Cerebral Small Vessel Disease (CSVD) – Lessons From the Animal Models

Abstract

Cerebral small vessel disease (CSVD) refers to a spectrum of clinical and imaging findings resulting from pathological processes of various etiologies affecting cerebral arterioles, perforating arteries, capillaries, and venules. Unlike large vessels, it is a challenge to visualize small vessels in vivo, hence the difficulty to directly monitor the natural progression of the disease. CSVD might progress for many years during the early stage of the disease as it remains asymptomatic. Prevalent among elderly individuals, CSVD has been alarmingly reported as an important precursor of full-blown stroke and vascular dementia. Growing evidence has also shown a significant association between CSVD’s radiological manifestation with dementia and Alzheimer’s disease (AD) pathology. Although it remains contentious as to whether CSVD is a cause or sequelae of AD, it is not far-fetched to posit that effective therapeutic measures of CSVD would mitigate the overall burden of dementia. Nevertheless, the unifying theory on the pathomechanism of the disease remains elusive, hence the lack of effective therapeutic approaches. Thus, this chapter consolidates the contemporary insights from numerous experimental animal models of CSVD, to date: from the available experimental animal models of CSVD and its translational research value; the pathomechanical aspects of the disease; relevant aspects on systems biology; opportunities for early disease biomarkers; and finally, converging approaches for future therapeutic directions of CSVD.

Neuroprotective Potentials of Natural Vitamin E for Cerebral Small Vessel Disease

“…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].…”

“…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].…”

“…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].…”

Correlation of carotid artery disease and tinnitus: is it an auditory phantom in vascular surgery practice? A wide evidence-based review

“…Yet, this emerged evidence did not yield a shred of conclusive pathophysiological evidence as to how it pertains to pulsatile tinnitus. It has been shown that increased arterial stiffness may lead to microvascular damage in the brain and this can manifest itself with a multitude of clinical symptoms and signs including tinnitus [19] . This had yielded to another entity related to carotid system arterial stiffness implicated in the development and severity of "idiopathic subjective tinnitus" [8] .…”