Chaur Jong Hu

Association between genetic variant on chromosome 12p13 and stroke survival and recurrence: a one year prospective study in Taiwan

BackgroundThe association between ischemic stroke and 2 single nucleotide polymorphisms (SNPs) on chromosome 12p13, rs12425791 and rs11833579 appears inconsistent across different samples. These SNPs are close to the ninjurin2 gene which may alter the risk of stroke by affecting brain response to ischemic injury. The purpose of this study was to investigate the association between these two SNPs and ischemic stroke risk, as well as prognostic outcomes in a Taiwanese sample.MethodsWe examined the relations of these two SNPs to the odds of new-onset ischemic stroke, ischemic stroke subtypes, and to the one year risk of stroke-related death or recurrent stroke following initial stroke in a case-control study. A total of 765 consecutive patients who had first-ever ischemic stroke were compared to 977 stroke-free, age-matched controls. SNPs were genotyped by Taqman fluorescent allelic discrimination assay. The association between ischemic stroke and SNPs were analyzed by multivariate logistic regression. Cox proportional hazard model was used to assess the effect of individual SNPs on stroke-related mortality or recurrent stroke.ResultsThere was no significant association between SNP rs12425791 and rs11833579 and ischemic stroke after multiple testing corrections. However, the marginal significant association was observed between SNP rs12425791 and large artery atherosclerosis under recessive model (OR, 2.30; 95%CI, 1.22-4.34; q-value = 0.062). Among the 765 ischemic stroke patients, 59 died or developed a recurrent stroke. After adjustment for age, sex, vascular risk factors and baseline stroke severity, Cox proportional hazard analysis indicated that the hazard ratios were 2.76 (95%CI, 1.34-5.68; q-value, 0.02) and 2.15 (95%CI, 1.15-4.02; q-value, 0.03) for individuals with homozygous variant allele of rs12425791 and rs11833579, respectively.ConclusionsThis is a precedent study that found genetic variants of rs12425791 and rs11833579 on chromosome 12p13 are independent predictors of stroke-related mortality or stroke recurrence in patients with incident ischemic stroke in Taiwan. Further study is needed to explore the details of the physiological function and the molecular mechanisms underlying the association of this genetic locus with ischemic stroke.

Alzheimer disease and risk of stroke A population-based cohort study

Objective: To investigate the risk of stroke in patients clinically diagnosed with Alzheimer disease (AD) compared with non-AD patients with similar vascular risk factors. Methods: Using data obtained from Taiwans National Health Insurance Research Database, we evaluated the risk of ischemic stroke (IS) and intracerebral hemorrhage (ICH) in patients with AD (n = 980) who had no history of stroke, vascular dementia, or other cerebral degenerative diseases. Our evaluation period spanned from 2000 to 2010. We performed a 1:5 case-control matched analysis, in which cases were matched to controls according to their estimated propensity scores, which were based on demographics and existing vascular risk factors. This approach reduced selection bias. Cox proportional hazards regression analysis was then used to estimate the risk of IS and ICH in AD, conditional for matched pairs. Results: Overall, patients with AD had a higher risk of IS and ICH than those without AD. The incidence of IS in AD cases and non-AD controls was 37.8 and 23.2 per 1,000 person-years, with an adjusted hazard ratio of 1.66 (95% confidence interval, 1.37–2.01, p < 0.001). The incidence of ICH in AD cases and non-AD controls was 5.2 and 3.0 per 1,000 person-years, with an adjusted hazard ratio of 1.70 (95% confidence interval, 1.03–2.79, p = 0.037). Conclusion: Clinical diagnosis of AD is associated with considerably increased risk of stroke development.

Functional Role of Soluble Receptor for Advanced Glycation End Products in Stroke

Objective—Little is known about the involvement of the soluble form of receptor for advanced glycation end products (sRAGE) in acute ischemic stroke (IS). Here, we aim to identify the role of plasma sRAGE and high mobility group box 1 (HMGB1) in imaging-confirmed IS patients, as well as mice subjected to focal ischemic stroke. Methods and Results—IS patients were recruited and plasma samples were collected for the measurement of sRAGE and HMGB1 after stroke. The relation of sRAGE and HMGB1 with acute IS was also investigated in a C57BL/6J mouse model of focal ischemic stroke and primary cortical neurons subjected to oxygen and glucose deprivation. Plasma levels of sRAGE and HMGB1 were both significantly increased within 48 hours after IS, and the sRAGE level was an independent predictor of functional outcome at 3 months poststroke. Immunoprecipitation assays revealed that the binding of plasma HMGB1 to sRAGE increased progressively after IS both in patients and mice. Administration of recombinant sRAGE significantly reduced infiltrating immune cells and improved the outcome of injury in mice, protected cultured neurons against oxygen and glucose deprivation–induced cell death, and ameliorated the detrimental effect of recombinant HMGB1. Conclusion—Early poststroke plasma sRAGE may play a protective role in IS by capturing HMGB1. Hence, recombinant sRAGE is a potential therapeutic agent in acute IS.

Frequency power and coherence of electroencephalography are correlated with the severity of Alzheimer's disease: A multicenter analysis in Taiwan

BACKGROUND/PURPOSEnSlowing of average electroencephalography (EEG) frequency in Alzheimers disease (AD) is well established, but whether EEG changes are able to reflect the severity of AD is uncertain. We attempt to establish quantitative EEG parameters that are suitable for evaluating AD in clinical practice.nnnMETHODSnNinety-five patients with newly diagnosed AD at different stages from four neurologic institutes were enrolled for the study. Standard scalp resting EEG data were collected for quantitative analysis. Global band power ratio and interhemispheric alpha band coherence were calculated.nnnRESULTSnPatients with advanced AD had a greater slow-to-fast wave power ratio. Among several power ratio parameters, global theta and delta to alpha and beta band power ratio showed the best correlation with stages of AD (p < 0.05 between any two patient groups). Patients with advanced AD had decreased coherence in multiple brain regions. The phenomenon was most prominent in the centroparietal region (p < 0.05 between any two patient groups).nnnCONCLUSIONnIncreased global slow-to-fast power ratio and decreased centroparietal interhemispheric alpha band coherence are strongly correlated with disease progress in AD patients. These two quantitative EEG parameters may help evaluate AD patients in daily clinical practice. Global power ratio changes may suggest a shift of dominant frequency, and decreased interhemispheric alpha band coherence may suggest functional disconnection and corpus callosum abnormalities in AD patients.

Cleaved but not endogenous secretory RAGE is associated with outcome in acute ischemic stroke.

Objective: To investigate the expression patterns of 2 soluble isoforms of receptor for advanced glycation end-product (RAGE), including endogenous secretory RAGE (esRAGE) and cleaved RAGE (cRAGE), and their associations with outcome in acute ischemic stroke (IS). Methods: Acute IS patients (n = 106) and age- and sex-matched controls (n = 150) were recruited. Plasma levels of total soluble RAGE (sRAGE) and esRAGE in patients at <48 hours and 48–72 hours after IS and in controls were measured by ELISA. The level of cRAGE was calculated by subtracting the level of sRAGE from that of esRAGE. Poor outcome was defined as modified Rankin Scale score >2 at 3 months after stroke. Results: The plasma levels of cRAGE were significantly higher and correlated to those of esRAGE (p < 0.001). The plasma levels of esRAGE and cRAGE were both significantly higher in IS patients <48 hours and 48–72 hours after onset than in controls, but only level of cRAGE at <48 hours was independently associated with poor outcome after adjusting for clinical variables (odds ratio 2.44; 95% confidence interval 1.16–5.16; p = 0.019). Conclusion: The plasma level of cRAGE at <48 hours after IS, rather than esRAGE, is a significant predictor of acute IS outcome.

Coexisting myasthenia gravis, myositis, and polyneuropathy induced by ipilimumab and nivolumab in a patient with non-small-cell lung cancer: A case report and literature review

Rationale: Immune checkpoint inhibitors have led to the development of new approaches for cancer treatment with positive outcomes. However, checkpoint blockade is associated with a unique spectrum of immune-related adverse events (irAEs), which may cause irreversible neurological deficits and even death. Patient concerns: We presented a case of a 57-year-old man with non-small-cell lung cancer.who developed ptosis, dyspnea, and muscle weakness as initial symptoms with progression after the treatment with ipilimumab and nivolumab. Diagnoses: Myasthenia gravis was confirmed by serum acetylcholine receptor antibody and single fiber electromyography. Myositis was identified by high level of serum creatine phosphokinase and electromyography. Polyneuropathy was identified by nerve conduction study. Interventions: The patient underwent treatment with steroid and pyridostigmine. Respiratory rehabilitation was also performed. Outcomes: Dyspnea and muscle weakness improved gradually. Ipilimumab and nivolumab were permanently discontinued. Lessons: This case has increased the clinical awareness by indicating that the checkpoint inhibitors-related neurological irAEs could be complicated and simultaneously involve multiple neurological systems. Early recognition and complete evaluation are critical in clinical practice.

Homozygous ALDH2*2 Is an Independent Risk Factor for Ischemic Stroke in Taiwanese Men.

Background and Purpose— The *2 allele of the aldehyde dehydrogenase 2 gene (ALDH2) is the most common variant in Asian populations. The variant resulting in enzyme dysfunction was highly related to coronary artery disease. Recently, genome-wide association studies also discovered that the 12q24 locus near ALDH2 gene was associated with hypertension and ischemic stroke. This study intended to further investigate whether the above variant of ALDH2 increases the risk for ischemic stroke in Taiwanese. Methods— A case–control study was conducted on 914 patients with acute ischemic stroke and 746 nonstroke controls. Polymerase chain reaction and sequencing were used to identify the ALDH2 genotype. Vascular risk factors, stroke subtypes, vascular stenosis, and stroke outcomes were analyzed. Results— ALDH2 genotypes differed significantly between male controls (*1/*1 versus *1/*2 versus *2/*2=53.8% versus 39.9% versus 6.4%) and male patients with ischemic stroke (*1/*1 versus *1/*2 versus *2/*2=51.5% versus 37.3% versus 11.2%; P=0.048). No significant difference was found between groups for female patients (P=0.228). Multivariate logistic regression analysis revealed that the ALDH2*2/*2 genotype was an independent risk factor for ischemic stroke in male patients (odds ratio, 1.93 [95% confidence interval, 1.07–3.46]; P=0.028). Further analysis of men with ischemic stroke demonstrated that the polymorphism of ALDH2 was not related to vascular risk factors, severity of vascular atherosclerosis, stroke subtypes, and stroke functional outcomes. Conclusions— The study demonstrated that ALDH2*2/*2 may be an independent risk factor for ischemic stroke in Taiwanese men, but not in Taiwanese women.

Association between cerebral lesions and emotional changes in acute ischemic stroke patients.

Abstract Controversies and interest are present in the associations between specific brain locations and depression or anxiety. This study investigated the association between stroke location and emotional changes in stroke patients. This prospective observational study analyzed the neuroimages and neuropsychiatric conditions of 26 patients with acute middle cerebral artery infarction. Each patient’s neurological and psychiatric condition was evaluated 1 week as well as 1 month after the stroke. We found that the right superior and middle temporal gyrus was associated with anxiety at 1 month after stroke. Moreover, better mentality is associated with deterioration of anxiety within 1 month after stroke, and larger lesion volume is associated with deterioration of depression within 1 month after stroke.

BDNF Val66Met Polymorphism on Functional MRI During n-Back Working Memory Tasks.

Abstract Val66Met polymorphism on the brain-derived neurotrophic factor (BDNF) gene is associated with hippocampal pathology and impaired episodic memory. However, the influence of this polymorphism on working memory (WM) performance and patterns of brain activation is controversial. This study investigated the effects of BDNF Val66Met polymorphism on functional magnetic resonance imaging (fMRI) during n-back WM tasks in healthy middle-aged adults. A total of 110 participants without subjective or objective cognitive impairment underwent BDNF genotyping. Eleven Met allele carriers and 9 noncarriers underwent fMRI during WM tasks. The WM performance was similar between the 2 groups. Increased brain activation in response to increases in WM loads was observed in both groups. The Met allele carrier group showed consistently lower brain activation in the right superior frontal gyrus (SFG) and the middle occipital gyrus than that of the noncarrier group (Pu200a<u200a0.001). No brain region showed increased activation during WM tasks in the Met allele group. BDNF Val66Met polymorphism may affect the WM network. Met allele carriers have lower brain activation in the right SFG and middle occipital gyrus than do noncarriers during WM tasks. Defective development of the WM network during brain maturation or differentiation is a possible mechanism. Additional studies with a larger sample and longer follow-up period are warranted.

Elevated Plasma Level of Soluble Form of RAGE in Ischemic Stroke Patients with Dementia

The receptor for advanced glycation end products (RAGE) and its downstream pathways are involved in various inflammatory and immune responses. Importantly, there is soluble RAGE (sRAGE) that forms either by alternative splicing of RAGE messenger ribonucleic acid as the endogenous soluble form of RAGE (esRAGE) or by proteolytic cleavage of full-length RAGE protein. This study aimed to investigate the associations of the plasma levels of sRAGE and esRAGE in ischemic stroke (IS) patients with and without dementia. This cross-sectional study recruited patients with IS at a university medical center. Vascular dementia was defined as the scale of Clinical Dementia Ranking (CDR)xa0≥xa01. Standard enzyme-linked immunosorbent assay was used to measure the plasma concentration of sRAGE and esRAGE. From November 2014 to October 2015, a total of 172 IS patients (mean age: 72.1xa0±xa07.5xa0years, 64.5% male) were recruited, including 73 with CDRxa0=xa00, 63 with CDRxa0=xa00.5, and 36 with CDRxa0≥xa01. In univariate analysis, IS patients with dementia were older and had more diabetes mellitus, less atrial fibrillation, and higher post-stroke modified Rankin Scale scores than those without dementia. Plasma levels of sRAGE and esRAGE were significantly higher in IS patients with than those without dementia (1.44xa0±xa01.29 vs. 1.03xa0±xa00.48 and 0.39xa0±xa00.40 vs. 0.24xa0±xa00.13xa0ng/mL, both pxa0<xa00.01). Importantly, both parameters remained independent after adjustment for clinical variables (OR 2.683, pxa0=xa00.013 and OR 39.192, pxa0=xa00.006, respectively). In summary, plasma sRAGE and esRAGE were elevated in those with dementia compared with those without dementia among IS patients.