Micro-Heterogeneity of Flow in a Mouse Model of Chronic Cerebral Hypoperfusion Revealed by Longitudinal Doppler Optical Coherence Tomography and Angiography

Abstract

Although microvascular dysfunction accompanies cognitive decline in aging, vascular dementia, and Alzheimer's disease, tools to study microvasculature longitudinally in vivo are lacking. Here, we use Doppler optical coherence tomography (OCT) and angiography for noninvasive, longitudinal imaging of mice with chronic cerebral hypoperfusion for up to 1 month. In particular, we optimized the OCT angiography method to selectively image red blood cell (RBC)-perfused capillaries, leading to a novel way of assessing capillary supply heterogeneity in vivo. After bilateral common carotid artery stenosis (BCAS), cortical blood flow measured by Doppler OCT dropped to half of baseline throughout the imaged tissue acutely. Microscopic imaging of the capillary bed with OCT angiography further revealed local heterogeneities in cortical flow supply during hypoperfusion. The number of RBC-perfused capillaries decreased, leading to increased oxygen diffusion distances in the days immediately after BCAS. Linear regression showed that RBC-perfused capillary density declined by 0.3% for a drop in flow of 1 mL/100 g per minute, and decreases in RBC-perfused capillary density as high as 25% were observed. Taken together, these results demonstrate the existence of local supply heterogeneity at the capillary level even at nonischemic global flow levels, and demonstrate a novel imaging method to assess this heterogeneity. Keywords: angiography; capillary recruitment; Doppler optical coherence tomography; hypoperfusion; vascular dementia INTRODUCTION Chronic cerebral hypoperfusion induced by small-artery occlusion or critical arterial stenosis is a pathophysiologic hallmark of vascular dementia. Histologically characterized by white matter changes and multifocal infarctions, chronic cerebral hypoperfusion is associated with cognitive decline. 1-3 Rodent models of chronic cerebral hypoperfusion that use common carotid artery stenosis or occlusion mimic many aspects of vascular cognitive impairment in patients, including decreased cerebral blood flow, inflammation and blood-brain barrier abnormalities, brain atrophy, white matter degeneration, decreased metabolism, as well as impaired working memory. 4 Bilateral common carotid artery occlusion has been widely used in the rat to model chronic cerebral hypoperfusion. 5 Recently, mouse bilateral common carotid artery stenosis (BCAS) models have emerged. 6 In these models, although the degree of hypoperfusion is correlated with the extent of ischemic lesions and neurologic impairment, 7 the magnitude of flow reductions after BCAS were moderate at best (~30 to 40%), 8 at least relative to classic ischemic thresholds of 80 to 85%, 9-11 and lasted only a few days before collateral development and recovery of flow. The lack of classic ischemia raises questions about the precise mechanism of tissue loss and cognitive impairment. Previous studies have used laser Doppler Journal of Cerebral Blood

Impaired Collateral Flow Compensation During Chronic Cerebral Hypoperfusion in the Type 2 Diabetic Mice

“…Consistent with our finding, a recent mouse model of bilateral chronic carotid stenosis using a steel coil also detected an immediate reduction of cortical blood flow upon the induction of bilateral CCA stenosis by OCT microangiography, followed by a gradual recovery of flow over the next 27 days 24 . There was no significant decrease in the size of ACA or pOA ipsilateral to occlusion in either strain at one day after CCAO in our study, suggesting the existence of collateral compensation in the anterior circulation likely via cross flow from the contralateral ICA and azygous ACA (murine equivalent of Acom).…”

Gradual common carotid artery occlusion as a novel model for cerebrovascular Hypoperfusion

“…However, a maximum reduction of CBF to approximately 50% of baseline occurred within 2 hours post-surgery, followed by a progressive recovery of CBF to approximately 80% of baseline by day 30 (Shibata et al, 2004). Also, a similar acute reduction of CBF to ~50% of baseline was observed on the first day in other studies (Kitamura, et al, 2016; Srinivasan et al, 2015; Hattori et al, 2016). Growth of collateral vessels occurs only after a few days of hypoperfusion resulting in a recovery of CBF over time (Srinivasan et al, 2015).…”

Micro-computed tomography in murine models of cerebral cavernous malformations as a paradigm for brain disease

“…Other techniques such as high field MRI (Shenkar et al, 2008) and second generation optical coherence tomography (optical frequency domain imaging allowing visualization of the live brain at depths greater than 2 mm) (Lin et al, 2014; Srinivasan et al, 2015) can certainly be applied to image blood vessel pathologies in vivo. In its current use, micro-CT is limited in its ex vivo applications, lacking the possibility of longitudinal monitoring of each single murine model, compared to in vivo MRI.…”