Refinement of Imaging Predictors of Recurrent Events following Transient Ischemic Attack and Minor Stroke

Background

TIA and minor stroke have a high risk of recurrent stroke. Abnormalities on CT/CTA and MRI predict recurrent events in TIA and minor stroke. However there are many other imaging abnormalities that could potentially predict outcome that have not been assessed in this population. Also the definition of recurrent events used includes deterioration due to stroke progression or recurrent stroke and whether imaging is either of these is not known.

Aims

To improve upon the clinical, CT/CTA and MRI parameters that predict recurrent events after TIA and minor stroke by assessing further imaging parameters. Secondary aim was to explore predictors of stroke progression versus recurrent stroke.

Methods

510 consecutive TIA and minor stroke patients had CT/CTA and most had MRI. Primary outcome was recurrent events (stroke progression or recurrent stroke) within 90 days. Further imaging parameters were assessed for prediction of recurrent events (combined outcome of stroke progression and recurrent stroke). We also explored predictors of symptom progression versus recurrence individually.

Results

36 recurrent events (36/510, 7.1% (95% CI: 5.0–9.6)) including 19 progression and 17 recurrent strokes. On CT/CTA: white matter disease, prior stroke, aortic arch focal plaque≥4 mm, or intraluminal thrombus did not predict recurrent events (progression or recurrent stroke). On MRI: white matter disease, prior stroke, and microbleeds did not predict recurrent events. Parameters predicting the individual outcome of symptom progression included: ongoing symptoms at initial assessment, symptom fluctuation, intracranial occlusion, intracranial occlusion or stenosis, and the CT/CTA metric. No parameter was strongly predictive of a distinct recurrent stroke.

Conclusions

There was no imaging parameter that could improve upon our original CT/CTA or MRI metrics to predict the combined outcome of stroke progression or a recurrent stroke after TIA and minor stroke. We are better at using imaging to predict stroke progression rather than recurrent stroke.     

A surgical model of permanent and transient middle cerebral artery stroke in the sheep

Background

Animal models are essential to study the pathophysiological changes associated with focal occlusive stroke and to investigate novel therapies. Currently used rodent models have yielded little clinical success, however large animal models may provide a more suitable alternative to improve clinical translation. We sought to develop a model of acute proximal middle cerebral artery (MCA) ischemic stroke in sheep, including both permanent occlusion and transient occlusion with reperfusion.

Materials and Methods

18 adult male and female Merino sheep were randomly allocated to one of three groups (n = 6/gp): 1) sham surgery; 2) permanent proximal MCA occlusion (MCAO); or 3) temporary MCAO with aneurysm clip. All animals had invasive arterial blood pressure, intracranial pressure and brain tissue oxygen monitoring. At 4 h following vessel occlusion or sham surgery animals were killed by perfusion fixation. Brains were processed for histopathological examination and infarct area determination. 6 further animals were randomized to either permanent (n = 3) or temporary MCAO (n = 3) and then had magnetic resonance imaging (MRI) at 4 h after MCAO.

Results

Evidence of ischemic injury in an MCA distribution was seen in all stroke animals. The ischemic lesion area was significantly larger after permanent (28.8%) compared with temporary MCAO (14.6%). Sham animals demonstrated no evidence of ischemic injury. There was a significant reduction in brain tissue oxygen partial pressure after permanent vessel occlusion between 30 and 210 mins after MCAO. MRI at 4 h demonstrated complete proximal MCA occlusion in the permanent MCAO animals with a diffusion deficit involving the whole right MCA territory, whereas temporary MCAO animals demonstrated MRA evidence of flow within the right MCA and smaller predominantly cortical diffusion deficits.

Conclusions

Proximal MCAO can be achieved in an ovine model of stroke via a surgical approach. Permanent occlusion creates larger infarct volumes, however aneurysm clip application allows for reperfusion.     

Development of a middle cerebral artery occlusion model in the nonhuman primate and a safety study of i.v. infusion of human mesenchymal stem cells

Background

Most experimental stroke research is carried out in rodents, but given differences between rodents and human, nonhuman primate (NHP) models may provide a valuable tool to study therapeutic interventions. The authors developed a surgical method for transient occlusion of the M1 branch of middle cerebral artery (MCA) in the African green monkey to evaluate safety aspects of intravenous infusion of mesenchymal stem cells (hMSCs) derived from human bone marrow.

Methods

The left Sylvian fissure was exposed by a small fronto-temporal craniotomy. The M1 branch of the MCA was exposed by microsurgical dissection and clipped for 2 to 4 hours. Neurological examinations and magnetic resonance imaging (MRI) were carried out at regular post-operative course. hMSCs were infused 1 hour after reperfusion (clip release) in the 3-hour occlusion model.

Results

During M1 occlusion, two patterns of changes were observed in the lateral hemisphere surface. One pattern (Pattern 1) was darkening of venous blood, small vessel collapse, and blood pooling with no venous return in cortical veins. Animals with these three features had severe and lasting hemiplegia and MRI demonstrated extensive MCA territory infarction. Animals in the second pattern (Pattern 2) displayed darkening of venous blood, small vessel collapse, and reduced but incompletely occluded venous flow and the functional deficit was much less severe and MRI indicated smaller infarction areas in brain. The severe group (Pattern 1) likely had less extensive collateral circulation than the less severe group (Pattern 2) where venous pooling of blood was not observed. The hMSC infused animals showed a trend for greater functional improvement that was not statistically significant in the acute phase and no additive negative effects.

Conclusions

These results indicate inter-animal variability of collateral circulation after complete M1 occlusion and that hMSC infusion is safe in the developed NHP stroke model.     

Use of Electrical Impedance Tomography to Monitor Regional Cerebral Edema during Clinical Dehydration Treatment

Objective

Variations of conductive fluid content in brain tissue (e.g. cerebral edema) change tissue impedance and can potentially be measured by Electrical Impedance Tomography (EIT), an emerging medical imaging technique. The objective of this work is to establish the feasibility of using EIT as an imaging tool for monitoring brain fluid content.

Design

a prospective study.

Setting

In this study EIT was used, for the first time, to monitor variations in cerebral fluid content in a clinical model with patients undergoing clinical dehydration treatment. The EIT system was developed in house and its imaging sensitivity and spatial resolution were evaluated on a saline-filled tank.

Patients

23 patients with brain edema.

Interventions

The patients were continuously imaged by EIT for two hours after initiation of dehydration treatment using 0.5 g/kg intravenous infusion of mannitol for 20 minutes.

Measurement and Main Results

Overall impedance across the brain increased significantly before and after mannitol dehydration treatment (p = 0.0027). Of the all 23 patients, 14 showed high-level impedance increase and maintained this around 4 hours after the dehydration treatment whereas the other 9 also showed great impedance gain during the treatment but it gradually decreased after the treatment. Further analysis of the regions of interest in the EIT images revealed that diseased regions, identified on corresponding CT images, showed significantly less impedance changes than normal regions during the monitoring period, indicating variations in different patients'' responses to such treatment.

Conclusions

EIT shows potential promise as an imaging tool for real-time and non-invasive monitoring of brain edema patients.     

Reversal of Ophthalmic Artery Flow and Stroke Outcomes in Asian Patients with Acute Ischemic Stroke and Unilateral Severe Cervical Carotid Stenosis

Background

The aim of this study was to assess the clinical implications of reversed ophthalmic artery flow (ROAF) for stroke risk and outcomes in subjects with unilateral severe cervical carotid stenosis/occlusion.

Methods

We investigated 128 subjects (101 with acute stroke and 27 without), selected from a large hospital patients base (n  =  14,701), identified with unilateral high-grade cervical carotid stenosis/occlusion by using duplex ultrasonography and brain magnetic resonance imaging. All clinical characteristics were compared for stroke risk between acute stroke and nonstroke groups. Patients with acute stroke were divided into 4 subgroups according to ophthalmic artery flow direction and intracranial stenosis severity, and stroke outcomes were evaluated.

Results

The acute stroke group had significantly higher percentages of ROAF (52.5%, p  =  0.003), carotid occlusion (33.7%, p  =  0.046), and severe intracranial stenosis (74.3%, p<0.001). However, multivariate analysis demonstrated that intracranial stenosis was the only significant risk factor (odds ratio  =  10.38; 95% confidence interval  =  3.64–29.65; p<0.001). Analysis of functional outcomes among the 4 subgroups of patients with stroke showed significant trends (p  =  0.018 to 0.001) for better stroke outcomes from ROAF and mild or no intracranial stenosis. ROAF improved 10–20% stroke outcomes, as compared to forward ophthalmic artery flow, among the patients with stroke and the same degree of severities of intracranial stenosis.

Conclusions

Patients with acute stroke and severe unilateral cervical carotid stenosis/occlusion significantly have high incidence of intracranial stenosis and ROAF. Intracranial stenosis is a major stroke risk indicator as well as a predictor for worse stroke outcomes, and ROAF may provide partial compensation for improving stroke outcomes.     

Altered Resting-State fMRI Signals in Acute Stroke Patients with Ischemic Penumbra

Background

Identifying the ischemic penumbra in acute stroke subjects is important for the clinical decision making process. The aim of this study was to use resting-state functional magnetic resonance singal (fMRI) to investigate the change in the amplitude of low-frequency fluctuations (ALFF) of these subjects in three different subsections of acute stroke regions: the infarct core tissue, the penumbra tissue, and the normal brain tissue. Another aim of this study was to test the feasilbility of consistently detecting the penumbra region of the brain through ALFF analysis.

Methods

Sixteen subjects with first-ever acute ischemic stroke were scanned within 27 hours of the onset of stroke using magnetic resonance imaging. The core of infarct regions and penumbra regions were determined by diffusion and perfusion-weighted imaging respectively. The ALFF were measured from resting-state blood oxygen level dependent (BOLD) fMRI scans. The averaged relative ALFF value of each regions were correlated with the time after the onset of stroke.

Results

Relative ALFF values were significantly different in the infarct core tissue, penumbra tissue and normal brain tissue. The locations of lesions in the ALFF maps did not match perfectly with diffusion and perfusion-weighted imagings; however, these maps provide a contrast that can be used to differentiate between penumbra brain tissue and normal brain tissue. Significant correlations between time after stroke onset and the relative ALFF values were present in the penumbra tissue but not in the infarct core and normal brain tissue.

Conclusion

Preliminary results from this study suggest that the ALFF reflects the underlying neurovascular activity and has a great potential to estimate the brain tissue viability after ischemia. Results also show that the ALFF may contribute to acute stroke imaging for thrombolytic or neuroprotective therapies.     

Susceptibility-Weighted Imaging in Heat Stroke

Objective

To assess the role of susceptibility-weighted imaging in the detection of intracranial hemorrhage after heat stroke and in the prognosis.

Materials and Methods

The study group consisted of eight patients after heat stroke, with a score of 3 to 9 in Glasgow Coma Scale. The MR studies were performed with a 1.5 T scanner. Susceptibility-weighted imaging data were collected within 2–5 days after heat stroke. The study was approved by ethics committee, and written informed consents were obtained from family members of the patients.

Results

Punctate hemorrhages were detected in brain stem, corona radiata and frontal lobe by susceptibility-weighted imaging for three patients. Among the three cases, two patients came to death in the 5th day and the 25th day after heat stroke respectively. Another patient became a persistent vegetative state and died about 3 months later. Five patients with no hemorrhage detected gradually recovered and cerebellar dysfunction remained to various degrees.

Conclusions

Heat stroke is a life-threatening condition characterized by hyperthermia and accompanied by various complications such as disseminated intravascular coagulation. Susceptibility-weighted imaging is a very useful tool for detection of intracranial hemorrhage and may probably evaluate the prognosis after heat stroke.     

Arrival Time Correction for Dynamic Susceptibility Contrast MR Permeability Imaging in Stroke Patients

Purpose

To determine if applying an arrival time correction (ATC) to dynamic susceptibility contrast (DSC) based permeability imaging will improve its ability to identify contrast leakage in stroke patients for whom the shape of the measured curve may be very different due to hypoperfusion.

Materials and Methods

A technique described in brain tumor patients was adapted to incorporate a correction for delayed contrast delivery due to perfusion deficits. This technique was applied to the MRIs of 9 stroke patients known to have blood-brain barrier (BBB) disruption on T1 post contrast imaging. Regions of BBB damage were compared with normal tissue from the contralateral hemisphere. Receiver operating characteristic (ROC) analysis was performed to compare the detection of BBB damage before and after ATC.

Results

ATC improved the area under the curve (AUC) of the ROC from 0.53 to 0.70. The sensitivity improved from 0.51 to 0.67 and the specificity improved from 0.57 to 0.66. Visual inspection of the ROC curve revealed that the performance of the uncorrected analysis was worse than random guess at some thresholds.

Conclusions

The ability of DSC permeability imaging to identify contrast enhancing tissue in stroke patients improved considerably when an ATC was applied. Using DSC permeability imaging in stroke patients without an ATC may lead to false identification of BBB disruption.     

Treadmill Pre-Training Ameliorates Brain Edema in Ischemic Stroke via Down-Regulation of Aquaporin-4: An MRI Study in Rats

Objective

Treadmill pre-training can ameliorate blood brain barrier (BBB) dysfunction in ischemia-reperfusion injury, however, its role in ischemic brain edema remains unclear. This study assessed the neuroprotective effects induced by treadmill pre-training, particularly on brain edema in transient middle cerebral artery occluded model.

Methods

Transient middle cerebral artery occlusion to induce stroke was performed on rats after 2 weeks of treadmill pre-training. Magnetic resonance imaging (MRI) was used to evaluate the dynamic impairment of cerebral edema after ischemia-reperfusion injury. In addition, measurements of wet and dry brain weight, Evans Blue assay and Garcia scores were performed to investigate the cerebral water content, BBB permeability and neurologic deficit, respectively. Moreover, during ischemia-reperfusion injury, the expression of Aquaporin 4 (AQP4) was detected using immunofluorescence and Western bloting analyses.

Results

Treadmill pre-training improved the relative apparent diffusion coefficient (rADC) loss in the ipsilateral cortex and striatum at 1 hour and 2.5 hours after cerebral ischemia. In the treadmill pre-training group, T2W1 values of the ipsilateral cortex and striatum increased less at 7.5 hours, 1 day, and 2 days after stroke while the brain water content decreased at 2 days after ischemia. Regarding the BBB permeability, the semi-quantitative amount of contrast agent leakage of treadmill pre-training group significantly decreased. Less Evans Blue exudation was also observed in treadmill pre-training group at 2 days after stroke. In addition, treadmill pre-training mitigated the Garcia score deficits at 2 days after stroke. Immunofluorescence staining and Western blotting results showed a significant decrease in the expression of AQP4 after treadmill ischemia following pre-training.

Conclusions

Treadmill pre-training may reduce cerebral edema and BBB dysfunction during cerebral ischemia/reperfusion injury via the down-regulation of AQP4.     

Motor network degeneration in amyotrophic lateral sclerosis: a structural and functional connectivity study

Background

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by motor neuron degeneration. How this disease affects the central motor network is largely unknown. Here, we combined for the first time structural and functional imaging measures on the motor network in patients with ALS and healthy controls.

Methodology/Principal Findings

Structural measures included whole brain cortical thickness and diffusion tensor imaging (DTI) of crucial motor tracts. These structural measures were combined with functional connectivity analysis of the motor network based on resting state fMRI. Focal cortical thinning was observed in the primary motor area in patients with ALS compared to controls and was found to correlate with disease progression. DTI revealed reduced FA values in the corpus callosum and in the rostral part of the corticospinal tract. Overall functional organisation of the motor network was unchanged in patients with ALS compared to healthy controls, however the level of functional connectedness was significantly correlated with disease progression rate. Patients with increased connectedness appear to have a more progressive disease course.

Conclusions/Significance

We demonstrate structural motor network deterioration in ALS with preserved functional connectivity measures. The positive correlation between functional connectedness of the motor network and disease progression rate could suggest spread of disease along functional connections of the motor network.     

Niaspan Attenuates the Adverse Effects of Bone Marrow Stromal Cell Treatment of Stroke in Type One Diabetic Rats

Aims

Our previous studies have found that bone-marrow-stromal cells (BMSC) therapy improves functional recovery after stroke in non-diabetic rats while increases brain hemorrhage and induces arteriosclerosis-like changes in type-one-diabetic (T1DM) rats. Niaspan treatment of stroke increases vascular stabilization, decreases brain hemorrhage and blood-brain-barrier (BBB) leakage in T1DM rats. We therefore tested the hypothesis that combination therapy of BMSC with Niaspan attenuates the side effects of BMSC monotherapy in T1DM rats.

Methods

T1DM-rats induced by streptozotocin were subjected to 2 hours of middle-cerebral-artery occlusion (MCAo) and treated with: 1) PBS; 2) BMSC (5×10⁶); 3) Niaspan (40 mg/kg) daily for 14 days; 4) BMSC (5×10⁶) +Niaspan (40 mg/kg, daily for 14 days) combination starting at 24 hours after MCAo. All rats were monitored for 14 days.

Results

Combination BMSC+Niaspan treatment of T1DM-MCAo rats did not increase brain hemorrhage, and significantly decreased BBB leakage and vascular arteriosclerosis-like changes as well as decreased Angiogenin, matrix metalloproteinase 9 (MMP9) and ED1 expression in ischemic brain and internal-carotid-artery compared to non-treatment control and BMSC monotherapy animals.

Conclusions

Combination therapy using BMSC with Niaspan decreases BBB leakage and cerebral arteriosclerosis-like changes. These beneficial effects may be attributed to the decreased expression of Angiogenin, MMP9 and ED1.     

In vivo near-infrared imaging of fibrin deposition in thromboembolic stroke in mice

Objectives

Thrombus and secondary thrombosis plays a key role in stroke. Recent molecular imaging provides in vivo imaging of activated factor XIII (FXIIIa), an important mediator of thrombosis or fibrinolytic resistance. The present study was to investigate the fibrin deposition in a thromboembolic stroke mice model by FXIIIa–targeted near-infrared fluorescence (NIRF) imaging.

Materials and Methods

The experimental protocol was approved by our institutional animal use committee. Seventy-six C57B/6J mice were subjected to thromboembolic middle cerebral artery occlusion or sham operation. Mice were either intravenously injected with the FXIIIa-targeted probe or control probe. In vivo and ex vivo NIRF imaging were performed thereafter. Probe distribution was assessed with fluorescence microscopy by spectral imaging and quantification system. MR scans were performed to measure lesion volumes in vivo, which were correlated with histology after animal euthanasia.

Results

In vivo significant higher fluorescence intensity over the ischemia-affected hemisphere, compared to the contralateral side, was detected in mice that received FXIIIa-targeted probe, but not in the controlled mice. Significantly NIRF signals showed time-dependent processes from 8 to 96 hours after injection of FXIIIa-targeted probes. Ex vivo NIRF image showed an intense fluorescence within the ischemic territory only in mice injected with FXIIIa-targeted probe. The fluorescence microscopy demonstrated distribution of FXIIIa-targeted probe in the ischemic region and nearby micro-vessels, and FXIIIa-targeted probe signals showed good overlap with immune-fluorescent fibrin staining images. There was a significant correlation between total targeted signal from in vivo or ex vivo NIRF images and lesion volume.

Conclusion

Non-invasive detection of fibrin deposition in ischemic mouse brain using NIRF imaging is feasible and this technique may provide an in vivo experimental tool in studying the role of fibrin in stroke.     

Nitric oxide facilitates delivery and mediates improved outcome of autologous bone marrow mononuclear cells in a rodent stroke model

Background

Bone marrow mononuclear cells (MNC) represent an investigational treatment for stroke. The objective of this study was to determine the relevance of vasoactive mediators, generated in response to MNC injection, as factors regulating cerebral perfusion (CP), the biodistribution of MNC, and outcome in stroke.

Methods

Long Evans rats underwent transient middle cerebral artery occlusion. MNC were extracted from the bone marrow at 22 hrs and injected via the internal carotid artery or the femoral vein 2 hours later. CP was measured with MRI or continuous laser Doppler flowmetry. Serum samples were collected to measure vasoactive mediators. Animals were treated with the Nitric Oxide (NO) inhibitor, L-NAME, to establish the relevance of NO-signaling to the effect of MNC. Lesion size, MNC biodistribution, and neurological deficits were assessed.

Results

CP transiently increased in the peri-infarct region within 30 min after injecting MNC compared to saline or fibroblast control. This CP increase corresponded temporarily to serum NO elevation and was abolished by L-NAME. Pre-treatment with L-NAME reduced brain penetration of MNC and prevented MNC from reducing infarct lesion size and neurological deficits.

Conclusions

NO generation in response to MNC may represent a mechanism underlying how MNC enter the brain, reduce lesion size, and improve outcome in ischemic stroke.     

In Vivo MR Imaging of Intraarterially Delivered Magnetically Labeled Mesenchymal Stem Cells in a Canine Stroke Model

Background

This study aimed to evaluate the feasibility of intraarterial (IA) delivery and in vivo MR imaging of superparamagnetic iron oxide (SPIO)-labeled mesenchymal stem cells (MSCs) in a canine stroke model.

Methodology

MSCs harvested from beagles’ bone marrow were labeled with home-synthesized SPIO. Adult beagle dogs (n = 12) were subjected to left proximal middle cerebral artery (MCA) occlusion by autologous thrombus, followed by two-hour left internal carotid artery (ICA) occlusion with 5 French vertebral catheter. One week later, dogs were classified as three groups before transplantation: group A: complete MCA recanalization, group B: incomplete MCA recanalization, group C: no MCA recanalization. 3×10⁶ labeled-MSCs were delivered through left ICA. Series in vivo MRI images were obtained before cell grafting, one and 24 hours after transplantation and weekly thereafter until four weeks. MRI findings were compared with histological studies at the time point of 24 hours and four weeks.

Principal Findings

Home-synthesized SPIO was useful to label MSCs without cell viability compromise. MSCs scattered widely in the left cerebral hemisphere in group A, while fewer grafted cells were observed in group B and no cell was detected in group C at one hour after transplantation. A larger infarction on the day of cell transplantation was associated with more grafted cells in the brain. Grafted MSCs could be tracked effectively by MRI within four weeks and were found in peri-infarction area by Prussian blue staining.

Conclusion

It is feasible of IA MSCs transplantation in a canine stroke model. Both the ipsilateral MCA condition and infarction volume before transplantation may affect the amount of grafted cells in target brain. In vivo MR imaging is useful for tracking IA delivered MSCs after SPIO labeling.     

Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) Deficient Mice Are Susceptible to Intracerebral Thrombosis and Ischemic Stroke

Background

Thrombus formation is a key step in the pathophysiology of acute ischemic stroke and results from the activation of the coagulation cascade. Thrombin plays a central role in this coagulation system and contributes to thrombus stability via activation of thrombin-activatable fibrinolysis inhibitor (TAFIa). TAFIa counteracts endogenous fibrinolysis at different stages and elevated TAFI levels are a risk factor for thrombotic events including ischemic stroke. Although substantial in vitro data on the influence of TAFI on the coagulation-fibrinolysis-system exist, investigations on the consequences of TAFI inhibition in animal models of cerebral ischemia are still lacking. In the present study we analyzed stroke development and post stroke functional outcome in TAFI^-/- mice.

Methodology/Principal Findings

TAFI^-/- mice and wild-type controls were subjected to 60 min transient middle cerebral artery occlusion (tMCAO) using the intraluminal filament method. After 24 hours, functional outcome scores were assessed and infarct volumes were measured from 2,3,5-Triphenyltetrazoliumchloride (TTC)-stained brain slices. Hematoxylin and eosin (H&E) staining was used to estimate the extent of neuronal cell damage. Thrombus formation within the infarcted brain areas was analyzed by immunoblot. Infarct volumes and functional outcomes did not significantly differ between TAFI^-/- mice and controls (p>0.05). Histology revealed extensive ischemic neuronal damage regularly including the cortex and the basal ganglia in both groups. TAFI deficiency also had no influence on intracerebral fibrin(ogen) formation after tMCAO.

Conclusion

Our study shows that TAFI does not play a major role for thrombus formation and neuronal degeneration after ischemic brain challenge.     

Estimation of the Long-Term Care Needs of Stroke Patients by Integrating Functional Disability and Survival

Objectives

This study aimed to estimate the dynamic changes of different physical functional disabilities and life-time care needs for patients with stroke.

Data Sources and Study Design

We examined a hospital-based cohort including 16,043 patients who had their first stroke during 1995–2010. The Barthel Index (BI) was used to measure disability levels in 1,162 consecutive patients, with a total of 1,294 measurements at the stroke clinics and the rehabilitation wards, and a cross-sectional design.

Extraction Methods

The survival function was extrapolated to lifetime by a semi-parametric method and multiplied with proportions of different disabilities over time to obtain the long-term care needs for different stroke subtypes.

Principal Findings

On average, stroke patients would suffer at least 0.86 years with mild disability, 1.24 years with moderate disability and 1.39 years with severe disability, as measured by the BI. Among these, patients with a cardio-embolic infarct or intracerebral hemorrhage (ICH) suffered more than 2 years of severe disability. Assistance in bathing was the most common need for care in stroke patients.

Conclusions

Among different subtypes of stroke, cardio-embolic infarct and ICH lead to the longest durations of severe physical functional disability. The method presented in this work may also be applied to other chronic diseases and different functional disabilities.     

K-134, a Phosphodiesterase 3 Inhibitor,Prevents Brain Damage by Inhibiting Thrombus Formation in a Rat Cerebral Infarction Model

Background

K-134 is a more potent antiplatelet drug with a selective inhibitory effect on phosphodiesterase 3 (PDE3) compared with its analogue, cilostazol.

Objectives

This study was performed to compare the ameliorating effects of K-134 and cilostazol on brain damage in an experimental photothrombotic cerebral infarction model.

Methods and Results

We investigated the effects of oral preadministration of PDE3 inhibitors in a rat stroke model established by photothrombotic middle cerebral artery (MCA) occlusion. K-134 significantly prolonged MCA occlusion time at doses >10 mg/kg, and reduced cerebral infarct size at 30 mg/kg in the stroke model (n = 12, 87.5±5.6 vs. 126.8±7.5 mm³, P<0.01), indicating its potent antithrombotic effect. On the other hand, the effects of cilostazol on MCA occlusion time and cerebral infarct size are relatively weak even at the high dosage of 300 mg/kg. Furthermore, K-134 blocked rat platelet aggregation more potently than cilostazol in vitro. Also in an arteriovenous shunt thrombosis model, K-134 showed an antithrombotic effect greater than cilostazol.

Conclusions

These findings suggest that K-134, which has strong antithrombotic activity, is a promising drug for prevention of cerebral infarction associated with platelet hyperaggregability.     

Genetic Variation at the BDNF Locus: Evidence for Association with Long-Term Outcome after Ischemic Stroke

Background and Purpose

Rates and extent of recovery after stroke vary considerably between individuals and genetic factors are thought to contribute to post-stroke outcome. Brain-derived neurotrophic factor (BDNF) plays important roles in brain plasticity and repair and has been shown to be involved in stroke severity, recovery, and outcome in animal models. Few clinical studies on BDNF genotypes in relation to ischemic stroke have been performed. The aims of the present study are therefore to investigate whether genetic variation at the BDNF locus is associated with initial stroke severity, recovery and/or short-term and long-term functional outcome after ischemic stroke.

Methods

Four BDNF tagSNPs were analyzed in the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS; 600 patients and 600 controls, all aged 18–70 years). Stroke severity was assessed using the NIH Stroke Scale (NIHSS). Stroke recovery was defined as the change in NIHSS over a 3-month period. Short- and long-term functional outcome post-stroke was assessed using the modified Rankin Scale at 3 months and at 2 and 7 years after stroke, respectively.

Results

No SNP was associated with stroke severity or recovery at 3 months and no SNP had an impact on short-term outcome. However, rs11030119 was independently associated with poor functional outcome 7-years after stroke (OR 0.66, 95% CI 0.46–0.92; P =  0.006).

Conclusions

BDNF gene variants were not major contributors to ischemic stroke severity, recovery, or short-term functional outcome. However, this study suggests that variants in the BDNF gene may contribute to poor long-term functional outcome after ischemic stroke.     

High Total Hospitalization Cost but Low Cost of Imaging Studies in Recurrent Acute Ischemic Stroke Patients

Background

Due to the high risk and severity of recurrence after stroke attack, recurrence is a major reason contributing to the disease burden. This study aims to determine whether recurrence is a significant contributor of hospitalization cost in items for ischemic stroke patients.

Methods

This study assessed acute ischemic stroke patients admitted to an academic medical center in 2003 through 2009. The t-test and Chi-square tests were used to compare first-ever and recurrent ischemic stroke groups in terms of total and categorized hospitalization cost, and multiple regression was performed to assess the influence of stroke recurrence.

Results

Recurrent ischemic strokes were associated with higher total cost, but examination cost showed no difference between the two groups. The recurrent stroke group showed higher laboratory but lower imaging cost. Of imaging studies, there was no significant difference in computed tomography scan cost while the first-ever stroke group spent more on magnetic resonance imaging and sonography. Controlling for other influential factors, recurrence was discovered to be a significant factor in lowering examination cost.

Conclusions

The findings of stroke recurrence in lowering examination cost could be explained from two perspectives, different clinical patterns of healthcare utilization and patients'' economic status in recurrent stroke.     

A Statistical Parametric Mapping Toolbox Used for Voxel-Wise Analysis of FDG-PET Images of Rat Brain

Purpose

PET (positron emission tomography) imaging researches of functional metabolism using fluorodeoxyglucose (¹⁸F-FDG) of animal brain are important in neuroscience studies. FDG-PET imaging studies are often performed on groups of rats, so it is desirable to establish an objective voxel-based statistical methodology for group data analysis.

Material and Methods

This study establishes a statistical parametric mapping (SPM) toolbox (plug-ins) named spmratIHEP for voxel-wise analysis of FDG-PET images of rat brain, in which an FDG-PET template and an intracranial mask image of rat brain in Paxinos & Watson space were constructed, and the default settings were modified according to features of rat brain. Compared to previous studies, our constructed rat brain template comprises not only the cerebrum and cerebellum, but also the whole olfactory bulb which made the later cognitive studies much more exhaustive. And with an intracranial mask image in the template space, the brain tissues of individuals could be extracted automatically. Moreover, an atlas space is used for anatomically labeling the functional findings in the Paxinos & Watson space. In order to standardize the template image with the atlas accurately, a synthetic FDG-PET image with six main anatomy structures is constructed from the atlas, which performs as a target image in the co-registration.

Results

The spatial normalization procedure is evaluated, by which the individual rat brain images could be standardized into the Paxinos & Watson space successfully and the intracranial tissues could also be extracted accurately. The practical usability of this toolbox is evaluated using FDG-PET functional images from rats with left side middle cerebral artery occlusion (MCAO) in comparison to normal control rats. And the two-sample t-test statistical result is almost related to the left side MCA.

Conclusion

We established a toolbox of SPM8 named spmratIHEP for voxel-wise analysis of FDG-PET images of rat brain.