Kyung-Sool Jang

In vivo Tracking of Transplanted Bone Marrow-Derived Mesenchymal Stem Cells in a Murine Model of Stroke by Bioluminescence Imaging

OBJECTIVE This study was designed to validate the cell trafficking efficiency of the in vivo bioluminescence image (BLI) study in the setting of transplantation of the luciferase expressing bone marrow-derived mesenchymal stem cells (BMSC), which were delivered at each different time after transient middle cerebral artery occlusion (MCAO) in a mouse model. METHODS Transplanting donor BMSC were prepared by primary cell culture from transgenic mouse expressing luciferase (LUC). Transient focal infarcts were induced in 4-6-week-old male nude mice. The experiment mice were divided into five groups by the time of MSC transplantation : 1) sham-operation group, 2) 2-h group, 3) 1-day group, 4) 3-day group, and 5) 1- week group. BLI for detection of spatial distribution of transplanted MSC was performed by detecting emitted photons. Migration of the transplanted cells to the infarcted area was confirmed by histological examinations. Differences between groups were evaluated by paired t-test. RESULTS A focal spot of bioluminescence was observed at the injection site on the next day after transplantation by signal intensity of bioluminescence. After 4 weeks, the mean signal intensities of 2-h, 1-day, 3-day, and 1-week group were 2.6×10(7) ± 7.4×10(6), 6.1×10(6) ± 1.2×10(6), 1.7×10(6) ± 4.4×10(5), and 8.9×10(6) ± 9.5×10(5), respectively. The 2-h group showed significantly higher signal intensity (p < 0.01). The engrafted BMSC showed around the infarct border zones on immunohistochemical examination. The counts of LUC-positive cells revealed the highest number in the 2-h group, in agreement with the results of BLI experiments (p < 0.01). CONCLUSION In this study, the results suggested that the transplanted BMSC migrated to the infarct border zone in BLI study and the higher signal intensity of LUC-positive cells seen in 2 hrs after MSC transplantation in MCAO mouse model. In addition, noninvasive imaging in real time is an ideal method for tracking stem cell transplantation. This method can be widely applied to various research fields of cell transplantation therapy.

Effect of combination therapy with sodium ozagrel and panax ginseng on transient cerebral ischemia model in rats.

Sodium ozagrel (SO) prevents platelet aggregation and vasoconstriction in the cerebral ischemia. It plays an important role in the prevention of brain damage induced by cerebral ischemia/reperfusion. Recently, many animal studies have suggested that the Panax ginseng (PG) has neuroprotective effects in the ischemic brain. In this study, we assessed the neuroprotective effects that come from a combination therapy of SO and PG in rat models with middle cerebral artery occlusion (MCAO). Animals with MCAO were assigned randomly to one of the following four groups: (1) control (Con) group, (2) SO group (3 mg/kg, intravenously), (3) PG group (200 mg/kg, oral feeding), and (4) SO + PG group. The rats were subjected to a neurobehavior test including adhesive removal test and rotarod test at 1, 3, 7, 10, and 15 days after MCAO. The cerebral ischemic volume was quantified by Metamorph imaging software after 2-3-5-triphenyltetrazolium (TTC) staining. The neuronal cell survival and astrocytes expansion were assessed by immunohistofluorescence staining. In the adhesive removal test, the rats of PG or SO + PG group showed significantly better performance than those of the control group (Con: 88.1 ± 24.8, PG: 43.6 ± 11, SO + PG: 11.8 ± 7, P < .05). Notably, the combination therapy group (SO + PG) showed better performance than the SO group alone (SO: 56 ± 12, SO + PG: 11.8 ± 7, P < .05). In TTC staining for infarct volume, cerebral ischemic areas were also significantly reduced in the PG group and SO + PG group (Con: 219 ± 32, PG: 117 ± 8, SO + PG: 99 ± 11, P < .05). Immunohistofluorescence staining results showed that the group which received SO + PG group therapy had neuron cells in the normal range. They also had a low number of astrocytes and apoptotic cells compared with the control or SO group in the peri-infarction area. During astrocytes staining, compared to the SO + PG group, the PG group showed only minor differences in the number of NeuN-positive cells and quantitative analysis of infarct volume. In conclusion, these studies showed that in MCAO rat models, the combination therapy with SO and PG may provide better neuroprotective effects such as higher neuronal cell survival and inhibition of astrocytes expansion than monotherapy with SO alone.

Novel aneurysm neck reconstruction device: initial experience in an experimental preclinical bifurcation aneurysm model.

Introduction Treatment of wide-necked bifurcation aneurysms often poses procedural and long-term outcome challenges. The initial preclinical experience with the Pulsar Vascular Aneurysm Neck Reconstruction Device (PVANRD) in a canine bifurcation model is described. Methods Experimental bifurcation vein pouch aneurysms were surgically created in the carotid arteries of eight dogs. Endovascular coiling of the aneurysms with assistance of the PVANRD was performed in all cases with acute performance compared with Y-stenting. Results Twelve devices were deployed in the eight cases. Deployment of the devices was straightforward and successfully protected the parent artery and maintained patency of the bifurcation in all cases, despite the use of oversized coils. Conclusion The PVANRD is a novel bifurcation stent that facilitates treatment of wide-necked bifurcation aneurysms compared with currently available adjunctive devices.

A Pilot Study for the Neuroprotective Effect of Gongjin-dan on Transient Middle Cerebral Artery Occlusion-Induced Ischemic Rat Brain

In this study, we investigated whether gongjin-dan improves functional recovery and has neuroprotective effects on reducing the infarct volume after transient middle cerebral artery occlusion (MCAo). Infarct volume was measured using TTC staining and glucose utilization by F-18 FDG PET. Functional improvement was evaluated with the Rota-rod, treadmill, Garcia score test, and adhesive removal test. At 14 days after MCAo, neuronal cell survival, astrocytes expansion, and apoptosis were assessed by immunohistofluorescence staining in the peri-infarct region. Also, the expression of neurotrophic factors and inflammatory cytokines such as VEGF, BDNF, Cox-2, TNF-α, IL-1β, and IL-1α was measured in ischemic hemisphere regions. The gongjin-dan-treated group showed both reduced infarct volume and increased glucose utilization. Behavior tests demonstrated a significant improvement compared to the control. Also in the gongjin-dan treated group, NeuN-positive cells were increased and number of astrocytes, microglia, and apoptotic cells was significantly decreased compared with the control group in the ischemic peri-infarct area. Furthermore, the expression of VEGF and BDNF was increased and level of Cox-2, TNF-α, IL-1β, and IL-1α was decreased. These results suggest that gongjin-dan may improve functional outcome through the rapid restoration of metabolism and can be considered as a potential neuroprotective agent.

Motor-Evoked Potential Confirmation of Functional Improvement by Transplanted Bone Marrow Mesenchymal Stem Cell in the Ischemic Rat Brain

This study investigated the effect of bone marrow mesenchymal stem cells (BMSCs) on the motor pathway in the transient ischemic rat brain that were transplanted through the carotid artery, measuring motor-evoked potential (MEP) in the four limbs muscle and the atlantooccipital membrane, which was elicited after monopolar and bipolar transcortical stimulation. After monopolar stimulation, the latency of MEP was significantly prolonged, and the amplitude was less reduced in the BMSC group in comparison with the control group (P < .05). MEPs induced by bipolar stimulation in the left forelimb could be measured in 40% of the BMSC group and the I wave that was not detected in the control group was also detected in 40% of the BMSC group. Our preliminary results imply that BMSCs transplanted to the ischemic rat brain mediate effects on the functional recovery of the cerebral motor cortex and the motor pathway.

Changes in brain FDG metabolism induced by acupuncture in healthy volunteers

Background: With the aid of newly developed functional brain imaging studies, studies are ongoing to see if acupuncture first acts on specific brain areas to induce effects on the human body. Purpose: To examine if stimulation at specific acupuncture points changes brain glucose metabolism patterns, including the limbic system and specific brain areas related to the acupuncture effect in healthy volunteers using fluorodeoxyglucose positron emission tomography combined computed tomography (FDG-PET/CT). Material and Methods: Twenty healthy volunteers (11 men and 9 women; mean age 49.1±7.3 years, age range 35–62 years) were included. Two sets of PET/CT scans were obtained from each volunteer, with and without stimulation by acupuncture. Two classic acupoints, LR3 (liver meridian) and ST44 (stomach meridian) were tested at the same time, using disposable sterile stainless steel needles. After initial acupuncture, the needle was kept in place without further stimulation. FDG-PET/CT scan of the brain began 45 min after FDG injection (185–222 MBq). Results: After stimulation of LR3 and ST44 by acupuncture, glucose metabolism in the brain was increased in the left insula (BA 13), bilateral thalami, superior frontal region of the right frontal lobe, and the inferior frontal region of left frontal lobe compared with baseline. On the other hand, glucose metabolism was decreased after acupuncture in the cingulate and parahippocampal (BA 36) regions of the left limbic lobe. Conclusion: Changes of glucose metabolism in specific brain areas following stimulation by acupuncture on LR3 and ST44 were documented using FDG-PET/CT.

Assessment of cerebrovascular reserve before and after STA-MCA bypass surgery by SPECT and SPM analysis.

Objective The purpose of this study was to objectively assess the efficacy of superficial temporal artery to middle cerebral artery (STA-MCA) bypass surgery using Technetium (Tc)-99m-ethyl cysteinate dimer (ECD) single photon emission computed tomography (SPECT) in patients who underwent STA-MCA bypass surgery. Materials and Methods Brain perfusion SPECT images obtained at baseline and after the administration of acetazolamide were reconstructed using statistical parametric mapping in 23 patients, both before and after STA-MCA bypass surgery. The clinical outcomes of the surgery were also recorded and compared with the hemodynamic changes. A voxel with an uncorrected p-value of less than 0.001 was considered to be statistically significant. Results SPECT images of the territory supplied by the bypass graft showed an increase in both cerebrovascular flow and reserve at baseline, and the increase was significantly higher following the administration of acetazolamide. All patients showed improvement of clinical symptoms and increased blood flow to the left temporal, parietal, and frontal cortices as well as the thalamus. Conclusion Brain SPECT effectively and objectively demonstrated the improved outcomes of STA-MCA bypass surgery, and thus may be used in postoperative analyses.

Association Factors for CT Angiography Spot Sign and Hematoma Growth in Korean Patients with Acute Spontaneous Intracerebral Hemorrhage : A Single-Center Cohort Study

Objective This study was conducted to clarify the association factors and clinical significance of the CT angiography (CTA) spot sign and hematoma growth in Korean patients with acute intracerebral hemorrhage (ICH). Methods We retrospectively collected the data of 287 consecutive patients presenting with acute ICH who arrived within 12 hours of ictus. Baseline clinical and radiological characteristics as well as the mortality rate within one month were assessed. A binary logistic regression was conducted to obtain association factors for the CTA spot sign and hematoma growth. Results We identified a CTA spot sign in 40 patients (13.9%) and hematoma growth in 78 patients (27.2%). An elapsed time to CT scan of less than 3 hours (OR, 5.14; 95% CI, 1.76-15.02; p=0.003) was associated with the spot sign. A CTA spot sign (OR, 5.70; 95% CI, 2.70-12.01; p<0.001), elevated alanine transaminase (GPT) level >40 IU (OR, 2.01; 95% CI, 1.01-4.01; p=0.047), and an international normalized ratio ≥1.8 or warfarin medication (OR, 5.64; 95% CI, 1.29-24.57; p=0.021) were independent predictors for hematoma growth. Antiplatelet agent medication (OR, 4.92; 95% CI, 1.31-18.50; p=0.019) was significantly associated with hematoma growth within 6 hours of ictus. Conclusion As previous other populations, CTA spot sign was a strong predictor for hematoma growth especially in hyper-acute stage of ICH in Korea. Antithrombotics medication might also be associated with hyper-acute hematoma growth. In our population, elevated GPT was newly identified as a predictor for hematoma growth and its effect for hematoma growth is necessary to be confirmed through a further research.

Assessment of cerebral blood perfusion changes after neurorehabilitation therapy in patients with middle cerebral artery infarction: An acetazolamide-challenged SPECT study

Stroke is a leading cause of death and disability worldwide. Although neuroimaging has been used to examine brain changes related to recovery from stroke, cerebral perfusion changes after rehabilitation have yet to be elucidated. The aim of this study was to evaluate the regional cerebral blood flow (rCBF) changes and their associations with gross motor functions after neurorehabilitation therapy in stroke patients. A total of 7 patients with middle cerebral artery (MCA) infarction received conventional neurorehabilitation therapy twice per day for 4‐6 weeks on admission. Brain perfusion images were acquired before and after the therapy using acetazolamide‐challenged single photon emission computed tomography. A whole‐brain voxel‐wise analysis found increased rCBF in the contralesional prefrontal, precentral, and postcentral cortical areas and decreased rCBF in the ipsilesional insula, posterior orbital gyrus, and central operculum. Moreover, a region of interest analysis revealed that rCBF of the ipsilesional basal ganglia was positively correlated with motor function at baseline and follow‐up, and perfusion changes in the ipsilesional basal ganglia was positively correlated with changes in motor function. These findings suggest that the contralesional prefrontal and sensorimotor cortex may play compensatory roles during the motor recovery and that perfusion in the ipsilesional basal ganglia is closely associated not only with current functional status but also with clinical improvement after neurorehabilitation therapy in patients with MCA infarction. Further studies with larger sample size are warranted to investigate whether assessment of cerebral perfusion may be clinically useful in rehabilitation of stroke patients.

Olfactory identification and white matter integrity in amnestic mild cognitive impairment: A preliminary study

Increasing evidence suggests that olfactory impairment is associated with an increased risk of conversion from mild cognitive impairment (MCI) to Alzheimers disease. This study was to explore how olfactory identification relates to white matter (WM) integrity, using diffusion tensor imaging (DTI) in individuals with amnestic MCI. DTI was performed from nineteen individuals with amnestic MCI (mean age: 69.95 ± 8.20 years). Olfactory identification was assessed using the Cross‐Cultural Smell Identification Test (CC‐SIT), a widely used test for odor identification involving a scratch and sniff test of 12 micro‐encapsulated odorants. Cross‐sectional voxel‐wise analyses of relationships between CC‐SIT scores and DTI indices were performed using Tract‐Based Spatial Statistics. Higher CC‐SIT scores were associated with lower mean, axial and radial diffusivities in areas such as the body and splenium of corpus callosum, frontal WM (lateral orbitofrontal, caudal middle frontal, precentral, left superior frontal, and right pars opercularis), right superior longitudinal fasciculus, anterior and superior corona radiata, and internal and external capsules, while CC‐SIT scores were not significantly associated with fractional anisotropy across all MCI participants. In individuals with amnestic MCI, impaired olfactory identification is associated with alterations in WM integrity expressed as a lower diffusivities value. This cross‐sectional preliminary study suggests that olfactory impairment contributes to WM microstructural alterations in individuals with amnestic MCI.