Cerebral atherosclerosis (AS), small vessel disease (SVD), and cerebral amyloid angiopathy (CAA) are the most prevalent arterial disorders in the aged brain. Pathogenetically, AS and SVD share similar mechanisms: plasma protein leakage into the vessel wall, accumulation of lipid-containing macrophages, and fibrosis of the vessel wall. CAA, on the other hand, is characterized by the deposition of the amyloid beta-protein in the vessel wall. Despite these differences between CAA, AS and SVD, apolipoprotein E (apoE) is involved in all three disorders. Such a pathogenetic link may explain the correlations between AS, SVD, CAA, and Alzheimer's disease in the brains of elderly individuals reported in the literature. In addition, AS, SVD, and CAA can lead to tissue lesions such as hemorrhage and infarction. Moreover, intracerebral SVD leads to plasma protein leakage into the damaged vessel wall and into the perivascular space resulting in a blood-brain barrier (BBB) dysfunction. This SVD-related BBB dysfunction is considered to cause white matter lesions (WMLs) and lacunar infarcts. In this review, we demonstrate the relationship between AS, SVD, and CAA as well as their contribution to the development of vascular tissue lesions and we emphasize an important role for apoE in the pathogenesis of vessel disorders and vascular tissue lesions as well as for BBB dysfunction on WML and lacunar infarct development.

Cerebral atherosclerosis (AS), small vessel disease (SVD), and cerebral amyloid angiopathy (CAA) are the most prevalent arterial disorders in the aged brain. Pathogenetically, AS and SVD share similar mechanisms: plasma protein leakage into the vessel wall, accumulation of lipid-containing macrophages, and fibrosis of the vessel wall. CAA, on the other hand, is characterized by the deposition of the amyloid β-protein in the vessel wall. Despite these differences between CAA, AS and SVD, apolipoprotein E (apoE) is involved in all three disorders. Such a pathogenetic link may explain the correlations between AS, SVD, CAA, and Alzheimer’s disease in the brains of elderly individuals reported in the literature. In addition, AS, SVD, and CAA can lead to tissue lesions such as hemorrhage and infarction. Moreover, intracerebral SVD leads to plasma protein leakage into the damaged vessel wall and into the perivascular space resulting in a blood–brain barrier (BBB) dysfunction. This SVD-related BBB dysfunction is considered to cause white matter lesions (WMLs) and lacunar infarcts. In this review, we demonstrate the relationship between AS, SVD, and CAA as well as their contribution to the development of vascular tissue lesions and we emphasize an important role for apoE in the pathogenesis of vessel disorders and vascular tissue lesions as well as for BBB dysfunction on WML and lacunar infarct development.

The diagnosis of vascular dementia (VaD) describes a group of various vessel disorders with different types of vascular lesions that finally contribute to the development of dementia. Most common forms of VaD in the elderly brain are subcortical vascular encephalopathy, strategic infarct dementia, and the multi infarct encephalopathy. Hereditary forms of VaD are rare. Most common is the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Sporadic forms of VaD are caused by degenerative vessel disorders such as atherosclerosis, small vessel disease (SVD) including small vessel arteriosclerosis, arteriolosclerosis, and lipohyalinosis, and cerebral amyloid angiopathy (CAA). Less frequently inflammatory vessel disorders and tumor-associated vessel lesions (e.g. angiocentric T-cell or angiotropic large cell lymphoma) can cause symptoms of dementia. Here, we review and discuss the impact of vessel disorders to distinct vascular brain tissue lesions and to the development of dementia in elderly individuals. The impact of coexisting neurodegenerative pathology in the elderly brain to VaD as well as the correlation between SVD and CAA expansion in the brain parenchyma with that of Alzheimer's disease (AD)-related pathology is highlighted. We conclude that "pure" VaD is rare and most frequently caused by infarctions. However, there is a significant contribution of vascular lesions and vessel pathology to the development of dementia that may go beyond tissue damage due to vascular lesions. Insufficient blood blow and alterations of the perivascular drainage mechanisms of the brain may also lead to a reduced protein clearance from extracellular space and subsequent increase of proteins in the brain parenchyma, such as the amyloid β-protein, and foster, thereby, the development of AD-related neurodegeneration. As such, it seems to be important for clinical practice to consider treatment of potentially coexisting AD pathology in cognitively impaired patients with vascular lesions.

Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.