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.