Noncognitive or behavioral and psychological symptoms (BPSD) are common in vascular dementia. Many occur with the same frequency as in Alzheimer's disease, though depression, emotional lability, and apathy may be more common and psychosis less so. There is a particularly strong relationship between cerebrovascular disease and depression.

Hypertension is a risk factor for stroke, ischemic white-matter lesions, cardiovascular disorders, and vascular dementia. This risk increases with increasing blood pressure. Several studies report that high blood pressure precedes Alzheimer's disease (AD) by decades, but blood pressure decreases the years before dementia onset and is lower in individuals with AD than in controls. High blood pressure has also been related to the neuropathological manifestations of AD. The exact mechanism behind these associations is not clear. Hypertension may cause cerebrovascular disease that may increase the likelihood that individuals with AD encephalopathy will express a dementia syndrome, this may accelerate the AD process, subclinical AD may lead to increased blood pressure, and similar biological mechanisms may be involved in the pathogenesis of both disorders. Hypertension is a common disorder and often untreated. Even if hypertension results only in a moderately increased risk of AD, or overall dementia, better treatment of hypertension may have an immense effect on the total number of individuals with dementia.

Multiple epidemiological and brain imaging studies show a strong association between elevations in systolic blood pressure and lesions of cerebral white matter. The association between white-matter lesions and systolic blood pressure persists even if individuals are receiving treatment, suggesting that these individuals may be undertreated. In addition, these studies suggest that lesions of cerebral white matter may serve as markers for atherosclerotic vascular disease. Treatment strategies, therefore, should focus on early and aggressive management of elevated blood pressure, but definitions of elevated blood pressure may need to be revised downward to achieve best results.

A pivotal role for cholesterol influence on production of the putative AD toxin, amyloid β (Aβ), has been amply demonstrated. More importantly, this relationship has consistently been identified in both in vivo and in vitro studies. Lowering cholesterol levels has been shown to cause a beneficial effect on Aβ levels in animal models, and epidemiological data indicate a beneficial effect on the risk of AD with prior statin use. Blinded, placebo-controlled clinical investigations assessing the benefit of statins on cognitive indices in mild to moderate AD are ongoing and one will be reported on soon. A prospective study assessing the effect of statin use on the risk of AD is under way as an observational component of a placebo-controlled primary prevention trial testing anti-inflammatory agents. Nevertheless, the foregoing suggests that routine monitoring and intervention for elevated cholesterol levels among the elderly could promote more than a healthy heart.

The treatment of patients with acute stroke is reviewed. Evidence of the existence of an ischemic penumbra in humans is presented. Different approaches to treatment of acute stroke include restoring blood flow by thrombolysis, neuroprotection, and early secondary prevention with aspirin. The evidence for each of these approaches is reviewed. Organization of stroke services, and particularly the use of stroke units, have been shown to significantly improve stroke outcome and these data are presented.

Stroke recurrence can be reduced substantially by intervention with the appropriate stroke preventive(s). Control of blood pressure, use of one of the antiplatelet agents aspirin, aspirin plus extended (modified)-release dipyridamole, or clopidogrel, administration of warfarin for patients with atrial fibrillation and high-risk profiles for stroke, and use of carotid endarterectomy in patients with high grades of symptomatic carotid artery stenosis are all proven therapies for prevention of stroke recurrence. Newer therapies to reduce the risk of infection and inflammation promise to further reduce the risk of first and recurrent stroke and are undergoing testing. In this article we review standard and more novel means to prevent stroke recurrence.

A three-year follow-up of 273 participants (mean age 60 years) of the Austrian Stroke Prevention Study provides the first information on the rate, clinical predictors, and cognitive consequences of MRI white-matter lesions in elderly individuals without neuropsychiatric disease. Lesion progression was found in 17.9% of individuals over a time period of 3 years. Diastolic blood pressure and early confluent or confluent white-matter hyperintensities at baseline were the only significant predictors of white-matter hyperintensity progression. Lesion progression had no influence on the course of neuropsychologic test performance over the observational period, but the statistical power of this analysis was low.

The therapy for vascular dementia has known several changes and updates since the use of niacin in the first years of the 20th century. These modifications were due to the parallel evolution of the concept of vascular dementia. Initially, treatments in this area were proposed because they were considered vasoactive and able to increase the blood flow of the brain. After these, other drugs were introduced because they were also able to ameliorate the oxygen usage by the suffering neurons. The more recent therapeutic proposals were made for drugs active on the metabolic activities of the brain, or with hemorrheological or antioxidant properties. As a consequence, a large array of different pharmacological properties were considered in proposing the several different kinds of drugs as useful in vascular dementia patients. The most recent attempt in this field consists of evaluating the usefulness of traditional antidementia drugs (those with anticholinesterase action) in patients with a prevalence of cerebrovascular disorders.

With increasing understanding of BPSD, the question of whether there are differences between BPSD of AD and VaD may be raised. The available evidence from the Cache County Study, the role of vascular risk factors in late-life depression, and vascular pathology in AD and VaD all converge to explore the impact of vascular burden on cerebral function and BPSD. This article argues that there may be domain differences in BPSD between AD and VaD and suggests that BPSVaD may be a concept to be pursued with possible useful clinical implications.

Vascular dementia (VaD) is a disorder with no cure and limited treatment options. Similarities between VaD and Alzheimer's disease (AD) arise on a number of levels. Both involve progressive decline in cognition, functional ability, and behavior, and there is evidence for a central role of reduced cholinergic neurotransmission in the two illnesses. Treatment strategies in VaD have historically focused on prevention, although evidence of cognitive benefits with preventative treatment is scarce. Acetylcholinesterase inhibitors represent a rational treatment possibility for symptomatic therapy of patients with VaD. A recent large-scale trial of galantamine in patients with VaD or AD with cerebrovascular disease (AD + CVD) represents the first placebo-controlled trial showing clinically relevant benefits in these important patient populations.

Background: There are difficulties in accurately defining patients with vascular dementia (VaD) and, therefore, little is known about the characteristics of this population. Objective: To examine the population characteristics in patients with VaD enrolled in two randomized, double-blind, placebo-controlled, 24-week clinical trials of the efficacy and tolerability of the acetylcholinesterase inhibitor donepezil. Methods: Enrolled patients had probable or possible VaD, classified according to NINDS-AIREN criteria. Patients were excluded if they had a diagnosis of Alzheimer's disease or dementia caused by other conditions not associated with the cardiovascular system. Results: A total of 1,219 patients, 73% with probable VaD and 27% with possible VaD, were enrolled. Patients had a mean Hachinski score of 9.7, with memory impairment the most prominent feature of their dementia. Sixty-eight percent of patients had a history of at least one stroke and 28% of patients had a history of transient ischemic attack before dementia. In the 99% of patients who had abnormal computer-assisted tomography or magnetic resonance imaging scans, cortical and subcortical infarcts were among the lesions observed, with significant white-matter lesions also present in some patients. Seventy-three percent of patients had experienced an abrupt onset of cognitive symptoms. Vascular risk factors were prominent and included hypertension (70%), smoking (62%), and hypercholesterolemia (39%). Conclusions: The patients enrolled in these trials had probable or possible VaD; these patients exhibited a history of cerebrovascular disease and a broad range of comorbid cardiovascular conditions. The large number of patients enrolled will permit a thorough examination of the efficacy and tolerability of donepezil in VaD.

Vascular dementia (VaD), like Alzheimer's disease (AD), is associated with cholinergic deficits. Rivastigmine provides sustained, brain-selective inhibition of acetylcholinesterase and butyrylcholinesterase. Preliminary data suggest that rivastigmine may provide significant benefits in patients with AD and cerebrovascular disease (mixed dementia), and in patients with VaD. Open-label rivastigmine treatment has been associated with improved cognitive and functional abilities, behavioral symptoms, and reduced caregiver stress in a small pilot study in these patients. Larger, prospective, double-blind studies of rivastigmine in patients with VaD are under way. These studies will confirm whether rivastigmine is an efficacious treatment option for a range of patients for whom, until now, there have been few symptomatic therapies.

The uncompetitive N-methyl-D-aspartate (NMDA) antagonist memantine was tested against placebo in two randomized controlled trials. In total, 900 patients suffering from mild-to-moderate “probable” VaD (according to NINDS-AIREN criteria) were included. In these prospective, 2-arm parallel, multicenter trials conducted in the United Kingdom (MMM500) and in France (MMM300), patients suffering from “probable” vascular dementia (according to NINDS-AIREN criteria) were recruited. Active treatment in both trials was memantine at the standard daily dose of 10 mg b.i.d. The cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) was a primary endpoint in both trials, and in both trials a statistically significant difference was seen between treatment groups after 28 weeks. In a pooled analysis of the data, various subgroups were examined. In a first analysis, patients were stratified by their severity of dementia (measured by the MMSE total scores at baseline). In this analysis, memantine was superior to placebo in all subgroups, but the magnitude of effect was clearly more pronounced in the more severely demented patients. A second analysis stratified the patients by the neuroradiological findings at baseline (“small vessel” versus “large vessel” type of VaD). The cognitive benefit by memantine treatment was larger for the small vessel group and, interestingly, also the decline in the placebo group was faster in the small vessel patients. In these trials, memantine at a dose of 10 mg b.i.d. was safe and very well tolerated with a frequency of dropouts due to adverse events that was close to placebo.

A general cognitive performance battery is needed as a primary outcome in vascular dementia clinical trials. Because there is considerable overlap between vascular dementia and Alzheimer's disease (AD) in the pattern of cognitive impairment, a reasonable approach to developing an optimal vascular dementia battery is to begin with a widely used AD measure and improve its sensitivity to the cognitive domains that are more prominent in vascular dementia. Thus the VaDAS-cog has evolved, which comprises the ADAS-cog with additional frontal lobe subtests covering attention, working memory, executive function, and verbal fluency. Validation of this new cognitive instrument will be supported by its successful use in vascular dementia clinical trials.

Cerebrovascular disease and stroke are related to high risk of cognitive impairment. One of the main neuropsychological features in vascular cognitive impairment and vascular dementia is executive dysfunction. Definition of the essential subcomponents and concepts of executive function is important before determining the methodology in clinical trials. The scientific research and new methods on this topic are rapidly growing. We present some most commonly used neuropsychological tests and discuss the methodological aspects in light of clinical trials.

Disability is a major negative consequence of aging, with impact on several domains of individual, familial, and social life, and a major source of expenditure for social systems. Preventing or delaying disability in the elderly depends not only on understanding the etiology of pathological processes causing disability, but also on the identification of the early stages of disability (preclinical disability). Vascular dementia may have an impact on disability with variable severity and patterns compared to nonvascular forms of dementia. Vascular cognitive impairment is consistent with a preclinical disability status in which cognitive impairment, already manifested, might not interfere substantially with everyday life activities, but might still cause subtle difficulties in selective performances, like those linked with executive functions. Instruments comprehensive and sensitive enough to describe global function in such a context should be specifically designed and validated.

Cerebrovascular small vessel disease is now believed to be the major source of vascular burden of the brain. Cerebrovascular small vessel disease and Alzheimer's disease appear to represent pathophysiologic and clinical continua, rather than dichotomous entities. It appears that common etiopathologic mechanisms underlie the clinical presentation of both of these conditions. Therefore, the staging procedures that have been developed for the clinical continuum of age-associated memory impairment, mild cognitive impairment, and the progressive dementia of Alzheimer's disease appear to be applicable for the same continua in cerebrovascular small vessel disease. Although temporal and prognostic aspects have been studied for the Alzheimer's-related portions of this clinical staging continuum, they remain to be elucidated for cerebrovascular small vessel disease.

Behavioral and psychological symptoms in dementia (BPSD) are an important aspect of the disorder that are now receiving more attention. The design of the trials in vascular dementia needs to account for these features. The specific area of BPSD in vascular dementia, their assessment, and relationship to the design of trials are considered in this article.

Research has shown that psychosocial intervention can have a significant benefit for patients and caregivers. Randomized controlled trials of psychosocial intervention for spouse-caregivers can improve social support and reduce depression among the caregivers and help prevent or postpone nursing home placement of their spouses with Alzheimer's disease.

Knowledge about the health economic implications of vascular dementia (VaD) is insufficient. The impact of cardiovascular comorbidities must also be taken into consideration when resource utilization and costs in patients with VaD are analyzed. It is also of great importance that the analysis be done from a societal perspective. In the rural Nordanstig cohort of the Kungsholmen project in Sweden, the major cost drivers in the RUD (Resource Utilization in Dementia) instrument were used. The cost from a societal perspective was 23% higher for patients with VaD compared with patients with Alzheimer's disease (p = .02).