Translational research in stroke: Taking advances in the pathophysiology and treatment of stroke from the experimental setting to clinical trials

Many advances have occurred regarding an increased understanding of the basic pathophysiology of ischemic brain injury that could lead to enhanced therapy for this disorder. Among the more important basic science advances are enhanced knowledge of the components of the ischemic cascade, the phenomenon of ischemic preconditioning, the potential relevance of hibernation, studies on gene expression in ischemic tissue, and imaging identification of the ischemic penumbra. The large number of unsuccessful prior clinical trials with a wide range of purported acute stroke therapies has provided many insights and lessons regarding how to perform better trials in the future. Translating these basic science and clinical trial design advances into effective and safe therapies will require increased interaction and cooperation between basic scientists and clinical researchers.     

New magnetic resonance techniques for evaluating cerebrovascular disease.

Magnetic resonance (MR) imaging of acute stroke has made important contributions to diagnosis. Several novel MR technologies, now in preclinical and clinical development, will contribute to stroke diagnosis and perhaps help to guide therapy. MR angiography is the most clinically advanced new MR technology and offers the clinician a method to image noninvasively the extra- and intracranial vasculature. Diffusion-weighted MR imaging can demonstrate ischemic lesions quantitatively within minutes of onset in experimental stroke models, and human application is proceeding. Perfusion MR studies can reveal the presence or absence of cerebral perfusion in specific arterial territories. MR spectroscopy can assess tissue metabolites in vivo and reveal changes in these metabolites associated with ischemic injury. The combination of these new MR techniques should provide a plethora of information about the extent of ischemic lesions, associated vascular and perfusion deficits, and metabolic consequences. This information will afford the clinician the opportunity to assess and subtype ischemic stroke patients more rapidly and could be used to monitor therapeutic responses.     

Neuroimaging of ischemia and infarction

Since the introduction of thrombolytic therapy as the foundation of acute stroke treatment, neuroimaging has rapidly advanced to empower therapeutic decision making. Diffusion-weighted imaging is the most sensitive and accurate method for stroke detection, and, allied with perfusion-weighted imaging, provides information on the functional status of the ischemic brain. It can also help to identify a response to thrombolytic and neuroprotective therapies. Additionally, multimodal magnetic resonance imaging, including magnetic resonance angiography, offers information on stroke mechanism and pathophysiology that can guide long-term medical management. Multimodal computed tomography is a comprehensive, cost-effective, and safe stroke imaging modality that can be easily implemented in the emergency ward and that offers fast and reliable information with respect to the arterial and functional status of the ischemic brain. Accessibility, contraindications, cost, speed, and individual patient-determined features influence which is the best imaging modality to guide acute stroke management.     

Relationship between magnetic resonance arterial patency and perfusion-diffusion mismatch in acute ischemic stroke and its potential clinical use.

BACKGROUND: In patients with acute ischemic stroke the magnetic resonance (MR) perfusion-diffusion mismatch pattern (perfusion lesion at least 20% larger than the lesion on diffusion-weighted imaging) may indicate ischemically threatened but viable tissue. To our knowledge, the relationship of this MR pattern to serial changes in MR angiography (MRA) has not been reported. OBJECTIVES: To investigate the relationship between MRA changes and patterns of diffusion-weighted imaging and perfusion abnormalities and to determine if the information obtained could be used in clinical management. METHODS: The MR studies of 35 patients who had undergone sequential multimodality MR imaging studies within the first 4 days of stroke were reviewed. All lesions were in the internal carotid artery territory distribution. Magnetic resonance angiographies were read by 2 observers blinded to the clinical data. RESULTS: During the first 24 hours a perfusion-diffusion mismatch was present in 22 (92%) of the 24 patients with an MRA arterial occlusive lesion. (At this time 5 [46%] of the 11 patients with a normal MRA [P =.006] also had a mismatch.) Two to 4 days after stroke, of these 22 patients resolution of the mismatch occurred in 8 (87%) of 9 patients with recanalization on MRA compared with 5 (39%) of 13 patients without arterial recanalization (P =.03). Resolution of mismatch occurred in 3 (60%) of 5 patients with a normal MRA and a mismatch at the first time point. CONCLUSIONS: Concordance between MRA and the MR perfusion-diffusion mismatch pattern provides supportive evidence for an arterial vascular basis for this MR signature in acute stroke. Discordance between MRA lesions and mismatch may result from arterial branch occlusions undetected by MRA or from an alternate mechanism for the mismatch. The MR imaging patterns identified extend our understanding of the pathophysiology of stroke and may contribute to the improvement of stroke management in the future.     

Neuroimaging advances and the transformation of acute stroke care

Neuroimaging techniques have transformed the delivery of stroke care. Multimodal computed tomography and magnetic resonance imaging rapidly illustrate the vascular and parenchymal correlates in acute ischemic and hemorrhagic stroke. Optimal selection of thrombolytic candidates and the characterization of ischemic sequelae may be achieved with imaging. The nature and topography of intracerebral hemorrhage may also be defined. Increasing use of multimodal imaging in acute stroke has expanded our current understanding of stroke pathophysiology and streamlined the care of stroke patients from the hyperacute to chronic phases. The integration of neuroimaging techniques in research studies has elucidated pitfalls in the translation of novel therapy into clinical practice. This review explores the impact of neuroimaging advances in stroke and emphasizes the critical role of these modalities in the care of patients with ischemic and hemorrhagic events.     

MR perfusion imaging in acute ischemic stroke

Magnetic resonance (MR) perfusion imaging offers the potential for measuring brain perfusion in acute stroke patients, at a time when treatment decisions based on these measurements may affect outcomes dramatically. Rapid advancements in both acute stroke therapy and perfusion imaging techniques have resulted in continuing redefinition of the role that perfusion imaging should play in patient management. This review discusses the basic pathophysiology of acute stroke, the utility of different kinds of perfusion images, and research on the continually evolving role of MR perfusion imaging in acute stroke care.     

Antithrombotic and hypofibrinogenetic therapy in acute ischemic stroke: what is the next step?

A thrombus occluding a brain artery is the leading mechanism underlying ischemic stroke. In the light of this pathophysiology, antithrombotic therapies have been among the most widely studied and used in the management of patients with ischemic stroke. Aspirin has a significant but modest benefit by reducing recurrent ischemic stroke and death given within 48 h of stroke onset. The use of anticoagulants including heparin, low molecular weight heparin, and heparinoids has not been supported by results of randomized clinical trials. Any reductions in ischemic stroke recurrence were offset by an increase in major bleeding. However, acute anticoagulation is widely used in specific disorders, including patients with high-risk cardiac sources of embolus, arterial dissection, venous sinus thrombosis, and hypercoagulable states. Early recurrent ischemic strokes in patients with atrial fibrillation and acute ischemic stroke have not been shown to be reduced with the heparins, when the effects of major bleeding and hemorrhagic worsening are considered. Recent clinical trials have suggested that other antithrombotic agents may be beneficial in acute ischemic stroke. Two such agents are ancrod and abciximab. Abciximab is currently being investigated in a large randomized clinical trial.     

Unenhanced CT and acute stroke physiology

Unenhanced CT remains the most widely used imaging technique and is the standard of care for acute stroke evaluation. Early ischemic signs (EIS) within the first 3 to 6 hours of symptom onset (eg, parenchymal hypodensity, sulcal effacement, and dense vessel) have been advocated as a triage tool for thrombolytic therapy. Recent studies have challenged the relevance of these EIS within 3 hours of stroke onset, with advanced MR and CT methods increasingly competing with unenhanced CT as the primary imaging modality for acute ischemia. Nonetheless, the insights regarding acute stroke physiology provided by studying the CT evolution of early ischemic signs continue to be valuable for the informed interpretation of all stroke images. It is these insights that comprise the topic of this article.     

Diffusion MR imaging of acute ischemic stroke

Diffusion MR imaging provides unique information about the physiologic state of ischemic tissue. It is highly sensitive and specific in the detection of acute and hyperacute ischemic stroke and has greatly improved the diagnosis and treatment of acute stroke. The DWI abnormality provides information about clinical outcome and final infarct size. Diffusion combined with perfusion MR imaging provides information about the operational ischemic penumbra and final infarct size. Diffusion MR imaging seems to be promising in the evaluation of candidates for thrombolysis.     

Imaging of brain ischemia

The extent of the penumbra and the core of an acute ischemic stroke influence, at the given time, the impact of the recanalization of the occluded vessel on the outcome. Research studies have demonstrated that quantitative MR diffusion imaging and, to a lesser extent, CT perfusion (CTP) could provide an acceptable estimation of the size of the core, while perfusion imaging thresholds could outline critically hypoperfused regions. Several software programs now automatically process reliable quantitative diffusion-weighted imaging (DWI) and perfusion maps in real time, making them available for clinical routine. Studies investigating whether acute MRI profile could select patient for acute recanalization after the 4.5 h time window approved for rtPA administration are ongoing. Transient ischemic attack (TIA) is a major risk factor for stroke but its clinical diagnosis is difficult. MRI can confirm the ischemic nature of transient neurological symptoms among 50% of the patients and the presence of an acute diffusion lesion is an independent risk factor for acute stroke. Multimodal imaging of ischemic stroke and TIA provides a tissue-based characterization of the ischemic lesion that is dramatically influencing the diagnosis and the management of the patients.     

Advanced MR techniques: diffusion MR imaging, perfusion MR imaging, and spectroscopy.

Recent technical advances in MR imaging have enabled the authors to investigate early physiological changes in acute ischemic stroke lesion. Diffusion and perfusion MR imaging can provide clinically useful information not only for early detection of ischemia, but also for prediction of tissue outcome. MR spectroscopy is a potentially powerful tool to study acute stroke, but its clinical value has been limited due to long examination time and low spatial resolution.     

Applications of diffusion-perfusion magnetic resonance imaging in acute ischemic stroke.

Diffusion-weighted imaging (DWI) and perfusion imaging (PI) are two new magnetic resonance technologies that are becoming increasingly available for evaluation of acute ischemic stroke patients. DWI provides information about the location of acute focal ischemic brain injury at early time points and PI can document the presence of disturbances in microcirculatory perfusion. DWI and PI are now being used in clinical practice and in clinical trials of potential acute stroke therapies to assess their utility. In the future, DWI and PI may aid in the development of effective acute stroke therapies and help identify which stroke patients are most likely to benefit from specific agents.     

The use of positron emission tomography in cerebrovascular disease

Even with rapid development of other neuroimaging modalities such as MR imaging and CT, PET is the only technique that provides accurate, quantitative measurements of regional hemodynamics and metabolism in human subjects. Through the use of these combined measurements, we have greatly expanded our knowledge of the pathophysiology of cerebrovascular disease of different types. It has been possible to document the compensatory responses of the brain to reductions in perfusion pressure and to directly relate these responses to prognosis. PET measurements of OEF identify a subgroup of patients who have carotid occlusion and who are at increased risk for recurrent stroke who cannot be identified by any other clinical or arteriographic means. These measurements of OEF are being used to identify high-risk patients for inclusion in a clinical trial to assess the efficacy of surgical revascularization in reducing the subsequence of ipsilateral ischemic stroke. In acute ischemic stroke, attempts have been made to define the "ischemic penumbra" and to predict tissue viability and clinical outcome, although the reliability of PET markers of ischemia in distinguishing viable from irreversibly damaged tissue needs to be confirmed with independent data sets. Much work has been devoted to the investigation of the metabolic effects of infarcts and hemorrhages on remote areas of the brain; the clinical importance of such findings appears to be minimal. Early studies of recovery from stroke suggested functional reorganization of the brain, but further investigations with more rigorous experimental design need to be performed. Given the case of performing such studies with functional MR imaging, it is likely that this technology will supplant PET for this specific indication. The importance of ischemia as a secondary mechanism of brain injury has been addressed in ICH and SAH. PET demonstrated that hematomas exert a primary depression of metabolism rather than inducing ischemia in the surrounding tissue. It also documented the integrity of autoregulation and provided clinically useful information regarding the safety of blood pressure reduction after ICH. Studies in SAH have differentiated the primary effects of the hemorrhage on cerebral hemodynamics and metabolism from those of vasospasm. PET studies are time-consuming, expensive, and require extensive facilities and technical support. In the field of cerebrovascular disease, PET has served as a specialized research tool at a few centers to help elucidate the pathophysiology of stroke. Up until now, however, PET scans in individual patients have not been demonstrated to be necessary for making patient care decisions. Whether the role of PET expands to impact the management of individual patients will depend on the results of investigations like the Carotid Occlusion Surgery Study that directly assess the ability of PET to influence patient outcome.     

New perspectives on developing acute stroke therapy

The development of additional acute stroke therapies to complement and supplement intravenous recombinant tissue-type plasminogen activator within the first 3 hours after stroke onset remains an important and pressing need. Much has been learned about the presumed target of acute stroke therapy, the ischemic penumbra, and clinically available imaging modalities such as magnetic resonance imaging and computed tomography hold great promise for at least partially identifying this region of potentially salvageable ischemic tissue. Understanding the biology of ischemia-related cell injury has also evolved rapidly. New treatment approaches to improve outcome after focal brain ischemia will likely be derived by looking at naturally occurring adaptive mechanisms such as those related to ischemic preconditioning and hibernation. Many clinical trials previously performed with a variety of neuroprotective and thrombolytic drugs provide many lessons that will help to guide future acute stroke therapy trials and enhance the likelihood of success in future trials. Combining knowledge from these three areas provides optimism that additional acute stroke therapies can be developed to maximize beneficial functional outcome in the greatest proportion of acute stroke patients possible.     

The ischemic penumbra: a new opportunity for neuroprotection

The development of acute stroke therapies has yielded only limited success and many failures in multiple clinical trials. The target of acute stroke therapy is that portion of the ischemic region that is still potentially salvageable, i.e. the ischemic penumbra. Neuroprotective drugs have the potential to prevent a portion of the ischemic penumbra from evolving into infracted tissue and designing trials that target neuroprotective drugs at patients with persistent penumbra should enhance the likelihood of a positive outcome. Currently, diffusion and perfusion MRI has the potential to approximate the location and persistence of the ischemic penumbra and can be used in clinical trials to select appropriate patients for inclusion and to evaluate a meaningful treatment effect. Perfusion CT may also have similar capabilities. Use of these imaging modalities in clinical trials and ultimately in clinical practice will likely help in the development and utilization of novel neuroprotective drugs.     

Clot composition and treatment approach to acute ischemic stroke: The road so far

Recent histological studies of thrombi retrieved from patients with an acute ischemic stroke using the endovascular thrombectomy devices and correlation with early vessel computed tomography (CT) and magnetic resonance imaging (MRI) characteristics have given relevant insights into the pathophysiology of thrombotic lesions and may facilitate the development of improved reperfusion treatment approaches. We present a review of recent studies on the histopathologic analysis of thrombi, studies of MRI, and CT imaging correlation with thrombus histology, and detailed structural analysis of thromboemboli retrieved by thrombectomy devices during an acute ischemic stroke.Key Words: Clot composition, histopathology, stroke, thrombus     

急性缺血性卒中血管内治疗筛选病例的研究进展

急性缺血性卒中发病率呈逐年上升趋势,并且具有很高的致残率和致死率。由于静脉阿替普酶溶栓治疗急性缺血性卒中的局限性,2015年以来5大临床前瞻随机双盲多中心临床研究证实新一代血管再通策略（主要是可回收支架）在大血管闭塞导致的急性缺血性卒中明显优于单独内科治疗,各国脑卒中指南也相应进行更新。本文围绕5大临床研究及欧洲、美国最新指南中关于筛选合适卒中患者进行机械取栓的研究进展综述如下。     

Update on stroke

PURPOSE OF REVIEW: This review highlights some advances in the areas of epidemiology, therapy, and imaging of acute stroke. RECENT FINDINGS: Studies published in 2003 provided new insights into the epidemiology of stroke. The African American Antiplatelet Stroke Prevention Study found that traditional stroke risk factors are still undiagnosed and undertreated, particularly in minorities. Cohort studies have identified incident silent infarcts as risk factors for stroke and history of type I diabetes as a risk factor for death in patients with acute stroke. Cervical artery dissection, on the other hand, seems to have a benign course. Imaging has become an important tool for understanding the pathophysiology of stroke, as demonstrated in recent publications. New studies have shown the prognostic value of magnetic resonance imaging: it can predict the volume of ischemic tissue that will progress to infarction and detects cerebral microbleeds - a risk factor for intracranial hemorrhage. Computed tomographic scanning may have a role in selecting patients for thrombolysis, particularly when validated scales are used. Despite the barriers to the use of tissue plasminogen activator in the treatment of patients with stroke, data published this year show that it is a safe medication when used routinely in community and university hospitals. In addition to thrombolysis, other general medical measures, such as glucose control and adequate attention to nutritional status, can help improve the outcome of patients with stroke. SUMMARY: In acute stroke, recognition and modification of risk factors continue to be challenging tasks. Treatment of acute stroke should involve thrombolysis and attention to medical conditions that may influence outcome. New applications of magnetic resonance imaging and computed tomography may help guide stroke therapy.     

Clinical applications of diffusion MR imaging for acute ischemic stroke

Diffusion magnetic resonance imaging is the best imaging tool for detecting acute ischemic brain injury. Studies have shown its high accuracy for delineating irreversible tissue damage within the first few hours after stroke onset; however, the true value of any diagnostic tool is whether it can be used to guide clinical management. This review discusses the role of diffusion imaging in the evaluation of the patient with acute ischemic stroke, and how this role is influenced by other important stroke-related variables, including the level of vessel occlusion and the clinical deficit. The review focuses on decision-making for intravenous and intra-arterial reperfusion therapies.     

磁共振斑块成像与缺血性卒中的相关性研究进展

动脉粥样硬化易损斑块破裂是导致缺血性卒中的主要原因。与组织病理学对照研究证实,
高分辨率磁共振成像可以无创性评价动脉粥样硬化斑块的负荷、成分及其易损性。大量研究显示,
脑血管粥样硬化斑块的磁共振表现特征与缺血性卒中具有明显的相关性。本文将从磁共振斑块成
分特征与缺血性脑血管事件的相关性方面进行综述,为缺血性卒中的病因学诊断和疾病的预防提供
重要依据。