Giia Sheun Peng

Polyglutamine (PolyQ) Diseases: Genetics to Treatments

The polyglutamine (polyQ) diseases are a group of neurodegenerative disorders caused by expanded cytosine– adenine–guanine (CAG) repeats encoding a long polyQ tract in the respective proteins. To date, a total of nine polyQ disorders have been described: six spinocerebellar ataxias (SCA) types 1, 2, 6, 7, 17; Machado–Joseph disease (MJD/SCA3); Huntingtons disease (HD); dentatorubral pallidoluysian atrophy (DRPLA); and spinal and bulbar muscular atrophy, X-linked 1 (SMAX1/SBMA). PolyQ diseases are characterized by the pathological expansion of CAG trinucleotide repeat in the translated region of unrelated genes. The translated polyQ is aggregated in the degenerated neurons leading to the dysfunction and degeneration of specific neuronal subpopulations. Although animal models of polyQ disease for understanding human pathology and accessing disease-modifying therapies in neurodegenerative diseases are available, there is neither a cure nor prevention for these diseases, and only symptomatic treatments for polyQ diseases currently exist. Long-term pharmacological treatment is so far disappointing, probably due to unwanted complications and decreasing drug efficacy. Cellular transplantation of stem cells may provide promising therapeutic avenues for restoration of the functions of degenerative and/or damaged neurons in polyQ diseases.

Preoperative APACHE II and GCS scores as predictors of outcomes in patients with malignant MCA infarction after decompressive hemicraniectomy

OBJECTIVEnDecompressive hemicraniectomy is accepted as the most effective life-saving treatment for malignant middle cerebral artery (MCA) infarction. However, the outcome remains hard to predict. This study examined the efficacy of using the Glasgow Coma Scale (GCS) and Acute Physiology and Chronic Health Evaluation (APACHE) II scores before emergency craniectomy for predicting clinical outcome in malignant MCA infarction.nnnMATERIALS AND METHODSnSeventy-nine consecutive patients with malignant MCA infarction treated from January 2006 to October 2010 were retrospectively analyzed. The GCS and APACHE II scores within the first 24 h of neurological deterioration or before decompressive hemicraniectomy, were used to predict short-term functional outcome rated by the modified Rankin Scale (mRS). The receiver operating characteristic (ROC) curve was obtained to determine the accuracy and best cut-off value for each scoring system.nnnRESULTSnAt 6 months, there was dramatic life-saving effect of surgery, with a significant reduction in mortality rate (from 71% to 19%, P < 0.001). After the ROC analysis, cut-off values of pre-operative GCS > 8 (P = 0.003) and APACHE II <13 (P = 0.006) were sufficiently sensitive and specific to predict favorable outcome (mRS 0-3).nnnCONCLUSIONSnPre-operative GCS and APACHE II scores are useful tools in predicting outcomes for patients with malignant MCA infarction who underwent decompressive hemicraniectomy.

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.

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 plasma levels of hyaluronic acid and functional outcome in acute stroke patients

BackgroundActivation of hyaluronic acid (HA) and associated enzyme synthesis has been demonstrated in experimental stroke animal models. Our study aimed to investigate the plasma levels of HA in acute stroke patients and the associations between HA levels and functional outcome.MethodsThis was a multicenter case–control study. Acute stroke patients and age- and sex-matched non-stroke controls were recruited. Plasma levels of HA in acute stroke patients were determined at <48 hours and at 48 to 72xa0hours after stroke onset by standard ELISA. Favorable functional outcome was defined as modified Rankin scale ≤2 at 3xa0months after stroke.ResultsThe study included 206 acute stroke patients, including 43 who had intracerebral hemorrhage and 163 who had ischemic stroke, and 159 controls. The plasma levels of HA in the acute stroke patients were significantly higher than those in the controls (219.7u2009±u2009203.4xa0ng/ml for <48xa0hours and 343.1u2009±u2009710.3xa0ng/ml for 48 to 72xa0hours versus 170.4u2009±u2009127.9xa0ng/ml in the controls; both Pu2009<u20090.05). For intracerebral hemorrhage patients, HA ≤500xa0ng/ml (<48xa0hours) was an independent favorable outcome predictor (Pu2009=u20090.016). For ischemic stroke patients, an inverted U-shaped association between plasma HA (48 to 72xa0hours) and outcome was noted, indicating that ischemic stroke patients with too high or too low plasma HA levels tended to have an unfavorable outcome.ConclusionHA plasma level was elevated in patients with acute stroke, and can predict 3-month functional outcome, particularly for patients with intracerebral hemorrhage.

Local intra-arterial thrombolytic therapy for patients with acute ischemic stroke

Background: Acute thrombolysis for ischemic stroke has been proposed to help some suitable patients. We investigated the application of local intra-arterial thrombolytic therapy to patients with ischemic stroke in different territories of vascular occlusion. Methods: Ten patients with ischemic stroke, five with middle cerebral artery (MCA) occlusion, three with internal carotid artery (ICA) occlusion, and two with basilar artery (BA) occlusion, were treated by local intra-arterial infusion of urokinase, early recanalization or suspicion of the occurrence of complications. Stroke scales were used to evaluate their clinical outcomes at the onset, and 7, 30 and 90 days after treatment. Results: The mean age was 59.4±12.2 (range 37 to 73) years; median baseline NIH Stroke Scale was 18.5±6.8 (range 8 to 30). Four of five patients with MCA occlusion had good recanalization and one had incomplete recanalization. Two patients with BA occlusion showed good recanalization and improvement of neurological deficits. In contrast, all the patients with ICA occlusion did not show recanalization and the clinical outcomes were poor. Four patients (three with MCA occlusion and one with BA occlusion) had favorable outcomes. Three patients had mild to moderate intracranial hemorrhage. Two patients died of acute myocardial infarction and symptomatic cerebral mass effect with tentorial herniation. Conclusions: Our results showed that local intra-arterial thrombolysis to treat some acute ischemic stroke due to MCA or BA occlusion might have fewer complications and better outcome than those with ICA occlusion.

Real-world evaluation of compliance and preference in Alzheimer’s disease treatment: An observational study in Taiwan

Purpose Among the medications approved for Alzheimer’s disease (AD), rivastigmine is the only one available as transdermal patch. The aim of this study was to evaluate compliance and caregivers’ preference with oral and transdermal (rivastigmine) monotherapy in patients with mild-to-moderate AD from Taiwan. Methods Real-world Evaluation of Compliance And Preference in Alzheimer’s disease treatment (RECAP) in Taiwan was a prospective, noninterventional, observational study with a 24-week (±8 weeks) observational period for each participant. Eligible patients were grouped into one of the two treatment cohorts based on the baseline AD therapy: oral (donepezil, galantamine, rivastigmine, or memantine) or transdermal (rivastigmine patch). The primary end points were caregiver preference and caregiver assessment of patients’ compliance to the current medication (oral or transdermal medication) at Week 24 (end of the study). Safety was assessed by recording any adverse events. Results A total of 301 patients (age: 77.6±7.19 years) were enrolled from nine centers in Taiwan, of whom 138 (45.8%) patients were in the transdermal monotherapy cohort. Caregivers of patients who were exposed to both forms of therapies demonstrated a higher preference for transdermal rivastigmine monotherapy than the oral monotherapy (82.4% [n=61] versus 17.6% [n=13], P<0.0001); for patients treated with only one therapy, the caregivers’ preference was significantly in favor of the treatment to which the patient was exposed (both P<0.0001). In both cohorts, patients showed good compliance, with an overall score of 8.65±1.38 on an 11-point scale. Of 301 enrolled patients, 102 (33.9%) reported at least one adverse event during the study (51 patients each in the two cohorts). Conclusion With the higher caregiver preference and a good patient compliance, the trans-dermal rivastigmine patch is a suitable treatment choice for patients with mild-to-moderate AD, especially for patients intolerant to oral therapies.

Clinical and radiologic manifestations of H1N1 virus infection associated with neurological complications: A case report

Encephalitis complicating novel influenza A (H1N1) viral infection is rare and has only been reported in children. We present cerebral magnetic resonance imaging findings from a confirmed adult case with H1N1 infection who presented with acute encephalitis and subsequent respiratory failure. Cerebral magnetic resonance imaging showed hyperintense abnormalities in the bilateral globus pallidus in T1-weighted images, and multiple hyperintense abnormalities in the right insular cortex, right parahippocampus, and the pontine tegmentum in fluid-attenuated inversion recovery images.

Involvement of Nigrostriatal Pathway in Japanese Encephalitis with Movement Disorders: Evidence from 99mTc-TRODAT-1 and 123I-IBZM SPECT Imagings

PurposeThe purpose of this study was to evaluate molecular evidence of nigrostriatal pathway involvement in Japanese encephalitis (JE) survivors with movement complications.MethodsThree JE patients were recruited. All had cranial magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) studies with 99mTc-TRODAT-1 and 123I-IBZM.ResultsCranial MRI revealed involvement of bilateral thalami, substantia nigra, and medial temporal lobes in all three patients, but only case 1 had additional bilateral basal ganglia involvement. The 99mTc-TRODAT-1 SPECT for presynaptic dopamine transporter imaging disclosed asymmetrical decreases in bilateral striatal uptake in all three patients. However, the 123I-IBZM SPECT imaging for postsynaptic D2 dopamine receptors (D2Rs) revealed inconsistent abnormalities including asymmetrical bilateral decreases (case 1), unilateral decrease (case 2), and bilateral increases (case 3) in striatal uptakes.ConclusionData have suggested that presynaptic dopaminergic neurons in JE patients are more susceptible to JE virus than postsynaptic striatal neurons. The degree of movement impairment was more closely correlated to the degree of D2Rs disruption seen in 123I-IBZM SPECT imaging.

Associations of estradiol levels and genetic polymorphisms of inflammatory genes with the risk of ischemic stroke

BackgroundEstrogen plays an important role as an anti-inflammatory and neuroprotective agent in ischemic stroke. In this study, we analyzed the effect of a polygenic risk score (PRS) constructed using inflammatory genes and estradiol levels on the risk of ischemic stroke.MethodsThis case-control study was conducted with 624 ischemic stroke patients and 624 age- and gender-matched controls. The PRS estimated the polygenic contribution of inflammatory genes from ischemic stroke susceptibility loci. Estradiol levels were measured using a radioimmunoassay. High and low estradiol levels were defined according to the log-transformed median estradiol levels in female and male controls.ResultsSubjects in the fourth quartile of the PRS had a significant 1.57-fold risk of ischemic stroke (95% confidence interval [CI], 1.12u2009~u20092.19), after adjusting for covariates compared to individuals in the lowest quartile. Compared to individuals with high estradiol levels and a low PRS as the reference group, those exposed to low estradiol levels and a high PRS had an increased risk of ischemic stroke (odds ratio, 3.35; 95% CI, 1.79u2009~u20096.28). Similar results were also observed in males when the analysis was stratified by gender.ConclusionsOur data suggest that the PRS can be useful in evaluating a high risk of ischemic stroke among patients, especially those exposed to low estradiol levels.