Progresión De La Enfermedad De Pequeño Vaso Cerebral: Factores De Riesgo, Mecanismos Implicados y Consecuencias Clínicas.

Abstract

Cerebral small vessel disease may be the cause of up to 20-25% of ischemic strokes and 45% of dementia cases. CSVD is principally studied by assessing its consequences via magnetic resonance imaging (MRI) —white matter hyperintensities (WMH), cerebral microbleeds, lacunar infarcts and enlarged perivascular spaces—. _x000D_ _x000D_ CSVD presents a long subclinical course in which these markers may accumulate on brain parenchyma. Although we know the radiological markers of cSVD, nowadays the vascular risk factors and implicated mechanisms in their progression are not well understood. Furthermore, it is unknown whether to present a marked progression of cSVD is associated with a worse clinical evolution. _x000D_ _x000D_ This thesis has been conducted in the ISSYS study (Investigating Silent Strokes in hYpertensives, a magnetic resonance imaging Study). This cohort is composed of 976 patients with hypertension aged 50-70, and dementia and stroke-free. Between 2010 and 2012 they underwent a clinical visit, a MRI, a cognitive evaluation, the ambulatory blood pressure monitoring (ABPM), and a urine and blood sampling collection. Between 2014 and 2016 a sample consisting of 356 subjects underwent a second visit with the same characteristics as at the baseline. In this sample we could evaluate the progression of cSVD, as well as the change in the rest of variables. _x000D_ _x000D_ Thereby, we observed that the progression of cSVD is a prevalent phenomenon in patients with hypertension. Concretely, 26.2% and 9.9% of subjects showed 1 and ≥ 2 incident cSVD lesions over the follow-up, respectively. This progression was correlated with the decline in cognition and incident mild cognitive impairment diagnosis —9.1% of the sample—. However, this relationship depends on the severity of these changes, and the type and localization of the lesion/s. Periventricular WMH was the marker of cSVD which was more significantly associated with cognitive decline. Similarly, by means of a survival analysis conducted in the complete cohort (n=976) we found that patients with silent brain infarcts were at three-fold increased risk of suffer an incident cardiovascular event within 5 years. _x000D_ _x000D_ On the other hand, ABPM may help to predict the progression of cSVD, although its information should be combined with other variables (e.g., clinical information, blood biomarkers) in order to achieve a clinically significant predictive model. Markers of kidney function (microalbuminuria and estimated glomerular filtration rate) presented a parallel decline with the progression of cSVD and cognitive impairment. Hence, these markers may help to identify patients at risk of progression of cSVD. Moreover, by means of a proteomic study, we proposed several proteins which were correlated with the progression of WMH (MET, MMP9, ASAH-2). Therefore, to study the clinical usefulness of these molecules in future studies, as well as their role in the pathophysiology of WMH, may be of greater interest. _x000D_ _x000D_ Finally, we assessed the burden of hippocampal enlarged perivascular spaces in the sample. We found that these radiological markers were related to other cSVD lesions and to cognitive performance. These results may indicate that hippocampal enlarged perivascular spaces are part of cSVD manifestations. Hence, further research should determine their progression in additional longitudinal studies.

Date of Award	2 Mar 2020
Original language	Spanish
Supervisor	María Pilar Delgado Martínez (Director), I. Riba-Llena (Director) & Jose Rodriguez Alvarez (Tutor)