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).

This article reviews the evidence available from natural history studies and randomized clinical trials (RCT) concerning what is now coined as amnestic MCI and vascular MCI and will answer the question about the similarity and difference of their progression toward dementia. The issues to be resolved prior to the use of a survival design for conversion from vascular MCI to dementia will be discussed.

This article reviews the use of white-matter changes as identified on MRI as a surrogate marker in clinical trials on vascular dementia. As of yet, insufficient evidence is present to implement rating or volumetric assessment of the burden of white-matter changes as surrogate marker in such trials, in view of the limited sensitivity to change of current methods and the high measurement error.

Functional brain imaging represents cerebrovascular status, neuronal status, and neuronetwork status, and plays an increasingly important role in the evaluation of vascular cognitive impairment or vascular dementia. In this article, the roles of functional brain imaging are discussed in evaluation of subcortical lesions disrupting cortico-subcortical circuits and in the study of white-matter changes in dementia. Also mentioned is an ongoing clinical trial of extracranial-intracranial artery bypass surgery for hemispheric hemodynamic misery perfusion where single-photon emission tomography is used as a surrogate measure.

Imaging should be included in the workup of dementia patients and is mandatory for the diagnosis of vascular dementia (VaD). MRI is the preferred imaging modality and should include axial T2 and FLAIR, preferably accompanied by a 3D T1-weighted sequence in clinical trials to determine white-matter lesions, infarcts, lacunes, and atrophy. Gradient echo images are needed for microbleeds. Diagnostic criteria should be operationalized and validated visual rating scales are available. In clinical trials, standardized acquisition protocols and central data analysis are mandatory. More work is needed to determine the natural progression in VaD and the possible use of MRI-based outcome measures.

The development of new drugs to treat vascular dementia and other conditions in which cognitive impairment is due at least in part to vascular pathology will require future interaction among academic, industry, and government regulatory clinicians and scientists. This article offers the author's perspective on the positive involvement of the Food and Drug Administration in development of conceptual frameworks and practical approaches to treatment of conditions characterized by vascular burden of the brain.

Any medical decision generates consequences for the patient and for society. Medical practice should, therefore, be performed under the guidance of the following ethical principles: beneficence, nonmaleficence, autonomy, justice, integrity, dignity, and vulnerability. The overarching objective of clinical research is to develop knowledge to improve health, and the subjects who participate are the means to securing such knowledge. Clinical research, as part of medical practice, should be ruled by the same ethical principles.

Regulatory reforms, together with large patient pools and increasing numbers of well-trained clinicians, have facilitated the development of clinical trials in Asia. Current regulatory and ethical issues are discussed.

There is significant interest in the development of new drugs to treat vascular dementia. However, before US approval of new drugs for this entity is possible, certain issues with regulatory implications need to be addressed. Is vascular dementia a distinct clinical syndrome with valid diagnostic criteria? Can this entity be distinguished from Alzheimer's disease (AD) and other causes of dementia? What design features are important for clinical trials in this disorder? The US Food and Drug Administration (FDA) convened a special meeting of the Peripheral and Central Nervous System Advisory Committee in an attempt to answer these questions. The conclusions from this meeting indicate that vascular dementia (VaD) is a pathologically heterogeneous disorder but appears to be reasonably distinguishable from AD dementia. The NINDS-AIREN diagnostic criteria are suitable as entry criteria for vascular dementia trials. Trials should be similar in duration to AD dementia trials and should employ a dual outcome strategy (cognitive + global/functional measures). For drugs that are believed to have a disease-modifying effect, clinical trials should study specific vascular dementia subtypes and would need to employ substantially different designs from those used currently. The term “vascular dementia” may not be entirely appropriate to describe this population.