Pathology of Vascular Dementia

About VaD[15]

Vascular dementia (VaD) is the second most prevalent subset of dementia next to Alzheimer's Disease (AD) as it is found in 5-20% of dementia cases[1]. VaD can result from any condition that damages the vascular system of the brain[2]. The vascular system supplies the brain with blood filled with oxygen and nutrients which are vital to the brain’s function. Damage to the vascular system system results in hypoperfusion (reduced blood flow to the brain). Hypoperfusion may eventually lead to the loss of brain cells, and the onset of VaD[2].

The brain damage which causes VaD cannot be reversed. As a result, most treatments aim to slow or prevent the progression of the disease. Prevention of VaD can be accomplished by treating pre-existing conditions which are able to cause vascular damage. These conditions include hypertension, diabetes, stroke, and heart problems[2]. In particular, hypertension is a major risk factor for VaD independent of its role as a risk factor for stroke[3]. Hypertension can be controlled by way of lifestyle changes and medications; therefore, implementation of these interventions in hypertensive individuals can decrease their risk for VaD. Damage to the vascular system induced by hypertension includes inflammation and oxidative stress in blood vessels[2]. One of the major contributors to oxidative stress in the brain is thought to be nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. NADPH oxidases are a class of enzymes which generate reactive oxygen species (ROS). Since this discovery, NADPH oxidase inhibitors have been examined as potential treatments for the reduction of damage caused by oxidative stress[4].

Causes of Vascular Dementia

VaD is a heterogeneous group of disorders which emerge as a result of cerebral hypoperfusion, or ischemic or hemorrhagic brain damage. As a consequence of this heterogeneity, VaD can be classified into different forms based on the heritability of the disorder, and the types of lesions the disorder causes. The onset of VaD can be attributed to both genetic and sporadic disorders; however, genetic causes of VaD are very rare[2]. The most well known genetic cause of VaD is cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL). CADASIL affects individuals with a frame shift mutation in the Notch-3 gene[5]. This mutation is associated with the destruction of vascular smooth muscle cells, and the thickening and fibrosis of cerebral blood vessel walls[5]. The subsequent hypoperfusion to the brain can result in recurrent strokes, and eventually VaD.

Subsets of VaD
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The gray areas indicate regions affected by an infarct or lesion [3].

Sporadic forms of VaD are much more common than genetic forms. They are most often the result of degenerative vessel disorders which cause lesions in the brain. These vessel disorders include atherosclerosis of the cerebral arteries, cerebral small vessel disease, and cerebral amyloid angiopathy (CAA)[3]. Atherosclerosis is the accumulation of cholesterol, proteins and lipids in large and medium sized artery walls which calcify into plaques. Plaque buildup results in stenosis of the artery causing hypoperfusion to the brain. Plaques are also at risk of rupturing and inducing thrombosis (blood clot formation)[3]. The types of infarcts caused by atherosclerosis are diverse. Small vessel disease results from atherosclerosis, arteriolosclerosis and lipohyalinosis of the small vessels. Small vessel disease can cause lacunar and micro-infarcts which damage the basal ganglia, peripheral white matter, and thalamic and cerebellar white matter vessels[3]. CAA is caused by deposits of beta amyloid protein in the wall of cerebral blood vessels. It can lead to the rupture of vessel walls, hemorrhage, micro-bleeds, capillary occlusion and blood flow disturbances in the brain[3].

The sporadic forms of VaD are characterized by the type of lesions they create in the brain. The characterizations include multi-infarct dementia, strategic infarct dementia, and subcortical vascular encephalopathy (Binswanger’s Disease)[3]. Multi-infarct dementia is the result of multiple micro-infarcts, large infarcts or lacunar infarcts in the gray matter of the brain. Strategic infarcts occur when there is an infarct in a specific region of the brain needed for cognitive function. The behavioural impairment resulting from the infarct is specific to the brain region damaged. For example, an infarct in the hippocampus would result in memory loss. Subcortical vascular encephalopathy results from lesions in the white matter of central and peripheral areas of the brain[3].

Hypertension as a Risk Factor

Hypertension is defined as an elevation in blood pressure above 140 mmHg systolic and 90 mmHg diastolic pressure[6]. It is a major risk factor for both VaD and AD in the elderly due to the changes it makes to both the structure and function of cerebral blood vessels. Structural changes made to the vessels act in concert to reduce the lumenal diameter of cerebral blood vessels, and harden blood vessel walls. This, in turn, attenuates the ability of the cerebral blood vessels to carry out normal functions including functional hemodynamic responses, autoregulation, and endothelium-dependent responses[6].

Changes to Cerebral Blood Vessel Structure

Hypertension's Effects on Vascular Structure
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Different structural changes made to the vascular structure and the types of infarcts they cause[2].

The normal structure of cerebral blood vessels are degenerated by vessel disorders induced by hypertension such as atherosclerosis and lipohyalinosis[6]. Lipohyalinosis is the fibrinoid necrosis of vascular walls resulting in vessel wall thickening and lumen narrowing. It most often affects vessels which supply the white matter of the brain, and can result in white matter strokes or brain hemorrhages[6]. Both atherosclerosis and lipohyalinosis can cause occlusions in the cerebral vasculature, which can lead to ischemic injury.

Furthermore, hypertension causes hypertrophic and eutrophic remodelling of the cerebral arteries. Hypertrophic remodelling describes a process in which the thickness of the cerebral artery wall is increased; consequently, the diameter of the lumen is reduced[6]. This is a direct result of the vascular smooth muscle cells undergoing hypertrophy. Eutrophic remodelling describes the narrowing of the vessel lumen due to the movement of smooth muscle cells, without a change in the thickness of the vessel wall[6]. Alterations to the composition and structure of the vascular walls by these mechanisms have profound negative effects on the function of the vessels.

Changes to Cerebral Blood Vessel Function

Hypertension's Effects on Vascular Function[6]
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Changes made to the structure of cerebral blood vessels reduce cerebral blood flow (CBF) and impair their adaptive responses. Adaptive responses of cerebral blood vessels ensure that the energy needs of the brain are met by way of proper CBF. Proper CBF is essential due to the brain’s dependence on a constant supply of oxygen and energy from the blood. The adaptive responses attenuated in the event of chronic hypertension include functional hyperemia, autoregulation, and endothelium-dependent vasodilation[6]. Functional hyperemia is the increase in blood flow to active regions of the brain. This function is controlled by the neurovascular unit made up of neurons, glia and vascular cells [1]. Hypertension disrupts the neurovascular unit which results in hypoperfusion during cognitive activation[1]. This effect contributes to neuronal dysfunction, and leads to cognitive deficits. Endothelium dependent vasodilation refers to the ability of endothelial cells to respond to physiological stimuli through the production of vasodilators or vasoconstrictors in order to regulate arterial vascular tone[7]. Nitric oxide (NO) is a vasodilator which is a key regulator of vascular tone. In hypertensive individuals NO availability decreases which can cause endothelial dysfunction[7]. Cerebrovascular autoregulation is one’s ability to maintain CBF in response to changing arterial pressures[6]. In a hypertensive individual, a higher blood pressure is required to maintain a normal range of CBF. Poor autoregulation can increase the susceptibility of white matter to damage during changes in blood pressure[6]. It could also result in a more extreme brain injury after ischemia because the vessels need proper autoregulation to respond to the reduction in blood flow.

Damage to the Brain by Oxidative Stress

In the brain, proper function of cells is reliant on the balance between ROS generation and degeneration. When this balance is disrupted by an increase in ROS generation, a state of oxidative stress ensues[4]. The brain has multiple sources of ROS; however, it has been shown that membrane bound NADPH oxidase enzymes are the primary sources of ROS during hypoperfusion, stroke and hypertension[4]. In both humans and animal models of hypertension, these enzymes are shown to be overactive[4]. Overactivity of NADPH oxidases increases the number of ROS which results in a state of oxidative stress. In a hypertensive state, the NOX2 homolog of NADPH oxidase has been implicated as the source of the increased number of ROS[8].

Oxidative stress has been shown to play a large role in the cerebrovascular dysfunction underlying VaD. Oxidative stress in brain vasculature impairs endothelium dependent responses which may increase one’s susceptibility to cell dysfunction, cell death, and dementia[9]. NOX2 generates a type of ROS called superoxide anions which bind to and inactivate NO. NO is a vasodilator made by endothelium nitric oxide synthase (eNOS) in endothelial cells. The inactivation of NO reduces the amount of NO available to the cells. Reduced NO availability alters the resting tone of vessels, and endothelium-dependent vasodilation. It can also lead to hypertrophy in cerebral arterioles and arteries[6]. Furthermore, an oxidant called peroxynitrite is formed when NO reacts with superoxide anions[10].Peroxynitrite inactivates antioxidant enzymes which sustains an increased level of ROS. Peroxynitrite also plays a role in eNOS uncoupling, which is a process that has been implicated in endothelial dysfunction caused by oxidative stress. eNOS requires the cofactor tetrahydrobiopterin (BH4) to synthesize NO from its precursor, L-arginine[11]. In a state of oxidative stress, BH4 is oxidized by peroxynitrite and eNOS begins reducing oxygen to make superoxide anions instead of reducing L-arginine to make NO[11]. This perpetuates the effects of oxidative stress in the brain by further increasing the number of oxidants.


Current Treatments

There are currently no approved drug treatments for VaD. Some clinical trials have shown that drugs that are effective for AD, such as acetylcholinesterase inhibitors, may also be useful in the treatment of VaD[12]. Treatments for VaD primarily aim to prevent the recurrence of vascular injury or minimize further damage to the brain. This is done through the use of antihypertensive and anti-platelet medications[13].

Potential Treatment: NADPH Oxidase Inhibitors

A lot of research has focused on the contribution of NADPH oxidases to oxidative stress in models of hypertension, aging, and stroke. It has been determined that overactivity of NADPH oxidases play a major role in oxidative stress induced damage to the brain. This was demonstrated in a study by Chen et al. in which mice with a NOX2 subunit knockout, and mice treated with a NOX2 inhibitor (apocynin) had less oxidative stress and inflammation after ischemia in comparison to wildtype mice[14]. Furthermore, the infarction volume of the mouse brains reflected the reduction in oxidative stress. In knockout and apocynin treated mice, the infarction volume was much lower than in wildtype mice[14]. These results show that NOX2 has a substantial role in mediating oxidative damage to the brain.  They also show the potential of NADPH oxidase inhibitors such as apocynin to be used clinically as treatment to reduce oxidative damage following stroke. In order to determine if NADPH oxidase inhibitors could be used as treatment for VaD, a relationship between cognitive function and NADPH oxidase inhibition needs to be found.

Neuroprotective effect of NOX2 inhibition
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NOX2 knockout mice (KO) and apocynin (Apo) treated mice display less 
oxidative stress after ischemia in comparison to wildtype (WT) mice. Oxidative
stress levels were determined by measuring the amount of
8-hydroxy-2-deoxyguanosine (8-OHdG)-a biomarker of DNA damage.
Data from Chen, H., Song, Y. S., & Chan, P. H.(2009). Inhibition of NADPH oxidase is
neuroprotective after ischemia-reperfusion. J. Cerebr. Blood F. Met. 29, 1262-1272.[14]

Neuroprotective effect of NOX2 inhibition
Image Unavailable
NOX2 knockout mice (KO) and apocynin (Apo) treated mice display a smaller
infarction volume after ischemia in comparison to wildtype (WT) mice.
Data from Chen, H., Song, Y. S., & Chan, P. H.(2009). Inhibition of NADPH oxidase
is neuroprotective after ischemia-reperfusion. J. Cerebr. Blood F. Met. 29, 1262-1272.[14]

As it stands, NADPH oxidase inhibitors appear to have the potential to prevent and reduce damage induced by oxidative stress. Oxidative stress underlies the endothelial dysfunction induced by hypertension. Consequently, NADPH oxidase inhibitors could be used to prevent VaD by reducing the negative effects hypertension has on the brain. Because NADPH oxidase inhibitors target the effects of hypertension which precede the initial onset of the VaD, they may be able to prevent initial damage to the brain. This is especially important in the case of VaD because the vascular damage which causes VaD cannot be reversed.  Furthermore, there is a great need for a VaD treatment because a treatment which helps to prevent VaD could reduce morbidity and healthcare costs while improving quality of life in the growing elderly population. 

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