New Concept in Stroke Diagnosis

Stroke is a life-threatening event that is expected to more than double over the next 40 years. Approximately 85% of strokes are ischemic in nature and result from thromboembolic occlusion of a major cerebral artery or its branches. One of the diagnostic methods for detection of the cerebral ischemia is the gadolinium-enhanced MRI imaging. It is mainly used in patients to detect brain tissue damaged by an ischemic stroke and brain hemorrhage. These techniques are expensive, require sophisticated machines and are time consuming. A recent study in acute stroke patients showed gadolinium leakage into ocular structures (GLOS) during MRI imaging with gadolinium administration. The results indicate that at 2 hours after administration of the contrast agent, GLOS was more common in the aqueous chamber alone, compared to the vitreous chamber with increasing amount in 24 hours after the administration of the contrast agent. This could be due to disruption of blood-ocular barrier similar to the disruption of blood-brain barrier in acute stroke. A new approach to diagnosis of acute stroke and transient ischemic attack (TIA) is through the detection of sodium fluorescein contrast agent in the eye by i.v. injection. The agent is safe and is used routinely in eye fluorescein angiography. Fluorescein fluorescence occurs at the visible wavelengths and can be detected by fluorescein angiography camera. The fluorescein angiography camera prices are affordable for any medical clinic. The innovation of this method is to leverage the eye as the window to the brain. The method can potentially detect acute stroke and TIA without MRI. This can have a far-reaching impact on the healthcare system. The eventual feature of the device will be portability and simplicity of operation that can be used by a medical technician in medical office, emergency outfits and even in ambulances given the portability.     

The role of polymorphic variants of gene of inducible NO-synthase NOS2 in brain infarction in patients with acute ischemic stroke

Cerebrovascular diseases including stroke are an important problem of public health. Stroke development depends on external factors and individual genetic specificity of patient. Excessive NO production by inducible NO-synthase (iNOS) damages brain tissue at various stages of the disease. The goal of this work was to study the role of 4 polymorphic variants of gene of inducible NO-synthase iNOS (-2447C/G, -1659C/T, -0,7(OTTA)n I/D, S608L (150C/T)) in brain infarction in patients with acute ischemic stroke. A statistically significant correlation between S608L (150C/T) polymorphism and infarction dynamics was observed during days 1-3 and 7-21 after infarction. These parameters correlated with neurological status estimated using the Orgogozo scale during days 1-7 of the disease development. It was demonstrated that genotype N150N was associated with ischemic focus propagation regardless of its volume and neurological status by Orgogozo scale in patients with acute stroke. It was also observed that genotype N150N had effect on ischemic damage during days 1-3 in case of low initial volume.     

The immunology of stroke: from mechanisms to translation

Immunity and inflammation are key elements of the pathobiology of stroke, a devastating illness second only to cardiac ischemia as a cause of death worldwide. The immune system participates in the brain damage produced by ischemia, and the damaged brain, in turn, exerts an immunosuppressive effect that promotes fatal infections that threaten the survival of people after stroke. Inflammatory signaling is involved in all stages of the ischemic cascade, from the early damaging events triggered by arterial occlusion to the late regenerative processes underlying post-ischemic tissue repair. Recent developments have revealed that stroke engages both innate and adaptive immunity. But adaptive immunity triggered by newly exposed brain antigens does not have an impact on the acute phase of the damage. Nevertheless, modulation of adaptive immunity exerts a remarkable protective effect on the ischemic brain and offers the prospect of new stroke therapies. As immunomodulation is not devoid of deleterious side effects, a better understanding of the reciprocal interaction between the immune system and the ischemic brain is essential to harness the full therapeutic potential of the immunology of stroke.     

MRI study on reversible and irreversible electroporation induced blood brain barrier disruption

Electroporation, is known to induce cell membrane permeabilization in the reversible (RE) mode and cell death in the irreversible (IRE) mode. Using an experimental system designed to produce a continuum of IRE followed by RE around a single electrode we used MRI to study the effects of electroporation on the brain. Fifty-four rats were injected with Gd-DOTA and treated with a G25 electrode implanted 5.5 mm deep into the striata. MRI was acquired immediately after treatment, 10 min, 20 min, 30 min, and up to three weeks following the treatment using: T1W, T2W, Gradient echo (GE), serial SPGR (DCE-MRI) with flip angles ranging over 5-25°, and diffusion-weighted MRI (DWMRI). Blood brain barrier (BBB) disruption was depicted as clear enhancement on T1W images. The average signal intensity in the regions of T1-enhancement, representing BBB disruption, increased from 1887±83 (arbitrary units) immediately post treatment to 2246±94 20 min post treatment, then reached a plateau towards the 30 min scan where it reached 2289±87. DWMRI at 30 min showed no significant effects. Early treatment effects and late irreversible damage were clearly depicted on T2W. The enhancing volume on T2W has increased by an average of 2.27±0.27 in the first 24-48 hours post treatment, suggesting an inflammatory tissue response. The permanent tissue damage, depicted as an enhancing region on T2W, 3 weeks post treatment, decreased to an average of 50±10% of the T2W enhancing volumes on the day of the treatment which was 33±5% of the BBB disruption volume. Permanent tissue damage was significantly smaller than the volume of BBB disruption, suggesting, that BBB disruption is associated with RE while tissue damage with IRE. These results demonstrate the feasibility of applying reversible and irreversible electroporation for transient BBB disruption or permanent damage, respectively, and applying MRI for planning/monitoring disruption volume/shape by optimizing electrode positions and treatment parameters.     

Cell Treatment for Stroke in Type Two Diabetic Rats Improves Vascular Permeability Measured by MRI

Treatment of stroke with bone marrow stromal cells (BMSC) significantly enhances brain remodeling and improves neurological function in non-diabetic stroke rats. Diabetes is a major risk factor for stroke and induces neurovascular changes which may impact stroke therapy. Thus, it is necessary to test our hypothesis that the treatment of stroke with BMSC has therapeutic efficacy in the most common form of diabetes, type 2 diabetes mellitus (T2DM). T2DM was induced in adult male Wistar rats by administration of a high fat diet in combination with a single intraperitoneal injection (35mg/kg) of streptozotocin. These rats were then subjected to 2h of middle cerebral artery occlusion (MCAo). T2DM rats received BMSC (5x10⁶, n = 8) or an equal volume of phosphate-buffered saline (PBS) (n = 8) via tail-vein injection at 3 days after MCAo. MRI was performed one day and then weekly for 5 weeks post MCAo for all rats. Compared with vehicle treated control T2DM rats, BMSC treatment of stroke in T2DM rats significantly (p<0.05) decreased blood-brain barrier disruption starting at 1 week post stroke measured using contrast enhanced T₁-weighted imaging with gadopentetate, and reduced cerebral hemorrhagic spots starting at 3 weeks post stroke measured using susceptibility weighted imaging, although BMSC treatment did not reduce the ischemic lesion volumes as demarcated by T₂ maps. These MRI measurements were consistent with histological data. Thus, BMSC treatment of stroke in T2DM rats initiated at 3 days after stroke significantly reduced ischemic vascular damage, although BMSC treatment did not change infarction volume in T2DM rats, measured by MRI.     

Visualization of irreparable ischemic damage in brain by selective labeling of double strand blunt-ended DNA breaks

BACKGROUND: Double-strand DNA breaks with blunt ends represent the most serious type of DNA damage, and cannot be efficiently repaired by cells. They are generated in apoptosis or necrosis and are absent in normal or transiently damaged cells. Consequently, they can be used as a molecular marker of irreparable cellular damage. We evaluated the effects of focal brain ischemia using selective labeling of blunt-ended DNA breaks as a marker of irreversible tissue damage. A new approach permitting such analysis in situ is introduced. MATERIALS AND METHODS: Rat brain sections taken 6, 24, 48 and 72 hr after the onset of focal brain ischemia were used. Double-strand DNA breaks were detected directly in the tissue sections via ligation of blunt-ended hairpin-shaped oligonucleotide probes. The probes were attached to the ends of the breaks by T4 DNA ligase. Conventional cresyl violet co-staining and terminal transferase based labeling (TUNEL) were employed to analyze the distribution of labeled cells. RESULTS: Double-strand blunt-ended DNA breaks rapidly accumulate in brain cells after focal brain ischemia. At 24 hr, they concentrate in the peripheral areas of stroke, which are prone to ischemia-reoxygenation. By 48-72 hr, this type of DNA damage spreads inward, covering the internal areas of the ischemic zone. CONCLUSIONS: Selective labeling of blunt-ended DNA breaks delineates the dynamics of stroke-induced irreversible DNA damage and provides highly specific detection of brain cells with irreparable DNA injury. It can be used for comparing the efficiency of various anti-ischemic drugs, particularly those that target DNA damage, as well as for monitoring stroke-induced damage.     

MRI Features in a Canine Model of Ischemic Stroke: Correlation between Lesion Volume and Neurobehavioral Status during the Subacute Stage

The purpose of this study was to evaluate the diagnostic value of magnetic resonance imaging (MRI) and assess the correlation between the volume of the ischemic lesion and neurobehavioral status during the subacute stage of ischemic stroke. Ischemic stroke was induced in 6 healthy laboratory beagles through permanent occlusion of the middle cerebral artery (MCAO). T2-weighted and fluid-attenuated inversion recovery (FLAIR) imaging, diffusion-weighted imaging (DWI), measurement of the apparent diffusion coefficient (ADC) ratio, and neurobehavioral evaluation were performed 3 times serially by using a 1.5-T MR system: before and 3 and 10 d after MCAO. Ischemic lesions demonstrated T2 hyperintensity, FLAIR hyperintensity, and DWI hyperintensity. The ADC ratio was decreased initially but then was increased at 10 d after MCAO. Ischemic lesion volumes on T2-weighted and FLAIR imaging were not significantly different from those on DWI. The lesion volume and neurobehavioral score showed strong correlation. Our results suggest that conventional MRI may be a reliable diagnostic tool during the subacute stage of canine ischemic stroke.Abbreviations: ADC, apparent diffusion coefficient; DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion recovery; MCAO, middle cerebral artery occlusion; MRI, magnetic resonance imaging; PWI, perfusion-weighted imagingIn human medicine, stroke is a leading cause of adult mortality and neurologic disability worldwide.¹ Strokes previously were thought to be uncommon in small animals, but the true prevalence is unknown.⁴ These events are now recognized more frequently in dogs because of increased use of magnetic resonance imaging (MRI).^5,14,17Because the infusion of thrombolytic agents, such as urokinase or tissue plasminogen activator, within 3 to 6 h of the onset symptoms is effective in restoring blood flow and improving stroke outcome in humans,¹⁹ the detection of early ischemic changes is now thought to be necessary to improve patient outcome. Computed tomography and conventional MRI are not sufficiently sensitive to predict the presence and extent of ischemic damage during the acute stage after a stroke.^12,20 Therefore several MRI sequences, such as fluid-attenuated inversion recovery (FLAIR), diffusion-weighted imaging (DWI), perfusion-weighted imaging (PWI), and MR angiography, have been developed for early diagnosis and subsequent follow-up of ischemic stroke.³ High-field magnetic strengths (at least 1.5 T) are necessary to perform these sequences.In contrast to the situation in humans, ischemic stroke in many dogs is diagnosed during the subacute stage—24 h to 6 wk after the vascular insult—due to the time lag between the onset of clinical signs to referral and to the lack of standard diagnostic protocols for ischemic stroke in dogs. In most reports of strokes in dogs, the median interval between the onset of neurologic dysfunction and performance of an MRI was more than 2 d.^5,14,17 Whereas DWI has marked sensitivity to very early ischemic changes in the brain, T2-weighted and FLAIR images gradually become more hyperintense later (that is, during the first 24 h after the insult).³ Therefore, hyperintensity on T2-weighted and FLAIR images is believed to be representative of mature lesions.¹⁵ In light of these findings, we hypothesized that conventional MR sequences, such as T2-weighted and FLAIR imaging as well as DWI would be used for the diagnosis of the subacute stage of ischemic stroke in dogs.The purpose of this study was to evaluate the diagnostic value of MRI and assess the correlation between the volume of ischemic lesions and neurobehavioral status during the subacute stage of ischemic stroke in dogs. We therefore investigated the lesion volume of T2-weighted and FLAIR images compared with that on DWI images. Furthermore, we assessed the relationship between the apparent diffusion coefficient (ADC) of the ischemic lesions and the neurobehavioral status of the dogs.     

Inflammatory regulators of redirected neural migration in the injured brain

Brain injury following stroke or trauma induces the migration of neuroblasts derived from subventricular zone neural precursor cells (NPCs) towards the damaged tissue, where they then have the potential to contribute to repair. Enhancing the recruitment of new cells thus presents an enticing prospect for the development of new therapeutic approaches to treat brain injury; to this end, an understanding of the factors regulating this process is required. During the neuroinflammatory response to ischemic and traumatic brain injuries, a plethora of pro- and anti-inflammatory cytokines, chemokines and growth factors are released in the damaged tissue, and recent work indicates that a variety of these are able to influence injury-induced migration. In this review, we will discuss the contribution of specific chemokines and growth factors towards stimulating NPC migration in the injured brain.     

Neuroprotective Mechanism of BNG-1 against Focal Cerebral Ischemia: A Neuroimaging and Neurotrophin Study

BNG-1 is a herb complex used in traditional Chinese medicine to treat stroke. In this study, we attempted to identify the neuroprotective mechanism of BNG-1 by using neuroimaging and neurotrophin analyses of a stroke animal model. Rats were treated with either saline or BNG-1 for 7 d after 60-min middle cerebral artery occlusion by filament model. The temporal change of magnetic resonance (MR) imaging of brain was studied using a 7 Tesla MR imaging (MRI) system and the temporal expressions of neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) in brain were analyzed before operation and at 4 h, 2 d, and 7 d after operation. Compared with the saline group, the BNG-1 group exhibited a smaller infarction volume in the cerebral cortex in T2 image from as early as 4 h to 7 d, less edema in the cortex in diffusion weighted image from 2 to 7 d, earlier reduction of postischemic hyperperfusion in both the cortex and striatum in perfusion image at 4 h, and earlier normalization of the ischemic pattern in the striatum in susceptibility weighted image at 2 d. NT-3 and BDNF levels were higher in the BNG-1 group than the saline group at 7 d. We concluded that the protective effect of BNG-1 against cerebral ischemic injury might act through improving cerebral hemodynamics and recovering neurotrophin generation.     

Transcranial low-level laser therapy in an in vivo model of stroke: Relevance to the brain infarct,microglia activation and neuroinflammation

Stroke is the main cause of death and functional disability. The available therapy affects only 5% of patients, and new therapeutic approaches have been constantly tested. Transcranial photobiomodulation (PBM) is promising for its neuroprotective effect on brain injuries. Thus, the present study investigated the PBM effects in an in vivo model of ischemic stroke induced by photothrombosis (PT). Five different groups of Wistar rats were submitted or not to a daily dose of fish oil or/and laser sessions for 2 months. The ischemia volume was evaluated by stereology; GFAP, Iba and NeuN by immunohistochemistry; TNF-α, IL-1β, IL-6, IL-10 and TGF-β by ELISA assay. PBM influenced both the lesion volume and the GFAP. Furthermore, PBM and Ω-3 or both reduced Iba RNAm. PBM reduced TNF-α, IL-1β, IL-6, brain damage, neuroinflammation and microglial activation, and it increased astroglial activity in peri-lesioned region after stroke.     

Protective Effect of Shikonin in Experimental Ischemic Stroke: Attenuated TLR4, p-p38MAPK, NF-κB, TNF-α and MMP-9 Expression, Up-Regulated Claudin-5 Expression, Ameliorated BBB Permeability

Inflammatory damage plays an important role in cerebral ischemic pathogenesis and represents a new target for treatment of stroke. Shikonin has gained attention for its prominent anti-inflammatory property, but up to now little is known about shikonin treatment in acute ischemic stroke. The aim of this study was to evaluate the potential neuroprotective role of shikonin in cerebral ischemic injury, and investigate whether shikonin modulated inflammatory responses after stroke. Focal cerebral ischemia in male ICR mice was induced by transient middle cerebral artery occlusion. Shikonin (10 and 25 mg/kg) was administered by gavage once a day for 3 days before surgery and another dosage after operation. Neurological deficit, infarct volume, brain edema, blood–brain barrier (BBB) dysfunction, and inflammatory mediators were evaluated at 24 and 72 h after stroke. Compared with vehicle group, 25 mg/kg shikonin significantly improved neurological deficit, decreased infarct volume and edema both at 24 and 72 h after transient ischemic stroke, our data also showed that shikonin inhibited the pro-inflammatory mediators, including TLR4, TNF-α, NF-κB, and phosphorylation of p38MAPK in ischemic cortex. In addition, shikonin effectively alleviated brain leakage of Evans blue, up-regulated claudin-5 expression, and inhibited the over-expressed MMP-9 in ischemic brain. These results suggested that shikonin effectively protected brain against ischemic damage by regulating inflammatory responses and ameliorating BBB permeability.     

Erythropoietin therapy for acute stroke is both safe and beneficial

BACKGROUND: Erythropoietin (EPO) and its receptor play a major role in embryonic brain, are weakly expressed in normal postnatal/adult brain and up-regulated upon metabolic stress. EPO protects neurons from hypoxic/ ischemic injury. The objective of this trial is to study the safety and efficacy of recombinant human EPO (rhEPO) for treatment of ischemic stroke in man. MATERIALS AND METHODS: The trial consisted of a safety part and an efficacy part. In the safety study, 13 patients received rhEPO intravenously (3.3 X 10(4) IU/50 ml/30 min) once daily for the first 3 days after stroke. In the double-blind randomized proof-of-concept trial, 40 patients received either rhEPO or saline. Inclusion criteria were age <80 years, ischemic stroke within the middle cerebral artery territory confirmed by diffusion-weighted MRI, symptom onset <8 hr before drug administration, and deficits on stroke scales. The study endpoints were functional outcome at day 30 (Barthel Index, modified Rankin scale), NIH and Scandinavian stroke scales, evolution of infarct size (sequential MRI evaluation using diffusion-weighted [DWI] and fluid-attenuated inversion recovery sequences [FLAIR]) and the damage marker S100ss. RESULTS: No safety concerns were identified. Cerebrospinal fluid EPO increased to 60-100 times that of nontreated patients, proving that intravenously administered rhEPO reaches the brain. In the efficacy trial, patients received rhEPO within 5 hr of onset of symptoms (median, range 2:40-7:55). Admission neurologic scores and serum S100beta concentrations were strong predictors ofoutcome. Analysis of covariance controlled for these two variables indicated that rhEPO treatment was associated with an improvement in follow-up and outcome scales. A strong trend for reduction in infarct size in rhEPO patients as compared to controls was observed by MRI. CONCLUSION: Intravenous high-dose rhEPO is well tolerated in acute ischemic stroke and associated with an improvement in clinical outcome at 1 month. A larger scale clinical trial is warranted.     

TLR2 has a detrimental role in mouse transient focal cerebral ischemia

A significant up-regulation of Toll-like-receptor (TLR) mRNAs between 3 and 48 h reperfusion time after induction of transient focal cerebral ischemia for 1h was revealed by applying global gene expression profiling in postischemic mouse brains. Compared to TLR4 and TLR9, TLR2 proved to be the most significantly up-regulated TLR in the ipsilateral brain hemisphere. TLR2-protein was found to be expressed mainly in microglia in the postischemic brain tissue, but also in selected endothelial cells, neurons, and astrocytes. Additionally, TLR2-related genes with pro-inflammatory and pro-apoptotic capabilities were induced. Therefore we hypothesized that TLR2-signaling could exacerbate the primary brain damage after ischemia. Two days after induction of transient focal cerebral ischemia (1h), we found a significant decrease of the infarct volume in TLR2 deficient mice compared to wild type mice (75+/-5 vs. 42+/-7 mm(3)). We conclude that TLR2 up-regulation and TLR2-signaling are important events in focal cerebral ischemia and contribute to the deterioration of ischemic damage.     

中药活性成分改善缺血缺氧所致脑微血管内皮 屏障功能损伤的研究进展

缺血性脑卒中发生时,基质金属蛋白酶等效应分子以及炎症反应、氧化应激等会破坏血脑屏障,增加缺血区有害产物进入脑组织, 产生脑水肿,引起继发性脑损伤。所以,保护与维持脑微血管内皮屏障功能的完整性,是脑卒中防治的重要策略之一。从调节效应分子 和相关信号通路的角度出发,综述中药活性成分对模拟缺血性脑卒中的体内外脑微血管内皮屏障功能损伤模型的改善作用研究进展,以 期为进一步阐释中药活性成分防治缺血性脑卒中的作用机制以及新药创制提供参考和依据。     

Role of ischemia and deformation in the onset of compression-induced deep tissue injury: MRI-based studies in a rat model.

A rat model was used to distinguish between the different factors that contribute to muscle tissue damage related to deep pressure ulcers that develop after compressive loading. The separate and combined effects of ischemia and deformation were studied. Loading was applied to the hindlimb of rats for 2 h. Muscle tissue was examined using MR imaging (MRI) and histology. An MR-compatible loading device allowed simultaneous loading and measurement of tissue status. Two separate loading protocols incorporated uniaxial loading, resulting in tissue compression and ischemic loading. Uniaxial loading was applied to the tibialis anterior by means of an indenter, and ischemic loading was accomplished with an inflatable tourniquet. Deformation of the muscle tissue during uniaxial loading was measured using MR tagging. Compression of the tissues for 2 h led to increased T2 values, which were correlated to necrotic regions in the tibialis anterior. Perfusion measurements, by means of contrast-enhanced MRI, indicated a large ischemic region during indentation. Pure ischemic loading for 2 h led to reversible tissue changes. From the MR-tagging experiments, local strain fields were calculated. A 4.5-mm deformation, corresponding to a surface pressure of 150 kPa, resulted in maximum shear strain up to 1.0. There was a good correlation between the location of damage and the location of high shear strain. It was concluded that the large deformations, in conjunction with ischemia, provided the main trigger for irreversible muscle damage.     

Global changes in phospholipids identified by MALDI MS in rats with focal cerebral ischemia

Neuronal membrane phospholipids are highly affected by oxidative stress caused by ischemic injury. Thus, it is necessary to identify key lipid components that show changes during ischemia to develop an effective approach to prevent brain damage from ischemic injury. The recent development of MALDI imaging MS (MALDI IMS) makes it possible to identify phospholipids that change between damaged and normal regions directly from tissues. In this study, we conducted IMS on rat brains damaged by ischemic injury and detected various phospholipids that showed unique distributions between normal and damaged areas of the brain. Among them, we confirmed changes in phospholipids such as lysophosphatidylcholine, phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin by MALDI IMS followed by MS/MS analysis. These lipids were present in high concentrations in the brain and are important for maintenance of cellular structure as well as production of second messengers for cellular signal transduction. Our results emphasize the identification of phospholipid markers for ischemic injury and successfully identified several distinctly located phospholipids in ischemic brain tissue.     

Ischemic preconditioning induces XRCC1, DNA polymerase-beta, and DNA ligase III and correlates with enhanced base excision repair

Neuronal protection induced by ischemic preconditioning has an important role in the reduction of stroke volume and attenuation of neuronal cell death. Ischemic injury is associated with increased oxidative DNA damage, and failure to efficiently repair these oxidatively damaged lesions results in the accumulation of mutations and neuronal cell death. Although the effects of ischemic tolerance can have profound implications, the precise mechanisms mediating this phenomenon remain unclear. The base excision repair (BER) pathway has a major role in the repair of oxidative DNA base damage after ischemic injury. Using a rat model of ischemic preconditioning, we now report that the neuronal protection observed after induction of ischemic tolerance is associated with increased BER. In situ detection of single-strand breaks and apurinic/apyrimidinic sites reduced to baseline levels after reperfusion following ischemic preconditioning. By contrast, no change was seen in the quantity of in situ lesions after reperfusion in non-ischemic preconditioned brain. Induction of the BER proteins XRCC1, DNA polymerase-beta, and DNA ligase III was seen after reperfusion in ischemically conditioned brain. Moreover, an increase in binding between XRCC1 and DNA polymerase-beta was seen under these conditions, as might be expected during formation of functional BER complexes. Using in vitro BER oligonucleotides, we directly demonstrated an increase in total BER capacity of nuclear extracts prepared from ischemic-conditioned brain after reperfusion compared with sham-operated brain. These findings provide direct evidence that increased BER is associated with the neuroprotection induced after ischemic preconditioning, and provides important new mechanistic insight into the important biologic pathways that protect neurons against irreversible ischemic injury.     

The Application of MRI for Depiction of Subtle Blood Brain Barrier Disruption in Stroke

The development of imaging methodologies for detecting blood-brain-barrier (BBB) disruption may help predict stroke patient''s propensity to develop hemorrhagic complications following reperfusion. We have developed a delayed contrast extravasation MRI-based methodology enabling real-time depiction of subtle BBB abnormalities in humans with high sensitivity to BBB disruption and high spatial resolution. The increased sensitivity to subtle BBB disruption is obtained by acquiring T1-weighted MRI at relatively long delays (~15 minutes) after contrast injection and subtracting from them images acquired immediately after contrast administration. In addition, the relatively long delays allow for acquisition of high resolution images resulting in high resolution BBB disruption maps. The sensitivity is further increased by image preprocessing with corrections for intensity variations and with whole body (rigid+elastic) registration. Since only two separate time points are required, the time between the two acquisitions can be used for acquiring routine clinical data, keeping the total imaging time to a minimum.A proof of concept study was performed in 34 patients with ischemic stroke and 2 patients with brain metastases undergoing high resolution T1-weighted MRI acquired at 3 time points after contrast injection. The MR images were pre-processed and subtracted to produce BBB disruption maps. BBB maps of patients with brain metastases and ischemic stroke presented different patterns of BBB opening. The significant advantage of the long extravasation time was demonstrated by a dynamic-contrast-enhancement study performed continuously for 18 min. The high sensitivity of our methodology enabled depiction of clear BBB disruption in 27% of the stroke patients who did not have abnormalities on conventional contrast-enhanced MRI. In 36% of the patients, who had abnormalities detectable by conventional MRI, the BBB disruption volumes were significantly larger in the maps than in conventional MRI.These results demonstrate the advantages of delayed contrast extravasation in increasing the sensitivity to subtle BBB disruption in ischemic stroke patients. The calculated disruption maps provide clear depiction of significant volumes of BBB disruption unattainable by conventional contrast-enhanced MRI.