Cerebral Small Vessel Disease, Hypertension, and Vascular Contributions to Cognitive Impairment and Dementia

Abstract

Hypertension-associated cerebral small vessel disease is a common finding in older people. Strongly associated with age and hypertension, small vessel disease is found at autopsy in over 50% of people aged ≥65 years, with a spectrum of clinical manifestations. It is the main cause of lacunar stroke and a major source of vascular contributions to cognitive impairment and dementia. The brain areas affected are subcortical and periventricular white matter and deep gray nuclei. Neuropathological sequelae are diffuse white matter lesions (seen as white matter hyperintensities on T2-weighted magnetic resonance imaging), small ischemic foci (lacunes or microinfarcts), and less commonly, subcortical microhemorrhages. The most common form of cerebral small vessel disease is concentric, fibrotic thickening of small penetrating arteries (up to 300 microns outer diameter) termed arteriolosclerosis. Less common forms are small artery atheroma and lipohyalinosis (the lesions described by C. Miller Fisher adjacent to lacunes). Other microvascular lesions that are not reviewed here include cerebral amyloid angiopathy and venous collagenosis. Here, we review the epidemiology, neuropathology, clinical management, genetics, preclinical models, and pathogenesis of hypertensive small vessel disease. Knowledge gaps include initiating factors, molecular pathogenesis, relationships between arterial pathology and tissue damage, possible reversibility, pharmacological targets, and molecular biomarkers. Progress is anticipated from multicell transcriptomic and proteomic profiling, novel experimental models and further target-finding and interventional clinical studies.

Hypertension, Neurodegeneration, and Cognitive Decline

“…30 Pial Vessels and Penetrating Arterioles Pial and penetrating arteries and arterioles are uniquely sensitive to chronic elevations in BP. 16 In humans, hypertensioninduced microatheroma in pial arteries and small perforating arteries (300-800 µm external diameter [42][43][44] ) can occlude vessels and instigate lacunar infarction or microinfarction. 44 Moving further into the brain, small penetrating arteries and arterioles, from 300 to 20 µm, [42][43][44] arising from either the first segment of the middle cerebral artery or terminal branches of the pial arteries, converge on deep white matter territories.…”

“…Lipohyalinosis involves asymmetrical deposition of an amorphous, glass-like material composed of collagen and degenerated smooth muscle tissue into the vascular wall, whereas fibrinoid necrosis, observed in more advanced lesions, is signified by infiltration of fibrin and its degradation by products. [42][43][44] More common is arteriolosclerosis, 43 characterized by myocyte degradation and loss of elastin alongside concentric accumulation of fibro-hyaline materials and collagens in the vascular wall, leading to stenosis and reduced elasticity (hyaline arteriolosclerosis), [42][43][44] or the extensive intimal fibromuscular proliferation, luminal narrowing, and necrotic degeneration often associated with malignant hypertension (hyperplastic arteriolosclerosis). [42][43][44] Capillaries and precapillary arterioles are also affected, marked by loss of endothelial cells and pericytes (string vessels), increased thickness of the basal lamina and accompanying tortuosity, fibrin deposition, and overall rarefaction.…”

“…[42][43][44] Capillaries and precapillary arterioles are also affected, marked by loss of endothelial cells and pericytes (string vessels), increased thickness of the basal lamina and accompanying tortuosity, fibrin deposition, and overall rarefaction. 47 Collectively, these changes form the basis of hypertensionassociated small vessel disease (SVD), a disorder affecting arterioles, venules, and capillaries of the subcortical and periventricular white matter in a segment-specific manner [42][43][44] ; atheromatous lesions are typically observed in larger arteries/arterioles situated upstream of distal perforating vessels supplying the deep parenchymal tissues, which are in turn affected by arteriolosclerosis, lipohyalinosis, and fibrinoid necrosis (Figure 1). [42][43][44] The sequelae of SVD, detectable via magnetic resonance imaging (MRI), include white matter lesion (WML), small ischemic foci (lacunes and microinfarcts) and microhemorrhages, 48 venous collagenosis, 49 and enlarged PVS.…”

“…47 Collectively, these changes form the basis of hypertensionassociated small vessel disease (SVD), a disorder affecting arterioles, venules, and capillaries of the subcortical and periventricular white matter in a segment-specific manner [42][43][44] ; atheromatous lesions are typically observed in larger arteries/arterioles situated upstream of distal perforating vessels supplying the deep parenchymal tissues, which are in turn affected by arteriolosclerosis, lipohyalinosis, and fibrinoid necrosis (Figure 1). [42][43][44] The sequelae of SVD, detectable via magnetic resonance imaging (MRI), include white matter lesion (WML), small ischemic foci (lacunes and microinfarcts) and microhemorrhages, 48 venous collagenosis, 49 and enlarged PVS. 50 SVD is also influenced by short-term and long-term BPV, evidenced by brain imaging and autopsy data (arteriolosclerosis, microinfarcts, WMLs, enlarged perivascular spaces, and atherosclerosis of the circle of Willis).…”

“…16 In humans, hypertensioninduced microatheroma in pial arteries and small perforating arteries (300-800 µm external diameter [42][43][44] ) can occlude vessels and instigate lacunar infarction or microinfarction. 44 Moving further into the brain, small penetrating arteries and arterioles, from 300 to 20 µm, [42][43][44] arising from either the first segment of the middle cerebral artery or terminal branches of the pial arteries, converge on deep white matter territories. 16 As these vessels display vulnerability to shifts in upstream pressure, scant collateralization, and limited anastomosis, 16 they are strongly implicated in formation of the white matter damages attendant to vascular dysfunction.…”