Abstract 14024: High-Field MRI Advanced Neuroimaging Characterization of Cerebrovascular Damage in a Mouse Model of Hypertension-Induced Cognitive Impairment

Introduction: Hypertension in 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 explorable in humans. To ease the translational potential of these findings it is fundamental to characterize the brain damage with techniques easily applicable to the cognitive-declining patient, like MRI. Methods: Transverse aortic constriction (TAC) was performed in C57Bl/6J mice to induce severe hypertension to the cerebral vasculature and long term VCI. The cognitive performance at the Morris Water Maze (MWM) and Novel Object Recognition (NOR), the cerebrovascular injury by macro and microstructural MRI and cerebral blood flow (CBF) were analyzed. T2w volumetric images, diffusion tensor imaging, CBF sequences were performed on a small-animal dedicated 7 Tesla MRI. Results: TAC-hypertensive mice displayed significantly reduced learning capabilities, evidenced in the acquisition phase of MWM, and a marked impairment in spatial and short-term memory shown by probe trial in MWM and NOR test. At the structural MRI, TAC mice showed white matter microstructural degradation in the Fimbria, evidenced by a reduction of Fractional Anisotropy (SHAM vs TAC: 0.52±0.01 vs 0.44±0.02, p=0.047), coupled with a hypothalamic swelling (Right: SHAM vs TAC: 7.14±0.09 vs 7.50±0.11mm 3 , p=0.035; Left: SHAM vs TAC: 7.18±0.20 vs 7.91±0.17mm 3 , p=0.019). Hemodynamic alterations resulted in reduced cortical and hypothalamic CBF (Cortex: SHAM vs TAC: 96.6±3.4 vs 77.1±6.8 mL/100mg/min, p=0.046; Hypothalamus: SHAM vs TAC: 140±6 vs 122±4 mL/100mg/min, p=0.025). Furthermore the histological analysis evidenced a capillary rarefaction and reduced capillary-pericyte coverage in the prefrontal cortex, suggestive of a severe impact of the elevated blood pressure on the brain vasculature. Conclusions: In conclusion we have developed a mouse model of hypertension that reproduces typical tracts of the human pathology and a pipeline of analysis that will ease translate findings from bench to bedside.