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A non-human primate model of stroke reproducing endovascular thrombectomy and allowing long-term imaging and neurological read-outs.

ABSTRACT: Stroke is a devastating disease. Endovascular mechanical thrombectomy is dramatically changing the management of acute ischemic stroke, raising new challenges regarding brain outcome and opening up new avenues for brain protection. In this context, relevant experiment models are required for testing new therapies and addressing important questions about infarct progression despite successful recanalization, reversibility of ischemic lesions, blood-brain barrier disruption and reperfusion damage. Here, we developed a minimally invasive non-human primate model of cerebral ischemia (Macaca fascicularis) based on an endovascular transient occlusion and recanalization of the middle cerebral artery (MCA). We evaluated per-occlusion and post-recanalization impairment on PET-MRI, in addition to acute and chronic neuro-functional assessment. Voxel-based analyses between per-occlusion PET-MRI and day-7 MRI showed two different patterns of lesion evolution: "symptomatic salvaged tissue" (SST) and "asymptomatic infarcted tissue" (AIT). Extended SST was present in all cases. AIT, remote from the area at risk, represented 45% of the final lesion. This model also expresses both worsening of fine motor skills and dysexecutive behavior over the chronic post-stroke period, a result in agreement with cortical-subcortical lesions. We thus fully characterized an original translational model of ischemia-reperfusion damage after stroke, with consistent ischemia time, and thrombus retrieval for effective recanalization.

SUBMITTER: Debatisse J

PROVIDER: S-EPMC7983495 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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A non-human primate model of stroke reproducing endovascular thrombectomy and allowing long-term imaging and neurological read-outs.

Debatisse Justine J Wateau Océane O Cho Tae-Hee TH Costes Nicolas N Mérida Inés I Léon Christelle C Langlois Jean-Baptiste JB Taborik Fabrice F Verset Michaël M Portier Karine K Aggour Mohamed M Troalen Thomas T Villien Marjorie M Makris Nikolaos N Tourvieille Christian C Bars Didier Le DL Lancelot Sophie S Confais Joachim J Oudotte Adrien A Nighoghossian Norbert N Ovize Michel M Vivien Denis D Contamin Hugues H Agin Véronique V Canet-Soulas Emmanuelle E Eker Omer Faruk OF

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20200519 4

Stroke is a devastating disease. Endovascular mechanical thrombectomy is dramatically changing the management of acute ischemic stroke, raising new challenges regarding brain outcome and opening up new avenues for brain protection. In this context, relevant experiment models are required for testing new therapies and addressing important questions about infarct progression despite successful recanalization, reversibility of ischemic lesions, blood-brain barrier disruption and reperfusion damage. ...[more]

PMID: 32428423

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Project description:Background and purpose: Rodent models have demonstrated the key pathogenic role of the lectin pathway (LP) of complement activation in brain ischemic injury. Here we assessed the LP activation and its association with stroke severity and outcome in a well-characterized model of stroke mimicking mechanical thrombectomy in non-human primates. Methods: Transient middle cerebral artery occlusion was performed in Macaca fascicularis randomly allocated in cyclosporine A or placebo group. Neurological status was serially assessed. The occlusion lesion, the ischemic penumbra, the final lesion, the lesion growth between occlusion and day 7 as well as the blood-brain barrier permeability using quantitative transfer constant Ktrans ratio and inflammation by quantitative [11C]PK11195 imaging were assessed using positron emission tomography–magnetic resonance (PET-MRI) imaging. Functional residual LP-specific C3b deposition assay was performed in plasma. C3b/iC3b, mannose binding lectin (MBL), MBL associated serine proteases-2 (MASP-2) and interleukin-6 were measured in plasma, cerebrospinal fluid and brain homogenates. Brain tissue was used to perform immunofluorescence and confocal analyses (C3b/iC3b, MBL and MASP-2 and glycocalyx) as well as transcriptomic analysis. Results: Twenty-three subjects were included with a mean age of 6.7 +/- 0.5 years. LP residual activation in plasma collected late after recanalization was significantly decreased compared to baseline conditions. C3b/iC3b peaked at day 7 and this increase correlated with a more severe neurological deficit at day 1 and day 7, a larger final lesion and lesion growth volumes as well as a greater Ktrans ratio. C3b/iC3b, MBL and MASP-2 were found in microvascular thrombi at day 30. At this time point, 760 genes were differentially expressed within the lesion, including 13 LP-related genes. Conclusions: Our results support that the LP of complement activation is involved in thromboinflammation in a non-human primate model of stroke mimicking mechanical thrombectomy in humans.

Project description:BACKGROUND AND PURPOSE:Mechanical thrombectomy in acute ischemic stroke within 6 hours of symptom onset is effective and safe. However, in many patients, information on the beginning of symptoms is not available. Patients can be divided into those with wake-up stroke and daytime-unwitnessed stroke. Evidence on outcome and complications after mechanical thrombectomy in wake-up stroke and daytime-unwitnessed stroke is rare. A potential beneficial effect of mechanical thrombectomy in selected patients with wake-up stroke or daytime-unwitnessed stroke is suspected. MATERIALS AND METHODS:We analyzed 1073 patients with anterior circulation stroke undergoing mechanical thrombectomy between 2010 and 2016. Patients with wake-up stroke and daytime-unwitnessed stroke were compared with controls receiving mechanical thrombectomy as the standard of care. We assessed good functional outcome (mRS ≤ 2 at 3 months), mortality rates, and frequencies of symptomatic intracranial hemorrhage. Subgroup analyses tried to detect influences of patient selection via further imaging modalities (MR imaging, CTP; wake-up stroke [advanced], daytime-unwitnessed stroke [advanced]) on outcome and safety. RESULTS:There was no significant difference in good functional outcome between patients with wake-up stroke and controls (35.9% versus 38.3%, P = .625). Outcome in patients with daytime-unwitnessed stroke was inferior compared with controls (27.3%, P = .007). Groups did not differ in all-cause mortality at day 90 (P = .224) and the rate of symptomatic intracranial hemorrhage (P = .292). Advanced imaging improved the frequency of good functional outcome (non-wake-up stroke [advanced] versus wake-up stroke [advanced]: OR, 2.92; 95% CI, 1.32-6.45; non-daytime-unwitnessed stroke [advanced] versus daytime-unwitnessed stroke [advanced]: OR, 2.09; 95% CI, 1.03-4.25) with an additional reduction in all-cause mortality (non-daytime-unwitnessed stroke [advanced] versus daytime-unwitnessed stroke [advanced]: OR, 0.42; 95% CI, 0.20-0.88). CONCLUSIONS:Mechanical thrombectomy in selected patients with wake-up stroke allows a good functional outcome comparable with that of controls. Outcome after mechanical thrombectomy in daytime-unwitnessed stroke seems to be inferior compared with that in controls. Advanced imaging modalities may increase the frequency of good functional outcome in both patients with wake-up stroke and daytime-unwitnessed stroke.

Project description:BackgroundRecent randomized trials have suggested that endovascular thrombectomy (EVT) alone may provide similar functional outcomes as the current standard of care, EVT combined with intravenous alteplase treatment, for acute ischemic stroke secondary to large vessel occlusion. We conducted an economic evaluation of these 2 therapeutic options.MethodsWe constructed a decision analytic model with a hypothetical cohort of 1000 patients to assess the cost-effectiveness of EVT with intravenous alteplase treatment versus EVT alone for acute ischemic stroke secondary to large vessel occlusion from both the societal and public health care payer perspectives. We used studies and data published in 2009-2021 for model inputs, and acquired cost data for Canada and China, representing high- and middle-income countries, respectively. We calculated incremental cost-effectiveness ratios (ICERs) using a lifetime horizon and accounted for uncertainty using 1-way and probabilistic sensitivity analyses. All costs are reported in 2021 Canadian dollars.ResultsIn Canada, the difference in quality-adjusted life-years (QALYs) gained between EVT with alteplase and EVT alone was 0.10 from both the societal and health care payer perspectives. The difference in cost was $2847 from a societal perspective and $2767 from the payer perspective. In China, the difference in QALYs gained was 0.07 from both perspectives, and the difference in cost was $1550 from the societal perspective and $1607 from the payer perspective. One-way sensitivity analyses showed that the distributions of modified Rankin Scale scores at 90 days after stroke were the most influential factor on ICERs. For Canada, compared to EVT alone, the probability that EVT with alteplase would be cost-effective at a willingness-to-pay threshold of $50 000 per QALY gained was 58.7% from a societal perspective and 58.4% from a payer perspective. The corresponding values for at a willingness-to-pay threshold of $47 185 (3 times the Chinese gross domestic product per capita in 2021) were 65.2% and 67.4%.InterpretationFor patients with acute ischemic stroke due to large vessel occlusion eligible for immediate treatment with both EVT alone and EVT with intravenous alteplase treatment, it is uncertain whether EVT with alteplase is cost-effective compared to EVT alone in Canada and China.

Project description:Endovascular thrombectomy for large vessel ischaemic stroke substantially reduces disability, with recent positive randomised trials leading to guideline changes worldwide. This review discusses in detail the evidence provided by recent randomised trials and meta-analyses, the remaining areas of uncertainty and the future directions for research. The data from existing trials have demonstrated the robust benefit of endovascular thrombectomy for internal carotid and proximal middle cerebral artery occlusions. Uncertainty remains for more distal occlusions where the efficacy of alteplase is greater, less tissue is at risk and the safety of endovascular procedures is less established. Basilar artery occlusion was excluded from the trials, but with a dire natural history and proof of principle that rapid reperfusion is effective, it seems reasonable to continue treating these patients pending ongoing trial results. There has been no evidence of heterogeneity in treatment effect in clinically defined subgroups by age, indeed, those aged >80 years have at least as great an overall reduction in disability and reduced mortality. Similarly there was no heterogeneity across the range of baseline stroke severities included in the trials. Evidence that routine use of general anaesthesia reduces the benefit of endovascular thrombectomy is increasing and conscious sedation is generally preferred unless severe agitation or airway compromise is present. The impact of time delays has become clearer with description of onset to imaging and imaging to reperfusion epochs. Delays in the onset to imaging reduce the proportion of patients with salvageable brain tissue. However, in the presence of favourable imaging, rapid treatment appears beneficial regardless of the onset to imaging time elapsed. Imaging to reperfusion delays lead to decay in the clinical benefit achieved, particularly in those with less robust collateral flow. The brain imaging options to assess prognosis have various advantages and disadvantages, but whatever strategy is employed must be fast. Ongoing trials are investigating extended time windows, using advanced brain imaging selection. There is also a need for further technical advances to maximise rates of complete reperfusion in the minimum time.

Project description:BackgroundMost disabling strokes are due to a blockage of a large artery in the brain by a blood clot. Prompt removal of the clot with intra-arterial thrombolytic drugs or mechanical devices, or both, can restore blood flow before major brain damage has occurred, leading to improved recovery. However, these so-called endovascular interventions can cause bleeding in the brain. This is a review of randomised controlled trials of endovascular thrombectomy or intra-arterial thrombolysis, or both, for acute ischaemic stroke.ObjectivesTo assess whether endovascular thrombectomy or intra-arterial interventions, or both, plus medical treatment are superior to medical treatment alone in people with acute ischaemic stroke.Search methodsWe searched the Trials Registers of the Cochrane Stroke Group and Cochrane Vascular Group (last searched 1 September 2020), CENTRAL (the Cochrane Library, 1 September 2020), MEDLINE (May 2010 to 1 September 2020), and Embase (May 2010 to 1 September 2020). We also searched trials registers, screened reference lists, and contacted researchers.Selection criteriaRandomised controlled trials (RCTs) of any endovascular intervention plus medical treatment compared with medical treatment alone in people with definite ischaemic stroke.Data collection and analysisTwo review authors (MBR and MJ) applied the inclusion criteria, extracted data, and assessed trial quality. Two review authors (MBR and HL) assessed risk of bias, and the certainty of the evidence using GRADE. We obtained both published and unpublished data if available. Our primary outcome was favourable functional outcome at the end of the scheduled follow-up period, defined as a modified Rankin Scale score of 0 to 2. Eighteen trials (i.e. all but one included trial) reported their outcome at 90 days. Secondary outcomes were death from all causes at in the acute phase and by the end of follow-up, symptomatic intracranial haemorrhage in the acute phase and by the end of follow-up, neurological status at the end of follow-up, and degree of recanalisation.Main resultsWe included 19 studies with a total of 3793 participants. The majority of participants had large artery occlusion in the anterior circulation, and were treated within six hours of symptom onset with endovascular thrombectomy. Treatment increased the chance of achieving a good functional outcome, defined as a modified Rankin Scale score of 0 to 2: risk ratio (RR) 1.50 (95% confidence interval (CI) 1.37 to 1.63; 3715 participants, 18 RCTs; high-certainty evidence). Treatment also reduced the risk of death at end of follow-up: RR 0.85 (95% CI 0.75 to 0.97; 3793 participants, 19 RCTs; high-certainty evidence) without increasing the risk of symptomatic intracranial haemorrhage in the acute phase: RR 1.46 (95% CI 0.91 to 2.36; 1559 participants, 6 RCTs; high-certainty evidence) or by end of follow-up: RR 1.05 (95% CI 0.72 to 1.52; 1752 participants, 10 RCTs; high-certainty evidence); however, the wide confidence intervals preclude any firm conclusion. Neurological recovery to National Institutes of Health Stroke Scale (NIHSS) score 0 to 1 and degree of recanalisation rates were better in the treatment group: RR 2.03 (95% CI 1.21 to 3.40; 334 participants, 3 RCTs; high-certainty evidence) and RR 3.11 (95% CI 2.18 to 4.42; 268 participants, 3 RCTs; high-certainty evidence), respectively.Authors' conclusionsIn individuals with acute ischaemic stroke due to large artery occlusion in the anterior circulation, endovascular thrombectomy can increase the chance of survival with a good functional outcome without increasing the risk of intracerebral haemorrhage or death.

Project description:Background and purposeUsing post-treatment methods to predict functional outcomes of acute ischemic stroke (AIS) patients undergoing endovascular thrombectomy (EVT) is crucial in stroke medicine. The National Institute of Health Stroke Scale (NIHSS) score at 24 h has been widely used; however, there is a paucity of data on using earlier NIHSS scores and their association with outcome. In this study, we aimed to investigate the usage of NIHSS at 1-h time window -ultra-early neurological improvement (UENI)- as a surrogate marker associated with the functional outcomes of AIS patients treated with EVT.MethodsWe included 485 adults (≥18 years old) who underwent emergency EVT at four academic comprehensive stroke centers between 2020 and 2021. Patients with pre-EVT Alberta Stroke Program Early CT Score (ASPECTS) < 6, missing follow-up data, and missing data of the first hour NIHSS were excluded (n = 20). UENI was defined as post-EVT NIHSS reduction of 4 points or more or NIHSS as 0-1 within 1-h post-EVT. An mRS score of 0-2 after three months was defined as favorable outcome, and independent walking independence was defined as mRS of 3.ResultsA total of 465 patients were included in our final analysis. We identified 122 (26.2%) patients with UENI. While 82.79% of the patients with UENI achieved favorable functional outcomes at 3-months, only 32.36% of patients without UENI had favorable functional outcome (p < 0.0001). In addition, lower hospitalization costs were associated with patients who had UENI, compared to No-UENI (p = 0.003). A multivariate logistic regression analysis revealed that younger age (p < 0.0001), shorter last know normal to puncture time (LKNPT) (p = 0.013), higher pre-treatment ASPECTS (p = 0.039), final modified thrombolysis in cerebral infarction (mTICI) ≥2b (p = 0.002), and fewer number of EVT attempts (p = 0.002) were variables independently associated with UENI. The presence of UENI was independently associated with a better outcome OR: 7.999 (95% C.I. 4.415-14.495).ConclusionUENI was observed in about a quarter of patients with AIS undergoing EVT. Younger age, shorter LKNPT, higher pre-treatment ASPECTS, final mTICI≥2b, and fewer number of EVT attempts, were independently associated with UENI. The presence of UENI was independently associated with better functional outcome at 3 months.

Dataset Information

A non-human primate model of stroke reproducing endovascular thrombectomy and allowing long-term imaging and neurological read-outs.

Publications

A non-human primate model of stroke reproducing endovascular thrombectomy and allowing long-term imaging and neurological read-outs.

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