Jae-Kyu Roh

Stem cell therapy is currently being studied with a view to rescuing various neurological diseases. Such studies require not only the discovery of potent candidate cells but also the development of methods that allow optimal delivery of those candidates to the brain tissues. Given that the blood-brain barrier (BBB) precludes cells from entering the brain, the present study was designed to test whether hyperosmolar mannitol securely opens the BBB and enhances intra-arterial cell delivery. A noninjured normal canine model in which the BBB was presumed to be closed was used to evaluate the feasibility and safety of the tested protocol. Autologous adipose tissue-derived pericytes with platelet-derived growth factor receptor β positivity were utilized. Cells were administered 5 min after mannitol pretreatment using one of following techniques: ( 1 ) bolus injection of a concentrated suspension, ( 2 ) continuous infusion of a diluted suspension, or ( 3 ) bolus injection of a concentrated suspension that had been shaken by repeated syringe pumping. Animals administered a concentrated cell suspension without mannitol pretreatment served as a control group. Vital signs, blood parameters, neurologic status, and major artery patency were kept stable throughout the experiment and the 1-month posttreatment period. Although ischemic lesions were noted on magnetic resonance imaging in several mongrel dogs with concentrated cell suspension, the injection technique using repeated syringe shaking could avert this complication. The cells were detected in both ipsilateral and contralateral cortices and were more frequent at the ipsilateral and frontal locations, whereas very few cells were observed anywhere in the brain when mannitol was not preinjected. These data suggest that intra-arterial cell infusion with mannitol pretreatment is a feasible and safe therapeutic approach in stable brain diseases such as chronic stroke.

Cerebellar degeneration is a devastating manifestation of cerebellar-type multiple-system atrophy (MSA), a rapidly progressive neurodegenerative disease, and the exact pathogenesis is unknown. Here, we examined the expression of micro-RNAs (miRNAs), which are short noncoding RNAs, in the cerebellum of MSA and the key target genes. miRNA microarray found 11 miRNAs with significantly different expression in MSA cerebellum compared to cerebellum from age-, sex-, and postmortem interval-matched controls. miR-202 was the most upregulated in the MSA samples. In silico analysis, followed by target gene luciferase assay, in vitro transfection, and Western blotting in human samples showed that miR-202 downregulates Oct1 (Pou2f1), a transcription factor expressed in cerebellar Purkinje cells. Transfection of Neuro-2a cells with miR-202 enhanced oxidative stress-induced cell death, and an antagomir to miR-202 inhibited this effect of miR-202. This study provides novel insight into the role of miRNA in cerebellar degeneration and suggests that miR-202 is a key miRNA mediating the pathogenesis of MSA.

Although use of antithrombotic agents is recommended after ischaemic stroke or transient ischaemic attack (TIA), long-term outcome of secondary prevention between stroke subtypes has not yet been explored. We used data from the Korean Stroke Registry (KSR), a nationwide, multicentre, prospective registry for acute stroke patients. Patients with acute ischaemic stroke or TIA within 7 days of onset were consecutively enrolled between January 2002 and September 2010. A total of 46 108 patients with ischaemic stroke and TIA were included in this study. Among the major stroke subtypes, stroke due to small vessel occlusion (SVO) showed the lowest mortality, whereas cardioembolic stroke (CE) was associated with the fatal prognosis during the follow-up [for SVO: hazard ratio (HR) 0.66, 95% CI 0.62–0.71; for CE: HR 1.41, 95% CI 1.30–1.53; large artery atherosclerosis (LAA) group as a reference]. Regarding secondary prevention, antiplatelet polytherapy was better than monotherapy in the patients with LAA-related stroke in prognosis [HR 0.89, 95% CI 0.80–0.98]. Anticoagulant therapy was associated with better outcome than antiplatelet monotherapy in CE-related stroke [HR 0.66, 95% CI 0.59–0.74]. In SVO-related stroke group, antiplatelet polytherapy failed to show benefits over monotherapy. Additionally, the risk of death was higher with anticoagulant therapy in the patients with SVO-related stroke [HR 1.44, CI 95% 1.06–1.97]. Our study demonstrated that stroke subtype affects prognosis and also determines the effectiveness of secondary prevention.

Background and purpose: We investigated the effect of celecoxib, a selective inhibitor of cyclo‐oxygenase 2, in patients with intracerebral hemorrhage (ICH).Methods: We conducted a multicenter, randomized, controlled, and open with blinded end‐point trial of 44 Korean patients 18 years or older with ICH within 24 h of onset. The intervention group (n = 20) received celecoxib (400 mg twice a day) for 14 days. The control group (n = 24) received the standard medical treatment for ICH. The primary end‐point was the number of patients with a change in the volume of perihematomal edema (PHE) from the 1st to the 7th ± 1 day (cut‐off value, 20%).Results: The time from onset to computed tomography scan slightly differed between groups (177 ± 160 min for control vs. 297 ± 305 min for the celecoxib group; P = 0.10). In the primary end‐point analysis using cut‐off values, there was a significant shift to reduced expansion of PHE in the celecoxib group (P = 0.005). With respect to the secondary end‐points, there was also a significant shift to reduced expansion of ICH in the celecoxib group (P = 0.046). In addition, the expansion rate of PHE at follow‐up tended to be higher in the control group than in the celecoxib group (90.6 ± 91.7% vs. 44.4 ± 64.9%; P = 0.058).Conclusions: In our small, pilot trial, administration of celecoxib in the acute stage of ICH was associated with a smaller expansion of PHE than that observed in controls.

Cancer related stroke may have different phenotypes from non-cancer stroke, especially in terms of stroke progression and recurrence. We performed a case–control study to identify their incidences and risk factors in cancer related stroke. Between January 2001 and December 2009, we conducted a retrospective review of acute ischemic stroke patients with cancer who were admitted to Seoul National University Hospital, Seoul, Korea. The stroke patients without cancer served as control. We collected demographic variables, vascular risk factors, stroke phenotype, clinical course, and cancer information including diagnosis, stage, and treatment status. Among cancer stroke patients, the potential risk factor of stroke recurrence was evaluated. The mean age of the 102 cancer patients was 66.4 ± 10.8 years, and 64.7 % were men. The mean time interval from cancer diagnosis to stroke onset was 39.7 ± 60.9 months. The principal lesion pattern of cancer stroke was multiple dots extending single vascular territory (39.2 %), and they were associated with low hemoglobin and high fibrinogen levels. Stroke progression and recurrence were noted in 9.8 and 27.5 % of cancer stroke patients, and in 9.3 and 12.7 % of control patients, respectively. The stroke subtype was independently associated with recurrence of cancer stroke after multiple logistic regression (odds ratio = 3.165, 95 % confidence interval = 1.080–9.277, p = 0.036). Cancer related stroke has a distinct phenotype in terms of infarction pattern and laboratory findings. Stroke recurrence is frequently observed among cancer stroke patients, and its risk is related with stroke subtype.

Atherosclerotic disease of the intracranial vessels is commonly observed among Asian and African stroke patients, and several studies have demonstrated that its presence predicts the likelihood of frequent stroke recurrence in the future.^1,2 The possible stroke mechanisms in middle cerebral artery (MCA) atherosclerosis are variable including thrombosis obstructing single or multiple perforating arteries, arterial emboli formation disseminating into the distal branches, and hemodynamic compromise in the watershed area.^3-5 Evaluation of intracranial atheromatous plaque is challenging because of limited imaging resolution and approach technique in conventional imaging modalities, although it may help to understand the pathology of intracranial atherosclerosis regarding plaque stability and mechanism of subsequent infarction.

Background—: A dynamic change in industry, lifestyle, and healthcare structure brings a corresponding change in disease patterns. Limited data exist with respect to secular trends in stroke epidemiology in Korea, a rapidly developed country. Methods and Results—: We analyzed individual patient data registered the Korean Stroke Registry, a nationwide hospital-based stroke database, between January 2002 and November 2010. Mortality data were obtained from a national death certificate system. Linear or logistic regression analyses were performed to assess secular trends. A total of 46 098 patients were included in this study. Mean±SD age was 66.1±12.3 years, and 57.6% of the patients were men. Over the 9-year period, patient ages steadily increased by 0.24 year annually ( P P <0.05 for all). However, dyslipidemia frequency showed a complex pattern of an initial decline and then an increase. For relative proportions of subtypes, cardioembolism increased, small vessel occlusion decreased, and large artery atherosclerosis remained stable. Still, intracranial stenosis overwhelms extracranial stenosis, but extracranial stenosis is on the rise. Arrival within 3 hours increased from 20% to 29%, and reperfusion therapy increased from 5.3% to 7.0%. Age-adjusted all-cause mortality did not decrease at 30 days but decreased at 1 year over time. Conclusions—: During the first decade of 21st century, stroke characteristics in Korea changed, likely because of increased lifespan, westernized lifestyle, and improved public awareness. Stroke experts need to cope with these distinguishing trends to establish a better strategy for prevention and acute therapy.

Activated endothelial cells release plasma membrane submicron vesicles expressing CD62E (E-selectin) into blood, known as endothelial microparticles (EMPs). We studied whether the levels of endothelial microparticles expressing CD62E⁺, CD31⁺/Annexin-V⁺, or CD31⁺/CD42⁻ predict cardiovascular outcomes in patients with stroke history. Patients with stroke history at least 3 months prior to enrolment were recruited. Peripheral blood EMP levels were measured by flow cytometry. Major cardiovascular events and death were monitored for 36 months. Three hundred patients were enrolled, of which 298 completed the study according to protocol. Major cardiovascular events occurred in 29 patients (9.7%). Nine patients died, five from cardiovascular causes. Cumulative event-free survival rates were lower in patients with high levels of CD62E⁺ microparticles. Multivariate Cox regression analysis adjusted for cardiovascular risk factors, medications and stroke etiologic groups showed an association between a high CD62E⁺ microparticle level and a risk of major cardiovascular events and hospitalization. Levels of other kinds of EMPs expressing CD31⁺/Annexin-V⁺ or CD31⁺/CD42⁻ markers were not predictive of cardiovascular outcomes. A high level of CD62E⁺ microparticles is associated with cardiovascular events in patients with stroke history, suggesting that the systemic endothelial activation increases the risk for cardiovascular morbidities.

Objective: Alzheimer disease (AD) brains are deficient in brain‐derived neurotrophic factor (BDNF), which regulates synaptic plasticity and memory. MicroRNAs (miRNAs) are ∼22‐nucleotide small noncoding RNAs that control a variety of physiological and disease processes. Here, we show that miR‐206 regulates BDNF and memory function in AD mice.Methods: Expression of miRNAs was analyzed in Tg2576 AD transgenic mice and human AD brain samples. Regulation of BDNF by a selected miRNA was validated by in silico prediction, target gene luciferase assay, and dendritic spine responses in neurons. AM206, a neutralizing inhibitor of miR‐206 (antagomir), was injected into the third ventricle of Tg2576 mice, after which memory function, synaptogenesis, neurogenesis, and target gene expression were assessed. For noninvasive delivery, antagomirs were administered intranasally.Results: The brains of Tg2576 mice and the temporal cortex of human AD brains had increased levels of miR‐206. This miRNA targeted BDNF transcripts, and AM206 prevented the detrimental effects of amyloid‐β42 on BDNF and dendritic spine degeneration in Tg2576 neurons. Injection of AM206 into the cerebral ventricles of AD mice increased the brain levels of BDNF and improved their memory function. In parallel, AM206 enhanced the hippocampal synaptic density and neurogenesis. Furthermore, intranasally administered AM206 also reached the brain and increased BDNF levels and memory function in AD mice.Interpretation: Our findings demonstrate a novel miRNA‐dependent regulation of BDNF in AD and suggest possible therapeutic approaches, such as noninvasive intranasal delivery of AM206. ANN NEUROL 2012;72:269–277.