Abstract
Large vessel disease and carotid stenosis are key mechanisms contributing to vascular cognitive impairment (VCI) and dementia. Our previous work, and that of others, using rodent models, demonstrated that bilateral common carotid stenosis (BCAS) leads to cognitive impairment via gradual deterioration of the neuro-glial-vascular unit and accumulation of amyloid-β (Aβ) protein. Since brain-wide drainage pathways (glymphatic) for waste clearance, including Aβ removal, have been implicated in the pathophysiology of VCI via glial mechanisms, we hypothesized that glymphatic function would be impaired in a BCAS model and exacerbated in the presence of Aβ. Male wild-type and Tg-SwDI (model of microvascular amyloid) mice were subjected to BCAS or sham surgery which led to a reduction in cerebral perfusion and impaired spatial learning acquisition and cognitive flexibility. After 3 months survival, glymphatic function was evaluated by cerebrospinal fluid (CSF) fluorescent tracer influx. We demonstrated that BCAS caused a marked regional reduction of CSF tracer influx in the dorsolateral cortex and CA1-DG molecular layer. In parallel to these changes increased reactive astrogliosis was observed post-BCAS. To further investigate the mechanisms that may lead to these changes, we measured the pulsation of cortical vessels. BCAS impaired vascular pulsation in pial arteries in WT and Tg-SwDI mice. Our findings show that BCAS influences VCI and that this is paralleled by impaired glymphatic drainage and reduced vascular pulsation. We propose that these additional targets need to be considered when treating VCI.
Highlights
Cerebral vascular disease (CVD) is a major contributor to vascular cognitive impairment (VCI) and dementia such as Alzheimer’s disease (Gorelick et al, 2011; Montine et al, 2014)
Our work and others using animal models have shown that chronic cerebral hypoperfusion as a result of bilateral carotid stenosis leads to cognitive decline through mechanisms that involve hypoxiainduced white matter damage and gradual deterioration of the neuro-glial-vascular unit including endothelial dysfunction, microvascular inflammation and BBB leakage (Shibata et al, 2004; Holland et al, 2015; Fowler et al, 2017; Kitamura et al, 2017; Roberts et al, 2018)
At the outset of the studies, we determined whether carotid stenosis affected cerebral blood flow (CBF) in Transgenic mouse containing the Swedish (Tg-SwDI) compared to WT mice using arterial spin labeling (ASL)
Summary
Cerebral vascular disease (CVD) is a major contributor to vascular cognitive impairment (VCI) and dementia such as Alzheimer’s disease (Gorelick et al, 2011; Montine et al, 2014). Global reductions in blood flow are associated with increased risk of progression from mild cognitive impairment to dementia suggesting that perfusion plays a key role in disease progression (Alsop et al, 2010; Chao et al, 2010). Reduced cerebral perfusion has been linked to white matter attenuation, a key feature common to both Alzheimer’s disease and dementia associated with CVD (Schuff et al, 2009; Barker et al, 2014). Our work and others using animal models have shown that chronic cerebral hypoperfusion as a result of bilateral carotid stenosis leads to cognitive decline through mechanisms that involve hypoxiainduced white matter damage and gradual deterioration of the neuro-glial-vascular unit including endothelial dysfunction, microvascular inflammation and BBB leakage (Shibata et al, 2004; Holland et al, 2015; Fowler et al, 2017; Kitamura et al, 2017; Roberts et al, 2018). A causal relationship remains a matter of controversy largely due to the cross-sectional nature of clinical studies and, in the few longitudinal studies conducted, reduced blood flow occurs
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