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.

In many studies vascular dementia (VaD) is the second most frequent cause of organic acquired cognitive dysfunction; accounting for 10% to 50% of the cases, depending on the geographical area, patient population, and diagnostic criteria used. There is growing evidence that VaD does not include only multi-infarct dementia (MID) but relates to complex interactions of different etiologies (risk factors, cerebrovascular disease), structural changes in the brain, host factors and cognition. This resulted in reconceptualization of VaD to emphasize the differences from Alzheimer's disease (AD). However, the diagnostic criteria used (DSM-IV, ICD-10, NINDS-AIREN, or ADDTC) are based on the experience with AD and as such have their limitations and are not interchangeable. From a regulatory point of view, therefore, future research is needed to better define VaD in general and possible subtypes of VaD as targets for drug trials. Methodological issues in VaD trials, as opposed to AD, will be emphasized. The European Medicinal Products Evaluation Agency (EMEA) has adopted a guideline for trials of symptomatic treatments of dementia, particularly in AD. There is no explicit guideline for VaD trials; however, many of the recommendations for AD are already applicable to VaD for drugs aiming at alleviating symptoms of dementia. On the other hand, VaD may be potentially preventable, underscoring the importance of primary and secondary prevention as in other cerebrovascular disorders. Large long-term trials are necessary to study the importance of different risk factors and possible intervention strategies with special reference to VaD.