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BackgroundCerebral small vessel disease (SVD) has been suggested to be more common in Asians compared with Caucasians. However, data from population-based studies in Asia are lacking. We report on the prevalence, risk factors and consequences of SVD from contemporary studies in three Asian countries using 3-Tesla MRI for the evaluation of SVD.MethodsClinical, cognitive and 3-Tesla brain MRI assessments were performed among participants of three studies from Singapore, Hong Kong and Korea. SVD markers include white matter hyperintensities (WMHs) using the modified Fazekas scale, lacunes and microbleeds. Cognition was assessed using the Mini Mental Status Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Adjustments were made for age, sex and cardiovascular risk factors.ResultsA total of 1797 subjects were available for analysis (mean age: 70.1±6.3 years and 57% women). The prevalence of confluent WMH was 36.6%, lacunes, 24.6% and microbleeds, 26.9%. Presence of all three SVD markers showed a steeper increase with increasing age rising from 1.9% in the lowest to 46.2% in the highest 5-year age strata. The major risk factors for the increased severity of SVD markers were advancing age and hypertension. Moreover, increasing severity of SVD markers was independently associated with worse performance on MMSE and MoCA.ConclusionElderly Asians have a high burden of SVD which was associated with cognitive dysfunction. This suggests that SVD markers should be a potential target for treatment in clinical trials so as to delay progression of cerebrovascular disease and potentially cognitive decline.

Cerebral small vessel disease (CSVD) is a broad category of cerebrovascular diseases which primarily affect the perforating arterioles, capillaries and venules with multiple distinct etiologies. In spite of distinctive pathogenesis, CSVD shares similar neuroimaging markers, including recent small subcortical infarct, lacune of presumed vascular origin, white matter hyperintensity of presumed vascular origin, perivascular space and cerebral microbleeds. The radiological features of neuroimaging markers are indicative for etiological analysis. Furthermore, in sporadic arteriosclerotic pathogenesis associated CSVD, the total CSVD burden is a significant predictor for stroke events, global cognitive impairment, psychiatric disorders and later life quality. This review aims to summarize the radiological characteristics as well as the clinical implication of CSVD markers and neuroimaging interpretation for CSVD symptomatology.

Objective： Alzheimer＇s disease and vascular dementia are responsible for more than 80% of dementia cases. These two conditions share common risk factors including hypertension. Cerebral small vessel disease （CSVD） is strongly associated with both hypertension and cognitive impairment. In this review, we identify the pathophysiological changes in CSVD that are caused by hypertension and further explore the relationship between CSVD and cognitive impairment. Data Sources： We searched and scanned the PubMed database for recently published literatures up to December 2017. We used the keywords of＂hypertension＂, ＂cerebral small vessel disease＂, ＂＇white matter lesions＂, ＂enlarged perivascular spaces＂, ＂lacunar infarcts＂, ＂cerebral microbleeds＂, and ＂cognitive impairment＂ in the database of PubMed. Study Selection： Articles were obtained and reviewed to analyze the hypertension-induced pathophysiological changes that occur in CSVD and the correlation between CSVD and cognitive impairment. Results： In recent years, studies have demonstrated that hypertension-related changes （e.g., small vascular lesions, inflarnmator3, reactions, hypoperfusion, oxidative stress, damage to autoregulatory processes and the blood-brain barrier, and cerebral amyloid angiopathy） can occur over time in cerebral small vessels, potentially leading to lower cognitive function when blood pressure （BP） control is poor or lacking. Both isolated and co-occurrent CSVD can lead to cognitive deterioration, and this effect may be attributable to a dysfunction in either the cholinergic system or the functionality of cortical and subcortical tracts. Conclusions： We explore the currently available evidence about the hypertensive vasculopathy and inflammatory changes that occur in CSVD. Both are vital prognostic indicators of the development of cognitive impairment. Future studies should be performed to validate the relationship between BP levels and CSVD progression and between the nunabers, volumes, and anatomical locations of CSVD and cognitive impairment.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common and best known monogenic small vessel disease. Here, we review the clinical, neuroimaging, neuropathological, genetic, and therapeutic aspects based on the most relevant articles published between 1994 and 2016 and on the personal experience of the authors, all directly involved in CADASIL research and care. We conclude with some suggestions that may help in the clinical practice and management of these patients.

Cerebral small vessel disease (CSVD) is a group of pathologies that affect the cerebral blood vessels. CSVD accounts for 25% of strokes and contributes to 45% of dementia. However, the pathogenesis of CSVD remains unclear, involving a variety of complex mechanisms. CSVD may result from dysfunction in the glymphatic system (GS). The GS contains aquaporin-4 (AQP-4), which is in the perivascular space, at the endfeet of the astrocyte. The GS contributes to the removal of waste products from the central nervous system, occupying perivascular spaces and regulating the exchange and movement of cerebrospinal fluid and interstitial fluid. The GS involves astrocytes and aquaporin channels, which are components of the blood–brain barrier, and problems with them may constitute the pathogenesis of CSVD. Vascular risk factors, including diabetes, dilate the perivascular space, disrupting the glymphatic system and the active regulation of AQP-4. CSVD exacerbation due to disorders of the GS is associated with multiple vasculopathies. Dysfunction of the glymphatic system and AQP-4 interferes with the functioning of the blood–brain barrier, which exacerbates CSVD. In a long-term follow-up of CSVD patients with microbleeds, lacunar infarcts, and white matter hyperintensity, several vascular risk factors, including hypertension, increased the risk of ischemic stroke. Dysfunction of the GS may be the cause of CSVD; however, the underlying treatment needs to be studied further.

Dementia resulting from small vessel diseases (SVDs) of the brain is an emerging epidemic for which there is no treatment. Hypertension is the major risk factor for SVDs, but how hypertension damages the brain microcirculation is unclear. Here, we show that chronic hypertension in a mouse model progressively disrupts on-demand delivery of blood to metabolically active areas of the brain (functional hyperemia) through diminished activity of the capillary endothelial cell inward-rectifier potassium channel, Kir2.1. Despite similar efficacy in reducing blood pressure, amlodipine, a voltage-dependent calcium-channel blocker, prevented hypertension-related damage to functional hyperemia whereas losartan, an angiotensin II type 1 receptor blocker, did not. We attribute this drug class effect to losartan-induced aldosterone breakthrough, a phenomenon triggered by pharmacological interruption of the renin-angiotensin pathway leading to elevated plasma aldosterone levels. This hypothesis is supported by the finding that combining losartan with the aldosterone receptor antagonist eplerenone prevented the hypertension-related decline in functional hyperemia. Collectively, these data suggest Kir2.1 as a possible therapeutic target in vascular dementia and indicate that concurrent mineralocorticoid aldosterone receptor blockade may aid in protecting against late-life cognitive decline in hypertensive patients treated with angiotensin II type 1 receptor blockers.

Cerebral small vessel disease (CSVD) is a leading cause of ischemic stroke and vascular cognitive impairment. Despite well-defined neuroimaging features and a substantial clinical burden, the underlying pathological mechanisms of CSVD remain poorly understood, and effective interventions are still lacking. Current human and experimental evidence suggest that endothelial dysfunction and neuroinflammation are closely coupled and may form a mutually reinforcing process in many CSVD-relevant settings. This review synthesizes available evidence into a working framework in which vascular risk factors promote endothelial phenotypic switching and blood-brain barrier (BBB) dysfunction, thereby facilitating neuroinflammatory activation. Pericytes, astrocytes, and microglia within the neurovascular unit can then amplify barrier injury and inflammatory signaling through context-dependent feedback interactions, including matrix metalloproteinase-mediated proteolysis. In turn, the chronic inflammatory milieu may sustain persistent endothelial dysfunction or alter endothelial responsiveness to subsequent inflammatory stimuli, potentially allowing pathological processes to continue even after the original triggers are attenuated. Based on this evidence-guided framework, we also evaluate therapeutic strategies directed at distinct nodes of the endothelial dysfunction-neuroinflammation network.

Cerebral small vessel disease (CSVD) is one of the main causes of vascular dementia in older individuals. Apart from risk containment, efforts to prevent or treat CSVD are ineffective due to the unknown pathogenesis of the disease. CSVD, a subtype of stroke, is characterized by recurrent strokes and neurodegeneration. Blood-brain barrier (BBB) impairment, chronic inflammatory responses, and leukocyte infiltration are classical pathological features of CSVD. Understanding how BBB disruption instigates inflammatory and degenerative processes may be informative for CSVD therapy. Antigens derived from the brain are found in the peripheral blood of lacunar stroke patients, and antibodies and sensitized T cells against brain antigens are also detected in patients with leukoaraiosis. These findings suggest that antigen-specific immune responses could occur in CSVD. This review describes the neurovascular unit features of CSVD, the immune responses to specific neuronal and glial processes that may be involved in a distinct mechanism of CSVD, and the current evidence of the association between mechanisms of inflammation and interventions in CSVD. We suggest that autoimmune activity should be assessed in future studies; this knowledge would benefit the development of effective therapeutic interventions in CSVD.

RationaleThe role of hypertension in cerebral small vessel disease is poorly understood. At the base of the brain (the ‘vascular centrencephalon’), short straight arteries transmit blood pressure directly to small resistance vessels; the cerebral convexity is supplied by long arteries with many branches, resulting in a drop in blood pressure. Hypertensive small vessel disease (lipohyalinosis) causes the classically described lacunar infarctions at the base of the brain; however, periventricular white matter intensities (WMIs) seen on MRI and WMI in subcortical areas over the convexity, which are often also called ‘lacunes’, probably have different aetiologies.ObjectivesWe studied pressure gradients from proximal to distal regions of the cerebral vasculature by mathematical modelling.Methods and resultsBlood flow/pressure equations were solved in an Anatomically Detailed Arterial Network (ADAN) model, considering a normotensive and a hypertensive case. Model parameters were suitably modified to account for structural changes in arterial vessels in the hypertensive scenario. Computations predict a marked drop in blood pressure from large and medium-sized cerebral vessels to cerebral peripheral beds. When blood pressure in the brachial artery is 192/113 mm Hg, the pressure in the small arterioles of the posterior parietal artery bed would be only 117/68 mm Hg. In the normotensive case, with blood pressure in the brachial artery of 117/75 mm Hg, the pressure in small parietal arterioles would be only 59/38 mm Hg.ConclusionThese findings have important implications for understanding small vessel disease. The marked pressure gradient across cerebral arteries should be taken into account when evaluating the pathogenesis of small WMIs on MRI. Hypertensive small vessel disease, affecting the arterioles at the base of the brain should be distinguished from small vessel disease in subcortical regions of the convexity and venous disease in the periventricular white matter.

While hypercholesterolemia plays a causative role for the development of ischemic stroke in large vessels, its significance for cerebral small vessel disease (CSVD) remains unclear. We thus aimed to understand the detailed relationship between hypercholesterolemia and CSVD using the well described Ldlr-/- mouse model. We used Ldlr-/- mice (n = 16) and wild-type (WT) mice (n = 15) at the age of 6 and 12 months. Ldlr-/- mice develop high plasma cholesterol levels following a high fat diet. We analyzed cerebral capillaries and arterioles for intravascular erythrocyte accumulations, thrombotic vessel occlusions, blood-brain barrier (BBB) dysfunction and microbleeds. We found a significant increase in the number of erythrocyte stases in 6 months old Ldlr-/- mice compared to all other groups (P < 0.05). Ldlr-/- animals aged 12 months showed the highest number of thrombotic occlusions while in WT animals hardly any occlusions could be observed (P < 0.001). Compared to WT mice, Ldlr-/- mice did not display significant gray matter BBB breakdown. Microhemorrhages were observed in one Ldlr-/- mouse that was 6 months old. Results did not differ when considering subcortical and cortical regions. In Ldlr-/- mice, hypercholesterolemia is related to a thrombotic CSVD phenotype, which is different from hypertension-related CSVD that associates with a hemorrhagic CSVD phenotype. Our data demonstrate a relationship between hypercholesterolemia and the development of CSVD. Ldlr-/- mice appear to be an adequate animal model for research into CSVD.