Abstract 3106: Vascular Cognitive Impairment (VCI) Risk Factors Produce Deficits in Cognition and Gait-Balance with Fiber Tract Pathology and Inflammation in a Rat Model of VCI

Abstract

Background: Cerebrovascular risk factors are important to model VCI. VCI symptoms include cognitive deficits in executive function and gait associated with reduced forebrain perfusion and fiber tract injury. Ischemia mobilizes progenitor CD34+ cells from bone marrow. Here important risk factors are incorporated into a translational VCI model. Methods: Clinic: The relationship between blood pressure and carotid lesions on cognitive outcome were assessed in linear regression models. Preclinic : Bilateral common carotid artery Stenosis surgery (guided by reduced forebrain perfusion) or Sham surgery was performed in spontaneously hypertensive rats (SHR). Measurements of neurological (gait-balance, sensory-motor and activity) and cognitive (avoidance tests: active place; APA and passive; PA) functions were made. Quantitative histological measurements were made of CA1 neurons (NeuN) and corpus collosum (CC) myelin (Luxol Fast Blue) and astro- (GFAP) and micro- (Iba1) gliosis. Circulating CD34+ progenitor cells were measured using a fluorescence-activated cell analyzer. Results: Clinic: Carotid lesions (p < 0.01) and hypertension (p< 0.05) were independent predictors of cognitive impairment. Preclinic : Stenosis decreased forebrain perfusion and impaired APA and gait-balance within 3 weeks (p<0.01). Motor activity, blood pressure, heart rate, body weight and simple PA performance were not affected. CC myelin was reduced (48%; p<0.01) with increased astro- (69%; p<0.05) and micro- (140%; p<0.01) gliosis. CA1 neurons were not changed. Circulating CD34+ progenitor cells were significantly increased (p< 0.02). Conclusions: Clinic: Carotid stenosis and hypertension are associated with cognitive impairment. Preclinic : Carotid stenosis in the hypertensive rat results in cognitive and gait-balance deficits that mimic VCI. APA mimics “executive function-like” decision making and is a sensitive indicator of preclinical VCI. Deficits are associated with CC injury and inflammation-gliosis but not CA1 cell loss. Increased progenitor cells suggest a potential for carotid reperfusion, cellular and/or growth factor restorative therapy. This VCI model provides an important tool to probe white matter injury, mechanisms and interventions in VCI.