Human Placenta-Derived Adherent Cell Treatment of Experimental Stroke Promotes Functional Recovery after Stroke in Young Adult and Older Rats

Background

Human Placenta-Derived Adherent Cells (PDAC®) are a novel mesenchymal-like cell population derived from normal human placental tissue. PDA-001 is a clinical formulation of PDAC® developed for intravenous administration. In this study, we investigated the efficacy of PDA-001 treatment in a rat model of transient middle cerebral artery occlusion (MCAo) in young adult (2–3 month old) and older rats (10–12 months old).

Methods

To evaluate efficacy and determine the optimal number of transplanted cells, young adult Wistar rats were subjected to MCAo and treated 1 day post MCAo with 1×10⁶, 4×10⁶ or 8×10⁶ PDA-001 cells (i.v.), vehicle or cell control. 4×10⁶ or 8×10⁶ PDA-001 cells were also tested in older rats after MCAo. Treatment response was evaluated using a battery of functional outcome tests, consisting of adhesive-removal test, modified Neurological Severity Score (mNSS) and foot-fault test. Young adult rats were sacrificed 56 days after MCAo, older rats were sacrificed 29 days after MCAo, and lesion volumes were measured using H&E. Immunohistochemical stainings for bromodeoxyuridine (BrdU) and von Willebrand Factor (vWF), and synaptophysin were performed.

Results

In young adult rats, treatment with 4×10⁶ PDA-001 cells significantly improved functional outcome after stroke (p<0.05). In older rats, significant functional improvement was observed with PDA-001 cell therapy in both of the 4×10⁶ and 8×10⁶ treatment groups. Functional benefits in young adult and older rats were associated with significant increases in the number of BrdU immunoreactive endothelial cells, vascular density and perimeter in the ischemic brain, as well as significantly increased synaptophysin expression in the ischemic border zone (p<0.05).

Conclusion

PDA-001 treatment significantly improved functional outcome after stroke in both young adult and older rats. The neurorestorative effects induced by PDA-001 treatment may be related to increased vascular density and synaptic plasticity.     

Stroke Code Improves Intravenous Thrombolysis Administration in Acute Ischemic Stroke

Background and Purpose

Timely intravenous (IV) thrombolysis for acute ischemic stroke is associated with better clinical outcomes. Acute stroke care implemented with “Stroke Code” (SC) may increase IV tissue plasminogen activator (tPA) administration. The present study aimed to investigate the impact of SC on thrombolysis.

Methods

The study period was divided into the “pre-SC era” (January 2006 to July 2010) and “SC era” (August 2010 to July 2013). Demographics, critical times (stroke symptom onset, presentation to the emergency department, neuroimaging, thrombolysis), stroke severity, and clinical outcomes were recorded and compared between the two eras.

Results

During the study period, 5957 patients with acute ischemic stroke were admitted; of these, 1301 (21.8%) arrived at the emergency department within 3 h of stroke onset and 307 (5.2%) received IV-tPA. The number and frequency of IV-tPA treatments for patients with an onset-to-door time of <3 h increased from the pre-SC era (n = 91, 13.9%) to the SC era (n = 216, 33.3%) (P<0.001). SC also improved the efficiency of IV-tPA administration; the median door-to-needle time decreased (88 to 51 min, P<0.001) and the percentage of door-to-needle times ≤60 min increased (14.3% to 71.3%, P<0.001). The SC era group tended to have more patients with good outcome (modified Rankin Scale ≤2) at discharge (49.5 vs. 39.6%, P = 0.11), with no difference in symptomatic hemorrhage events or in-hospital mortality.

Conclusion

The SC protocol increases the percentage of acute ischemic stroke patients receiving IV-tPA and decreases door-to-needle time.     

Chloride Co-transporter NKCC1 Inhibitor Bumetanide Enhances Neurogenesis and Behavioral Recovery in Rats After Experimental Stroke

Bumetanide, a selective Na⁺-K⁺-Cl^?-co-transporter inhibitor, is widely used in clinical practice as a loop diuretic. In addition, bumetanide has been reported to attenuate ischemia-induced cerebral edema and reduce neuronal injury. This study examined whether bumetanide could influence neurogenesis and behavioral recovery in rats after experimentally induced stroke. Adult male Wistar rats were randomly assigned to four groups: sham, sham treated with bumetanide, ischemia, and ischemia treated with bumetanide. Focal cerebral ischemia was induced by injection of endothelin-1. Bumetanide (0.2 mg/kg/day) was infused into the lateral ventricle with drug administration being initiated 1 week after ischemia and continued for 3 weeks. Behavioral impairment and recovery were evaluated by tapered/ledged beam-walking test on post-stroke days 28. Then, the rats were perfused for BrdU/DCX (neuroblast marker), BrdU/NeuN (neuronal marker), BrdU/GFAP (astrocyte marker), and BrdU/Iba-1 (microglia marker) immunohistochemistry. The numbers of neuroblasts in the subventricular zone (SVZ) were significantly increased after the experimentally induced stroke. Bumetanide treatment increased migration of neuroblasts in the SVZ towards the infarct area, enhanced long-term survival of newborn neurons, and improved sensorimotor recovery, but it did not exert any effects on inflammation. In conclusion, our results demonstrated that chronic bumetanide treatment enhances neurogenesis and behavioral recovery after experimentally induced stroke in rats.     

Enhanced Proteostasis in Post-ischemic Stroke Mouse Brains by Ubiquilin-1 Promotes Functional Recovery

Stroke is pathologically associated with oxidative stress, protein damage, and neuronal loss. We previously reported that overexpression of a ubiquitin-like protein, ubiquilin-1 (Ubqln), protects neurons against ischemia-caused brain injury, while knockout of the gene exacerbates cerebral ischemia-caused neuronal damage and delays functional recovery. Although these observations indicate that Ubqln is a potential therapeutic target, transgenic manipulation-caused overexpression of Ubqln occurs before the event of ischemic stroke, and it remains unknown whether delayed Ubqln overexpression in post-ischemic brains within a clinically relevant time frame is still beneficial. To address this question, we generated lentiviruses (LVs) either overexpressing or knocking down mouse Ubqln, and treated post-ischemic stroke mice 6 h following the middle cerebral artery occlusion with the LVs before animal behaviors were evaluated at day 1, 3, 5, and 7. Our data indicate that post-ischemic overexpression of Ubqln significantly promoted functional recovery, whereas post-ischemic downregulation of Ubqln expression delays functional recovery. To further understand the mechanisms underlying how Ubqln functions, we also isolated protein aggregates from the brains of wild-type mice or the mice overexpressing Ubqln following ischemia/reperfusion. Western blot analysis indicates that overexpression of Ubqln significantly reduced the accumulation of protein aggregates. These observations not only suggest that Ubqln is a useful candidate for therapeutic intervention for ischemic stroke but also highlight the significance of proteostasis in functional recovery following stroke.     

Exercise Promotes Axon Regeneration of Newborn Striatonigral and Corticonigral Projection Neurons in Rats after Ischemic Stroke

Newborn striatal neurons induced by middle cerebral artery occlusion (MCAO) can form functional projections targeting into the substantia nigra, which should be very important for the recovery of motor function. Exercise training post-stroke improves motor recovery in clinic patients and increases striatal neurogenesis in experimental animals. This study aimed to investigate the effects of exercise on axon regeneration of newborn projection neurons in adult rat brains following ischemic stroke. Rats were subjected to a transient MCAO to induce focal cerebral ischemic injury, followed by 30 minutes of exercise training daily from 5 to 28 days after MCAO. Motor function was tested using the rotarod test. We used fluorogold (FG) nigral injection to trace striatonigral and corticonigral projection neurons, and green fluorescent protein (GFP)-targeting retroviral vectors combined with FG double labeling (GFP⁺ -FG⁺) to detect newborn projection neurons. The results showed that exercise improved the recovery of motor function of rats after MCAO. Meanwhile, exercise also increased the levels of BDNF and VEGF, and reduced Nogo-A in ischemic brain. On this condition, we further found that exercise significantly increased the number of GFP⁺ -FG⁺ neurons in the striatum and frontal and parietal cortex ipsilateral to MCAO, suggesting an increase of newborn striatonigral and corticonigral projection neurons by exercise post-stroke. In addition, we found that exercise also increased NeuN⁺ and FG⁺ cells in the striatum and frontal and parietal cortex, the ischemic territory, and tyrosine hydroxylase (TH) immunopositive staining cells in the substantia nigra, a region remote from the ischemic territory. Our results provide the first evidence that exercise can effectively enhance the capacity for regeneration of newborn projection neurons in ischemic injured mammalian brains while improving motor function. Our results provide a very important cellular mechanism to illustrate the effectiveness of rehabilitative treatment post-stroke in the clinic.     

Plasma Midregional Pro-Adrenomedullin Improves Prediction of Functional Outcome in Ischemic Stroke

Background

To evaluate if plasma levels of midregional pro-adrenomedullin (MR-proADM) improve prediction of functional outcome in ischemic stroke.

Methods

In 168 consecutive ischemic stroke patients, plasma levels of MR-proADM were measured within 24 hours from symptom onset. Functional outcome was assessed by the modified Rankin Scale (mRS) at 90 days following stroke. Logistic regression, receiver operating characteristics (ROC) curve analysis, net reclassification improvement (NRI), and Kaplan-Meier survival analysis were applied.

Results

Plasma MR-proADM levels were found significantly higher in patients with unfavourable (mRS 3–6) compared to favourable (mRS 0–2) outcomes. MR-proADM levels were entered into a predictive model including the patients'' age, National Institutes of Health Stroke Scale (NIHSS), and the use of recanalization therapy. The area under the ROC curve did not increase significantly. However, category-free NRI of 0.577 (p<0.001) indicated a significant improvement in reclassification of patients. Furthermore, MR-proADM levels significantly improved reclassification of patients in the prediction of outcome by the Stroke Prognostication using Age and NIHSS-100 (SPAN-100; NRI = 0.175; p = 0.04). Kaplan-Meier survival analysis showed a rising risk of death with increasing MR-proADM quintiles.

Conclusions

Plasma MR-proADM levels improve prediction of functional outcome in ischemic stroke when added to the patients'' age, NIHSS on admission, and the use of recanalization therapy. Levels of MR-proADM in peripheral blood improve reclassification of patients when the SPAN-100 is used to predict the patients'' functional outcome.     

Upregulation of Microglial ZEB1 Ameliorates Brain Damage after Acute Ischemic Stroke

1. Download high-res image (285KB)
2. Download full-size image

     

Granulocyte Colony-Stimulating Factor (G-CSF) Protects Oligpdendrocyte and Promotes Hindlimb Functional Recovery after Spinal Cord Injury in Rats

Background

Granulocyte colony-stimulating factor (G-CSF) is a protein that stimulates differentiation, proliferation, and survival of cells in the granulocytic lineage. Recently, a neuroprotective effect of G-CSF was reported in a model of cerebral infarction and we previously reported the same effect in studies of murine spinal cord injury (SCI). The aim of the present study was to elucidate the potential therapeutic effect of G-CSF for SCI in rats.

Methods

Adult female Sprague-Dawley rats were used in the present study. Contusive SCI was introduced using the Infinite Horizon Impactor (magnitude: 200 kilodyne). Recombinant human G-CSF (15.0 µg/kg) was administered by tail vein injection at 1 h after surgery and daily the next four days. The vehicle control rats received equal volumes of normal saline at the same time points.

Results

Using a contusive SCI model to examine the neuroprotective potential of G-CSF, we found that G-CSF suppressed the expression of pro-inflammatory cytokine (IL-1 beta and TNF- alpha) in mRNA and protein levels. Histological assessment with luxol fast blue staining revealed that the area of white matter spared in the injured spinal cord was significantly larger in G-CSF-treated rats. Immunohistochemical analysis showed that G-CSF promoted up-regulation of anti-apoptotic protein Bcl-Xl on oligpodendrocytes and suppressed apoptosis of oligodendrocytes after SCI. Moreover, administration of G-CSF promoted better functional recovery of hind limbs.

Conclusions

G-CSF protects oligodendrocyte from SCI-induced cell death via the suppression of inflammatory cytokines and up-regulation of anti-apoptotic protein. As a result, G-CSF attenuates white matter loss and promotes hindlimb functional recovery.     

Resveratrol Pretreatment Decreases Ischemic Injury and Improves Neurological Function Via Sonic Hedgehog Signaling After Stroke in Rats

Resveratrol has neuroprotective effects for ischemic cerebral stroke. However, its neuroprotective mechanism for stroke is less well understood. Beneficial actions of the activated Sonic hedgehog (Shh) signaling pathway in stroke, such as improving neurological function, promoting neurogenesis, anti-oxidative, anti-apoptotic, and pro-angiogenic effects, have been noted, but relatively little is known about the role of Shh signaling in resveratrol-reduced cerebral ischemic injury after stroke. The present study tests whether the Shh pathway mediates resveratrol to decrease cerebral ischemic injury and improve neurological function after stroke. We observed that resveratrol pretreatment significantly improved neurological function, decreased infarct volume, enhanced vitality, and reduced apoptosis of neurons in vivo and vitro after stroke. Meanwhile, expression levels of Shh, Ptc-1, Smo, and Gli-1 mRNAs were significantly upregulated and Gli-1 was relocated to the nucleus. Intriguingly, in vivo and in vitro inhibition of the Shh signaling pathway with cyclopamine, a Smo inhibitor, completely reversed the above effects of resveratrol. These results suggest that decreased cerebral ischemic injury and improved neurological function by resveratrol may be mediated by the Shh signaling pathway.     

Off-Hour Effect on 3-Month Functional Outcome after Acute Ischemic Stroke: A Prospective Multicenter Registry

Background and Purpose

The time of hospital arrival may have an effect on prognosis of various vascular diseases. We examined whether off-hour admission would affect the 3-month functional outcome in acute ischemic stroke patients admitted to tertiary hospitals.

Methods

We analyzed the ‘off-hour effect’ in consecutive patients with acute ischemic stroke using multi-center prospective stroke registry. Work-hour admission was defined as when the patient arrived at the emergency department between 8 AM and 6 PM from Monday to Friday and between 8 AM and 1 PM on Saturday. Off-hour admission was defined as the rest of the work-hours and statutory holidays. Multivariable logistic regression was used to analyze the association between off-hour admission and 3-month unfavorable functional outcome defined as modified Rankin Scale (mRS) 3–6. Multivariable model included age, sex, risk factors, prehospital delay time, intravenous thrombolysis, stroke subtypes and severity as covariates.

Results

A total of 7075 patients with acute ischemic stroke were included in this analysis: mean age, 67.5 (±13.0) years; male, 58.6%. In multivariable analysis, off-hour admission was not associated with unfavorable functional outcome (OR, 0.89; 95% CI, 0.72–1.09) and mortality (OR, 1.09; 95% CI, 0.77–1.54) at 3 months. Moreover, off-hour admission did not affect a statistically significant shift of 3-month mRS distributions (OR, 0.90; 95% CI, 0.78–1.05).

Conclusions

‘Off-hour’ admission is not associated with an unfavorable 3-month functional outcome in acute ischemic stroke patients admitted to tertiary hospitals in Korea. This finding indicates that the off-hour effects could be overcome with well-organized stroke management strategies.     

Photomechanical Wave-Driven Delivery of siRNAs Targeting Intermediate Filament Proteins Promotes Functional Recovery after Spinal Cord Injury in Rats

The formation of glial scars after spinal cord injury (SCI) is one of the factors inhibiting axonal regeneration. Glial scars are mainly composed of reactive astrocytes overexpressing intermediate filament (IF) proteins such as glial fibrillary acidic protein (GFAP) and vimentin. In the current study, we delivered small interfering RNAs (siRNAs) targeting these IF proteins to SCI model rats using photomechanical waves (PMWs), and examined the restoration of motor function in the rats. PMWs are generated by irradiating a light-absorbing material with 532-nm nanosecond laser pulses from a Q-switched Nd:YAG laser. PMWs can site-selectively increase the permeability of the cell membrane for molecular delivery. Rat spinal cord was injured using a weight-drop device and the siRNA(s) solutions were intrathecally injected into the vicinity of the exposed SCI, to which PMWs were applied. We first confirmed the substantial uptake of fluorescence-labeled siRNA by deep glial cells; then we delivered siRNAs targeting GFAP and vimentin into the lesion. The treatment led to a significant improvement in locomotive function from five days post-injury in rats that underwent PMW-mediated siRNA delivery. This was attributable to the moderate silencing of the IF proteins and the subsequent decrease in the cavity area in the injured spinal tissue.     

Predicting Functional Recovery after Acute Ankle Sprain

Introduction

Ankle sprains are among the most common acute musculoskeletal conditions presenting to primary care. Their clinical course is variable but there are limited recommendations on prognostic factors. Our primary aim was to identify clinical predictors of short and medium term functional recovery after ankle sprain.

Methods

A secondary analysis of data from adult participants (N = 85) with an acute ankle sprain, enrolled in a randomized controlled trial was undertaken. The predictive value of variables (age, BMI, gender, injury mechanism, previous injury, weight-bearing status, medial joint line pain, pain during weight-bearing dorsiflexion and lateral hop test) recorded at baseline and at 4 weeks post injury were investigated for their prognostic ability. Recovery was determined from measures of subjective ankle function at short (4 weeks) and medium term (4 months) follow ups. Multivariate stepwise linear regression analyses were undertaken to evaluate the association between the aforementioned variables and functional recovery.

Results

Greater age, greater injury grade and weight-bearing status at baseline were associated with lower function at 4 weeks post injury (p<0.01; adjusted R square=0.34). Greater age, weight-bearing status at baseline and non-inversion injury mechanisms were associated with lower function at 4 months (p<0.01; adjusted R square=0.20). Pain on medial palpation and pain on dorsiflexion at 4 weeks were the most valuable prognostic indicators of function at 4 months (p< 0.01; adjusted R square=0.49).

Conclusion

The results of the present study provide further evidence that ankle sprains have a variable clinical course. Age, injury grade, mechanism and weight-bearing status at baseline provide some prognostic information for short and medium term recovery. Clinical assessment variables at 4 weeks were the strongest predictors of recovery, explaining 50% of the variance in ankle function at 4 months. Further prospective research is required to highlight the factors that best inform the expected convalescent period, and risk of recurrence.     

血清超敏C-反应蛋白水平与急性缺血性脑卒中预后的关系

目的:探讨急性缺血性脑卒中患者血清超敏C-反应蛋白(hs-CRP)的水平对卒中后功能障碍的预测价值.方法:分别在发病后第1和7天,采用颗粒增强免疫透射比浊法对92例急性缺血性脑卒中患者检测血清hs-CRP水平,并选取40例健康受试者作为对照.随访并记录患者1月、3月和6月mRS评分.结果:①急性缺血性脑卒中患者血清hs-CRP水平较对照组显著升高.②急性缺血性卒中患者入院1d和7d血清hs-CRP水平与1月、3月和6月mRS评分,均有明显的相关性.与入院1d血清hs-CRP水平相比,入院7d血清hs-CRP水平与mRS评分相关性更好.③与无颈动脉粥样硬化危险因素的缺血性卒中患者相比,有颈动脉粥样硬化危险因素的缺血性卒中患者入院7d血清hs-CRP水平明显升高.结论:与入院1d血清hs-CRP水平相比,入院7d血清hs-CRP水平对卒中后功能障碍的预测价值更好.     

FTY720 Treatment in the Convalescence Period Improves Functional Recovery and Reduces Reactive Astrogliosis in Photothrombotic Stroke

Background

The Sphingosine-1-phosphate (S1P) signaling pathway is known to influence pathophysiological processes within the brain and the synthetic S1P analog FTY720 has been shown to provide neuroprotection in experimental models of acute stroke. However, the effects of a manipulation of S1P signaling at later time points after experimental stroke have not yet been investigated. We examined whether a relatively late initiation of a FTY720 treatment has a positive effect on long-term neurological outcome with a focus on reactive astrogliosis, synapses and neurotrophic factors.

Methods

We induced photothrombotic stroke (PT) in adult C57BL/6J mice and allowed them to recover for three days. Starting on post-stroke day 3, mice were treated with FTY720 (1 mg/kg b.i.d.) for 5 days. Behavioral outcome was observed until day 31 after photothrombosis and periinfarct cortical tissue was analyzed using tandem mass-spectrometry, TaqMan®analysis and immunofluorescence.

Results

FTY720 treatment results in a significantly better functional outcome persisting up to day 31 after PT. This is accompanied by a significant decrease in reactive astrogliosis and larger post-synaptic densities as well as changes in the expression of vascular endothelial growth factor α (VEGF α). Within the periinfarct cortex, S1P is significantly increased compared to healthy brain tissue.

Conclusion

Besides its known neuroprotective effects in the acute phase of experimental stroke, the initiation of FTY720 treatment in the convalescence period has a positive impact on long-term functional outcome, probably mediated through reduced astrogliosis, a modulation in synaptic morphology and an increased expression of neurotrophic factors.     

Determinants of Fatigue after First-Ever Ischemic Stroke during Acute Phase

Background and Purpose

Fatigue after stroke is common and has a negative impact on rehabilitation and survival. However, its pathogenesis and contributing factors remain unclear. The purpose of this study was to identify factors influencing the occurrence of fatigue after first-ever ischemic stroke in acute phase.

Methods

We examined 265 consecutive patients with first-ever ischemic stroke during acute phase (within 2 weeks) in two tertiary stroke care hospitals in Henan, China. We documented patients’ demographic and clinical characteristics through face-to-face interviews using structured questionnaires and reviews of medical records. Post-stroke fatigue was defined as a score of ≥4 using the Fatigue Severity Scale. Multivariate logistic regression was used to examine post-stroke fatigue in relation to socio-demographic, lifestyle, clinical characteristics and family function.

Results

About 40% first-ever ischemic stroke patients experienced post-stroke fatigue in acute phase. Post-stroke fatigue was associated with lack of exercise before stroke (adjusted odds ratio 4.01, 95% CI 1.95–8.24), family dysfunction (2.63, 1.20–5.80), depression (2.39, 1.02–5.58), the presence of pre-stroke fatigue (4.89, 2.13–11.21), use of sedative medications (4.14, 1.58–10.88), coronary heart disease (3.38, 1.46–7.79) and more severe Modified Rankin Scale (2.55, 1.65–3.95).

Conclusions

The causes of post-stroke fatigue are multifaceted. More physical exercise, improving family function, reducing depression and appropriate use of sedative medications may be helpful in preventing post-stroke fatigue.     

Umbilical Cord Blood Stem Cell Mediated Downregulation of Fas Improves Functional Recovery of Rats after Spinal Cord Injury

Human umbilical cord blood stem cells (hUCB), due to their primitive nature and ability to develop into nonhematopoietic cells of various tissue lineages, represent a potentially useful source for cell-based therapies after spinal cord injury (SCI). To evaluate their therapeutic potential, hUCB were stereotactically transplanted into the injury epicenter, one week after SCI in rats. Our results show the presence of a substantial number of surviving hUCB in the injured spinal cord up to five weeks after transplantation. Three weeks after SCI, apoptotic cells were found especially in the dorsal white matter and gray matter, which are positive for both neuron and oligodendrocyte markers. Expression of Fas on both neurons and oligodendrocytes was efficiently downregulated by hUCB. This ultimately resulted in downregulation of caspase-3 extrinsic pathway proteins involving increased expression of FLIP, XIAP and inhibition of PARP cleavage. In hUCB-treated rats, the PI3K/Akt pathway was also involved in antiapoptotic actions. Further, structural integrity of the cytoskeletal proteins α-tubulin, MAP2A&2B and NF-200 has been preserved in hUCB treatments. The behavioral scores of hind limbs of hUCB-treated rats improved significantly than those of the injured group, showing functional recovery. Taken together, our results indicate that hUCB-mediated downregulation of Fas and caspases leads to functional recovery of hind limbs of rats after SCI.     

Local Administration of AAV-BDNF to Subventricular Zone Induces Functional Recovery in Stroke Rats

Migration of new neuroprogenitor cells (NPCs) from the subventricular zone (SVZ) plays an important role in neurorepair after injury. Previous studies have shown that brain derived neurotrophic factor (BDNF) enhances the migration of NPCs from SVZ explants in neonatal mice in vitro. The purpose of this study was to identify the role of BDNF in SVZ cells using AAV-BDNF in an animal model of stroke. BDNF protein production after AAV‐BDNF infection was verified in primary neuronal culture. AAV-BDNF or AAV-RFP was injected into the left SVZ region of adult rats at 14 days prior to right middle cerebral artery occlusion (MCAo). SVZ tissues were collected from the brain and placed in Metrigel cultures 1 day after MCAo. Treatment with AAV-BDNF significantly increased the migration of SVZ cells in the stroke brain in vitro. In another set of animals, AAV-GFP was co-injected with AAV-BDNF or AAV-RFP to label cells in left SVZ prior to right MCAo. Local administration of AAV-BDNF significantly enhanced recovery of locomotor function and migration of GFP-positive cells from the SVZ toward the lesioned hemisphere in stroke rats. Our data suggest that focal administration of AAV-BDNF to the SVZ increases behavioral recovery post stroke, possibly through the enhancement of migration of cells from SVZ in stroke animals. Regional manipulation of BDNF expression through AAV may be a novel approach for neurorepair in stroke brains.     

Comparison of Statistical and Clinical Predictions of Functional Outcome after Ischemic Stroke

Background

To determine whether the predictions of functional outcome after ischemic stroke made at the bedside using a doctor’s clinical experience were more or less accurate than the predictions made by clinical prediction models (CPMs).

Methods and Findings

A prospective cohort study of nine hundred and thirty one ischemic stroke patients recruited consecutively at the outpatient, inpatient and emergency departments of the Western General Hospital, Edinburgh between 2002 and 2005. Doctors made informal predictions of six month functional outcome on the Oxford Handicap Scale (OHS). Patients were followed up at six months with a validated postal questionnaire. For each patient we calculated the absolute predicted risk of death or dependence (OHS≥3) using five previously described CPMs. The specificity of a doctor’s informal predictions of OHS≥3 at six months was good 0.96 (95% CI: 0.94 to 0.97) and similar to CPMs (range 0.94 to 0.96); however the sensitivity of both informal clinical predictions 0.44 (95% CI: 0.39 to 0.49) and clinical prediction models (range 0.38 to 0.45) was poor. The prediction of the level of disability after stroke was similar for informal clinical predictions (ordinal c-statistic 0.74 with 95% CI 0.72 to 0.76) and CPMs (range 0.69 to 0.75). No patient or clinician characteristic affected the accuracy of informal predictions, though predictions were more accurate in outpatients.

Conclusions

CPMs are at least as good as informal clinical predictions in discriminating between good and bad functional outcome after ischemic stroke. The place of these models in clinical practice has yet to be determined.     

Stem Cell Mediation of Functional Recovery after Stroke in the Rat

Background

Regenerative strategies of stem cell grafting have been demonstrated to be effective in animal models of stroke. In those studies, the effectiveness of stem cells promoting functional recovery was assessed by behavioral testing. These behavioral studies do, however, not provide access to the understanding of the mechanisms underlying the observed functional outcome improvement.

Methodology/Principal Findings

In order to address the underlying mechanisms of stem cell mediated functional improvement, this functional improvement after stroke in the rat was investigated for six months after stroke by use of fMRI, somatosensory evoked potentials by electrophysiology, and sensorimotor behavior testing. Stem cells were grafted ipsilateral to the ischemic lesion. Rigorous exclusion of spontaneous recovery as confounding factor permitted to observe graft-related functional improvement beginning after 7 weeks and continuously increasing during the 6-month observation period. The major findings were i) functional improvement causally related to the stem cells grafting; ii) tissue replacement can be excluded as dominant factor for stem cell mediated functional improvement; iii) functional improvement occurs by exclusive restitution of the function in the original representation field, without clear contributions from reorganization processes, and iv) stem cells were not detectable any longer after six months.

Conclusions/Significance

A delayed functional improvement due to stem cell implantation has been documented by electrophysiology, fMRI and behavioral testing. This functional improvement occurred without cells acting as a tissue replacement for the necrotic tissue after the ischemic event. Combination of disappearance of grafted cells after six months on histological sections with persistent functional recovery was interpreted as paracrine effects by the grafted stem cells being the dominant mechanism of cell activity underlying the observed functional restitution of the original activation sites. Future studies will have to investigate whether the stem cell mediated improvement reactivates the original representation target field by using original connectivity pathways or by generating/activating new ones for the stimulus.