Abstract P740: Late Effects of Bilateral Carotid Artery Stenosis in an Aged Mouse Model

Bilateral carotid artery stenosis (BCAS) or global hypoperfusion is an experimental model of vascular dementia known to effect cognition. Chronic global hypoperfusion increases astrogliosis within the cortex and hippocampus, leading to reduced cognition. It is unknown if global hypoperfusion leads to respiratory deficits that could contribute to cognitive decline. We hypothesized that chronic global hypoperfusion in cerebral blood flow will lead to brain stem gliosis, respiratory dysfunction and progressive cognitive impairment. Female C57Bl/6 mice aged 18 months underwent BCAS (n=8) or sham (n=8) surgery to investigate changes in respiration (frequency, tidal volume, apneas), cognition (y-maze-spatial working memory and fear conditioning-contextual working memory), and changes in cortical and brain stem astrogliosis. Results demonstrated BCAS mice had decreased respiratory frequency and apneas (p<0.05), decreased cognition in both spatial and contextual working memory (p<0.05), and increased astrogliosis (p<0.01) within the cortex and brain stem. To determine if increased astrogliosis within the cortex and brain stem contributes to changes in respiration and delayed cognitive deficits, we administered a TGF-β inhibitor (Gw788388 Hydrate) through an osmotic pump 7 days post-BCAS or sham surgery and followed the mice for 56 days post-surgery. Results demonstrated a reduction in periodic apneas (p<0.01), cognitive deficits (p<0.05), and amelioration in gliosis (p<0.01) when comparing BCAS and sham mice. In conclusion, this study demonstrated global hypoperfusion leads to disrupted respiratory function, late cognitive deficits, and increased brain stem gliosis, that can be rescued through administration of TGF-β inhibitor. Respiratory instability may contribute to post-stroke cognitive deficits, and could be a therapeutic target to improve outcomes in patients with vascular dementia.