<i>Background:</i> Secondary degeneration following supratentorial stroke has been detected by some studies using diffusion tensor imaging (DTI), but the anterograde and retrograde degeneration in pyramidal tract after pontine infarction and its potential clinical significance are not well understood. <i>Methods:</i> Fourteen patients with a recent pontine infarct underwent three DTIs at week 1, week 4, and week 12 after onset. Fourteen age- and gender-matched controls underwent DTI once. Mean diffusivity and fractional anisotropy (FA) were measured. Neurological deficit, motor deficit and life independence were assessed with the NIH Stroke Scale, Fugl-Meyer scale and Barthel index, respectively, 2 h before each DTI examination. <i>Results:</i> FA values at the ipsilateral medulla and the proximal portion of the pyramidal tract, including centrum semiovale, internal capsule and cerebral peduncle, significantly decreased progressively from week 1 to week 12 (p < 0.01). The NIH Stroke Scale decreased; Fugl-Meyer scale and Barthel index increased significantly over the time points (p < 0.01). The absolute values of percent reduction of FA value at the ipsilateral medulla and the proximal portion of pyramidal tract correlated negatively with the absolute values of percent reduction of the NIH Stroke Scale and percent increase of the Fugl-Meyer scale. <i>Conclusions:</i> Progressive anterograde and retrograde degeneration in pyramidal tract revealed by DTI may hinder the process of neurological recovery after a pontine infarct. To confirm the clinical significance, future studies with a longer observation period and a larger sample size of patients with more homogeneous pontine infarcts are still needed.
Stroke is common during the first few weeks after a transient ischemic attack (TIA) or minor ischemic stroke. Combination therapy with clopidogrel and aspirin may provide greater protection against subsequent stroke than aspirin alone.In a randomized, double-blind, placebo-controlled trial conducted at 114 centers in China, we randomly assigned 5170 patients within 24 hours after the onset of minor ischemic stroke or high-risk TIA to combination therapy with clopidogrel and aspirin (clopidogrel at an initial dose of 300 mg, followed by 75 mg per day for 90 days, plus aspirin at a dose of 75 mg per day for the first 21 days) or to placebo plus aspirin (75 mg per day for 90 days). All participants received open-label aspirin at a clinician-determined dose of 75 to 300 mg on day 1. The primary outcome was stroke (ischemic or hemorrhagic) during 90 days of follow-up in an intention-to-treat analysis. Treatment differences were assessed with the use of a Cox proportional-hazards model, with study center as a random effect.Stroke occurred in 8.2% of patients in the clopidogrel-aspirin group, as compared with 11.7% of those in the aspirin group (hazard ratio, 0.68; 95% confidence interval, 0.57 to 0.81; P<0.001). Moderate or severe hemorrhage occurred in seven patients (0.3%) in the clopidogrel-aspirin group and in eight (0.3%) in the aspirin group (P=0.73); the rate of hemorrhagic stroke was 0.3% in each group.Among patients with TIA or minor stroke who can be treated within 24 hours after the onset of symptoms, the combination of clopidogrel and aspirin is superior to aspirin alone for reducing the risk of stroke in the first 90 days and does not increase the risk of hemorrhage. (Funded by the Ministry of Science and Technology of the People's Republic of China; CHANCE ClinicalTrials.gov number, NCT00979589.).
Background: Stroke rehabilitation improves functional recovery among stroke patients. However, little is known about clinical practice in China regarding the assessment and provision of rehabilitation among patients with acute ischemic stroke (AIS). Aims: We examined the frequency and determinants of an assessment for rehabilitation among AIS patients from the China National Stroke Registry II. Methods: Data for 19,294 AIS patients admitted to 219 hospitals from June 2012 to January 2013 were analyzed. The multivariable logistic regression model with the generalized estimating equation method accounting for in-hospital clustering was used to identify patient and hospitals factors associated with having a rehabilitation assessment during the acute hospitalization. Results: Among 19,294 AIS patients, 11,451 (59.4%) were assessed for rehabilitation. Rehabilitation assessment rates varied considerably among centers: median 64.8% (interquartile range: 41.4%-83.3%). Factors associated with increased likelihood of a rehabilitation assessment in the multivariable model (p<0.05) included disability prior to this stroke, increasing NIHSS on admission, receiving dysphagia screening, deep venous thrombosis prophylaxis, and carotid vessel imaging, longer length of stay, and increasing hospital beds (per 100 units). In contrast, patients with a history of atrial fibrillation, and increasing annual stroke discharges (per 100 patients) were less likely to receive rehabilitation assessment during the acute stroke hospitalization. Conclusions: Up to a third of patients in China do not receive rehabilitation assessment follow an AIS. Thus, there appears to be opportunities to improve adherence to recommended care for stroke survivors in China.
Abstract Background The association between body mass index (BMI) and Alzheimer's disease (AD) remains controversial. Genetic and environmental factors are now considered contributors to AD risk. However, little is known about the potential interaction between genetic risk and BMI on AD risk. Objective To study the causal relationship between BMI and AD, and the potential interaction between AD genetic risk and BMI on AD risk. Methods and Results Using the UK Biobank database, 475,813 participants were selected for an average follow-up time of more than 10 years. Main findings: 1) there was a nonlinear relationship between BMI and AD risk in participants aged 60 years or older ( p for non-linear < 0.001), but not in participants aged 37–59 years ( p for non-linear = 0.717) using restricted cubic splines; 2) for participants aged 60 years and older, compared with the BMI (23–30 kg/m 2 ) group, the BMI (< 23 kg/m 2 ) group was associated with a higher AD risk (HR = 1.585; 95% CI 1.304–1.928, p < 0.001) and the BMI (> 30 kg/m 2 ) group was associated with a lower AD risk (HR = 0.741; 95% CI 0.618–0.888, p < 0.01) analyzed using the Cox proportional risk model; 3) participants with a combination of high AD genetic risk score (AD-GRS) and BMI (< 23 kg/m 2 ) were associated with the highest AD risk (HR = 3.034; 95% CI 2.057–4.477, p < 0.001). In addition, compared with the BMI (< 23 kg/m 2 ), the higher BMI was associated with a lower risk of AD in participants with the same intermediate or high AD-GRS; 4) there was a reverse causality between BMI and AD when analyzed using bidirectional Mendelian randomization (MR). Conclusion There was a reverse causality between BMI and AD analyzed using MR. For participants aged 60 years and older, the higher BMI was associated with a lower risk of AD in participants with the same intermediate or high AD genetic risk. BMI (23–30 kg/m 2 ) may be a potential intervention for AD.
Exosomes contribute to cell–cell communications. Emerging evidence has shown that microglial exosomes may play crucial role in regulation of neuronal functions under ischemic conditions. However, the underlying mechanisms of microglia-derived exosome biosynthesis are largely unknown. Herein, we reported that the microglial PDE1-B expression was progressively elevated in the peri-infarct region after focal middle cerebral artery occlusion. By an oxygen-glucose-deprivation (OGD) ischemic model in cells, we found that inhibition of PDE1-B by vinpocetine in the microglial cells promoted M2 and inhibited M1 phenotype. In addition, knockdown or inhibition of PDE1-B significantly enhanced the autophagic flux in BV2 cells, and vinpocetine-mediated suppression of M1 phenotype was dependent on autophagy in ischemic conditions. Co-culture of BV2 cells and neurons revealed that vinpocetine-treated BV2 cells alleviated OGD-induced neuronal damage, and treatment of BV2 cells with 3-MA abolished the observed effects of vinpocetine. We further demonstrated that ischemia and vinpocetine treatment significantly altered microglial exosome biogenesis and release, which could be taken up by recipient neurons and regulated neuronal damage. Finally, we showed that the isolated exosome per se from conditioned BV2 cells is sufficient to regulate cortical neuronal survival in vivo . Taken together, these results revealed a novel microglia-neuron interaction mediated by microglia-derived exosomes under ischemic conditions. Our findings further suggest that PDE1-B regulates autophagic flux and exosome biogenesis in microglia which plays a crucial role in neuronal survival under cerebral ischemic conditions.
Thrombolytic therapy within 4.5 h from symptom onset is a recognized effective and standard therapy for acute ischemic stroke (AIS), but some patients still have a poor clinical outcome. The evaluation and control of predictors for AIS poor clinical outcomes is integral to achieving optimal treatments, but the prognostic value of admission blood glucose (ABG) for this purpose is unclear and still under debate. ABG evaluated in patients without diabetes mellitus (DM) often suggests acute stress hyperglycemia, while ABG may have a close relationship with long-term blood glucose control in patients with DM. However, in most studies about the influence of ABG on the prognosis of recombinant tissue-type plasminogen activator (rtPA) therapy after AIS, patients were not classified into those with and without DM. The present study was designed to investigate the prognostic value of ABG for clinical outcomes of AIS after thrombolysis according to DM status in a Chinese population. The Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS-China) study comprised a prospective, multicenter, open-label, observational study conducted from January 2000 to November 2008 at 67 investigative sites in China. Patients who were treated with intravenous rtPA (Actilyse; Boehringer Ingelheim, Germany) within 4.5 h after ischemic stroke onset were recruited. All patients underwent a standard investigation protocol comprising blood tests, electrocardiography, magnetic resonance imaging, and cranial computed tomography (CT). Ethics committees at the participating hospitals approved data collection for the TIMS-China study. All patients or their legal representatives were fully informed of the study and provided their written consent before study entry. We measured ABG of all patients at the emergency department before intravenous thrombolysis, recorded the metabolic parameters and stroke risk factors in our computer-based laboratory system. All patients underwent brain CT examination at admission. DM was defined as a history of DM or use of insulin and/or oral hypoglycemic agents. According to the American Diabetes Association guidelines, random glucose testing in an average adult produces values ranging from 80 to 140 mg/dL (4.4–7.8 mmol/L), with ≥200 mg/dL (11.1 mmol/L) considered to show diabetes. Herein, ABG ≥7.8 mmol/L was defined as hyperglycemia and ≥11.1 mmol/L was defined as severe hyperglycemia. Primary outcome measurements included 90-day functional outcome and 90-day mortality. Functional dependence was defined by the modified Rankin Scale (mRS) score at 3 months and categorized as favorable (mRS score 0–2) or poor (mRS score 3–6). Secondary outcomes included early neurological deterioration (END) and 7-day mortality. END in AIS was defined according to a National Institutes of Health Stroke Scale score increase of ≥4 points between admission and at 24 h. Mortality included deaths from all causes. The safety evaluation was based on the incidence of symptomatic intracranial hemorrhage (sICH) at 36 h. sICH following rtPA administration was defined according to the modified Safe Implementation of Treatment in Stroke-Monitoring Study (SITS-MOST) definition. The data were statistically analyzed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). We conducted univariate comparisons between groups with and without a history of DM. Analysis of the χ2 test and variance was made to assess univariate differences between categorical and continuous variables. Measurement data expressed as means ± standard deviations were analyzed by t-test. A logistic regression model adjusted for potential confounding effects selected according to their significance in univariate analyses was used to assess the effects of a history of DM and ABG on clinical outcomes. P ≤ 0.05 was considered to be statistically significant Analyses were also conducted in patients with different ABG levels and diabetic and non-diabetic statuses. Out of all 1440 patients in the TIMS-China registry, 1128 received treatment of intravenous rtPA within 4.5 h after onset. Forty-four patients were excluded for a lack of information on their history of DM (n = 10) or missing ABG levels (n = 34), so 1084 patients were analyzed [Supplementary Figure 1, https://links.lww.com/CM9/A272]. Baseline characteristics for the patients are given in Supplementary Tables 1, https://links.lww.com/CM9/A273 and 2, https://links.lww.com/CM9/A274. A DM history was found in 191 (17.62%) patients. In total, 726 (66.97%) patients had ABG <7.8 mmol/L, 257 (23.71%) had 7.8 to 11.1 mmol/L, and 101 (9.32%) had ABG ≥11.1 mmol/L. Univariate and multivariate analyses showed that a history of diabetes was related to an increased risk of sICH according to the SITS-MOST. sICH occurred in 3.66% and 1.46% of patients with and without diabetes, respectively (P = 0.016). A history of DM was associated with an elevated risk of END, 7-day mortality, 90-day functional outcome, and 90-day mortality, but the associations were not significant. When ABG levels were stratified by diagnostic threshold (<7.8 or ≥11.1 mmol/L), we noted that the risk of poor outcomes increased in a graded fashion as ABG increased. The risk of poor outcomes was significantly higher in the severe hyperglycemia group (END-adjusted odds ratio [OR], 2.23; 95% confidence interval [CI], 1.13–4.41, P = 0.020; and mRS >2-adjusted OR, 1.55; 95% CI, 1.00–2.41; P = 0.0490). Similar results were evident for deaths (7-day mortality-adjusted OR, 2.70; 95% CI, 1.32–5.54; P = 0.007 and 90-day mortality-adjusted OR, 2.31; 95% CI, 1.31–4.07; P = 0.004). The ABG level was not significantly associated with sICH according to the SITS-MOST. The adjusted OR per 1 standard deviation increase in the glucose level was 2.68 (95% CI, 0.84–8.58; P = 0.10) for the univariate analysis and 2.54 (95% CI, 0.77–8.35; P = 0.13) for the multivariate analysis [Supplementary Table 3, https://links.lww.com/CM9/A275]. Elevated ABG was an independent predictor of poor outcomes only among patients without DM where the risk exposure of poor clinical outcomes was significantly greater in those with severe hyperglycemia (END-adjusted OR, 4.082; 95% CI, 1.625–10.254; P = 0.0028). Similar results were observed in the mortality rate (7-day mortality-adjusted OR, 4.250; 95% CI, 1.591–11.352, P = 0.0038 and 90-day mortality-adjusted OR, 3.704; 95% CI, 1.647–8.326; P = 0.0015). sICH and 90-day functional outcome were not associated with ABG, and ABG was not significantly related to poor outcome or sICH in patients with diabetes and AIS [Table 1].Table 1: Effect of ABG on outcome after stroke thrombolysis with or without diabetes.Our data show that elevated ABG is a predictor of poor outcomes in AIS patients with non-DM, not those with DM. Our results are in line with studies investigating the prognostic value of ABG on intracerebral hemorrhage, myocardial infarction, and other critical conditions.[1] The likely explanations for this are as follows: first, higher ABG in non-diabetes, usually defined as stress hyperglycemia, tends to occur in patients with critical illness. Second, diabetic patients with long-term exposure to increased glucose may have reduced the adverse effects of hyperglycemia on metabolism. Moreover, other cardiovascular risk factors, such as blood pressure and lipid levels, were required to maintain near-normal ranges in addition to glycemia control in the clinical treatment of diabetic patients. Ischemic stroke patients with and without DM are likely to have different glucose cut-off values. Snarska et al[2] found that the ABG cut-off value for mortality prediction in AIS patients without DM was >113.5 mg/dL, compared with >210.5 mg/dL in those with DM. Farrokhnia et al[3] showed that the cut-off value of mean blood glucose >6.3 mmol/L predicted 30-day mortality in non-DM patients. However, in patients with diabetes, the corresponding value was 10.3 mmol/L. The ABG cut-off value for poor outcomes varies between non-diabetic and diabetic patients, which may explain why patients with AIS and diabetes with ABG ≥11.1 mmol/L had an elevated risk of mortality and neurological dysfunction in our study, but without statistical significance. Further studies are needed to investigate the ABG cut-off value for worse clinical outcome in patients with ischaemic stroke and diabetes. sICH after thrombolytic therapy for AIS is a potentially devastating event incurring high mortality. ABG has been recognized as an independent risk factor for sICH after intravenous rtPA in ischemic stroke patients. However, the specific links between elevated ABG and sICH in patients with ischaemic stroke are still inconsistent. Some studies demonstrated that sICH is related to ABG in patients treated with rtPA and that a high ABG increases sICH.[4] However, this has not been shown in all observational studies of stroke.[5] We found that a history of diabetes rather than ABG was a predictor of sICH in patients with AIS. Our findings may be explained by the hypothesis that chronic microvascular injury rather than acute stress-induced hyperglycemia results in an increased risk of sICH. Glucose toxicity and pathophysiological changes caused by chronically elevated blood glucose play a major role in cerebral microvascular and macrovascular damage through metabolic and structural derangements. Because of multiple confounding factors in the AIS patient population, the relationship between ABG and diabetes with clinical outcomes has varied considerably among studies. The major limitation of our study was the use of retrospective data. For example, we only investigated ABG, with no data for fasting blood glucose or post-prandial blood glucose at 2-h, and without hemoglobin A1c data. Additionally, our diagnosis was based on a history of previous diagnoses of diabetes as well as patient medical records, medical histories, and medical treatments. This may have resulted in missed diagnoses, especially for new patients with diabetes who were previously undiagnosed. Moreover, no data were collected on the duration of diabetes or type of treatment. Larger prospective trials are needed to directly investigate these blood glucose parameters. In summary, elevated ABG (≥11.1 mmol/L) was an independent predictor of poor clinical outcomes after thrombolysis for AIS in non-diabetic patients instead of diabetic ones, while a history of DM independently correlated with an increased risk of thrombolysis-related sICH. Our observations should help improve the management of AIS patients. In accordance with our findings, we emphasize the importance of better glycemic control by primary prevention, and suggest that attention should be paid to control sICH when thrombolysis is given to DM patients. Funding This study was supported by grants from the Ministry of Science and Technology of the People's Republic of China (No. 2015BAI12B04), the National Natural Science Foundation of China (No. 31672375), Beijing Municipal Science and Technology Commission (D151100002015001), Beijing Natural Science Foundation (7182049), Basic-Clinical Research Cooperation Funding of Capital Medical University (17JL34), and Beijing Municipal Administration of Hospitals' Youth Programme (QML20160501). Conflicts of interest None.
The aim of the study was to investigate the difference of resting-state default-mode network (DMN) between patients with leukoaraiosis (LA)-associated subcortical vascular cognitive impairment (SVCI) and control subjects, and to provide functional imaging evidence of SVCI.All subjects (n = 58) were divided into two groups based on their clinical diagnosis: a LA-associated SVCI group (n = 31, 14 males) and a control group (n = 27, 14 males). Demographic information and resting-state functional MRI (rs-fMRI) data were obtained. These subjects were assessed using the Hamilton Anxiety Depression Scale, Clinical Dementia Rating, Mini Mental State Exam, and Montreal Cognitive Assessment. Experimental data and confounding factors were described with a General Liner Model. Independent components of fMRI data were analyzed with an fMRI toolbox.The active areas involved in DMN of LA-associated SVCI group were similar to those of the control group. However, several active areas of LA-associated SVCI group, especially the left anterior cingulate cortex and the right parahippocampal gyrus, showed significantly lower blood oxygen level-dependent (BOLD) signals compared with the control group (p ≤ 0.05); whereas the left caudate nucleus (p = 0.015), the right frontal lobe (p = 0.004), and the superior temporal gyrus/inferior parietal gyrus (p = 0.001) exhibited significantly higher BOLD signals compared with the control group.The present study provides neuroimaging evidence for the recognition of LA-associated SVCI. Moreover, the differences in the functional alterations of the resting-state DMN might be a distinguishing feature between SVCI and amnestic mild cognitive impairment patients.
Objectives: To analyse quantitatively for the secondary injury to the perihematoma region of intracerebral hemorrhage (ICH) patients by functional MR imaging technique. Methods: 35 ICH patients were recruited and performed T1, T2, perfusion weight imaging (PWI), diffusion weight imaging (DWI) and FLAIR sequence scanning. Hematoma volume and edema volume of perihematomal area as well as parameters of blood volume [regional cerebral blood volume (rCBV), mean transit time (MTT)] alteration were calculated. Results: Varied blood flow decline was detected in the patients on the perihematoma sides, compared with the corresponding area of the opposite sides. There was significant difference of rCBV and MTT (p=0.00) and mild negative correlation between rCBV and hematoma volume (p=0.00) among groups; edema volume of perihematoma region and hematoma volume showed a linear correlation (p=0.00). Moreover, positive correlation between edema intensity and rCBV was detected, (p=0.00); the most significant perihematoma edema was in the group of day 10 to day 14; the lowest rCBV occurred in the early stage. (days 2–5 from symptom onset). Conclusion: We have concluded that rCBV and MTT of perihematoma region decreased remarkably compared with the contralateral side, and the decline would last over 3 weeks. Quantitative research suggested edema intensity is closely related with rCBV. We believe that the reduced regional blood flow of perihematoma contributes to the secondary ischemic injury of perihematoma tissue. However, the peak of edema would appear later than the onset of the peak of ischemia, it suggests that edema surrounding the hematoma is not only the result from the single ischemic factor, but also results from multiple disadvantage mechanisms.
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