Clinical study of cerebral small vessel disease

Abstract

Introduction Cerebral small vessel disease (SVD) refers to the damage of the small arteries, arterioles, venules, and capillaries of the brain. The term is commonly used to describe a range of neuroimaging (such as leukoaraiosis, lacunar infarcts, microhaemorrhages and spontaneous intracerebral haemorrhages), neuropathological (such as sporadic cerebral amyloid angiopathy and hypertensive arteriopathy), and associated clinical features mainly cognitive impairment and stroke. Ageing and hypertension are the main causes known until today. Incidence of these disease is increasing nowadays. Phenomena like endothelial dysfunction, rupture of blood-brain barrier (BBB) and protein elimination failure angiopathy have become important in the pathophysiology of SVD. The role of AB 1-40, peptide related to cerebral amyloid angiopathy, metalloproteinases (MMPs) and the circulating soluble TNF related weak inducer apoptosis (sTWEAK) related to the endothelial dysfunction, rupture of BBB and neurovascular disruption are currently important subjects of research in this field. Hypothesis ¿Is the dysfunction of the blood brain barrier implicated in the progression of SVD? Justification Most of previous studies has been focused in advanced stages of the disease, but there is a lack of studies that evaluate the factors that lead to the development of SVD in early stages, and there are no early diagnostic markers of SVD. Objectives The main objective is identify the clinical risk profile associated with the development of any phenotype. The secondary objectives are to identify biomarkers of cognitive impairment (A 1-40), endothelial dysfunction (sTWEAK) and extracellular matrix dysfunction (MMPs) associated with initial phases or with the development of any phenotype and identify ultrasonographic and neuroimaging markers. Material and methods We designed a prospective study including patients with hypertension and/or diabetes mellitus type 2 with more than 5 years of evolution, with age between 60-75 years, without previous vascular disease or cognitive impairment. A vascular risk factors control, cognitive, neuroradiological and ultrasonography evaluation was done. The primary endpoint is the progression of any SVD phenotypes defined as appearance or increase of leucoaraiosis or WMH, lacunar infarcts, microhaemorrhages and cognitive impairment during the evolution. The secondary endpoints are the appearance or increase of each one of the SVD phenotypes during the follow-up period. ELISA test were performed to determinate the serum concentration of sTWEAK, AB1-40, TIMP1 and also the metalloproteinases MMP-1, MMP-10, MMP-7, MMP-9, MMP-12, MMP-13 and MMP-3. Results 101 patients were included, mean time of follow-up was 24±4,86 months. 87,1% of patients have radiological or clinical markers of SVD, the most frequent finding is leukoaraiosis grade I. Progression of any SVD was detected in 42,6% of patients during the follow-up. Bad clinical control of hypertension was the only variable associated with the progression of any SVD phenotype, specially with progression of leukoaraiosis. Poor control of hypertension is associated with progression of leukoaraiosis OR was 7,8 (95% CI 1,5-40,4) p 0,015. High levels of sTWEAK are associated with a greater development of new lacunar infarcts and new microhaemorrhages in patients with previous lacunar infarcts. High levels of MMP-7 and MMP-9 are associated with greater development of new microhaemorrhages. Elevated levels of AB 1-40 are associated with a greater risk of developing cognitive progression in patients with SVD. Higher body mass index was an independent protective factor for progression of SVD. Conclusions Bad clinical control of hypertension is the main factor associated with progression of SVD; sTWEAK, MMP7, MMP9 and AB 1-40 could be potential biomarkers related with progression of different phenotypes of SVD.