Cerebral blood flow and glucose metabolism in ischemic stroke : multimodal imaging investigations in a clinically relevant rat model

Ischemic stroke is one of the leading causes of death worldwide. Ischemic stroke is also a major cause of long-term disability with vast socioeconomic results for patients, their relatives and health services. Over the last decades, experimental research has resulted in significant progress of our understanding of mechanisms leading to brain injury after ischemic stroke. However, so far, translational research targeting these mechanisms has failed. This failure has resulted in a general consensus that a more integrative approach is needed to account for not only neurobiology under ischemia, but also the ischemic impact on the neurovascular interface. Accordingly, new tools for simultaneously imaging and perturbing this interface needs to be established. The aims of the present work were firstly to develop an ischemic stroke model in rats that more closely mimics human stroke. Secondly, our goal was to incorporate the model with perfusion- and metabolic imaging using high-field magnetic resonance imaging (HF-MRI) and positron emission tomography (PET). Finally we wanted to apply the model in a treatment study targeting the neurovascular interface, and use HF-MRI and PET to assess treatment outcome. We translated endovascular techniques from bedside to bench in the interest of realizing a new rat model for focal cerebral ischemia, in which a microwire is navigated under X-ray fluoroscopy to an occluding position in the middle cerebral artery (MCA). Furthermore, we were able to use the endovascular technique to facilitate intra-arterial microcatheter access to the cerebrovascular system in the rat accommodating injections with varying degree of selectivity. Next, we established protocols for HF-MRI and PET to obtain imaging of pathophysiological events following acute and subacute ischemic stroke. Finally we applied the aforementioned techniques in a treatment study targeting vascular endothelial growth factor B (VEGF-B) in ischemic stroke. We found that the translation of clinical endovascular techniques to the experimental setting opened up several possibilities to access and perturb the neurovascular interface. In comparison with earlier models for focal stroke in the rat, the model for ischemic stroke presented in Paper I produces an injury and pathophysiology more resembling human stroke. Furthermore, the model showed to be highly compatible with small animal imaging systems with the possibility to occlude the MCA and to inject substances directly to the cerebrovascular supply before, during and after imaging (Paper II). The model also makes it possible to control blood flow during scanning with various modalities. HF-MRI and [2-18F]- 2-Fluoro-2-deoxy-D-glucose PET investigations of acute ischemia in Paper III provided evidence for hypermetabolism of glucose occurring in parallel with diffusion restriction of brain water, suggesting an extension of the current paradigm of the mechanisms behind infarct-related diffusion restriction of water. In Paper IV, we found that VEGF-B antagonism result in a reduction of stroke volume, indicating a mechanism of action of VEGF-B in ischemic stroke warranting further treatment studies targeting VEGF-B in ischemic stroke

Endovascular thrombectomy for acute ischemic stroke

This review describes the evolution of endovascular treatment for acute ischemic stroke, current state of the art, and the challenges for the next decade. The rapid development of endovascular thrombectomy (EVT), from the first attempts into standard of care on a global scale, is one of the major achievements in modern medicine. It was possible thanks to the establishment of a scientific framework for patient selection, assessment of stroke severity and outcome, technical development by dedicated physicians and the MedTech industry, including noninvasive imaging for patient selection, and radiological outcome evaluation. A series of randomized controlled trials on EVT in addition to intravenous thrombolytics, with overwhelmingly positive results for anterior circulation stroke within 6 h of onset regardless of patient characteristics with a number needed to treat of less than 3 for any positive shift in outcome, paved the way for a rapid introduction of EVT into clinical practice. Within the “extended” time window of 6–24 h, the effect has been even greater for patients with salvageable brain tissue according to perfusion imaging with a number needed to treat below 2. Even so, EVT is only available for a small portion of stroke patients, and successfully recanalized EVT patients do not always achieve excellent functional outcome. The major challenges in the years to come include rapid prehospital detection of stroke symptoms, adequate clinical and radiological diagnosis of severe ischemic stroke cases, enabling effective recanalization by EVT in dedicated angiosuites, followed by personalized post-EVT stroke care

Survival and functional outcome following endovascular thrombectomy for anterior circulation acute ischemic stroke caused by large vessel occlusion in Sweden 2017–2019 : a nationwide, prospective, observational study

Background: Endovascular thrombectomy (EVT) is standard of care for anterior circulation acute ischemic stroke (AIS) caused by large vessel occlusion (LVO), but data on nationwide performance in routine healthcare are sparse. The study aims were to describe EVT patients with LVO AIS, analyze mortality and functional outcome, and compare results with randomized controlled trials (RCTs). Methods: Data from the Riksstroke and the Swedish Endovascular Treatment of Acute Stroke Registry (RSEVAS) on pre-stroke independent patients, with LVO AIS in 2017–2019, defined as occlusion of the intracranial internal carotid artery, or the M1 or M2 segments of the middle cerebral artery, and groin puncture <6 h of onset, were compared to aggregated HERMES collaboration RCT data. We assessed 90-day survival and function, defined by the modified Rankin Scale. Specific analyzes were stratified by occlusion location. Results: In all, 1011/2560 of RSEVAS patients matched RCT inclusion criteria. Compared with RCT data, patients were older (73 vs. 68), fewer received intravenous thrombolysis (63.1% vs. 83%), and M2 occlusions were more common (24.5% vs. 8%). 90-day survival in RSEVAS was 85.3%, 42.8% achieved good outcome and 5% had symptomatic intracerebral hemorrhage (sICH). Corresponding outcomes in RCT data were 84.7% survival, 46% good outcome, and 4.4% sICH. Functional outcome was most favorable following M2 occlusions. Conclusions: EVT patients from our large real-world national dataset differed from RCT patients in several baseline factors including distribution of vascular occlusion site. However, the overall outcome of EVT in our Swedish cohort appeared to well match the pivotal trial findings

Mortality in vitamin K antagonist-related intracerebral bleeding treated with plasma or 4-factor prothrombin complex concentrate

Prothrombin complex concentrates (PCC) can rapidly normalise prolonged prothrombin time, induced by vitamin K antagonists (VKA). We conducted a multicentre retrospective study to investigate whether reversal of VKA coagulopathy with 4-factor PCC improves the survival of patients with VKA-related intracerebral haemorrhage as compared to plasma. We included 135 consecutive patients with VKA-related intracerebral haemorrhage treated either with plasma (mainly in Canada) or 4-factor PCC (The Netherlands and Sweden) for the reversal of VKA. Data on characteristics of the patients and the haemorrhage were collected. The volume of intracerebral haematoma was calculated from the first computed tomography (CT) scan. The unadjusted and adjusted odds ratio (OR) for 30-day all-cause mortality in both treatment groups was compared using logistic regression. Patients who received plasma (n=35, median 4 units) more often had diabetes, antiplatelet therapy, and intraventricular haemorrhage on the initial CT scans than patients who received PCC (n=100, median 22.5 IU/kg [interquartile range 20-26 IU], median of total dose 1,700 IU). The volume of intracerebral haematoma was larger in the plasma-treated group compared to the PCC-treated group (haematoma, mean 64.5 vs 36.0 cm(3); p=0.021). The unadjusted OR for all-cause 30-day mortality in the PCC group was 0.40 (95% confidence interval, 0.18-0.87; p=0.021) compared to the plasma group. After adjusting for the haematoma volume, bleeding localisation and age, the effect of PCC on mortality became non-significant. In conclusion, treatment with 4-factor PCC for VKA reversal in patients with intracerebral haemorrhage does not seem to reduce the 30-day all-cause mortality compared to plasma

Endovascular thrombectomy for anterior circulation stroke beyond 6 hours of onset in Sweden 2015 to 2020 : Rates and outcomes in a nationwide register-based study

Background: Endovascular thrombectomy (EVT) for ischemic stroke (IS) beyond 6 hours has been proven effective in randomized controlled trials. We present data on implementation and outcomes for EVT beyond 6 hours in Sweden. Methods: We included all cases of anterior circulation IS caused by occlusion of the intracranial carotid artery, and the M1 or M2 segment of the middle cerebral artery, registered in two nationwide quality registers for stroke in 2015-2020. Three groups were defined from onset-to-groin-puncture (OTG) time: early window (<6 hours), late window (6-24 hours) known onset, late window last seen well (LSW). Favorable outcome (modified Rankin Scale (mRS) 0-2) and all-cause mortality at 90 days were the main outcomes, and symptomatic intracerebral hemorrhage (sICH) was the safety outcome. Results: Late window EVT increased from 0.3% of all IS in 2015 to 1.8% in 2020, and from 17.4% of all anterior circulation EVTs in 2015 to 32.9% in 2020. Of 2199 patients, 76.9% (n=1690) were early window EVTs and 23.1% late window EVTs (n=509; 141 known onset, 368 LSW). Median age was 73 years, and 46.2% were female, with no differences between groups. Favorable outcome did not differ between groups (early window 42.4%, late window known onset 38.9%, late window LSW 37.3% (p=0.737)) and remained similar when adjusted for baseline differences. sICH rates did not differ (early window 4.0%, late window known onset 2.1%, late window LSW 4.9% (p=0.413)). Conclusion: Late window EVTs have increased substantially over time, and currently account for one third of anterior circulation treatments. Early and late window patients had similar outcomes

The cellular basis of increased PET hypoxia tracer uptake in focal cerebral ischemia with comparison between [¹⁸F]FMISO and [⁶⁴Cu]CuATSM

PET hypoxia imaging can assess tissue viability in acute ischemic stroke (AIS). [(18)F]FMISO is an established tracer but requires substantial accumulation time, limiting its use in hyperacute AIS. [(64)Cu]CuATSM requires less accumulation time and has shown promise as a hypoxia tracer. We compared these tracers in a M2-occlusion model (M2CAO) with preserved collateral blood flow. Rats underwent M2CAO and [(18)F]FMISO (n = 12) or [(64)Cu]CuATSM (n = 6) examinations. [(64)Cu]CuATSM animals were also examined with MRI. Pimonidazole was used as a surrogate for [(18)F]FMISO in an immunofluorescence analysis employed to profile levels of hypoxia in neurons (NeuN) and astrocytes (GFAP). There was increased [(18)F]FMISO uptake in the M2CAO cortex. No increase in [(64)Cu]CuATSM activity was found. The pimonidazole intensity of neurons and astrocytes was increased in hypoxic regions. The pimonidazole intensity ratio was higher in neurons than in astrocytes. In the majority of animals, immunofluorescence revealed a loss of astrocytes within the core of regions with increased pimonidazole uptake. We conclude that [(18)F]FMISO is superior to [(64)Cu]CuATSM in detecting hypoxia in AIS, consistent with an earlier study. [(18)F]FMISO may provide efficient diagnostic imaging beyond the hyperacute phase. Results do not provide encouragement for the use of [(64)Cu]CuATSM in experimental AIS

Preserved Collateral Blood Flow in the Endovascular M2CAO Model Allows for Clinically Relevant Profiling of Injury Progression in Acute Ischemic Stroke

<div><p>Interventional treatment regimens have increased the demand for accurate understanding of the progression of injury in acute ischemic stroke. However, conventional animal models severely inhibit collateral blood flow and mimic the malignant infarction profile not suitable for treatment. The aim of this study was to provide a clinically relevant profile of the emergence and course of ischemic injury in cases suitable for acute intervention, and was achieved by employing a M2 occlusion model (M2CAO) that more accurately simulates middle cerebral artery (MCA) occlusion in humans. Twenty-five Sprague-Dawley rats were subjected to Short (90 min), Intermediate (180 min) or Extended (600 min) transient M2CAO and examined longitudinally with interleaved diffusion-, T2- and arterial spin labeling perfusion-weighted magnetic resonance imaging before and after reperfusion. We identified a rapid emergence of cytotoxic edema within tissue regions undergoing infarction, progressing in several distinct phases in the form of subsequent moderation and then reversal at 230 min (p < 0.0001). We identified also the early emergence of vasogenic edema, which increased consistently before and after reperfusion (p < 0.0001). The perfusion of the penumbra correlated more strongly to the perfusion of adjacent tissue regions than did the perfusion of regions undergoing infarction (p = 0.0088). This was interpreted as an effect of preserved collateral blood flow during M2CAO. Accordingly, we observed only limited recruitment of penumbra regions to the infarction core. However, a gradual increase in infarction size was still occurring as late as 10 hours after M2CAO. Our results indicate that patients suffering MCA branch occlusion stand to benefit from interventional therapy for an extended time period after the emergence of ischemic injury.</p></div

Evidence-Based Updates to Thrombectomy: Targets, New Techniques, and Devices

10.3389/fneur.2021.712527FRONTIERS IN NEUROLOGY1

The recruitment of the penumbra to the ischemic core.

<p>(A) The progression of absolute growth of the ischemic lesion, defined by the decrease of the apparent diffusion coefficient (ADC), during M2 occlusion (M2CAO), presented as means and standard deviations (SD) for all 25 animals in the Short, Intermediate and Extended M2CAO groups. (B) The growth of the ADC lesion, presented as means and standard deviations of the percentage of the perfusion deficit volume at the initial examination in the Short (n = 4 animals), Intermediate (n = 7) and Extended M2CAO groups (n = 6).</p

Regions of interest (ROIs).

<p>(A) Apparent diffusion coefficient (ADC) maps and (B) T2 weighted images with examples of ADC lesion and T2 lesion ROIs (red). (C) Cerebral blood flow (CBF) maps. (D) CBF maps with ADC overlay. ROIs used to examine the CBF of the Ischemic Core (cyan) were drawn initially in ADC maps at 60 min after reperfusion and subsequently transferred to CBF maps. ROIs delineating the Penumbra (white), regions supplied by the anterior cerebral artery (purple), and regions supplied by the posterior cerebral artery (yellow) were drawn in CBF maps.</p