risk of cognitive impairment and dementia. Traditional vascular risk factors and stroke are also independent factors for the clinical presentation of Alzheimer's disease (AD). In addition to these vascular factors, CVD/strokes, infarcts and white-matter lesions may trigger and modify the progression of AD as the most common cause of neurodegenerative dementia. The main subtypes of previously defined vascular dementia (VaD) include the cortical VaD or multi-infarct dementia also referred as poststroke VaD, subcortical ischaemic vascular disease and dementia or small-vessel dementia and strategic-infarct dementia. Whilst CVD is preventable and treatable, it is clearly a major factor in the prevalence of cognitive impairment in the elderly worldwide.     

Prevention and early intervention for vascular dementia in community dwelling elderly: Findings from the Nakayama study

Cerebrovascular disease (CVD) may be the single most common risk factor for age‐associated dementia (in particular for vascular dementia (VaD)), and there is definite potential for prevention and treatment of CVD. After one of the most comprehensive and precise type‐specific prevalence surveys of dementia (first Nakayama study), we have continued the preventive and early interventional approaches to CVD and VaD, including treatment of cardiovascular risk factors. In this cohort study, 88% of patients with ‘vascular cognitive impairment without dementia’, who were alive at 3‐years follow up, were still diagnosed with ‘vascular cognitive impairment without dementia’ and only 12% progressed to dementia. Compared with the results of previous studies, active control of risk factors and prevention of recurrent stroke may reduce the incidence of dementia and slow the progression of cognitive impairment in patients with ‘vascular cognitive impairment without dementia’.     

Vascular factors and Alzheimer disease

Vascular risk factors are normally associated with cerebrovascular disease, which may lead to vascular dementia (VaD). Several recent studies suggest that there is increased risk of developing Alzheimer disease when exposed to these same vascular risk factors. In addition to old age, hypertension, peripheral arterial disease, certain types of cardiovascular disorders, diabetes mellitus, and smoking are now considered risk factors for late-onset Alzheimer disease. In this review, we examine several vascular factors and peripheral vascular pathophysiology implicated in Alzheimer disease and suggest certain mechanisms that might promote the association of vascular factors and late-onset Alzheimer disease. We support the implication that prevention or management of peripheral vascular disease may prevent or delay the onset of Alzheimer disease or mixed dementia.     

The relationship of hypertension in the elderly to AD, vascular dementia, and cognitive function

BACKGROUND: Hypertension at the age of 45 to 50 years may predispose to AD later in life. It is not known whether hypertension after age 65 years also contributes to AD risk, and its effect on cognitive function is also not fully understood. METHODS: Data were analyzed from 1,259 Medicare recipients free of dementia in a longitudinal study covering a 7-year period (1991 to 1998). The effect of hypertension was first examined in relationship to the risk for incident AD and then to incident vascular dementia (VaD) using Cox proportional hazards models. Changes in performance over time on tasks of memory, language, and visuospatial/cognitive function were compared in those with and without hypertension using generalized estimating equations. RESULTS: Of the 1,259 subjects, 731 (58.1%) had a history of hypertension associated with diabetes, stroke, and heart disease. A history of hypertension was not associated with an increased risk for AD (rate ratio [RR] 0.9, 95% CI 0.7 to 1.3) but was associated with an increased risk for VaD (1.8 [1.0 to 3.2]). Hypertension was not associated with changes in memory, language, and general cognitive function in normal individuals over time. Compared with individuals with neither hypertension nor heart disease, those with hypertension or heart disease alone had no increase in risk for VaD. However, when both were present, there was a threefold increase in risk for VaD. A sixfold increase in risk was observed when both hypertension and diabetes were present. CONCLUSIONS: Hypertension after age 65 years is not associated with AD and does not adversely affect memory, language, or general cognitive function. A history of hypertension may be an antecedent to VaD, particularly in the presence of heart disease or diabetes.     

Vascular risk factors for incident Alzheimer disease and vascular dementia: the Cache County study

Vascular risk factors for Alzheimer disease (AD) and vascular dementia (VaD) have been evaluated; however, few studies have compared risks by dementia subtypes and sex. We evaluated relationships between cardiovascular risk factors (hypertension, high cholesterol, diabetes mellitus, and obesity), events (stroke, coronary artery bypass graft surgery, and myocardial infarction), and subsequent risk of AD and VaD by sex in a community-based cohort of 3264 Cache County residents aged 65 or older. Cardiovascular history was ascertained by self-report or proxy-report in detailed interviews. AD and VaD were diagnosed using standard criteria. Estimates from discrete-time survival models showed no association between self-reported history of hypertension and high cholesterol and AD after adjustments. Hypertension increased the risk of VaD [adjusted hazard ratio (aHR) 2.42, 95% confidence interval (CI) 0.95-7.44]. Obesity increased the risk of AD in females (aHR 2.23, 95% CI 1.09-4.30) but not males. Diabetes increased the risk of VaD in females after adjustments (aHR 3.33, 95% CI 1.03-9.78) but not males. The risk of VaD after stroke was increased in females (aHR 16.90, 95% CI 5.58-49.03) and males (aHR 10.95, 95% CI 2.48-44.78). The results indicate that vascular factors increase risks for AD and VaD differentially by sex. Future studies should focus on specific causal pathways for each of these factors with regard to sex to determine if sex differences in the prevalence of vascular factors have an influence on sex differences in dementia risk.     

Vascular dementia today

This decade witnessed a resurgence of interest in vascular dementia (VaD) as an increasingly important cause of senile dementia. Although definitions of dementia in general, and of VaD in particular, are still controversial recent diagnostic criteria for VaD acknowledge that pathogenetic mechanisms different from multi-infarct dementia are important in dementia causation. These include subcortical strokes, mainly lacunes, global hypoxic-ischemic events during acute stroke, and ischemic periventricular white matter lesions of the Binswanger type. These lesions tend to be manifested primarily by alterations of frontal executive function control. The importance of these ischemic vascular lesions in the clinical expression of Alzheimer's disease (AD) in very old subjects has also been recognized. Clinically, VaD may present in two forms: Acute VaD includes large-vessel infarction, and lacunar dementia due to small-vessel disease, including thalamic and caudate strokes. Subacute VaD includes Binswanger's disease (BD), cerebral angiopathy with leukoencephalopathy and CADASIL. The discovery of CADASIL, a genetic form of VaD mapped to chromosome 19 as a mutation of the Notch 3 gene, opened research avenues into the pathogenesis of BD. Finally, epidemiological evidence suggests that it may be possible to prevent VaD--and perhaps degenerative senile dementia--by controlling hypertension and other vascular risk factors. These findings offer hope for prevention of this growing public health problem.     

Diagnosis and management of vascular cognitive impairment and dementia

Vascular dementias (VaDs) are the second most common cause of dementia. Cerebrovascular disease (CVD) and stroke relates to high risk of cognitive impairment, but also relate to Alzheimer's disease (AD): Vascular cognitive impairment (VCI) and dementias extend beyond the traditional multi-infarct dementia. Pathophysiology of VaD incorporates interactions between vascular etiologies (CVD and vascular risk-factors), changes in the brain (infarcts, white matter lesions, atrophy), host factors (age, education) and cognition. Variation in defining the cognitive syndrome, in vascular etiologies, and allowable brain changes in current criteria have resulted in variable estimates of prevalence, of groups of subjects, and of the types and distribution of putative causal brain lesions. Should new criteria be developed? Ideally in constructing new criteria the diagnostic elements should be tested with prospective studies with clinical-pathological correlation: replace dogma with data. Meanwhile focus on more homogenous subtypes of VaD, and on imaging criteria could be a solution. Subcortical ischemic vascular disease and dementia (SIVD) incorporate small vessel disease as the chief vascular etiology, lacunar infarct and ischaemic white matter lesions as primary type of brain lesions, subcortical location as the primary location of lesions, and subcortical syndrome as the primary clinical manifestation. It incorporates two clinical entities "Binswanger's disease" and "the lacunar state". AD with VaD (mixed dementia) has been underestimated as a prevalent cause in the older population. In addition to simple co-existence, VaD and AD have closer interaction: several vascular risk factors and vascular brain changes relate to clinical manifestation of AD, and they share also common pathogenetic mechanisms. Vascular cognitive impairment (VCI) is a category aiming to replace the "Alzhemerized" dementia concept in the setting of CVD, and substitute it with a spectrum that includes subtle cognitive deficits of vascular origin, post-stroke dementia, and the complex group of the vascular dementias. As far there is no standard treatment for VaDs, and still little is known on the primary prevention (brain at risk for CVD) and secondary prevention (CVD brain at risk for VCI/VaD). There is no standard symptomatic treatment for VaD. Recently symptomatic cholinergic treatment has shown promise in AD with VaD, as well as probable VaD. Future focus should be directed to the distinct etiological and pathological factors: the vascular and the AD burden of the brain.     

Risk factors for vascular dementia in elderly psychiatric outpatients with preserved cognitive functions

The aim of the study was to assess risk factors for vascular dementia (VaD) in elderly psychiatric outpatients without dementia, and to determine to what extent clinical interventions targeted such risk factors. Out of 250 clinical charts, 78 were selected of patients over 60 years old, who showed no signs of dementia. Information was obtained regarding demographics, clinical conditions (diagnosis according to ICD-10), complementary investigation, cognitive functions (via CAMCOG), neuroimaging, and the presence of risk factors for VaD. Depression was the most prevalent psychiatric disorder (74%). A great majority of the patients (86%) had at least one risk factor for VaD. One-third of the sample showed three or more risk factors for VaD. The clinical conditions related to risk factors for VaD were hypertension (48.7%), heart disease (30.8%), hypercholesterolemia (25.6%), diabetes mellitus (23.1%), stroke (12.8%), tryglyceride (12.8%), and obesity (5.1%). In terms of lifestyle, smoking (19.2%), alcohol abuse (16.7%), and sedentarism (14.1%) were other risk factors found. Definite risk factors for VaD were found in 83.3% of the patients. Previous interventions targeting risk factors were found in only 20% of the cases. The high rates of risk factors for VaD identified in this sample suggest that psychiatrists should be more attentive to these factors for the prevention of VaD.     

Neuroprotection in vascular dementia

Vascular dementia (VaD) is the second most common form of dementia after Alzheimer's disease (AD), and one of the major causes of mental and physical disability in developed countries. As such, the identification and implementation of strategies which prevent the development of the condition or enable improvements in patients with VaD are healthcare objectives of the first order. VaD is now regarded as a combined group of clinical-pathological entities rather than one disease, that is, multiple pathogenic mechanisms and lesion types underlie a cognitive impairment of vascular origin. The clinical diagnosis of VaD is complex and difficult because of the heterogeneous nature of its clinical presentation and progression and the low sensitivity of existing clinical criteria. Moreover, there is growing evidence of the epidemiological significance of mixed forms of dementia, and that ischemic processes may precipitate and exacerbate cognitive impairment in AD. Numerous compounds have been proposed as potentially useful in the treatment of patients with VaD, comprising vasodilatative, antithrombotic, hemorrheological, nootropic, antiserotoninergic and, most recently, antiglutamatergic and cholinergic approaches. In spite of some initially favorable reports based on the use of memantine, donepezil and galantamine, there is as yet no conclusive evidence of a definitive treatment for VaD. Unsatisfactory results from VaD drug trials may be attributed in part to the diversity of the patients included (underlying pathogenic mechanisms, number, type, and location of vascular lesions), and to methodological limitations in the design of the trials (outcome measures, end-points, size, follow-up period). The treatment of modifiable vascular risk factors - hypertension, diabetes mellitus, hypercholesterolemia and heart disease - is an important strategy for the reduction of the risk of dementia, and is likely to slow the progress of cognitive decline.     

Rethinking the dementia diagnoses in a population-based study: what is Alzheimer's disease and what is vascular dementia?. A study from the kungsholmen project

OBJECTIVE: To explore the hypothesis that older adults often are affected by more than one disease, making the differential diagnosis between Alzheimer's disease (AD) and vascular dementia (VaD) difficult. METHODS: Incident dementia cases (n = 308) from a population-based longitudinal study of people 75+ years were investigated. The DSM-III-R criteria were used for the clinical diagnosis of dementia. Data on vascular disorders (hypertension, cerebrovascular and ischemic heart diseases, heart failure, atrial fibrillation, diabetes) as well as type of onset/course of dementia were used retrospectively to reclassify dementias. RESULTS: Only 47% of the AD cases were reclassified as pure AD without any vascular disorder. Among subjects with AD and with a vascular component, cerebrovascular disease was the most common (41%). Only 25% of VaD were reclassified as pure VaD. Further, 26% of the pure AD subjects developed a vascular disorder in the following 3 years. CONCLUSIONS: Both vascular and degenerative mechanisms may often contribute to the expression of dementia among the elderly. Most of the AD cases have vascular involvements, and pure dementia types in very old subjects constitute only a minority of dementia cases.     

Vascular aspects of cognitive impairment and dementia

Hypertension and stroke are highly prevalent risk factors for cognitive impairment and dementia. Alzheimer''s disease (AD) and vascular dementia (VaD) are the most common forms of dementia, and both conditions are preceded by a stage of cognitive impairment. Stroke is a major risk factor for the development of vascular cognitive impairment (VCI) and VaD; however, stroke may also predispose to AD. Hypertension is a major risk factor for stroke, thus linking hypertension to VCI and VaD, but hypertension is also an important risk factor for AD. Reducing these two major, but modifiable, risk factors—hypertension and stroke—could be a successful strategy for reducing the public health burden of cognitive impairment and dementia. Intake of long-chain omega-3 polyunsaturated fatty acids (LC-n3-FA) and the manipulation of factors involved in the renin–angiotensin system (e.g. angiotensin II or angiotensin-converting enzyme) have been shown to reduce the risk of developing hypertension and stroke, thereby reducing dementia risk. This paper will review the research conducted on the relationship between hypertension, stroke, and dementia and also on the impact of LC-n3-FA or antihypertensive treatments on risk factors for VCI, VaD, and AD.     

Treatment of vascular dementia-evidence from clinical trials with cholinesterase inhibitors

Cerebrovascular disease (CVD), as well as secondary ischemic brain injury from cardiovascular disease, are common causes of dementia and cognitive decline in the elderly. Also, CVD frequently contributes to cognitive loss in patients with Alzheimer's disease (AD). Progress in understanding the pathogenetic mechanism involved in vascular cognitive impairment and vascular dementia (VaD) has resulted in promising treatments of these conditions. Cholinergic deficits in VaD are due to ischemia of basal forebrain nuclei and of cholinergic pathways and can be treated with the use of the cholinesterase inhibitors used in AD. Controlled clinical trials with donepezil, galantamine, and rivastigmine in VaD, as well as in patients with AD plus CVD, have demonstrated improvement in cognition, behavior and activities of daily living.     

Treatment of vascular dementia--evidence from clinical trials with cholinesterase inhibitors

Cerebrovascular disease (CVD), as well as secondary ischemic brain injury from cardiovascular disease, are common causes of dementia and cognitive decline in the elderly. In addition, CVD frequently contributes to cognitive loss in patients with Alzheimer's disease (AD). Progress in understanding the pathogenetic mechanism involved in vascular cognitive impairment (VCI) and vascular dementia (VaD) has resulted in promising treatments of these conditions. Cholinergic deficits in VaD are due to ischemia of basal forebrain nuclei and of cholinergic pathways and can be treated with the use of the cholinesterase inhibitor agents used in AD. Controlled clinical trials with donepezil, galantamine and rivastigmine in VaD, as well as in patients with AD plus CVD, have demonstrated improvements in cognition, behavior and activities of daily living.     

Vascular cognitive disorder: a new diagnostic category updating vascular cognitive impairment and vascular dementia

Vascular cognitive impairment (VCI) was proposed as an umbrella term to include subjects affected with any degree of cognitive impairment resulting from cerebrovascular disease (CVD), ranging from mild cognitive impairment (MCI) to vascular dementia. VCI may or may not exclude the host of "focal" circumscribed impairments of specialized functions such as language (aphasia), intentional gesture (apraxia), or categorical recognition (agnosia), among others, that may result from a stroke. Therefore, there are no universally accepted diagnostic criteria for VCI. We conclude that this concept could be more useful if it were to be limited to cases of vascular MCI without dementia, by analogy with the concept of amnestic MCI, currently considered the earliest clinically diagnosable stage of Alzheimer disease (AD). In agreement with our view,the Canadian Study on Health and Aging successfully implemented a restricted definition of VCI, excluding cases of dementia (i.e., vascular cognitive impairment no dementia, VCI-ND). The Canadian definition and diagnostic criteria could be utilized for future studies of VCI. This definition excludes isolated impairments of specialized cognitive functions.Vascular dementia (VaD): The main problem of this diagnostic category stems from the currently accepted definition of dementia that requires memory loss as the sine qua non for the diagnosis. This may result in over-sampling of patients with AD worsened by stroke (AD+CVD). This problem was minimized in controlled clinical trials of VaD by excluding patients with a prior diagnosis of AD, those with pre-existing memory loss before the index stroke, and those with amnestic MCI. We propose a definition of dementia in VaD based on presence of abnormal executive control function, severe enough to interfere with social or occupational functioning. Vascular cognitive disorder (VCD): This term, proposed by Sachdev [P. Sachdev, Vascular cognitive disorder. Int J Geriat Psychiatry 14 (1999)402-403.] would become the global diagnostic category for cognitive impairment of vascular origin, ranging from VCI to VaD. It would include specific disease entities such as post-stroke VCI, post-stroke VaD, CADASIL, Binswanger disease, and AD plus CVD. This category explicitly excludes isolated cognitive dysfunctions such as those mentioned above.     

Body mass index in midlife and risk of Alzheimer disease and vascular dementia

Prior work has suggested that obesity and overweight as measured by body mass index (BMI) increases risk of dementia. It is unknown if there is a difference in the risk of developing Alzheimer disease (AD) versus vascular dementia (VaD) associated with high body weight. The goal of this study was to examine the association between midlife BMI and risk of both AD and VaD an average of 36 years later in a large (N= 10,136) and diverse cohort of members of a health care delivery system. Participants aged 40-45 participated in health exams between 1964 and 1968. AD and VaD diagnoses were obtained from Neurology visits between January 1, 1994 and June 15, 2006. Those with diagnoses of general dementia from primary care providers were excluded from the study. BMI was analyzed in WHO categories of underweight, overweight and obese, as well as in subdivisions of WHO categories. All models were fully adjusted for age, education, race, sex, marital status, smoking, hyperlipidemia, hypertension, diabetes, ischemic heart disease and stroke. Cox proportional hazard models showed that compared to those with a normal BMI (18.5-24.9), those obese (BMI > or = 30) at midlife had a 3.10 fold increase in risk of AD (fully adjusted model, Hazard Ratio=3.10, 95% CI 2.19-4.38), and a five fold increase in risk of VaD (fully adjusted model, HR=5.01, 95% CI 2.98-8.43) while those overweight ( BMI > or = 25 and <30) had a two fold increase in risk of AD and VaD (fully adjusted model, HR=2.09, 95% CI 1.69-2.60 for AD and HR=1.95, 95% CI 1.29-2.96 for VaD). These data suggest that midlife BMI is strongly predictive of both AD and VaD, independent of stroke, cardiovascular and diabetes co morbidities. Future studies need to unveil the mechanisms between adiposity and excess risk of AD and VaD.     

Treatment of vascular dementia—evidence from clinical trials with cholinesterase inhibitors

Abstract

Cerebrovascular disease (CVD), as well as secondary ischemic brain injury from cardiovascular disease, are common causes of dementia and cognitive decline in the elderly. Also, CVD frequently contributes to cognitive loss in patients with Alzheimer's disease (AD). Progress in understanding the pathogenetic mechanism involved in vascular cognitive impairment and vascular dementia (VaD) has resulted in promising treatments of these conditions. Cholinergic deficits in VaD are due to ischemia of basal forebrain nuclei and of cholinergic pathways and can be treated with the use of the cholinesterase inhibitors used in AD. Controlled clinical trials with donepezil, galantamine, and rivastigmine in VaD, as well as in patients with AD plus CVD, have demostrated improvement in cognition, behavior and activites of daily living.     

Cerebrovascular disease and dementia

Cerebrovascular disease (CVD) is an important cause of psychiatric disability in the elderly. Much of this disability can be attributed to dementia and lesser degrees of cognitive impairment, which result from strokes and other forms of cerebrovascular pathology. While vascular dementia is common, estimates of its frequency vary due to its clinical and pathologic heterogeneity, the challenges involved in its measurement and its frequent co-occurrence with Alzheimer's disease. Nevertheless the clinical features and natural histories of vascular dementia can be described, and risk factors have been identified and include hypertension, diabetes mellitus, hyperlipidaemia, other conditions that promote atherosclerosis, and rare genetic mutations. While vascular dementia is not curable, treatments are available. For example, a few recent clinical trials suggest that cholinesterase inhibitors have some efficacy. Our knowledge of the risk factors has also provided opportunities for the primary and secondary prevention of vascular dementia, and indicates promising avenues for research.     

Treatment of vascular dementia: the route of prevention

Vascular dementia (VaD), rather than being considered as a univocal nosological entity, should be regarded as a heterogeneous clinical entity which differs in clinical-pathological phenotype as well as in pathophysiological mechanisms, but shares cerebrovascular disease (CVD), resulting from vascular or circulatory pathology, as the cause of dementia. The aim of this review is to discuss VaD treatment focusing particularly on more prevalent ischemic forms. Due to the fact that there are presently no treatments capable of obtaining considerable results once VaD is clinically established, specific emphasis will be given to the therapeutic strategies aimed at the prevention of CVD risk factors. The therapeutic strategies aimed at slowing the progression of the disease will also be discussed.     

Dementia Poststroke

Abstract : The frequency of dementia poststroke is high, and stroke considerably increases the risk of dementia. The risk factors for dementia related to stroke are still incompletely understood. In addition to age and low level of education, different combinations of vascular risk factors and stroke features have been associated with poststroke dementia. A single explanation for poststroke dementia is not adequate; rather, multiple factors including stroke features (dysphasia, major dominant stroke syndrome), infarct features (type, side, site, number, and volume), extent and type of white matter lesions (WMLs), degree and site of atrophy, host characteristics (e.g. age, educational level), and risk factors for stroke (e.g. prior cerebrovascular disease, diabetes) each contribute to the risk of dementia poststroke.
Dementia after first ever clinical stroke is also frequent. Cognitive decline is present prior to stroke in up to one-third of patients developing post-stroke dementia. Medial temporal lobe atrophy, a marker of an increased risk of Alzheimer's disease (AD), is more frequent in stroke patients who have preexisting dementia or cognitive decline, as well as poststroke dementia. This may be explained by co-existing AD and cerebrovascular disease (CVD). The magnitude of this mixed dementia (AD with CVD/Vascular Dementia (VaD)) group has been previously underestimated, and it is a diagnostic challenge in the older population.
Dementia due to CVD is a rather advanced stage of is chemic brain changes, and outcome of treatment and prevention may be limited. Accordingly, the focus should be placed on the entire spectrum of cognitive impairment related to CVD, focusing especially the early cognitive changes.