Ruey-Tay Lin

Serum microRNA-21 and microRNA-221 as potential biomarkers for cerebrovascular disease.

Background/Aims: MicroRNA miR-21, miR-221 and miR-145 have been implicated in the cardiovascular system. We aimed to compare the serum levels of the three microRNAs (miRNAs) in different severities of cerebrovascular diseases and evaluate the feasibility of using these miRNAs as biomarkers for stroke. Methods: We enrolled 167 subjects with ischemic stroke, 66 atherosclerosis subjects with any carotid plaque score and 157 healthy controls. These three types of subjects represent three levels of severity in cerebrovascular diseases. Analysis of covariance was used to evaluate the relationship between miRNAs and disease severity with adjustment for conventional risk factors. To test the prediction for stroke, we built regression models containing the serum miRNA levels and risk factors. Prediction capabilities were compared by the receiver operating characteristic curves. Results: Stroke patients and atherosclerosis subjects had significantly higher miR-21 and lower miR-221 serum levels than healthy controls, while the miR-145 expression was too low to provide useful information in this regard. The best model showed that miR-21 and miR-221 were independent predictors. There was a 6.2-fold increase for stroke risk when miR-21 levels increase by log102-ΔCt = 1, while a 10.4-fold increase was observed as miR-221 decreases by log102-ΔCt = 1. Conclusions: Serum miR-145 was not detected in over 50% of the patients and it may not be an ideal marker to predict stroke. MiR-21 and miR-221 are novel biomarkers for atherosclerosis and stroke.

The role of event-related potentials in cognitive decline in Alzheimer’s disease

OBJECTIVES Early diagnosis and monitoring of disease progression have become vital in clinical practice as disease modifying treatments for Alzheimers disease (AD) become available. This one-year prospective study aimed to clarify the usefulness of event-related potentials (ERPs) in cognitive decline and elucidate their cognitive significance in AD. METHODS Using the Cognitive Abilities Screening Instrument (CASI) and ERPs, probable AD patients, mild cognitive impairment (MCI) patients, and normal controls were recruited. RESULTS The AD and MCI patients had significantly decreased cognitive function and manifested a delay of P300 latency. The P300 latencies demonstrated significantly more prolongation than their baseline values in probable AD and MCI patients, although their CASI scores showed no statistically significant decline. Whereas N100, P200, and N200 components did not reach statistical differences between groups either in the baseline or follow-up assessments and did not show significant change on follow-up. CONCLUSION The combination of neuropsychological tests and P300 measurements proved useful in improving reliability and increasing sensitivity to early cognitive decline or disease progression in AD patients. SIGNIFICANCE The P300 latency may reflect cognitive decline more sensitively than neuropsychological tests in the longitudinal follow-up of AD patients.

Prediction of poststroke dementia

Objective: To investigate prospectively the frequency and clinical determinants of poststroke dementia (PSD) in a cohort of consecutive ischemic stroke inpatients in southern Taiwan. Methods: A standard stroke evaluation protocol was conducted at admission and 3 months after an ischemic stroke. The protocol included clinical, neurologic, neurobehavioral, and functional assessments as well as neuroimaging examinations. Diagnoses were made according to the Neurologic Adaptation of the 10th edition of the International Classification of Diseases criteria for dementia. Results: Excluding patients with prestroke dementia, a total of 283 patients were surveyed at 3 months after stroke; 26 (9.2%) of them met the criteria for PSD. The correlates of PSD in logistic regression analyses were age 65 years or older (odds ratio [OR] 6.6) vs <65 years, previous occupation as a laborer (OR 3.3), prior stroke (OR 3.1), left carotid vascular territory (OR 12.5) vs vertebrobasilar and unknown territories, moderate to severe stroke severity (OR 3.4), and cognitive impairment (OR 4.5) and poorer functional status at admission (OR 4.5). Based on the significant predictors identified, the logistic regression model correctly classified PSD in 93.4% of subjects. Conclusion: The lower frequency of PSD in this study from Taiwan compared with previous studies from Western countries may have been due to the relatively younger age of the elderly population and the use of stricter diagnostic criteria.

Cerebral White Matter Hyperintensities Predict Functional Stroke Outcome

Background: Growing evidence suggests that white matter hyperintensities (WMHs) are implicated in stroke recurrence and mortality, and their location can be a critical factor. This study evaluated the impact of periventricular WMHs (PVWMHs) and subcortical WMHs (SWMHs) on poststroke functional outcomes. Methods: Brain MRI was performed on 187 acute ischemic stroke patients (57.8% male; mean age = 64.3 years) recruited from the Kaohsiung Municipal Hsiao-Kang Hospital from February 2007 to January 2008. A Fazekas score ≥2 in the periventrcular or subcortical white matter was taken as presence of WMHs. Demographic data and risk factors for stroke were assessed. Functional stroke outcomes were evaluated 30 days after stroke using the Barthel Index (BI) and the modifiedRankin Scale (mRS). Results: WMHs were inversely linked to favorable functional outcome measured by mRS (p = 0.001) and BI (p = 0.003). Evaluating different locations, PVWMHs were associated with unfavorable functional outcomes (p = 0.002, mRS; p = 0.001, BI). SWMHs were related to mRS (p = 0.026) but not BI (p = 0.069). After controlling other stroke risk factors, infarct volumes and initial stroke severity, PVWMHs were a significant indicator for both mRS (OR = 2.76; 95% CI = 1.03–7.40) and BI (OR = 3.07; 95% CI = 1.13–8.40), but SWMHs were not. Conclusions: Unfavorable functional stroke outcome is associated with MRI WMHs. In terms of location, PVWMHs but not SWMHs are related to functional stroke outcome.

The risk of the metabolic syndrome on carotid thickness and stiffness: sex and age specific effects.

BACKGROUND AND PURPOSE The metabolic syndrome (MS) is associated with a high risk for cardiovascular disease. Intima-media thickness (IMT) and stiffness reflect structure and functional alterations in arteries. We investigated the relationship of MS on IMT and stiffness and also dissected its gender and age specific effect. METHODS Carotid segment-specific IMT and stiffness were obtained in 1245 stroke- and myocardial infarction free volunteers between the ages of 15 and 87. The MS was defined according to the National Cholesterol Education Program Adult Treatment Panel III with Asian modification. RESULTS The prevalence of MS was 22.2% in our study population. The MS was associated with increased IMT in the common carotid artery (CCA IMT) and stiffness modalities (including Ep, beta, and PWV), but was not associated with bifurcation and internal carotid artery IMT. The relationship of MS on atherosclerosis was more prominent in women than in men. Only women revealed a significant interaction between MS and age for CCA IMT (p=0.013), which was more pronounced in young women (< or = 45 years) than in elderly. Comparing the risk components between young and elderly women in regard to MS, high triglycerides were more common in the affected young women (p=0.007). CONCLUSIONS MS is associated with a risk for increased CCA IMT and stiffness, and this relationship is particularly pronounced in women. Age can modify the MS impact on atherosclerosis. Young women with MS who often have high triglycerides experience the highest risk to associate with atherosclerosis. Young MS women who are easily overlooked for atherosclerotic diseases need more detailed assessment for atherosclerosis to prevent premature cardiovascular disease.

Apolipoprotein E Polymorphism in Ischemic Cerebrovascular Diseases and Vascular Dementia Patients in Taiwan

This study aims to clarify the association between apolipoprotein E gene (ApoE) polymorphism, ischemic cerebrovascular diseases (ICVD) and vascular dementia (VaD) in Taiwan Chinese. 277 patients with ICVD, 49 patients with probable VaD and 112 controls were recruited for this study. Distributions of ApoE Ε4 carriers and allele frequencies were 28.5 and 14.5% for patients with ICVD, 20.4 and 10.2% for patients with VaD, whereas these values were 22.9 and 11.6% for controls. Distributions of ApoE Ε2 carriers and allele frequencies were 10.1 and 5.2% for ICVD patients, 6.1 and 3.1% for VaD patients, but 12.5 and 8.0% for controls. There were no differences between ICVD patients and controls, or VaD patients and controls in their Ε4 carriers. Those patients aged 65 and under, carrying the Ε2 allele, had a lower risk of developing ICVD and VaD than did their counterparts. These findings suggest that ApoE Ε4 plays no significant role in the development of ICVD and VaD, but that ApoE Ε2 has a protective effect with regard to the development of ICVD and VaD for Taiwan Chinese below the age of 65.

Eligibility for Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke

Background: The eligibility for recombinant tissue plasminogen activator (rtPA) is rare. We analyze the reasons for exclusion from rtPA among patients who were admitted to our hospital within 3 h. Methods: A strict protocol for hyperacute stroke was set in a university teaching hospital. Consecutive patients activating the protocol from June 2004 to October 2005 were prospectively registered and entered into a computerized database. The patients were excluded from rtPA according to the modified exclusion criteria from the National Institute of Neurological Disorders and Stroke rtPA trial. Results: Of the 182 patients activating the protocol, only 11 (6.04%) received intravenous rtPA and 4 (2.2%) IA thrombolysis. Patients were excluded for multiple reasons, and the main reasons for exclusion were minor or improving stroke (46.15%), hypertension (35.16%), insufficient time to complete studies or onset beyond 3 h after reconfirmation (24.17%) and intracranial hemorrhage (15.93%). Of 167 excluded patients, 72 (43.11%) were excluded by a single criterion, 53 (31.73%) by 2 criteria and 29 (17.36%) by 3 criteria. The mean time from hospital arrival to presentation to a neurologist was 9.24 ± 15.11 min (n = 164, median = 8.00, mode = 10, range = 0–65). The mean time from hospital arrival to computed tomography (CT) was 21.67 ± 23.95 min (n = 167, median = 20.00, mode = 10, range = 4–68). Conclusion: An intrahospital stroke code was implemented to minimize intrahospital delay. However, only 11 patients received intravenous rtPA and 4 IA thrombolysis at our hospital from June 2004 to October 2005. The result brings into question the neurologist’s conservative interpretation of the criteria and the necessity to clearly define some criteria. Furthermore an intrahospital stroke code should also be implemented for inpatients to maximize the eligibility for rtPA.

Eligibility and rate of treatment for recombinant tissue plasminogen activator in acute ischemic stroke using different criteria.

OBJECTIVES The rate of recombinant tissue plasminogen activator (rtPA) use for stroke is low among the Chinese-Taiwanese. The study objective was to determine if less restrictive exclusion criteria for rtPA would increase eligibility and the rate of treatment. METHODS This retrospective before-and-after study was conducted from 2006 to 2009. The authors compared stroke patients treated under the old rtPA exclusion criteria (January 2006 to December 2008) with those treated with less restrictive rtPA exclusion criteria (January to December 2009). Rates of eligibility and treatment and reasons for exclusion from rtPA between the two phases were assessed. RESULTS Of 461 eligible patients during the study period, 333 were evaluated by the old criteria and 128 were evaluated by the less restrictive criteria. Minor or improving stroke was the primary exclusion reason in both groups (194/333, 58% vs. 70/128, 55%). Eligibility for rtPA was increased in the less restrictive criteria (35/127, 27%, 95% confidence interval [CI] = 20% to 36%) compared to the old criteria (40/333, 12%, 95% CI = 8.7% to 16%; p = 0.0001). Fewer patients were excluded due to old age in the less restrictive criteria (0/128, 0%) compared to the old criteria (37/333, 11%; p = 0.0001). The rate of consent refusal increased in the less restrictive criteria (27/128, 21%, 95% CI = 14% to 29%) compared to the old criteria (23/333, 6.9%, 95% CI = 4.4% to 10%; p < 0.0001). Rate of rtPA treatment was unchanged between the less restrictive criteria (8/128, 6.3%, 95% CI = 2.7% to 12%) and the old criteria (17/333, 5.1%, 95% CI = 3% to 8%; p = 0.63). CONCLUSIONS Increasing eligibility for rtPA does not increase the rate of treatment, possibly due to the high symptomatic intracerebral hemorrhage rate among Chinese-Taiwanese, which is a major concern among emergency physicians (EPs), neurologists, and patients. Dealing with perceived safety issues of rtPA is crucial before the rate of treatment can be increased.

Sex Differential Genetic Effect of Chromosome 9p21 on Subclinical Atherosclerosis

Background Chromosome 9p21 has recently been shown to be a risk region for a broad range of vascular diseases. Since carotid intima-media thickness (IMT) and plaque are independent predictors for vascular diseases, the association between 9p21 and these two phenotypes was investigated. Methodology/Principal Findings Carotid segment-specific IMT and plaques were obtained in 1083 stroke- and myocardial infarction-free volunteers. We tested the genotypes and haplotypes of key single nucleotide polymorphisms (SNPs) on chromosome 9p21 for the associations with carotid IMT and plaque. Multivariate permutation analyses demonstrated that carriers of the T allele of SNP rs1333040 were significantly associated with thicker common carotid artery (CCA) IMT (p = 0.021) and internal carotid artery (ICA) IMT (p = 0.033). The risk G allele of SNP rs2383207 was associated with ICA IMT (p = 0.007). Carriers of the C allele of SNP rs1333049 were found to be significantly associated with thicker ICA IMT (p = 0.010) and the greater risk for the presence of carotid plaque (OR = 1.57 for heterozygous carriers; OR = 1.75 for homozygous carriers). Haplotype analysis showed a global p value of 0.031 for ICA IMT and 0.115 for the presence of carotid plaque. Comparing with the other haplotypes, the risk TGC haplotype yielded an adjusted p value of 0.011 and 0.017 for thicker ICA IMT and the presence of carotid plaque respectively. Further analyzing the data separated by sex, the results were significant only in men but not in women. Conclusions Chromosome 9p21 had a significant association with carotid atherosclerosis, especially ICA IMT. Furthermore, such genetic effect was in a gender-specific manner in the Han Chinese population.

Reappraisal of heart rate variability in acute ischemic stroke.

Cardiac autonomic dysfunction is a common complication after acute ischemic stroke (IS). Prior investigators have emphasized that infarction of brain stem or hemispheres with insular involvement is related to this dysfunction and may predict poor clinical outcome. From the viewpoint of stroke physicians, however, all stroke patients, particularly large‐artery atherosclerosis (LAA) should be monitored for possible cardiac complications after acute IS. This study aimed to investigate cardiac autonomic impaction in patients with acute IS and to make the comparison between LAA and small‐vessel occlusion (SVO) subtypes. Of the 126 acute IS patients prospectively enrolled in this study, 32 had LAA, 56 had SVO, and 38 had undetermined etiology according to the Trial of Org 10172 in Acute Stroke Treatment criteria. Cardiac autonomic function of all patients was assessed by measuring heart rate variability (HRV). The low‐ and high‐frequency components of HRV in all stroke patients were significantly lower than those of control subjects after comparing multivariable models, including additional adjustments for age, gender, and all risk factors. There were no significant differences on HRV between LAA and SVO although post hoc comparisons showed that stroke patients of SVO had increased sympathetic modulation and reduced vagal activity. In conclusion, in acute IS patients, both LAA and SVO are predisposed to have cardiac autonomic dysfunction, manifesting as abnormalities in HRV, whether in hemispheric or brain stem lesions. Stroke patients of SVO are at higher risks of cardiac abnormalities, which might suggest an early cardiac dysfunction because of long‐term hypertension. The HF component of HRV thought to be for vagal control might be a cardinal marker for predicting cardiac autonomic dysfunction after acute IS. Short‐term HRV spectral analysis is a convenient approach for stroke clinicians to assess autonomic function in acute stroke. Long‐term follow‐up for HRV and clinical outcome relative to LAA and SVO stroke subtypes is warranted, particularly when an abnormal HRV is found at admission.