Hypertension is one of the main risk factors for vascular cognitive impairment (VCI) and neurodegenerative pathologies as Alzheimer's Disease (AD). To identify the underlying mechanisms, it is important to use experimental models that present the pathophysiological characteristics of AD and VCI, hence allowing the investigation of molecular processes not directly explorable in humans. To ease the translational potential of these findings it is fundamental to characterize the resulting brain damage with techniques easily applicable to the cognitive-declining patient too, like MRI.
We will perform transverse aortic constriction (TAC) in C57Bl/6J mice to induce severe hypertension to the cerebral vasculature and development of long term VCI. We will characterize a) cognitive performance with the Morris Water Maze (MWM) and the Novel Object Recognition (NOR) tests, b) cerebrovascular injury by macro and microstructural MRI, c) and cerebral blood flow (CBF). T2-weighted volumetric images, diffusion tensor imaging, CBF sequences will be performed on a small-animal dedicated 7 Tesla MRI. Carotid remodeling and blood flow will be assessed by ultrasound imaging. The analysis of brain vasculature remodeling will be carried out in vivo, by 2-photon imaging, and ex vivo, by immunofluorescence analysis of cerebral vasculature and by vascular reactivity studies executed on cerebral arteries. Brain immune cells and neuronal markers of damage will be used to assess the overall cerebral injury induced by hypertension. By using mice lacking mature lymphocyte or mice deficient for chemokine receptors responsible for monocyte migration, we will investigate the potential contribution of adaptive vs innate immune cells in the process of cerebrovascular damage induced by hypertension.
In conclusion we will develop a mouse model of hypertension that reproduces typical tracts of the human pathology and a pipeline of analysis that will ease translate molecular findings from bench to bedside.
Advancements in clinical treatments and quality of life significantly improved the life expectancy, determining an increased global impact of age-associated pathologies, like dementias. Recent World Health Organization research (14) have recognized non-communicable diseases, like dementias and cognitive impairment, as one of the main threats to global health, in particular for older people. With 35.6 million estimated clinically diagnosed dementias, with 7.7 million yearly new diagnosis, the social and economic cost of this pathology will soon be unbearable for the global health system. This calls for new biomarkers that can predict the onset of cognitive impairment to prevent this pathology in subjects at high risk, to improve their quality of life and to cut the social health system costs for demented patients.
With our project we aim at finding multimodal features of cerebral damage induced by hypertension in the experimental model of hypertension-induced cognitive impairment. These features will be obtained by techniques easily translatable to humans, to identify novel potential cognitive impairment biomarkers and the associated underlying pathological mechanisms. The multi-modal nature of the obtained features (structural imaging, functional imaging, immunophenotyping, cognitive phenotyping) will be fundamental to stratify the level of damage induced by chronic hypertension and to evaluate whether different features of cerebral injury are associated with specific underlying immune mechanisms, guiding further analyses on molecular pathways involved in VCI onset.
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