Pathology and pathogenesis of vascular cognitive impairment—a critical update

Vascular cognitive impairment (VCI) [vascular cognitive disorder (VCD), vascular dementia] describes a continuum of cognitive disorders ranging from mild cognitive impairment (MCI) to dementia, in which vascular brain injury involving regions important for memory, cognition and behavior plays an important role. Clinical diagnostic criteria show moderate sensitivity (ca 50%) and variable specificity (range 64-98%). In Western clinical series, VaD is suggested in 8-10% of cognitively impaired elderly subjects. Its prevalence in autopsy series varies from 0.03 to 58%, with means of 8 to 15% (in Japan 22-35%). Major types of sporadic VaD are multi-infarct encephalopathy, small vessel and strategic infarct type dementias, subcortical arteriosclerotic leukoencephalopathy (SAE) (Binswanger), multilacunar state, mixed cortico-subcortical type, granular cortical atrophy (rare), postischemic encephalopathy, and a mixture of cerebrovascular lesions (CVLs). They result from systemic, cardiac and local large or small vessel disease (SVD); their pathogenesis is multifactorial. Hereditary forms of VaD caused by gene mutations are rare. Cognitive decline is commonly associated with widespread small ischemic vascular lesions involving subcortical brain areas (basal ganglia and hemispheral white matter). The lesions affect neuronal networks involved in cognition, memory, and behavior (thalamo-cortical, striato-subfrontal, cortico-subcortical, limbic systems). CVLs often coexist with Alzheimer-type lesions and other pathologies; 25-80% of elderly demented show mixed pathologies. The lesion pattern of "pure" VaD differs from that in mixed dementia (AD + CVLs) suggesting different pathogenesis of both phenotypes. Minor CVLs, except for severe amyloid angiopathy, appear not essential for cognitive impairment in full-blown AD, while both mild AD-type pathology and SVD may interact synergistically in promoting dementia. However, in a large percentage of non-demented elderly individuals, both AD-related and vascular brain pathologies have been reported. Despite recent suggestions for staging and grading CVLs in specific brain areas, due to the high variability of CVLs associated with cognitive impairment, no validated neuropathological criteria are currently available for VaD and mixed dementia. Further clinico-pathological studies and harmonization of neuropathological procedures are needed to validate the diagnostic criteria for VaD and mixed dementia in order to clarify the impact of CVLs and other coexistent pathologies on cognitive impairment as a basis for further successful therapeutic options.