Man-Seok Park

Associations of BDNF Genotype and Promoter Methylation with Acute and Long-Term Stroke Outcomes in an East Asian Cohort

Background Brain derived neurotrophic factor (BDNF) has been shown to play an important role in poststroke recovery. BDNF secretion is influenced by genetic and epigenetic profiles. This study aimed to investigate whether BDNF val66met polymorphism and promoter methylation status were associated with outcomes at two weeks and one year after stroke. Methods and Findings A total of 286 patients were evaluated at the time of admission and two weeks after stroke, and 222 (78%) were followed one year later in order to evaluate consequences of stroke at both acute and chronic stages. Stroke outcomes were dichotomised into good and poor by the modified Rankin Scale. Stroke severity (National Institutes of Health Stroke Scale), physical disability (Barthel Index), and cognitive function (Mini-Mental State Examination) were measured. Associations of BDNF genotype and methylation status on stroke outcomes and assessment scale scores were investigated using logistic regression, repeated measures ANOVA and partial correlation tests. BDNF val66met polymorphism was independently associated with poor outcome at 2 weeks and at 1 year, and with worsening physical disability and cognitive function over that period. Higher BDNF promoter methylation status was independently associated with worse outcomes at 1 year, and with the worsening of physical disability and cognitive function. No significant genotype-methylation interactions were found. Conclusions A role for BDNF in poststroke recovery was supported, and clinical utility of BDNF genetic and epigenetic profile as prognostic biomarkers and a target for drug development was suggested.

Proximal arterial occlusion in acute ischemic stroke with low NIHSS scores should not be considered as mild stroke.

Background Untreated acute mild stroke patients have substantial 90-day disability rates and worse outcomes than those who are treated with thrombolysis. There is little information regarding which patients with acute mild stroke will benefit from thrombolysis. We sought to investigate factors that are associated with early neurological deterioration (END) and poor prognosis in patients with acute mild stroke. Methods This was a retrospective study of consecutively registered patients with acute mild stroke (NIHSS ≤3) at our tertiary stroke center between October 2008 and December 2011. END was defined as an increase in NIHSS ≥2 points between hospital days 0 and 5. Modified Rankin Scale (mRS) scores of 0–1 at 90 days post-stroke were defined as favorable outcomes. Results A total of 378 (mean age, 65.9±13.0 years) patients were included in this study. END occurred in 55 patients (14.6%). IV-thrombolysis was performed in only 9 patients. Symptomatic arterial occlusion on the initial MRA was independently associated with END (OR, 2.206; 95% CI, 1.219–3.994; p = 0.009) by multivariate logistic regression. Of the 119 patients with symptomatic arterial occlusion, ICA occlusion was independently associated with END (OR, 8.606; 95% CI, 2.312–32.043; p = 0.001). Conclusions This study demonstrates that symptomatic arterial occlusion may be an important predictor of END in patients with acute mild stroke. It may therefore be important to consider that acute ischemic stroke with symptomatic arterial occlusion and low NIHSS scores may not represent mild stroke in acute periods.

Serotonergic and BDNF genes and risk of depression after stroke

BACKGROUND Polymorphisms of serotonin transporter (5-HTT) and brain-derived neurotrophic factor (BDNF) have been investigated as candidate genes for post-stroke depression (PSD). Serotonin 2a receptor (5-HTR2a) genes have not been yet investigated in PSD. This study aimed to investigate whether the 5-HTT, 5-HTR2a, and BDNF genes are associated with PSD independently and/or interactively in a Korean sample with high prevalence of risk alleles. METHODS In 276 stroke cases, depression was diagnosed using DSM-IV at 2 weeks after stroke, further classified to major PSD (N=29), all (major plus minor) PSD (N=77), and control (N=199) groups. Associations between PSD and 5-HTTLPR, STin2 VNTR, 5-HTR2a 1438A/G, 5-HTR2a 102T/C, and BDNF val66met genotypes were estimated using logistic regression models, and gene-gene interactions were investigated using the generalized multifactor dimensionality reduction method. RESULTS 5-HTR2a 1438 A/A genotype was associated with major PSD, while 5-HTTLPR s/s and BDNF met/met genotypes were associated with all PSD. There was a significant interaction between 5-HTR2a 1438A/G and BDNF val66met polymorphisms for major PSD and a borderline significant interaction between 5-HTTLPR and BDNF val66met polymorphisms for all PSD. CONCLUSIONS In a large cohort, we found evidence for serotonin and BDNF polymorphisms as susceptibility factors and gene-gene interactions between these systems for depression at 2 weeks post-stroke.

A longitudinal study of BDNF promoter methylation and genotype with poststroke depression

INTRODUCTION Brain derived neurotrophic factor (BDNF) has been shown to play an important role in the pathophysiology of mood disorders including poststroke depression (PSD). BDNF secretion is influenced by epigenetic and genetic profiles. This study aimed to investigate whether BDNF gene promoter methylation status and val66met polymorphism were associated with depression ascertained at two weeks and one year after stroke. METHODS A total of 286 patients were evaluated two weeks after stroke, and 222 (78%) were followed one year later. Depression (major or minor depressive disorder) was diagnosed according to DSM-IV criteria, and classified into prevalent, persistent, and incident PSD according to presence at the two examinations. Depression severity was assessed by the Hospital Anxiety and Depression Scale-depression subscale and the Hamilton Depression Rating Scale. The effects of BDNF methylation status and genotype on PSD status were investigated using multivariate logistic regression models. The associations of BDNF methylation status and genotype with score on depression assessment scales were estimated using partial correlation tests and general linear models, respectively. RESULTS Higher BDNF methylation status was independently associated with prevalent, persistent and particularly with incident PSD, and with worsening depressive symptoms over follow-up but not with baseline severity. The BDNF val66met polymorphism was independently associated with prevalent PSD, but not with persistent and incident PSD nor with depressive symptoms severity. No significant methylation-genotype interactions were found. LIMITATIONS Methylation status was investigated with limited area of the BDNF gene and sample size was relatively small. CONCLUSIONS A role for BDNF in PSD was supported, and associations with BDNF gene methylation status may represent a target for drug development.

Effects of Flavonoid Compounds on β-amyloid-peptide-induced Neuronal Death in Cultured Mouse Cortical Neurons

Excessive accumulation of β-amyloid peptide (Aβ) is one of the major mechanisms responsible for neuronal death in Alzheimers disease. Flavonoids, primarily antioxidants, are a group of polyphenolic compounds synthesized in plant cells. The present study aimed to identify flavonoid compounds that could inhibit Aβ-induced neuronal death by examining the effects of various flavonoids on the neurotoxicity of Aβ fragment 25-35 (Aβ25-35) in mouse cortical cultures. Aβ25-35 induced concentration- and exposure-time-dependent neuronal death. Neuronal death induced by 20 µM Aβ25-35 was significantly inhibited by treatment with either Trolox or ascorbic acid. Among 10 flavonoid compounds tested [apigenin, baicalein, catechin, epicatechin, epigallocatechin gallate (EGCG), kaempferol, luteolin, myricetin, quercetin, and rutin], all except apigenin showed strong 1,1-diphenyl-2-pycrylhydrazyl (DPPH) scavenging activity under cell-free conditions. The flavonoid compounds except apigenin at a concentration of 30 µM also significantly inhibited neuronal death induced by 20 µM Aβ25-35 at the end of 24 hours of exposure. Epicatechin, EGCG, luteolin, and myricetin showed more potent and persistent neuroprotective action than did the other compounds. These results demonstrated that oxidative stress was involved in Aβ-induced neuronal death, and antioxidative flavonoid compounds, especially epicatechin, EGCG, luteolin, and myricetin, could inhibit neuronal death. These findings suggest that these four compounds may be developed as neuroprotective agents against Alzheimers disease.

Comparative validity of depression assessment scales for screening poststroke depression

INTRODUCTION This study aimed to compare screening properties of four assessment scales for poststroke depression (PSD) at 2 weeks and 1 year after index stroke, and investigated factors contributing to misclassification. METHODS A total of 423 patients were evaluated 2 weeks after stroke and 288 (68%) were followed 1 year later, and were diagnosed as having major and minor PSD applying DSM-IV criteria gold standards. The Beck Depression Inventory (BDI), Hospital Anxiety and Depression Scale-depression subscale (HADS-D), Hamilton Rating Scale for Depression (HAMD), and Montgomery-Asberg Depression Rating Scale (MADRS) were administered. The balance of sensitivity and specificity was assessed using receiver operating characteristics (ROC) analysis. RESULTS Discriminating abilities of all the scales for major and all PSD were good (area under ROC values 0.88-0.93 and 0.88-0.92 at 2 weeks; and 0.93-0.96 and 0.89-0.91 at 1 year, respectively). Misclassification was influenced by demographic characteristics and stroke severity particularly for the BDI and HAMD, was more marked for all PSD than for major PSD, and was more prominent at 2 weeks than at 1 year after stroke. LIMITATIONS Patients with only mild to moderate stroke severity were included. CONCLUSIONS Although there were no marked differences in the screening abilities for PSD between the scales, differences were found in factors influencing misclassification. Assessment scales with less somatic items may be recommended for the screening of PSD, particularly at the acute phase of stroke.

Early Outcome of Combined Thrombolysis Based on the Mismatch on Perfusion CT

Background: Possible factors associated with early outcome after thrombolysis are the recanalization time and the status of tissue. We assessed whether combined intravenous (IV) and intra-arterial (IA) thrombolysis performed according to the status of tissue based on perfusion computed tomography (PCT) is beneficial for the early outcome in patients with acute ischemic stroke. Methods: To improve the recanalization time, we assumed that combined IA thrombolysis after IV thrombolysis would be beneficial. Eligible patients for combined thrombolysis were selected according to the status of tissue based on PCT. Recanalization was defined as Thrombolysis in Myocardial Infarction (TIMI) grade 2 or 3. ‘Good functional outcome’ was defined as a Modified Rankin Scale (mRS) score of 2 or less at discharge. Results: Eighteen patients (11 men) underwent combined IV/IA thrombolysis. The recanalization rate after combined IV/IA thrombolysis was 88.9% (TIMI 2, 4; TIMI 3, 12). A good functional outcome at discharge was noted in 12 patients (66.7%). The incidence of symptomatic intracranial hemorrhage was 5.6% (1/18). Conclusions: The results of this study suggest that combined IV/IA thrombolysis based on the presence of mismatches on PCT might have a relatively high rate of recanalization and a favorable early outcome. In addition, the incidence of symptomatic intracranial hemorrhage was acceptable.

Associations of cytokine gene polymorphisms with post-stroke depression

Abstract Objectives. Inflammatory cytokines are implicated in the pathophysiology of both stroke and depression, and their production is influenced by the transcriptional activity of particular gene polymorphisms. We hypothesised that alleles related to higher pro-inflammatory and/or lower anti-inflammatory cytokine production would be associated with post-stroke depression (PSD). Methods. In 276 stroke cases, depression was diagnosed using DSM-IV, and classified into major PSD (N = 29), all (major plus minor) PSD (N = 77), and control (N = 199) groups. Genotyping for six pro-inflammatory polymorphisms (TNF-α –850C/T and –308G/A, IL-1β –511C/T and + 3953C/T, IL-6 –174G/C, and IL-8 –251T/A) and two anti-inflammatory polymorphisms (IL-4 + 33T/C and IL-10 –1082G/A) was conducted. Individual associations with PSD were estimated using logistic regression models. Total numbers of potential risk alleles were calculated for pro-inflammatory and anti-inflammatory cytokine genes and analysed against depression using χ2-tests. Results. The IL-4 + 33C/C genotype was associated with major PSD, and the IL-10 –1082A/A genotype was associated with all PSD. Increasing numbers of risk alleles for these two anti-inflammatory cytokine genotypes were significantly associated with both PSD categories. No significant associations were found with any pro-inflammatory cytokine allele. Conclusions. Alleles associated with reduced anti-inflammatory cytokine function were associated with PSD, supporting the cytokine hypothesis in its etiology.

Endothelial nitric oxide gene T-786C polymorphism and subarachnoid hemorrhage in Korean population.

We aimed to elucidate whether the eNOS T-786C mutant allele is implicated in subarachnoid hemorrhage (SAH) susceptibility or vasospasm after SAH, and whether the mutant allele is differentially expressed in those with small and large ruptured aneurysms in Korean population. 136 consecutive patients diagnosed with aneurismal SAH and 113 controls were recruited. Polymerase chain reaction and direct sequencing of both strands were performed to determine genotypes with respect to the eNOS T-786C mutation. No significant difference was found between cases and controls with respect to the distributions of the two eNOS T-786C single nucleotide polymorphism (SNP) genotypes. No significant differences in the distributions of the eNOS T-786C SNP genotypes were found with regard to the sizes of ruptured aneurysms or the occurrence of vasospasm after SAH. Multiple logistic regression analysis after controlling for age and sex showed the eNOS T-786C SNP T/C genotype was independently associated with an unfavorable outcome (GOS grade 3-5) of SAH (Exp (β)=4.27, 95% CI 1.131-16.108, p=0.032). In conclusion, the eNOS T-786C mutation was not found to be associated with either a susceptibility to SAH or vasospasm after SAH, or with aneurysm size in Korean population. The eNOS T-786C SNP T/C genotype could be used as a prognostic marker in individuals with SAH.

Relationship between Flow Diversion on Transcranial Doppler Sonography and Leptomeningeal Collateral Circulation in Patients with Middle Cerebral Artery Occlusive Disorder

Flow diversion (FD) has been considered as indirect evidence of intracranial artery occlusion, and it was associated with early improvement in patients with MCA occlusion. It is not known whether FD can represent leptomeningeal collateral circulation or not in patients with middle cerebral artery (MCA) occlusive disorder.