This supplementary issue of International Psychogeriatrics, titled “Vascular Burden of the Brain,” is the product of a special meeting of the International Psychogeriatric Association (IPA), with involvement from Alzheimer's Disease International, the World Federation of Neurology Dementia Study Group, the United States Food and Drug Administration (FDA), and the European Commission for Pharmaceutical and Medicinal Compounds (CPMP). The meeting was held in Madrid in November 2001 and was a closed gathering of many leading international experts on various aspects of vascular brain disease. Attendees included basic scientists, psychiatrists, neurologists, epidemiologists, and neuroradiologists. This wealth of expertise, both from clinicians and scientists, emphasized the necessity for interdisciplinary research into vascular disorders of the brain that affect cognition and behavior. One aim of the meeting was to produce a position paper that summarized the current situation in this field, both highlighting recent advances and identifying important areas where further progress is required. This paper, entitled “Vascular Cognitive Impairment,” has been published in Lancet Neurology (O'Brien et al., Lancet Neurology, February 2003, 2, 11–20). This issue of International Psychogeriatrics contains the individual articles submitted by participants in the special IPA meeting in November 2001.

The history of vascular dementia can be traced back to cases of dementia postapoplexy described by Thomas Willis in 1672. During most of the 18th and early 19th century, “brain congestion” (due in all likelihood to the effects of untreated hypertension) was the most frequent diagnosis for conditions ranging from stroke to anxiety and to cognitive decline, and bloodletting became the commonplace therapy. The modern history of vascular dementia began in 1894 with the contributions of Otto Binswanger and Alois Alzheimer, who separated vascular dementia from dementia paralytica caused by neurosyphilis. In the 1960s, the seminal neuropathological and clinical studies of the New Castle school in England inaugurated the modern era of vascular dementia.

Monogenic disorders account for only a minority of strokes. Yet, they have been particularly helpful in exploring basic disease mechanisms. This article summarizes some recent data on monogenic stroke while focusing on two conditions: CADASIL, as a genetic variant of ischemic small vessel disease, and familial forms of cerebral amyloid angiopathy, which share many properties with sporadic disease.

Subcortical ischemic vascular disease and dementia (SIVD) incorporate small vessel disease as the chief vascular etiology, lacunar infarct and ischemic white-matter lesions (WMLs) 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 syndrome and the lacunar state. Patients with SIVD present with extensive white-matter lesions and multiple lacunae on neuroimaging. SIVD is expected to be a more homogenous subtype of vascular cognitive impairment and dementia. Recently modified NINDS-AIREN research criteria for SIVD have been proposed. Further empirical research is needed to refine the syndrome and stages and validate the brain imaging criteria, as well as to detail the natural history and outcomes of SIVD.

Vascular dementia (VaD) is a heterogeneous entity with a large clinicopathological spectrum. It has been classified and subclassified in many different ways. The difficulty in identifying the various subtypes is a problem in the diagnostic process. For clinical purposes, it is desirable to find subtypes of VaD that are homogeneous enough to allow meaningful comparisons across studies. This article presents candidates for such subtypes: poststroke dementia, subcortical VaD, and combined Alzheimer's disease and VaD (AD + VaD). The first two candidates are easy to identify. Poststroke dementia occurs with cognitive decline in close temporal relation to a transient ischemic attack. Subcortical VaD has a relatively homogeneous clinical picture for which detailed criteria are suggested. AD + VaD is more difficult to identify but is possible, sometimes with the aid of neuroimaging and/or biological markers.

“Mixed dementia” is traditionally defined as Alzheimer's disease with cerebrovascular disease (CVD). Because the risks of both neurodegenerative dementias and cerebrovascular disease increase with age, the mixed dementias are likely the most common. In practice, patients with mixed dementia are diagnosed by one of two routes: Either they have evidence of a neurodegenerative dementia and CVD at the outset, or, they have a classical neurodegenerative presentation but are found to have ischemic lesions by neuroimaging. These facts have implications for the development of evidence-based diagnostic criteria.

Vascular involvement in Alzheimer disease (AD) is not necessarily coincident. Current evidence suggests the neuropathology of Alzheimer type of dementia comprises more than amyloid plaques and neurofibrillary tangles. At least a third of recognized AD cases may exhibit cerebrovascular pathology, which also constitutes distinct small vessel disease. Cerebral amyloid angiopathy, microvascular degeneration affecting the cerebral endothelium and smooth muscle cells, basal lamina alterations, hyalinosis, and fibrosis are frequently evident in AD. These changes may be accompanied by perivascular denervation that is causal in the cognitive decline of AD. In addition, amyloid β protein appears directly involved in the degeneration of both the larger perforating arterial vessels as well as cerebral capillaries, which represent the blood-brain barrier. The cerebrovascular pathology in AD also encompasses macro- and micro-infarctions, hemorrhages, lacunas, and ischemic white-matter changes. An interaction of both perivascular mediators and derived factors would perturb the brain vasculature. Peripheral vascular factors such as long-standing hypertension, atrial fibrillation, coronary or carotid artery disease, and diabetes mellitus are also apparent in AD. These factors would modify the cerebral circulation such that a sustained hypoperfusion or oligemia is impacted upon the aging processes to induce the characteristic pathology.

In cerebrovascular disease of all kinds, the white matter bears a heavy burden – particularly in the early and late periods of life. The infarcts are of the complete and incomplete type, the latter accompanying and extending the white-matter damage of the former. Complete infarcts are mainly caused by vascular occlusions. Incomplete infarcts are mainly due to hypoperfusion, wherein pathogenic factors are, above all, different types of angiopathies leading to an inadequate autoregulatory response in the event of an episodic or more longstanding hypotension, acting as an etiological factor through hypoperfusion. There is growing consensus that white-matter lesions affect brain function. Correlation with symptoms and understanding of mechanisms behind the lesions would gain from more precise diagnostics as to tracts involved.

Cerebral small-vessel alterations play a central role in determining lesions of subcortical structures and eventually may lead to cognitive impairment. Small-vessel diseases are classified according to the pathological viewpoint. The most important ones are the changes in small arteries and arterioles caused by prolonged hypertension. These small-vessel changes may result in ischemic damage to the brain parenchyma and blood-barrier alterations. Both mechanisms are thought to contribute to the occurrence of white-matter changes and lacunar infarcts. Modern magnetic resonance techniques such as diffusion, perfusion, and spectroscopy may allow the in vivo study of the pathophysiology of small-vessel diseases and the consequences on the brain parenchyma.

Diseases of small cerebral blood vessels are heterogeneous in etiology and manifestations. Lipohyalinosis, venous collagenosis, amyloid angiopathy, and CADASIL affect different populations of blood vessels. Large and small hemorrhages, lacunae, cortical microinfarcts, and leukoaraiosis are the most important consequences of the small vessel angiopathies. Altered permeability as well as ischemia may be involved in the pathogenesis of the latter.

Understanding of vascular substrates of cognitive decline in the elderly is evoloving to include a major emphasis on the impact of small vessel disease (SVD). While existing concepts of multi-infarct dementia and strategic infarct dementia remain valid, they present difficulty in generalizing clinicopathological correlations from patient to patient. The range and significance of lesions that should be included as manifestations of SVD are unresolved, as is their impact on, and association with, neurodegenerative changes. This mini-review summarizes the authors' views on SVD substrates leading to cognitive decline and proposes priorities for pathological investigations of human cerebrovascular mechanisms leading to cognitive decline.

The link between Alzheimer's disease and cerebrovascular disease has been long recognized. However, the mechanisms that lead to the development of the two seemingly different pathologies are still elusive. Our studies concentrate on the understanding of the interaction between the two diseases and the deciphering of a possible common pathogenic mechanism. In this context the role of shared risk factors, such as ApoE and elevated plasma homocysteine, is also discussed.

A number of neurotransmitters, including acetylcholine, serotonin, noradrenaline, and dopamine, modulate cerebral perfusion. In vascular dementia, reductions in markers of cholinergic innervation are consistently reported, and there are some indications that the serotonergic and dopaminergic systems may also be affected. Limited data indicate that the numbers of nucleus basalis, locus coeruleus, and dorsal raphé neurons and the density of neurotransmitter receptors are not reduced in the majority of cases. These data suggest neurotransmitter systems as a potential therapeutic target in vascular dementia.

Cerebrovascular diseases can causes cognitive impairment and dementia by loss of neurons and synaptic connections, destruction of axons, and demyelinization. Biological markers including genetic tests, brain imaging techniques, and biochemical assays in the CSF are valuable for the identification and quantification of cerebrovascular diseases. Genetic tests may be used to detect mutations that cause hereditary cerebral amyloid angiopathies or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Structural CT and MR imaging is routinely used to visualize and quantify infarcts and white-matter changes. Functional SPET and PET imaging can demonstrate focal and remote effects of vascular lesions on cerebral blood flow and metabolism. Biochemical imaging using proton MRS is a nonspecific marker for neuronal and axonal damage. Among biochemical markers in the CSF, tau protein, phospho-tau, and beta amyloid protein are helpful to differentiate vascular dementia from Alzheimer's disease.

White-matter lesions (WML) detected on MRI may reflect different pathologies, but, in older persons, are thought to be mainly of ischemic origin. WML increase in prevalence with age. Several cardiovascular risk factors and cognitive, emotional, and physical function consequences of WML have been identified. These are reviewed briefly in this report.

Cognitive decline is a central component of the dementia process. Population-based prospective studies have confirmed the existence of age-related cognitive decline, although its conceptual basis and nosological status remain controversial. Healthy old people show decline with aging in global cognition and memory function in particular. Preclinical and clinical dementia patients exhibit deficits across multiple cognitive domains, with the largest and most consistent deficits in memory function. Cerebrovascluar disease may lead to cognitive decline and promote the clinical expression of dementia directly or by interaction with APOE η4. Early treatment and prevention of cerebrovascular disease may be the major measures for preventing and postponing the progression of the vascular disease related cognitive decline.

Although vascular dementia was described over a century ago, it remains a difficult and challenging diagnosis. Several sets of clinical criteria have been published in an effort to establish the presence or absence of vascular dementia in a standardized fashion. Clinical studies have demonstrated that they identify different groups of patients and are thus not interchangeable. Retrospective clinicopathological correlations have shown that most are insufficiently sensitive, although they are generally relatively specific. They accurately exclude pure Alzheimer's disease but may include 9% to 39% of mixed dementia cases (Alzheimer's disease and vascular dementia combined). Further studies are needed to develop better performing criteria that could lead to a broad consensus on the clinical diagnosis of vascular and mixed dementia.

There has been a move in recent years to recognize that the most effective treatment for vascular dementia, and for the mixed component of mixed vascular dementia and Alzheimer's disease, lies not in treatment but in prevention. This requires that cases be identified before the onset of vascular damage (a stage termed “brain-at-risk”) or, failing this, as soon as possible but certainly before dementia has developed. These early stages are termed vascular cognitive impairment (VCI). No criteria exist for this early stage of cognitive loss due to cerebrovascular disease and relatively little data exist to indicate how such cases might be identified. The data that do exist suggest that many of the traditional “vascular” features of sudden onset and stepwise progression, etc., are not common in VCI and new criteria will be needed to identify cases. This paper summarizes the data that describe the clinical, neuropsychological, and radiological features that are to be expected in VCI.

In 150 older stroke patients (>75) without dementia, the proportion of people meeting different criteria for early cognitive impairment varied from 17% to 23% depending upon the individual criteria used. Given this large disparity, prospective studies to clarify the utility of different criteria as a predictor of subsequent dementia are a priority.

It is still a challenge to identify typical features of cognitive function in vascular dementia (VaD) in clinical as well as in preclinical stages. Selective empirical findings are described to illuminate degrees of cognitive decline. In predementia stages, speeded performance (motor and mental) and executive functions may be affected as demonstrated by CADASIL subjects and stroke survivors. In dementia stages, motor and mental speed as well as executive functions is commonly affected in addition to typical cognitive dysfunction in dementia (memory, verbal, and visuospatial). To summarize characteristics during preclinical and clinical stages, VaD appears to be associated with impairment in motor and mental speed as well as in executive function.