Impaired Glymphatic Function and Pulsation Alterations in a Mouse Model of Vascular Cognitive Impairment

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.

Endovascular Treatment of Medial Tentorial Dural Arteriovenous Fistula Through the Dural Branch of the Pial Artery

Background: Tentorial dural arteriovenous fistula is a rare subtype of intracranial dural arteriovenous fistula (DAVF) with a deteriorating natural course, which may be attributed to its pial angioarchitecture. TDAVF often harbors feeders arising from pial arteries (FPAs). Reports have revealed that, if these feeders are not obliterated early, the restricted venous outflow during the embolization process may cause upstream congestion in the fragile pial network, which increases the risk of hemorrhagic complications. Because most reported cases of TDAVF were embolized through feeders from non-pial arteries (FNPAs), little is known of the feasibility of direct embolization through FPAs.Methods: We present three patients with medial TDAVFs that were embolized through the dural branches of the posterior cerebral and superior cerebellar arteries. Findings from brain magnetic resonance imaging, computed tomography, angiography, and clinical outcomes are described. Furthermore, we performed a review of the literature on TDAVFs with FPAs.Results: The fistulas were completely obliterated in two patients; both recovered well with no procedure-related complications. The fistula was nearly obliterated in one patient, who developed left superior cerebellum and midbrain infarct due to the reflux of the embolizer into the left superior cerebellar artery. Including our cases, eight cases of TDAVFs with direct embolization through the FPAs have been reported, and ischemic complications occurred in three (37.5%).Conclusions: Advancing microcatheter tips as close to the fistula point as possible and remaining highly aware of potential embolizer flow back into the pial artery are key factors in achieving successful embolization. Balloon-assisted embolization may be an option for treating TDAVFs with FPAs in the future.

Collateral Supply in Preclinical Cerebral Stroke Models

Enhancing the collateral blood supply during the acute phase of cerebral ischemia may limit both the extension of the core infarct, by rescuing the penumbra area, and the degree of disability. Many imaging techniques have been applied to rodents in preclinical studies, to evaluate the magnitude of collateral blood flow and the time course of responses during the early phase of ischemic stroke. The collateral supply follows several different routes at the base of the brain (the circle of Willis) and its surface (leptomeningeal or pial arteries), corresponding to the proximal and distal collateral pathways, respectively. In this review, we describe and illustrate the cerebral collateral systems and their modifications following pre-Willis or post-Willis occlusion in rodents. We also review the potential pharmaceutical agents for stimulating the collateral blood supply tested to date. The time taken to establish a collateral blood flow supply through the leptomeningeal anastomoses differs between young and adult animals and between different species and genetic backgrounds. Caution is required when transposing preclinical findings to humans, and clinical trials must be performed to check the added value of pharmacological agents for stimulating the collateral blood supply at appropriate time points. However, collateral recruitment appears to be a rapid, beneficial, endogenous mechanism that can be stimulated shortly after artery occlusion. It should be considered a treatment target for use in addition to recanalization strategies.

Hemodynamics of Leptomeningeal Collaterals after Large Vessel Occlusion and Blood Pressure Management with Endovascular Treatment

Endovascular therapy (EVT) is an effective treatment for ischemic stroke due to large vessel occlusion (LVO). Unlike intravenous thrombolysis, EVT enables visualization of the restoration of blood flow, also known as successful reperfusion in real time. However, until successful reperfusion is achieved, the survival of the ischemic brain is mainly dependent on blood flow from the leptomeningeal collaterals (LMC). It plays a critical role in maintaining tissue perfusion after LVO via pre-existing channels between the arborizing pial small arteries or arterioles overlying the cerebral hemispheres. In the ischemic territory where the physiologic cerebral autoregulation is impaired and the pial arteries are maximally dilated within their capacity, the direction and amount of LMC perfusion rely on the systemic perfusion, which can be estimated by measuring blood pressure (BP). After the EVT procedure, treatment focuses on mitigating the risk of hemorrhagic transformation, potentially via BP reduction. Thus, BP management may be a key component of acute care for patients with LVO stroke. However, the guidelines on BP management during and after EVT are limited, mostly due to the scarcity of high-level evidence on this issue. In this review, we aim to summarize the anatomical and physiological characteristics of LMC to maintain cerebral perfusion after acute LVO, along with a landscape summary of the literature on BP management in endovascular treatment. The objective of this review is to describe the mechanistic association between systemic BP and collateral perfusion after LVO and thus provide clinical and research perspectives on this topic.

Amyloid-β disrupts unitary calcium entry through endothelial NMDA receptors in mouse cerebral arteries

Transient increases in intracellular Ca2+ activate endothelium-dependent vasodilatory pathways. This process is impaired in cerebral amyloid angiopathy, where amyloid- β(1-40) accumulates around blood vessels. In neurons, amyloid- β impairs the Ca2+-permeable N-methyl-D-aspartate receptor (NMDAR), a mediator of endothelium-dependent dilation in arteries. We hypothesized that amyloid- β(1-40) reduces NMDAR-elicited Ca2+ signals in mouse cerebral artery endothelial cells, blunting dilation. Cerebral arteries isolated from 4-5 months-old, male and female cdh5:Gcamp8 mice were used for imaging of unitary Ca2+ influx through NMDAR ( NMDAR sparklets) and intracellular Ca2+ transients. The NMDAR agonist NMDA (10 µmol/L) increased frequency of NMDAR sparklets and intracellular Ca2+ transients in endothelial cells; these effects were prevented by NMDAR antagonists D-AP5 and MK-801. Next, we tested if amyloid- β(1-40) impairs NMDAR-elicited Ca2+ transients. Cerebral arteries incubated with amyloid- β(1-40) (5 µmol/L) exhibited reduced NMDAR sparklets and intracellular Ca2+ transients. Lastly, we observed that NMDA-induced dilation of pial arteries is reduced by acute intraluminal amyloid- β(1-40), as well as in a mouse model of Alzheimer’s disease, the 5x-FAD, linked to downregulation of Grin1 mRNA compared to wild-type littermates. These data suggest that endothelial NMDAR mediate dilation via Ca2+-dependent pathways, a process disrupted by amyloid- β(1-40) and impaired in 5x-FAD mice.

Imaging of the pial arterial vasculature of the human brain in vivo using high-resolution 7T time-of-flight angiography

The pial arterial vasculature of the human brain is the only blood supply to the neocortex, but quantitative data on the morphology and topology of these mesoscopic vessels (diameter 50-300 μm) remains scarce. Because it is commonly assumed that blood flow velocities in these vessels are prohibitively slow, non-invasive time-of-flight MRI angiography (TOF-MRA)-which is well-suited to high 3D imaging resolutions-has not been applied to imaging the pial arteries. Here, we provide a theoretical framework that outlines how TOF-MRA can visualize small pial arteries in vivo, by employing extremely small voxels at the size of individual vessels. We then provide evidence for this theory by imaging the pial arteries at 140-μm isotropic resolution using a 7T MRI scanner and prospective motion correction, and show that pial arteries one voxel-width in diameter can be detected. We conclude that imaging pial arteries is not limited by slow blood flow, but instead by achievable image resolution. This study represents the first targeted, comprehensive account of imaging pial arteries in vivo in the human brain. This ultra-high-resolution angiography will enable the characterization of pial vascular anatomy across the brain to investigate patterns of blood supply and relationships between vascular and functional architecture.

Pulsation changes link to impaired glymphatic function in a mouse model of vascular cognitive impairment

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 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 and memory. 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 using two-photon microscopy. BCAS impaired vascular pulsation in pial arteries in WT and Tg-SwDI mice. Since our findings show that BCAS may influence VCI by impaired glymphatic drainage and reduced vascular pulsation we propose that these additional targets need to be considered when treating VCI.