**3.2 Neuroepidemiology and health burden**

Different manifestations of CSVD based on neuroimaging findings result in different and overlapping health burden and epidemiology [54]. Increasing age has been reported to elevate the finding of WMHs, lacunes, perivascular spaces, and CMBs in healthy populations [54–56]. However, increased vascular risk factors are consistent with the prevalence of CMBs but not in other imaging findings [56, 57]. Race, ethnicity, and gender with adjusted age also explain the variability of these imaging findings, whereby some findings had reported that higher WMH grade and volume were found in ethnic or racial minorities than non-Hispanic white [58] and WMHs were much higher in women than men, although no definite mechanism

was reported for this gender difference [59]. In addition, previous study had reported stroke-free elderly Hispanic and/or Latino had SBI (16%), especially in subcortical region (82.9%) [60] and perivascular spaces (48%) [61].

In other ethnic groups, previous study had reported that the prevalence of WMHs in South Asians and Europeans is similar, although South Asian elderly individuals with known vascular risk are more likely to be associated with higher WMHs [62]. Meanwhile, data in three Asian countries (Singapore, Hong Kong, and Korea) have shown that elderly Asians with higher SVD burden are associated with cognitive decline [63]. This was further supported by the Taizhou Imaging Study, whereby the authors found increased incidental findings of WMHs (10.68%), lacunes (26.69%), CMBs (18.51%), and perivascular spaces (27.76%) in elderly Chinese with vascular risk [64]. However in the Japanese population, most are having moderate to mild dilated perivascular spaces, especially in the centrum semiovale and basal ganglia [65]. Thus, it is apparent that more data are required to understand the role of racial and/or ethnic contributions for the presence of different CSVD manifestations.

The effects of several manifestations of CSVD on cognition seem to be invariably influenced by the location of the lesion(s). The damaged and reduced white matter integrity in the frontal lobe and its dysfunction are associated with reduced transmission of information to other parts of the brain in the presence of WMHs [54], lacunes (deep nuclear [78.2%], posterior fossa [10.1%]) [66], and perivascular spaces [65, 67]. In contrast, temporal lobe lesion is more associated with the findings of lobar and deep CMBs [68, 69]. Several studies have reported that an increase in WMHs is associated with worse general and specific domain of cognitive performance, especially in executive function, processing speed, and episodic memory [70–73]. Intriguingly, an increase in WMHs with reduced cognitive performance is similar to the individual with amyloid load, mild parkinsonism, and functional impairments [70].

Furthermore, reduced cognitive ability has been reported in elderly and nondemented people with the presence of lacunes of presumed vascular origin [54, 72, 74]. Memory declines have also been associated with thalamic infarcts, whereas decreased psychomotor speed is associated with non-thalamic infarcts [75]. In contrast, the presence of a lesion in the perivascular spaces reduces the individual processing speed [76] and, in others, reported no effect on the cognitive performance [67]. Meanwhile, a decrease in global cognitive performance and domain specific has been linked with the location of CMBs [77].

#### **3.3 Pathomechanism**

Despite the growing insights from histopathological, epidemiological, and physiological studies in the past two decades, the underlying pathomechanism of CSVD remains contentious [46, 53]. In general, it is recognized that advanced age and the presence of chronic hypertension may reduce the ability to self-regulate cBF in response to various systemic blood pressure levels and increased arterial stiffness, hence the increased speed and flow pulsatility in cerebral arterioles [16]. These hemodynamic changes are postulated to inflict a certain degree of endothelial damage in the BBB and alter its permeability through an increase of the shear stress [17]. Hence, the BBB breakdown is an important etiopathogenesis feature of CSVD [17–19].

Another key factor thought to contribute to the pathogenesis of CSVD is endothelial dysfunction, with elevated biomarkers as the surrogates [78, 79]. The endothelial dysfunction involvement is also associated with metabolic syndrome [80, 81] and hence a strong link with CSVD. Furthermore, this dysfunction is also implicated for a higher risk of aging-related disease [82, 83]. In addition to the endothelium,

**195**

*Neuroprotective Potentials of Natural Vitamin E for Cerebral Small Vessel Disease*

cross-talk among cellular components of the BBB, such as pericytes, astrocytes, and oligodendrocyte precursor cells (OPCs), may be involved in the microvascular damage as precursors for the onset and progression of CSVD [84, 85]. In relation to this, reduced white matter integrity due to changes in oligodendrocytes has been shown in CSVD, whereby the EC-OPC signaling became compromised and altered the ECs' ability to secrete the releasing factor crucial for the growth and survival of OPCs to eventually cause oligodendrocytes prone to damage [86]. Therefore, the interaction of multiple BBB components may play a crucial role in the discovery and develop-

In parallel, an increased activity of matrix metalloproteinase-2 (MPP2) from endothelial cell membrane (ECM) also caused tight junctions (TJs) to dissemble. TJ damage eventually leads to basement membrane degradation and endothelial damage and, hence, endothelial dysfunction. This results in BBB damage, making it vulnerable to the infiltration of neutrophils, monocytes, and blood components into the ECM [53]. Activated neutrophils induce the activation of ROS, proteolytic enzymes, and cytokines, thus causing higher leukocyte-EC adhesion and reduced cBF (**Figure 5**). Meanwhile, activated monocytes will be induced by cytokine and neopterin to cause inflammation in the ECs. Cumulatively, the increased shear and oxidative stress from the system also lead to the activation of blood components and increased production of microparticles, reduced tissue factor pathway inhibitor, and increased fibrinogen accumulation that result in lumen narrowing and

Understandably, the role of hypoperfusion or reduced cBF in endothelial dysfunction for CSVD has been hypothesized [87]. Generally, the regulation of cBF is mediated by NO signaling; thus, NO serves as a marker for endothelial dysfunction [88]. Since endothelial dysfunction is associated with increased BBB permeability, this would worsen brain parenchyma and white matter lesions given the reduced integrity of ECs [89]. In addition, the increased expression of the mutated NOTCH3 gene (a genetic determinant of CADASIL) in pericytes was found to contribute to CSVD pathogenesis due to abnormal cross-talk between ECs and pericytes [87]. Therefore, one can posit that increased BBB permeability, reduced cBF, and impaired cerebral autoregulation serve as three main interrelated underlying pathogenesis precursors to the development and progression of CSVD, notwithstanding

Multiple studies have reported that the early detection of cognitive and motor decline in neurodegenerative disease has been linked with protein, lipids, sugar, and nucleic acid oxidation [90, 91]. Therefore, it can be postulated that changes or damage to the cerebral vasculature, BBB, and cBF is due to localized oxidative stress,

Generally, overproduction of oxidants by NADPH oxidases and malfunction or reduced activities of antioxidant enzymes may result in oxidative stress [52]. The imbalance between antioxidants and prooxidants in aging and age-related neurological disease is regarded to be mainly due to ROS [92] which is a large group of oxygen radicals (i.e., superoxide anion radical, hydroxyl radical, peroxyl radical, and alkoxyl radical) and non-radicals (i.e., hydrogen peroxide, organic hydroperoxide, singlet molecular oxygen, electronically excited carbonyls, and ozone) [52, 64]. NADPH oxidase- and superoxide dismutase-mediated enzymatic conversion of molecular oxygen to superoxide initiates the production of ROS; however, the production of ROS can also be mediated by spontaneous transformation of non-

hence initiating the neurodegenerative changes in the brain tissue.

*DOI: http://dx.doi.org/10.5772/intechopen.91028*

consequent cBF reduction [53].

the role of other potential and novel factors.

**3.4 Role of reactive oxygen species**

radical hydrogen peroxide [93].

ment of new prevention steps and therapies for CSVD.

#### *Neuroprotective Potentials of Natural Vitamin E for Cerebral Small Vessel Disease DOI: http://dx.doi.org/10.5772/intechopen.91028*

cross-talk among cellular components of the BBB, such as pericytes, astrocytes, and oligodendrocyte precursor cells (OPCs), may be involved in the microvascular damage as precursors for the onset and progression of CSVD [84, 85]. In relation to this, reduced white matter integrity due to changes in oligodendrocytes has been shown in CSVD, whereby the EC-OPC signaling became compromised and altered the ECs' ability to secrete the releasing factor crucial for the growth and survival of OPCs to eventually cause oligodendrocytes prone to damage [86]. Therefore, the interaction of multiple BBB components may play a crucial role in the discovery and development of new prevention steps and therapies for CSVD.

In parallel, an increased activity of matrix metalloproteinase-2 (MPP2) from endothelial cell membrane (ECM) also caused tight junctions (TJs) to dissemble. TJ damage eventually leads to basement membrane degradation and endothelial damage and, hence, endothelial dysfunction. This results in BBB damage, making it vulnerable to the infiltration of neutrophils, monocytes, and blood components into the ECM [53]. Activated neutrophils induce the activation of ROS, proteolytic enzymes, and cytokines, thus causing higher leukocyte-EC adhesion and reduced cBF (**Figure 5**). Meanwhile, activated monocytes will be induced by cytokine and neopterin to cause inflammation in the ECs. Cumulatively, the increased shear and oxidative stress from the system also lead to the activation of blood components and increased production of microparticles, reduced tissue factor pathway inhibitor, and increased fibrinogen accumulation that result in lumen narrowing and consequent cBF reduction [53].

Understandably, the role of hypoperfusion or reduced cBF in endothelial dysfunction for CSVD has been hypothesized [87]. Generally, the regulation of cBF is mediated by NO signaling; thus, NO serves as a marker for endothelial dysfunction [88]. Since endothelial dysfunction is associated with increased BBB permeability, this would worsen brain parenchyma and white matter lesions given the reduced integrity of ECs [89]. In addition, the increased expression of the mutated NOTCH3 gene (a genetic determinant of CADASIL) in pericytes was found to contribute to CSVD pathogenesis due to abnormal cross-talk between ECs and pericytes [87]. Therefore, one can posit that increased BBB permeability, reduced cBF, and impaired cerebral autoregulation serve as three main interrelated underlying pathogenesis precursors to the development and progression of CSVD, notwithstanding the role of other potential and novel factors.

#### **3.4 Role of reactive oxygen species**

Multiple studies have reported that the early detection of cognitive and motor decline in neurodegenerative disease has been linked with protein, lipids, sugar, and nucleic acid oxidation [90, 91]. Therefore, it can be postulated that changes or damage to the cerebral vasculature, BBB, and cBF is due to localized oxidative stress, hence initiating the neurodegenerative changes in the brain tissue.

Generally, overproduction of oxidants by NADPH oxidases and malfunction or reduced activities of antioxidant enzymes may result in oxidative stress [52]. The imbalance between antioxidants and prooxidants in aging and age-related neurological disease is regarded to be mainly due to ROS [92] which is a large group of oxygen radicals (i.e., superoxide anion radical, hydroxyl radical, peroxyl radical, and alkoxyl radical) and non-radicals (i.e., hydrogen peroxide, organic hydroperoxide, singlet molecular oxygen, electronically excited carbonyls, and ozone) [52, 64]. NADPH oxidase- and superoxide dismutase-mediated enzymatic conversion of molecular oxygen to superoxide initiates the production of ROS; however, the production of ROS can also be mediated by spontaneous transformation of nonradical hydrogen peroxide [93].

*Neuroprotection - New Approaches and Prospects*

ent CSVD manifestations.

the location of CMBs [77].

**3.3 Pathomechanism**

CSVD [17–19].

was reported for this gender difference [59]. In addition, previous study had reported stroke-free elderly Hispanic and/or Latino had SBI (16%), especially in

In other ethnic groups, previous study had reported that the prevalence of WMHs in South Asians and Europeans is similar, although South Asian elderly individuals with known vascular risk are more likely to be associated with higher WMHs [62]. Meanwhile, data in three Asian countries (Singapore, Hong Kong, and Korea) have shown that elderly Asians with higher SVD burden are associated with cognitive decline [63]. This was further supported by the Taizhou Imaging Study, whereby the authors found increased incidental findings of WMHs (10.68%), lacunes (26.69%), CMBs (18.51%), and perivascular spaces (27.76%) in elderly Chinese with vascular risk [64]. However in the Japanese population, most are having moderate to mild dilated perivascular spaces, especially in the centrum semiovale and basal ganglia [65]. Thus, it is apparent that more data are required to understand the role of racial and/or ethnic contributions for the presence of differ-

The effects of several manifestations of CSVD on cognition seem to be invariably influenced by the location of the lesion(s). The damaged and reduced white matter integrity in the frontal lobe and its dysfunction are associated with reduced transmission of information to other parts of the brain in the presence of WMHs [54], lacunes (deep nuclear [78.2%], posterior fossa [10.1%]) [66], and perivascular spaces [65, 67]. In contrast, temporal lobe lesion is more associated with the findings of lobar and deep CMBs [68, 69]. Several studies have reported that an increase in WMHs is associated with worse general and specific domain of cognitive performance, especially in executive function, processing speed, and episodic memory [70–73]. Intriguingly, an increase in WMHs with reduced cognitive performance is similar to the individual

with amyloid load, mild parkinsonism, and functional impairments [70].

Furthermore, reduced cognitive ability has been reported in elderly and nondemented people with the presence of lacunes of presumed vascular origin [54, 72, 74]. Memory declines have also been associated with thalamic infarcts, whereas decreased psychomotor speed is associated with non-thalamic infarcts [75]. In contrast, the presence of a lesion in the perivascular spaces reduces the individual processing speed [76] and, in others, reported no effect on the cognitive performance [67]. Meanwhile, a decrease in global cognitive performance and domain specific has been linked with

Despite the growing insights from histopathological, epidemiological, and physiological studies in the past two decades, the underlying pathomechanism of CSVD remains contentious [46, 53]. In general, it is recognized that advanced age and the presence of chronic hypertension may reduce the ability to self-regulate cBF in response to various systemic blood pressure levels and increased arterial stiffness, hence the increased speed and flow pulsatility in cerebral arterioles [16]. These hemodynamic changes are postulated to inflict a certain degree of endothelial damage in the BBB and alter its permeability through an increase of the shear stress [17]. Hence, the BBB breakdown is an important etiopathogenesis feature of

Another key factor thought to contribute to the pathogenesis of CSVD is endothelial dysfunction, with elevated biomarkers as the surrogates [78, 79]. The endothelial dysfunction involvement is also associated with metabolic syndrome [80, 81] and hence a strong link with CSVD. Furthermore, this dysfunction is also implicated for a higher risk of aging-related disease [82, 83]. In addition to the endothelium,

subcortical region (82.9%) [60] and perivascular spaces (48%) [61].

**194**

#### **Figure 5.**

*General pathomechanism and role of ROS in CSVD. ECs, endothelial cells; BBB, blood–brain barrier; ECM, extracellular matrix; cBF, cerebral blood flow; NO, nitric oxide; eNOS, endothelial nitric oxide synthase; ROS, reactive oxygen species; RNS, reactive nitrogen species; COX, cyclooxygenase; NADPH, nicotinamide adenine dinucleotide phosphate; MPs, microparticles; TNF-alpha, tumor necrosis factor-alpha; WMHs, white matter hyperintensities; CMBs, cerebral microbleeds; AD, Alzheimer's disease.*

There are multiple oxidative markers used to correlate with neurodegenerative disease including CSVD, for example, thioredoxins (positively correlate with severity of acute ischemic stroke and infarct volume) [94], thioredoxin reductase

**197**

CSVD are scarce.

*Neuroprotective Potentials of Natural Vitamin E for Cerebral Small Vessel Disease*

spectrum of CSVD and cerebral metabolic syndrome [82].

(reduced thioredoxin reductase attenuates the capacity of endothelium-dependent vasodilatory) [95], and peroxiredoxins (higher during stroke onset and traumatic brain injury) [96]. Moreover, reduced plasma levels of uric acid and vitamins E, A, and C have been used as antioxidant biomarkers for Alzheimer's disease and also Parkinson's disease [97–100]. Similarly, coenzyme Q10 (i.e., ubiquinone Q10) is another antioxidant that has been shown to provide potential protective effects for a

In CSVD, the elevated production of ROS is mainly due to reactions and process (i.e., high blood pressure, very low density of lipoproteins, diabetes, and homocysteinemia and smoking) that lead to inflammatory mechanism and oxidative stress hence causing endothelium dysfunction [20, 21]. Induction of oxidative stress further enhanced the releasing of adhesion molecules and recruiting of leukocytes causing higher leukocyte-EC adhesion and reduced cBF (**Figure 5**). NADPH oxidases induce oxidative stress (major source of ROS in vessel wall), and its destructive impact on EC-dependent NO signaling has been widely studied [22, 23]. The NADPH oxidases can be stimulated by mechanical forces and vasoactive agonists (i.e., thrombin, platelet-derived growth factor, and tumor necrosis factor-alpha) hence enhancing the production of ROS through superoxide anion

Another two key enzymes that facilitate the production of ROS include cyclooxygenase (COX) and enzymatic cascade in mitochondria (i.e., oxidative phosphorylation). COX is an important enzyme that produces superoxide in cerebral blood vessels through prostaglandin H2 synthesis mediated by AA [104, 105]. Superoxide can also be synthesized after endothelial nitric oxide synthase dysfunction that halts the NO production. This eventually reduces the bioavailability of NO and, in turn, facilitates the production of reactive nitrogen species (RNS) to cause reduced anti-inflammatory, reduced vasodilating, increased platelet aggregation, disinhibition of leukocyte adhesion, and reduced antiproliferative effects of NO [52, 106]. Hence, biomarkers of oxidative stress can be used to study the redox imbalance in individuals with WMHs while it draws a plausible therapeutic avenue with targeted dietary supplements to reduced ROS and RNS that would be neuroprotective

As remarked in the previous sections, increasing body of evidence indicated that oxidative stress might play a pivotal role in the largely elusive pathomechanism of CSVD and other neurodegenerative disease, including cognitive

impairment. Moreover, targeting oxidative stress, as a therapeutic approach of vascular-related disease, has been an area of continuing interest given its significance on the aging world population and the rising trend of noncommunicable disease burden, typically cardio-cerebrovascular disorders which include CSVD. However, informative and converging data on vitamin E and its neuroprotective potential for

Central to this proposition of vitamin E potential in CSVD is the involvement of ROS in the physiological role for normal regulation of cerebral vascular event. Hence, a balance between mitigating oxidative stress and normal physiological role should be considered in this ROS-centric approach for natural vitamin E in CSVD neuroprotective potentials. Nonetheless, the idea of attaining or sustaining certain levels of antioxidants to mitigate vascular oxidative stress remains a contentious issue. For instance, antioxidants such as vitamin E have been proven beneficial for vascular function in small clinical and experimental trials [108],

*DOI: http://dx.doi.org/10.5772/intechopen.91028*

radical synthesis [101–103].

against CSVD onset and/or manifestations [107].

**4. Prospects of vitamin E for CSVD neuroprotection**

#### *Neuroprotective Potentials of Natural Vitamin E for Cerebral Small Vessel Disease DOI: http://dx.doi.org/10.5772/intechopen.91028*

(reduced thioredoxin reductase attenuates the capacity of endothelium-dependent vasodilatory) [95], and peroxiredoxins (higher during stroke onset and traumatic brain injury) [96]. Moreover, reduced plasma levels of uric acid and vitamins E, A, and C have been used as antioxidant biomarkers for Alzheimer's disease and also Parkinson's disease [97–100]. Similarly, coenzyme Q10 (i.e., ubiquinone Q10) is another antioxidant that has been shown to provide potential protective effects for a spectrum of CSVD and cerebral metabolic syndrome [82].

In CSVD, the elevated production of ROS is mainly due to reactions and process (i.e., high blood pressure, very low density of lipoproteins, diabetes, and homocysteinemia and smoking) that lead to inflammatory mechanism and oxidative stress hence causing endothelium dysfunction [20, 21]. Induction of oxidative stress further enhanced the releasing of adhesion molecules and recruiting of leukocytes causing higher leukocyte-EC adhesion and reduced cBF (**Figure 5**). NADPH oxidases induce oxidative stress (major source of ROS in vessel wall), and its destructive impact on EC-dependent NO signaling has been widely studied [22, 23]. The NADPH oxidases can be stimulated by mechanical forces and vasoactive agonists (i.e., thrombin, platelet-derived growth factor, and tumor necrosis factor-alpha) hence enhancing the production of ROS through superoxide anion radical synthesis [101–103].

Another two key enzymes that facilitate the production of ROS include cyclooxygenase (COX) and enzymatic cascade in mitochondria (i.e., oxidative phosphorylation). COX is an important enzyme that produces superoxide in cerebral blood vessels through prostaglandin H2 synthesis mediated by AA [104, 105]. Superoxide can also be synthesized after endothelial nitric oxide synthase dysfunction that halts the NO production. This eventually reduces the bioavailability of NO and, in turn, facilitates the production of reactive nitrogen species (RNS) to cause reduced anti-inflammatory, reduced vasodilating, increased platelet aggregation, disinhibition of leukocyte adhesion, and reduced antiproliferative effects of NO [52, 106]. Hence, biomarkers of oxidative stress can be used to study the redox imbalance in individuals with WMHs while it draws a plausible therapeutic avenue with targeted dietary supplements to reduced ROS and RNS that would be neuroprotective against CSVD onset and/or manifestations [107].
