**3.1 Characteristic and classification**

*Neuroprotection - New Approaches and Prospects*

against oxidized LDL (*r* = −0.59; *p* = 0.002) [6].

the action of EDRF to maintain arterial compliance [7].

**3. Cerebral small vessel disease**

Vitamin E has also been associated with improved vascular health in studies measuring arterial compliance and endothelial dysfunction as biomarkers. Vascular endothelium, which lines the blood luminal surface of vessels, is involved in the regulation of vascular tone, platelet activity, and thrombosis and intimately involved in the pathogenesis of atherosclerosis [5, 6]. The endothelium is an integral part of the vasculature and is involved in promoting an atheroprotective environment via the complementary actions of endothelial cell-derived vasoactive factors [41]. Vasomotor tone is modulated through the release of endothelium-derived relaxing factors (EDRFs) such as NO [6]. Impaired vascular homeostasis can lead to endothelial dysfunction, which contributes to atherosclerosis [41]. Intact endothelium is also needed for normal arterial compliance, a predictor of cardiovascular events. Arterial compliance, which can be assessed by pulse wave velocity (PWV) and augmentation index (AI), can be improved in healthy subjects even with dietary interventions [7]. In a randomized controlled trial, subjects with the following risk factors, hypercholesterolemia (13 subjects), smokers (14 subjects), or both (15 subjects), were supplemented with placebo or vitamin E for 4 months. The authors hypothesized that long-term supplementation with vitamin E would improve endotheliumdependent relaxation in hypercholesterolemic patients and/or chronic smoking, two risk factors that have been associated with increased radical formation, impaired endothelial vasodilator function, and increased plasma levels of autoantibodies against oxidized LDL [6]. The study found the most severe endothelial vasodilator dysfunction in patients with both risk factors present. Vitamin E significantly improved endothelium-dependent relaxation in forearm resistance vessels of hypercholesterolemic smokers. There was a significant relationship between improvement in acetylcholine-induced vasodilation and the change in autoantibody titer

Moreover, in a randomized controlled trial, 36 healthy male volunteers were supplemented with placebo or tocotrienol-rich vitamin (50, 100, 200 mg/day) with self-emulsifying formula for 2 months [7]. Arterial compliance was assessed using carotid-femoral PWV and AI, at baseline and after 2 months of supplementation. Subjects treated with tocotrienols at doses of 100 and 200 mg/day showed significant improvement in arterial compliance with PWV reductions of 0.77 m/s (*p* = 0.007) and 0.65 m/s (*p* = 0.002), respectively. The placebo group did not show a reduction in PWV and AI compared with baseline. The treatment had no effect on blood pressure, serum total cholesterol, and LDL-C [7], which are potential confounding factors to the observed improvement in arterial compliance. The improvement in vascular function can be achieved through mechanisms involving enhanced NO production by the endothelium and inhibition of free radicals that inactivate EDRF. Vitamin E can potentially increase the production of NO, which relaxes the vascular smooth muscle cells, while also neutralizing free radicals which preserve

In addition to promoting vascular health, vitamin E is also postulated to exert anti-atherogenic effects via its ability to decrease LDL oxidation, quench free radicals, inhibit protein kinase C (PKC), inhibit expression of adhesion molecules and monocyte transmigration, and impair vascular smooth muscle cell proliferation [8].

The general ischemia implicated in CSVD of small blood vessels (i.e., arterial tree occlusion in particular) involving the subcortical and deeper parts of the brain

**2.4 Benefits in vascular health**

**192**

The complexity and overlapping pathophysiological mechanism of the disease make the interpretation of CSVD debatable. However, it is a widely accepted view that pathological consequences of small vessel disease (SVD) on the brain parenchyma rather than the underlying diseases of the vessels serve as the basis of CSVD [13]. Hence, the injury in the brain parenchyma that is linked with leptomeningeal and intracerebral vessel pathology that vascularizes with poor collaterals in the deep white matter and subcortical gray matter is the main diagnostic landmark of CSVD. Moreover, CSVD is generally due to several vasculo-pathological processes that affect and cause occlusion to the small perforating cerebral arterioles, capillaries, and venules (of sizes 50–400 mm), which are small arteries (chiefly of middle cerebral artery tributaries) that penetrate and supply the brain subcortical region, resulting in various lesions in the brain [42–46].

Several manifestations of CSVD can be seen through clinical, radiological (i.e., neuroimaging such as CT or MRI), or pathological phenomena with various etiologies [46–49]. Recent advancement in neuroimaging techniques had enabled the imaging-based (such as MRI) identification and characterization of multiple manifestation of CSVD including white matter hyperintensities (WMHs) of presumed vascular origin or leukoaraiosis, lacunes of presumed vascular origin (i.e., small subcortical infarcts and silent brain infarcts, SBI), perivascular spaces, microinfarcts, and cerebral microbleeds (CMBs) [46, 50, 51]. Alarmingly, the aforementioned lesions can be silent, and the affected individual may not have any clinical symptoms. More importantly, this silent lesion with higher number of single or multiple, is associated with higher risk of mild cognitive impairment, dementia, Alzheimer's disease, and full-blown stroke [14, 15].

There are several etiopathogenic classifications of CSVD. However, the most prevalent forms of CSVD are amyloidal CSVD (sporadic and hereditary cerebral amyloid angiopathy [CAA]) and non-amyloidal CSVD (arteriolosclerosis, agerelated, vascular risk-factor-related SVD, i.e., microatheroma, lipohyalinosis, fibrinoid necrosis, and segmental arterial disorganization) [42, 52, 53]. Other less common forms of CSVD include inherited or genetic CSVD that is recognizably different from CAA (i.e., Fabry's disease and cerebral autosomal dominant arteriopathy with subcortical ischemic strokes and leukoencephalopathy [CADASIL]), inflammatory and immunologically mediated CSVD (i.e., rheumatoid vasculitis, lupus erythematosus, and CNS vasculitis secondary to infection), venous collagenosis, and other CSVD (i.e., non-amyloid microvessel degeneration in AD and postradiation angiopathy) [42, 52, 53].
