Atheroma is the term used to define the caseous material, containing high amounts of lipids, found in plaque-like thickenings of the interior portion of the vessel wall. Accordingly, the term atherosclerosis reflects the fibrous character of these pathologic alterations affecting large and small peripheral arteries in aging. Atherosclerosis begins as a disease of the innermost layer of the vessel wall (the intima), where the main lesions responsible for its development have been categorized as fatty streaks, fibrous plaques, and complicated lesions.

Fibrous streaks consist mainly of monocyte-derived macrophages that have entered the intima from the blood stream. The abundant presence of lipid droplets, mainly cholesterol ester, within the cytoplasm transforms these macrophages into foam cells. In advanced fatty streaks, lipid infiltration may proceed to fill smooth muscle cells in the tunica media of the blood vessel wall.

The fibrous plaque is a dense fibrous cap at the inner surface of the atherosclerotic lesion that contains a connective tissue matrix rich in collagen that surrounds smooth muscle cells and macrophages on the side of the vessel wall, and is covered by endothelial cells on the side of the lumen. The complicated lesion is supposed to represent a calcification of a fibrous plaque, with the serious possibility of developing cracks, ulcerations, hemorrhages, and thrombosis. In turn, these changes may lead to a cerebral infarction. Specifically in hyper-cholesterolemic subjects, foam cells are particularly abundant in the area where a complicated lesion occurs in addition to the presence of several muscle cells and macrophages containing lipids that are localized beneath the dense fibrous cap. In advanced lesions, necrotic changes may be found, which results in consistent amounts of extracellular debris and caseous material. The frequent occurrence of cracks and fissures constitutes a further complication of these lesions and results in secondary intramural hemorrhages in large arteries leading to stenosis and thrombosis that obliterate the vessel. As mentioned earlier, these changes affect the intima, but are responsible for secondary damage to the tunica media that may progress to the lamina elastica interna with a final conclusion of a breakdown of the vessel wall.

As it appears from this description, atherogenesis is a very dynamic process involving not only the cells of the arterial blood vessel, but also circulating blood cells, that is, macrophages, monocytes, platelets, and lymphocytes. With the aim of repairing cell and tissue damage, various growth factors are produced by these cells, and their combined action serves to maintain or remodel the function of the vascular system. In this context, injuries to endothelial cells induce to express mitogens such as platelet-derived growth factor (PDGF) and interleukin-1. Activated macrophages are also capable of forming fibroblast growth factor (FGF), which plays a significant role in capillary formation and in secreting transforming growth factor (TGF-alpha) responsible for epithelial migration and proliferation and transforming growth factor (TGF-beta) that inhibits cell proliferation and induces collagen synthesis. The macrophages themselves may be responsible for further tissue injury and play a role in maintaining the progression of atherogenesis by acting as scavenger cells that oxidize ingested lipids through free radicals formation. Namely, secretion of oxidized material and hydrolytic enzymes may cause damage in the still healthy cells located close to the initial lesion. Activated platelets secrete an epidermal growth factor-like substance (TGF-beta) and play a major role in the coagulation and thrombosis process. In turn, proliferation of smooth muscle cells within the thrombi induces the deposition of connective tissue that is stimulated by many growth factors released by platelet aggregation and degranulation.

The many risk factors able to trigger the atherogenetic process have been revealed by several epidemiological studies. As primary determinants, these include hyper-cholesterolemia and hypertension, but several other causes and causative changes, such as diabetes and cigarette smoking, are reported to be seriously involved. A defective metabolism of lipoproteins is responsible for a high cholesterolemia that may be specifically due to a deficient cholesterol removal or overproduction, or to a combination of both these processes. Monogenic or polygenic hyperlipidemias also play a significant role in atherogenesis, as demonstrated by epidemiological studies reporting a clear correlation between these diseases and the incidence and severity of atherosclerosis. The mechanisms leading to cellular changes involved in atherogen-esis are not known in hypertensive patients; however, an acceleration of the atherogenetic process resulting in an increased incidence of cerebrovascular and coronary heart disease has been documented by epidemiological studies. It is suggested that increased monocyte adherence and the localization of monocyte-derived macrophages at the intima, associated with changes in humoral mediators of blood pressure (e.g., angiotensin and renin), as well as drugs and poisons and hemodynamic parameters may result in an overall unfavorable condition predisposing to the development of atherosclerosis.

Several hypotheses have been proposed to give a tenable interpretation of the different deteriorating phenomena participating in atherogenesis. Considering the many proposed assumptions, a unifying concept is represented by the fact that the organism responds to the initial injury of an atherogenetic process. Namely, any damage to the endothelium lining triggers a sequence of events leading to a migration, accumulation, and proliferation of intimal muscle cells. The very early step of this process may be represented by a functional change due to different factors such as side-effects of drugs or radiation injury. As a consequence, monocytes and lymphocytes adhere to the endothelium and trigger an accelerated endothelial turnover with the induction of the gene expression of growth factors that accelerate the smooth muscle cell proliferation up to the formation of a typical atherosclerotic plaque.

Cerebral atrophy is responsible for secondary changes of the artery wall that lead to pathological alterations of the aging brain. Narrowing or obliteration of the vessel lumen as well as the formation of thrombi with the consequence of disturbances of the blood circulation in the specifically irrigated cerebral zones are the unfavorable outcomes of atherosclerosis that frequently result in cerebral infarctions. Although the clinical manifestations due to a cerebral infarction are the consequences of the destroyed structures in the brain area where the lesion has occurred, further pathological development of damaged tissue may cause additional symptoms (e.g., multinfarct dementia). Multiple micro-infarctions, or lacunar infarcts (diameter: 3-20 mm) are lesions most common and most severe in hypertensive patients, although they also have been found in normo-tensive subjects. The frequency of lacunar infarcts increases in the fifth and sixth decade, but thereafter they become less common. This type of lesion affects the deeper neocortical parts of the brain and brainstem (basal ganglia, thalamus, pons) and is due to the occlusion of penetrating branches of the larger cerebral arteries. In addition to hypertension, vascular hyalinosis, and atheromatous degeneration of the vessels are reported to represent predisposing conditions in the development of a lacunar state. Cortical granular atrophy (CGA) is another development of cerebral infarcts. Namely, reactive gliosis substitutes the lesions of small cortical infarctions, resulting in multiple gliotic micro scars; this, in turn, results in multiple small shrinkages appearing as granuli on the surface of the gyri. In the majority of cases, CGA occurs at the territorial border zones of irrigation between the anterior, medial, and posterior cerebral arteries.

Thickening, hyalinosis, and fibrosis are responsible for the degeneration of arterioles with the consequence of perivascular demielinating lesions affecting axons and the cerebral white matter, specifically in frontal and occipital areas. Arteriolopathy due to hypertension is considered as the causative event of this pathological condition of the white matter (vasculogenic leuko-encephalopathy: Binswanger disease), although lacunar changes are found in several patients.

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