Relative Recirculation

Wu, Shengping; Thornhill, Rebecca E.; Chen, Shuo; Rammo, W.; Mikulis, David J.; Kassner, Andrea

doi:10.1097/rli.0b013e3181ae9c40

Cited by 34 publications

(15 citation statements)

References 27 publications

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“…(Jin et al, 2012) Animal and human studies found that thrombolysis-associated cerebral hemorrhage occurred in the brain regions where the BBB was compromised. (Bang et al, 2007; Hjort et al, 2008; Hom et al, 2011; Kassner et al, 2009; Sun et al, 2010; Wu et al, 2009) These studies suggest that loss of BBB integrity during cerebral ischemia may predispose ischemic brain tissue to bleeding during reperfusion with thrombolysis. In middle cerebral artery occlusion (MCAO) model, dextran leaks in the ischemic ventromedial striatum and the preoptic area, where high (2000 kDa) and low (70 kDa) molecular weight dextrans displayed almost identical leakage patterns.…”

Section: Introductionmentioning

confidence: 93%

Matrix metalloproteinases as therapeutic targets for stroke

2015

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Matrix metalloproteinases (MMPs) are important in injury and recovery in ischemic injury. They are proteolytic enzymes that degrade all components of the extracellular matrix (ECM). They are secreted in a latent form, protecting the cell from damage, but once activated induce injury prior to rapid inactivation by four tissue inhibitors to metalloproteinases (TIMPs). Normally the constitutive enzymes, MMP-2 and membrane type MMP (MMP-14), are activated in a spatially specific manner and act close to the site of activation, while the inducible enzymes, MMP-3 and MMP-9, become active through the action of free radicals and other enzymes during neuroinflammation. Because of the complex nature of the interactions with tissues during development, injury and repair, the MMPs have multiple roles, participating in the injury process in the early stages and contributing to recovery during the later stages. This dual role complicates the planning of treatment strategies.

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Section: Introductionmentioning

confidence: 93%

Matrix metalloproteinases as therapeutic targets for stroke

2015

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“…For example, measurements derived from the relative-recirculation method were shown to correlate significantly with K trans values derived from a Patlak model applied to DCE-MRI. 39 In the clinical setting, the availability and speed of CT make it the modality of choice when making treatment decisions for AIS. [41][42][43][44] BBB disruption can potentially be assessed by incorporating a DCE-CT protocol into the initial CT imaging of a patient with AIS.…”

Section: Strokementioning

confidence: 99%

“…39,40 Model-free approaches simplify data analysis and may therefore be easier to incorporate into a clinical setting. For example, measurements derived from the relative-recirculation method were shown to correlate significantly with K trans values derived from a Patlak model applied to DCE-MRI.…”

Section: Strokementioning

confidence: 99%

Assessment of Blood–Brain Barrier Disruption in Stroke

Kassner

Merali

2015

Stroke

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123

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T he disease burden of acute ischemic stroke (AIS) is rising in the United States and Canada. It is estimated that in the United States 795 000 people have a stroke each year, which amounts to $34 billion in medical expenses and lost productivity.1 Recent trials have shown the potential benefit of procedural thrombectomy in the management of AIS. 2 However, despite substantial research expenditures over the past 2 decades, there have been no new pharmacological agents for the initial treatment of AIS since the approval of recombinant tissue-type plasminogen activator in 1996. Recently, the role of the blood-brain barrier (BBB) in the pathogenesis of AIS has emerged as a focus for new therapeutic strategies. After the onset of AIS, the BBB is rapidly disrupted and this disruption persists for days through the acute and early subacute phases of AIS. The disruption of the BBB can be quantified as an increase in the permeability of the BBB (Figure 1). 4 In the setting of AIS, disruption of the BBB is thought to be a precursor to serious clinical consequences such as hemorrhagic transformation (HT), 5-7 which refers to the development of a hemorrhage within the ischemic brain tissue. Current research is attempting to elucidate the mechanisms of BBB disruption after AIS and develop therapeutic strategies to mitigate the clinical consequences of BBB disruption.Given these developments, a greater number of preclinical and clinical studies are incorporating assessment of BBB disruption into their study designs. Although assessment of BBB disruption may once have been technically difficult, a plethora of methods now exist to assess BBB disruption with relative ease in animal models and humans. When taken together, these methods cover a wide range of temporal and spatial resolutions and permit simultaneous assessment of cell morphology, protein expression and localization, cell electrophysiology, and gross neurological function. An awareness of the specifications and limitations of the methods of assessing BBB disruption is necessary to design effective studies and evaluate the literature.In the present review, we summarize the available methods of assessing BBB permeability in animal models and humans. We strive to highlight the relative strengths and weaknesses of these methods and provide suggestions for study design in stroke research. Finally, we discuss recent translational developments in assessing BBB disruption for the treatment of AIS. Ex Vivo Assessment of BBB DisruptionThe pioneering experiments of Max Lewandowsky first defined the BBB as a dynamic barrier separating the intravascular and extravascular compartments. This laid the groundwork for current methods of assessing BBB disruption in AIS animal models and human trials.8 All methods of assessing BBB disruption are common in their use of tracers, which can be either endogenous if they are naturally found in the blood or exogenous if introduced into the circulation by the experimenter. Table I in the online-only Data Supplement summarizes methods of ass...

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“…11–14 This concern is emphasized in several scientific articles and might lead physicians to forego tPA treatment, even when appropriate. Although logistical and diagnostic delays are important roadblocks to care, physician fear of hemorrhage remains a major obstacle to tPA treatment for ischemic stroke.…”

mentioning

confidence: 99%

Microbubbles Improve Sonothrombolysis In Vitro and Decrease Hemorrhage In Vivo in a Rabbit Stroke Model

Brown¹,

Flores²,

Hamilton³

et al. 2011

Investigative Radiology

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Introduction Tissue plasminogen activator (tPA) is the thrombolytic standard of care for acute ischemic stroke, but intracerebral hemorrhage (ICH) remains a common and devastating complication. We investigated using ultrasound (US) and microbubble (MB) techniques to reduce required tPA doses and to decrease ICH. Materials and Methods Fresh blood clots (3–5 hours) were exposed in vitro to tPA (0.02 or 0.1 mg/mL) plus pulsed 1 MHz US (0.1 W/cm2), with or without 1.12 × 108/mL MBs (Definity or albumin/dextrose MBs [adMB]). Clot mass loss was measured to quantify thrombolysis. New Zealand white rabbits (n = 120) received one 3- to 5-hour clot angiographically delivered into the internal carotid artery. All had transcutaneous pulsed 1 MHz US (0.8 W/cm2) for 60 minutes and intravenous tPA (0.1– 0.9 mg/kg) with or without Definity MBs (0.16 mL/mg/kg). After killing the animals, the brains were removed for histology 24 hours later. Results In vitro, MBs (Definity or adMB) increased US-induced clot loss significantly, with or without tPA (P < 0.0001). At 0 and 0.02 mg/mL, tPA clot loss was greater with adMBs compared with Definity (P ≤ 0.05). With MB, the tPA dose was reduced 5-fold with good efficacy. In vivo, both Definity MB and tPA groups had less infarct volume compared with controls at P < 0.0183 and P < 0.0003, respectively. Definity MB+tPA reduces infarct volume compared with controls (P < 0.0001), and ICH incidence outside of strokes was significantly lower (P = 0.005) compared with no MB. However, infarct volume in Definity MB versus tPA was not different at P = 0.19. Conclusion Combining tPAand MB yielded effective loss of clot with very low dose or even no dose tPA, and infarct volumes and ICH were reduced in acute strokes in rabbits. The ability of MBs to reduce tPA requirements may lead to lower rates of hemorrhage in human stroke treatment.

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Relative Recirculation

Cited by 34 publications

References 27 publications

Matrix metalloproteinases as therapeutic targets for stroke

Matrix metalloproteinases as therapeutic targets for stroke

Assessment of Blood–Brain Barrier Disruption in Stroke

Microbubbles Improve Sonothrombolysis In Vitro and Decrease Hemorrhage In Vivo in a Rabbit Stroke Model

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