Prognosis and Prediction of Asymptomatic Intracranial Hemorrhage After Endovascular Thrombectomy: A Multi-Center Study.

PURPOSE: The impact of asymptomatic intracranial hemorrhage (aICH) on functional outcomes after endovascular thrombectomy (EVT) remains unclear, and tools for forecasting this complication are lacking. We aim to evaluate the clinical relevance of aICH and establish a prediction model. METHODS: Data of patients who received EVT for acute anterior-circulation large vessel occlusion in 3 comprehensive hospitals were retrospectively analyzed. Asymptomatic intracranial hemorrhage was defined as any hemorrhage detected after EVT that did not fulfill the definition of symptomatic intracranial hemorrhage in the European Cooperative Acute Stroke Study. Logistic regression models were performed to assess the impact of aICH on 90-day functional outcomes and identify the predictors of aICH, which were then used to establish a prediction model. The discrimination, calibration, and clinical utility of the model were evaluated. RESULTS: This study included 460 patients, among whom 152 (33.0%) developed aICH after EVT. Asymptomatic intracranial hemorrhage was negatively associated with 90-day excellent outcomes (adjusted odds ratio [OR]: 0.414, 95% confidence interval [CI]: 0.230-0.745, p=0.003) and good outcome (adjusted OR: 0.603, 95% CI: 0.374-0.971, p=0.037), but not with mortality (adjusted OR: 1.110, 95% CI: 0.611-2.017, p=0.732) after adjusted for other predictors of functional outcome. Pre-stroke anticoagulant therapy (OR: 2.233, 95% CI: 1.073-4.647, p=0.032), Alberta stroke program early CT score (OR: 0.842, 95% CI: 0.754-0.939, p=0.002), site of occlusion (internal carotid artery occlusion as the reference; M1 segment of middle cerebral artery occlusion, OR: 2.827, 95% CI: 1.409-5.674, p=0.003; tandem occlusion, OR: 3.928, 95% CI: 1.752-8.806, p=0.001), intravenous thrombolysis (OR: 2.091, 95% CI: 1.362-3.209, p=0.001), and successful recanalization (OR: 0.383, 95% CI: 0.213-0.689, p=0.001) were identified as the predictors of aICH, which were incorporated into a nomogram model. The area under the receiver operating characteristic curve of the model was 0.707 (95% CI: 0.657-0.757), and the calibration plot demonstrated good consistency between actual observed and predicted probability of aICH. Decision curve analysis showed that patients might benefit from the model. CONCLUSION: Asymptomatic intracranial hemorrhage was negatively associated with favorable functional outcome after EVT. We established a nomogram model for predicting aICH, which requires external clinical validation. CLINICAL IMPACT: The impact of asymptomatic intracranial hemorrhage after endovascular thrombectomy on mid-term functional outcome has been controversial. We found that asymptomatic intracranial hemorrhage may also decreased the likelihood of 90-day favourable functional outcome after endovascular thrombectomy, supporting the notion that asymptomatic intracranial hemorrhage at the acute stage may not be benign. Moreover, we established a prediction model for this complication, which may improve clinical evaluation and management of patients who would receive endovascular thrombectomy for large vessel occlusion.

Prediction of Alzheimer's disease using multi-variants from a Chinese genome-wide association study.

Previous genome-wide association studies have identified dozens of susceptibility loci for sporadic Alzheimer's disease, but few of these loci have been validated in longitudinal cohorts. Establishing predictive models of Alzheimer's disease based on these novel variants is clinically important for verifying whether they have pathological functions and provide a useful tool for screening of disease risk. In the current study, we performed a two-stage genome-wide association study of 3913 patients with Alzheimer's disease and 7593 controls and identified four novel variants (rs3777215, rs6859823, rs234434, and rs2255835; Pcombined = 3.07 × 10-19, 2.49 × 10-23, 1.35 × 10-67, and 4.81 × 10-9, respectively) as well as nine variants in the apolipoprotein E region with genome-wide significance (P < 5.0 × 10-8). Literature mining suggested that these novel single nucleotide polymorphisms are related to amyloid precursor protein transport and metabolism, antioxidation, and neurogenesis. Based on their possible roles in the development of Alzheimer's disease, we used different combinations of these variants and the apolipoprotein E status and successively built 11 predictive models. The predictive models include relatively few single nucleotide polymorphisms useful for clinical practice, in which the maximum number was 13 and the minimum was only four. These predictive models were all significant and their peak of area under the curve reached 0.73 both in the first and second stages. Finally, these models were validated using a separate longitudinal cohort of 5474 individuals. The results showed that individuals carrying risk variants included in the models had a shorter latency and higher incidence of Alzheimer's disease, suggesting that our models can predict Alzheimer's disease onset in a population with genetic susceptibility. The effectiveness of the models for predicting Alzheimer's disease onset confirmed the contributions of these identified variants to disease pathogenesis. In conclusion, this is the first study to validate genome-wide association study-based predictive models for evaluating the risk of Alzheimer's disease onset in a large Chinese population. The clinical application of these models will be beneficial for individuals harbouring these risk variants, and particularly for young individuals seeking genetic consultation.

Lower Plasma α-Synuclein Levels are Associated with Cognitive Impairment in Parkinson's Disease.

BACKGROUND: α-Synuclein (α-syn) has a central role in the development of Parkinson's disease (PD). Plasma α-syn has been associated with the presence of cognitive impairment in PD although data have been inconsistent. The aim of this study was to explore the correlation between plasma α-syn levels and cognitive impairment in PD. METHODS: A total of 53 participants, 26 patients with PD and 27 healthy controls were included in the study. Unified Parkinson's Disease Rating Scale (UPDRS) part Ⅲ and Hohen-Yahr scale (H-Y scale) were used to detect PD severity. The cognitive function was assessed with Montreal Cognitive Assessment (MoCA) scale, Frontal Assessment Battery (FAB), Trail Making Test A (TMT-A), Verbal Function Test (VFT), Clock Drawing Test (CDT), and Rey's Auditory Verbal Learning Test (RAVLT). Enzyme-Linked Immunosorbent Assay (ELISA) method was used to measure α-syn and hemoglobin (Hb) concentration in the plasma samples collected from participants. RESULTS: Plasma α-syn in PD patients was significantly lower than those in the control group (p < 0.01). No associations were found between plasma α-syn and Hb or gender (p > 0.05). The decline in plasma α-syn in PD patients was negatively correlated with disease severity, including UPDRS Ⅲ scores and H-Y scale. Furthermore, lower plasma α-syn was negatively associated with the scores of MoCA, FAB, and RAVLT (immediate recall) scores in PD group. CONCLUSIONS: Our data suggest that lower plasma α-syn levels are associated with cognitive decline in PD. Thus, plasma α-syn may be a novel biomarker for patients at risk of cognitive decline.

Analysis influence factors and forecast energy-related CO2 emissions: evidence from Hebei.

With economic development and the acceleration of urbanization, China's energy demand has gradually increased and brought a lot of energy-related CO2 emissions. Energy-related CO2 emissions are affected by a variety of factors. Quantifying the correlation between energy-related CO2 and driving factors and constructing the driving factor system are conducive to predict the future energy-related CO2 emissions and analyze the impact of driving factors. In this paper, the improved grey relational analysis (IGRA) was proposed to screen the influencing factors of energy-related CO2 emissions considering the sample difference, and the factor analysis (FA) was used to reduce dimensionality of the influencing factors. Then, a carbon dioxide emission forecasting model based on the bacterial foraging optimization algorithm (BFO) and the least square support vector machine (LSSVM) was proposed. Empirical analysis results of Hebei show that the LSSVM optimized BFO significantly improves the accuracy of energy-related CO2 emissions forecasting, and IGRA-FA-BFOLSSVM model is significantly better than BP, PSOBP, SVM, and LSSVM models. The mean absolute percentage error (MAPE) of the proposed model is 0.374%. The forecasting results of the supplementary case show that the model has better generalization ability. In addition, education and technological progress have proven to be important drivers of energy-related CO2 emissions. Simultaneously, the research results can also offer more breakthrough points for policy makers to control carbon emissions.

Angiotensin II Receptor Type 1 Antagonists Modulate Vascular Smooth Muscle Cell Proliferation and Migration via AMPK/mTOR.

The aberrant proliferation and migration of vascular smooth muscle cells (VSMCs) in the vascular wall are crucial pathological events involved in cardiovascular impairments including hypertension, heart failure, and atherosclerosis. At the molecular level, the mammalian target of rapamycin (mTOR)-ribosomal protein S6 kinase beta-1 (p70S6K) signaling pathway is essential to potentiate VSMC proliferation and migration. Although angiotensin II receptor type 1 -(AT1-R) antagonists such as valsartan and telmisartan have a significant cardiovascular protective effect, the molecular basis of this class of drugs in VSMC proliferation and migration remains elusive. By using cultured VSMCs, adenosine monophosphate-activated protein kinase (AMPK) α2 knockout mice, and hypertensive rat models, this study investigated whether AT1-R antagonists can inhibit the mTOR-p70S6K signaling pathway in VSMCs and the vascular wall. Valsartan activated AMPK, which in turn suppressed reactive oxygen species production and consequently attenuated VSMC proliferation and migration. In vivo, a clinical dose of telmisartan significantly inhibited the mTOR-p70S6K signaling pathway in the vascular wall of wild-type but not AMPKα2-/- mice. Furthermore, spontaneously hypertensive rats had significantly elevated phosphorylation of mTOR and p70S6K in the aorta compared to Wistar-Kyoto rats, which were reduced by telmisartan administration. These data suggest that AT1-R antagonists inhibit VSMC proliferation and migration via their regulation of AMPK, mTOR, and p70S6K, which contribute to the cardioprotective effects of these drugs.

Postoperative intermittent fasting prevents hippocampal oxidative stress and memory deficits in a rat model of chronic cerebral hypoperfusion.

PURPOSE: Whether intermittent fasting (IF) treatment after stroke can prevent its long-term detrimental effects remains unknown. Here, we investigate the effects of postoperative IF on cognitive deficits and its underlying mechanisms in a permanent two-vessel occlusion (2VO) vascular dementia rat model. METHODS: Rats were subjected to either IF or ad libitum feeding 1 week after 2VO surgery. The cognition of rats was assessed using the novel object recognition (NOR) task and Morris water maze (MWM) 8 weeks after surgery. After behavioral testing, hippocampal malondialdehyde (MDA) and glutathione (GSH) concentrations, superoxide dismutase (SOD) activity, gene expression of antioxidative enzymes, inflammatory protein levels, and microglia density were determined. RESULTS: Postoperative IF significantly ameliorated the cognitive performance of 2VO rats in the NOR and MWM tests. Cognitive enhancement paralleled preservation of the PSD95 and BDNF levels in the 2VO rat hippocampus. Mechanistically, postoperative IF mitigated hippocampal oxidative stress in 2VO rats, as indicated by the reduced MDA concentration and mRNA and the protein levels of the reactive oxygen species-generating enzyme nicotinamide adenine dinucleotide phosphate oxidase 1. IF treatment also preserved the GSH level and SOD activity, as well as the levels of their upstream regulating enzymes, resulting in preserved antioxidative capability. In addition, postoperative IF prevented hippocampal microglial activation and elevation of sphingosine 1-phosphate receptor 1 and inflammatory cytokines in 2VO rats. CONCLUSIONS: Our results suggest that postoperative IF suppresses neuroinflammation and oxidative stress induced by chronic cerebral ischemia, thereby preserving cognitive function in a vascular dementia rat model.

Retrospective comparison of stereotactic body radiotherapy versus intensity-modulated radiotherapy for stage III ultra-central squamous non-small-cell lung cancer.

Aim: To analyze the efficacy and toxicity of stereotactic body radiotherapy (SBRT) versus intensity-modulated radiotherapy (IMRT) in stage III patients with ultra-central squamous non-small-cell lung cancer (sqNSCLC). Methods: Forty-four stage III patients with ultra-central sqNSCLC receiving SBRT (n = 15) or IMRT (n = 29) between December 2014 and August 2017 were reviewed. Results: At a median follow-up of 16.5 months, the 1-year local control rate of SBRT and IMRT was 60.8 and 37.5%, respectively (p = 0.23); the median overall survival was 17 versus 18 months (p = 0.48); ≥3 grade toxicity was 20 versus 24.1% (p = 0.83). Conclusion: SBRT is effective and patient friendly for stage III patients with ultra-central sqNSCLC. Toxicity might be tolerable with a moderate dose five to six fraction regimen. However, more prospective studies are warranted.

Prevalence and associated factors of elder abuse in family caregivers of older people with dementia in central China cross-sectional study.

OBJECTIVE: To explore the abuse risk and related important determinants among older people with dementia in central China. METHODS: In this cross-sectional descriptive study, a sample of 158 family caregivers of older people with dementia was conveniently recruited from the Clinical Medicine Research Center of Dementia and Cognitive Impairment in Hubei Province, China. A social-demographic questionnaire, the Simplified Coping Style Questionnaire (SCSQ), the Social Support Rating Scale (SSRS), the Caregiver Burden Inventory (CBI), and the Caregiver Abuse Screen (CASE) were used for data collection. Descriptive statistics, Mann-Whitney U tests, Kruskal-Wallis tests, Spearman's rank correlation coefficient, and logistic regression analysis were used for the data analyses. RESULTS: The results demonstrate that 77.8% reported a risk of the abuse of older people with dementia. Moreover, positive and negative reactions, subjective support, and emotional, social, and physical burden were associated with family caregivers' abusive behaviours. CONCLUSION: This was a study conducted to examine the risk of the abuse of older people with dementia by family caregivers in central China. Elder abuse is prevalent among people with dementia. The present results confirmed the need to focus on family caregiver burden, coping styles, and social support in future interventions to prevent elder abuse.

Time-domain simulation of ultrasound propagation with fractional Laplacians for lossy-medium biological tissues with complicated geometries.

Simulations of ultrasound wave propagation inside biological tissues have a wide range of practical applications. In previous studies, wave propagation equations in lossy biological media are solved either with convolutions, which consume a large amount of memory, or with pseudo-spectral methods, which cannot handle complicated geometries effectively. The approach described in the paper employed a fractional central difference method (FCD), combined with the immersed boundary (IB) method for the finite-difference, time-domain simulation. The FCD method can solve the fractional Laplace terms in Chen and Holm's lossy-medium equations directly in the physical domain without integral transforms. It also works naturally with the IB method, which enables a simple Cartesian-type grid mesh to be used to solve problems with complicated geometries. The numerical results agree very well with the analytical solutions for frequency power-law attenuation lossy media.

Adiponectin Attenuates Streptozotocin-Induced Tau Hyperphosphorylation and Cognitive Deficits by Rescuing PI3K/Akt/GSK-3ß Pathway.

Clinical studies have demonstrated that decreased adiponectin is associated with the development of Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD). We focused on determining the neuroprotective effect offered by adiponectin against streptozotocin-induced brain damage in ICV-STZ rat model. We found that adiponectin supplements significantly restored the cognitive deficits in ICV-STZ rat model including shorter escape latency, more crossing times and increased time spent in the target quadrant. Adiponectin supplements also increased number of dendritic branches and mushroom percentage. In addition, adiponectin supplements attenuated tau hyperphosphorylation at multiple AD-related sites through activation of protein Ser9-phosphorylated glycogen synthase kinase-3ß (Ser9-GSK-3ß) with increased the Akt and PI3K activity. Our data suggest that adiponectin supplements have neuroprotective effects on the ICV-STZ rat model, which may be mediated by the activation of the PI3K/Akt/GSK-3ß signaling pathway.

The cost of Alzheimer's disease in China and re-estimation of costs worldwide.

INTRODUCTION: The socioeconomic costs of Alzheimer's disease (AD) in China and its impact on global economic burden remain uncertain. METHODS: We collected data from 3098 patients with AD in 81 representative centers across China and estimated AD costs for individual patient and total patients in China in 2015. Based on this data, we re-estimated the worldwide costs of AD. RESULTS: The annual socioeconomic cost per patient was US $19,144.36, and total costs were US $167.74 billion in 2015. The annual total costs are predicted to reach US $507.49 billion in 2030 and US $1.89 trillion in 2050. Based on our results, the global estimates of costs for dementia were US $957.56 billion in 2015, and will be US $2.54 trillion in 2030, and US $9.12 trillion in 2050, much more than the predictions by the World Alzheimer Report 2015. DISCUSSION: China bears a heavy burden of AD costs, which greatly change the estimates of AD cost worldwide.

Intermittent Fasting Pretreatment Prevents Cognitive Impairment in a Rat Model of Chronic Cerebral Hypoperfusion.

Background: Whether intermittent fasting (IF) pretreatment can prevent vascular cognitive dysfunction remains unknown to our knowledge.Objective: We investigated the effects and underlying mechanisms of IF pretreatment on cognitive dysfunction in a permanent 2-vessel occlusion (2VO) vascular dementia rat model.Methods: Male Wistar rats weighing 200 g were subjected to either IF or ad libitum feeding for 12 wk before 2VO surgery. Rats in the IF protocol underwent alternative-day feed deprivation (FD). Memory of the animals was assessed by using the Morris water maze (MWM) and the novel object recognition (NOR) test 6 wk after the surgery. After behavioral testing, malondialdehyde and glutathione concentrations, superoxide dismutase (SOD) activity, gene expression of antioxidative enzymes, inflammatory protein concentrations, and microglia density were determined in the hippocampus of rats.Results: 2-vessel occlusion operation ad libitum (2VO-AL) rats had significantly longer escape latencies on day 4 of the training phase and spent a lower percentage of time in the target quadrant (25% compared with 38% and 41%) in the MWM, and had lower discrimination ratios (47% compared with 65% and 67%) in the NOR test than 2-vessel operation and alternate-day feed deprivation (2VO-FD) and sham operation ad libitum (Sham-AL) rats, respectively (P < 0.05). This indicates that IF helps to prevent vascular cognitive deficits. 2VO-AL rats also had higher malondialdehyde (3.54 compared with 2.15 and 1.66 nmol/mg protein) and lower glutathione concentrations (53.25 compared with 66.41 and 91.71 nmol/mg protein), lower SOD activity (100.1 compared with 133.3 and 138.5 U/mg protein), lower gene expression of antioxidative enzymes, higher expression of inflammatory proteins, and higher microglia density in the hippocampus than 2VO-FD and Sham-AL rats, respectively (P < 0.05). This suggests that IF has antioxidative and anti-inflammatory effects.Conclusions: IF pretreatment provided sustained neuroprotection in a rat model of vascular dementia. These effects were associated with reduced oxidative stress and neuroinflammation.

Impairments in Brain Perfusion, Metabolites, Functional Connectivity, and Cognition in Severe Asymptomatic Carotid Stenosis Patients: An Integrated MRI Study.

Carotid artery stenosis without transient ischemic attack (TIA) or stroke is considered as "asymptomatic." However, recent studies have demonstrated that these asymptomatic carotid artery stenosis (aCAS) patients had cognitive impairment in tests of executive function, psychomotor speed, and memory, indicating that "asymptomatic" carotid stenosis may not be truly asymptomatic. In this study, when 19 aCAS patients compared with 24 healthy controls, aCAS patients showed significantly poorer performance on global cognition, memory, and executive function. By utilizing an integrated MRI including pulsed arterial spin labeling (pASL) MRI, Proton MR Spectroscopy (MRS), and resting-state functional MRI (R-fMRI), we also found that aCAS patients suffered decreased cerebral blood flow (CBF) mainly in the Left Frontal Gyrus and had decreased NAA/Cr ratio in the left hippocampus and decreased connectivity to the posterior cingulate cortex (PCC) in the anterior part of default mode network (DMN).

Consensus-based recommendations for the management of rapid cognitive decline due to Alzheimer's disease.

INTRODUCTION: Rapid cognitive decline (RCD) occurs in dementia due to Alzheimer's disease (AD). METHODS: Literature review, consensus meetings, and a retrospective chart review of patients with probable AD were conducted. RESULTS: Literature review showed that RCD definitions varied. Mini-Mental State Examination scores <20 at treatment onset, vascular risk factors, age <70 years at symptom onset, higher education levels, and early appearance of hallucinations, psychosis, or extrapyramidal symptoms are recognized RCD risk factors. Chart review showed that RCD (Mini-Mental State Examination score decline ≥3 points/year) is more common in moderate (43.2%) than in mild patients (20.1%; P < .001). Rapid and slow decliners had similar age, gender, and education levels at baseline. DISCUSSION: RCD is sufficiently common to interfere with randomized clinical trials. We propose a 6-month prerandomization determination of the decline rate or use of an RCD risk score to ensure balanced allocation among treatment groups.

Hypoxia Inducible Factor 1α Promotes Endogenous Adaptive Response in Rat Model of Chronic Cerebral Hypoperfusion.

Hypoxia inducible factor 1α (HIF-1α), a pivotal regulator of gene expression in response to hypoxia and ischemia, is now considered to regulate both pro-survival and pro-death responses depending on the duration and severity of the stress. We previously showed that chronic global cerebral hypoperfusion (CCH) triggered long-lasting accumulation of HIF-1α protein in the hippocampus of rats. However, the role of the stabilized HIF-1α in CCH is obscure. Here, we knock down endogenous HIF-1α to determine whether and how HIF-1α affects the disease processes and phenotypes of CCH. Lentivirus expressing HIF-1α small hairpin RNA was injected into the bilateral hippocampus and bilateral ventricles to knock down HIF-1α gene expression in the hippocampus and other brain areas. Permanent bilateral common carotid artery occlusions, known as 2-vessel occlusions (2VOs), were used to induce CCH in rats. Angiogenesis, oxidative stress, histopathological changes of the brain, and cognitive function were tested. Knockdown of HIF-1α prior to 2VO significantly exacerbates the impairment of learning and memory after four weeks of CCH. Mechanically, reduced cerebral angiogenesis, increased oxidative damage, and increased density of astrocytes and microglia in the cortex and some subregions of hippocampus are also shown after four weeks of CCH. Furthermore, HIF-1α knockdown also disrupts upregulation of regulated downstream genes. Our findings suggest that HIF-1α-protects the brain from oxidative stress and inflammation response in the disease process of CCH. Accumulated HIF-1α during CCH mediates endogenous adaptive processes to defend against more severe hypoperfusion injury of the brain, which may provide a therapeutic benefit.

The effects of DL-3-n-butylphthalide in patients with vascular cognitive impairment without dementia caused by subcortical ischemic small vessel disease: A multicentre, randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Vascular cognitive impairment without dementia is very common among the aged and tends to progress to dementia, but there have been no proper large-scale intervention trials dedicated to it. Vascular cognitive impairment without dementia caused by subcortical ischemic small vessel disease (hereinafter, subcortical Vascular cognitive impairment without dementia) represents a relatively homogeneous disease process and is a suitable target for therapeutic trials investigating Vascular cognitive impairment without dementia. Preclinical trials showed that dl-3-n-butylphthalide (NBP) is effective for cognitive impairment of vascular origin. METHODS: In this randomized, double-blind, placebo-controlled trial, we enrolled patients aged 50-70 years who had a diagnosis of subcortical Vascular cognitive impairment without dementia at 15 academic medical centers in China. Inclusion criteria included a clinical dementia rating ≥0.5 on at least one domain and global score ≤0.5; a mini-mental state examination score ≥20 (primary school) or ≥24 (junior school or above); and brain magnetic resonance imaging consistent with subcortical ischemic small vessel disease. Patients were randomly assigned to NBP 200 mg three times daily or matched placebo (1:1) for 24 weeks according to a computer-generated randomization protocol. All patients and study personnel were masked to treatment assignment. Primary outcome measures were the changes in Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog) and clinician's interview-based impression of change plus caregiver input (CIBIC-plus) after 24 weeks. All patients were monitored for adverse events (AEs). Outcome measures were analyzed for both the intention-to-treat (ITT) population and the per protocol population. RESULTS: This study enrolled 281 patients. NBP showed greater effects than placebo on ADAS-cog (NBP change -2.46 vs. placebo -1.39; P = .03; ITT) and CIBIC-plus (80 [57.1%] vs. 59 [42.1%] patients improved; P = .01; ITT). NBP-related AE were uncommon and primarily consisted of mild gastrointestinal symptoms. DISCUSSION: Over the 6-month treatment period, NBP was effective for improving cognitive and global functioning in patients with subcortical vascular cognitive impairment without dementia and exhibited good safety.

Furin mediates brain-derived neurotrophic factor upregulation in cultured rat astrocytes exposed to oxygen-glucose deprivation.

This study investigated the changes in brain-derived neurotrophic factor (BDNF) expression and the role of furin in BDNF maturation in reactive astrocytes from rats exposed to oxygen-glucose deprivation (OGD). Furin, a proprotein convertase, is upregulated and cleaves certain substrates during hypoxia in cancer cells. In addition, during hypoxia in the central nervous system, astrocytes become reactive and release BDNF to protect neurons. Maturation of BDNF in astrocytes requires furin-mediated endoproteolytic processing of the precursor protein pro-BDNF to BDNF. To expand our knowledge about the role of furin in BDNF maturation in astrocytes, these cells were exposed to OGD, and expression of furin and BDNF was detected by Western blot analysis. Changes in BDNF expression were observed when furin activity was inhibited by furin prosegment. We found that protein expression of BDNF and furin was upregulated, and this upregulation correlated with OGD stimulation. Furin inhibition reduced BDNF maturation and secretion. These results indicate that furin mediates the upregulation of BDNF in reactive astrocytes exposed to OGD and that furin may impact the biological effect of reactive astrocytes.

Abnormal levels of brain metabolites may mediate cognitive impairment in stroke-free patients with cerebrovascular risk factors.

OBJECTIVE: conventional vascular risk factors (VRFs) are associated with cognitive impairment independent of stroke and detectable cerebral lesions. We used proton magnetic resonance spectroscopy ((1)H MRS) to examine the hypotheses that abnormal levels of brain metabolites may mediate the relationship between VRFs and cognitive impairment. METHODS: a group of 54 stroke-free subjects with various VRFs underwent comprehensive cognitive assessments and (1)H MRS scan of the left hippocampus and prefrontal cortex. We indirectly measured the concentrations of N-acetylaspartate (NAA), choline, inositol, creatine (Cr) and total concentrations of glutamate plus glutamine (Glx). VRFs were quantified by Framingham stroke risk profile (FSRP) score. Subjects were divided into low- (<10%), medium- (10-20%) and high-risk (>20%) groups according to their FSRP scores. Pearson and partial correlation analysis were used to investigate the correlation between FSRP scores and cognitive performance along with the brain metabolism. RESULTS: compared with subjects in low-risk group, high-risk group subjects had significantly poor performances on the tasks of working memory, delayed recall and executive function. In high-risk group, hippocampal Glx/Cr ratios and prefrontal NAA/Cr ratios were significantly lower than those in low-risk group. Lower prefrontal NAA/Cr ratios were associated with executive dysfunction, and lower hippocampal Glx/Cr ratios were associated with impaired delayed recall. CONCLUSION: abnormal concentrations of brain metabolites and decreased glutamate plus glutamine concentration may play an important role in the pathophysiology of VRF-associated cognitive impairment. Brain metabolites detected by (1)H MRS may serve as important markers for monitoring VRFs burden.

Change of Nrf2 expression in rat hippocampus in a model of chronic cerebral hypoperfusion.

Chronic cerebral hypoperfusion (CCH) is common in vascular dementia and Alzheimer's disease. CCH-related oxidative damage plays a significant role in the development of cognitive impairment. Nuclear factor-erythroid 2-related factor-2 (Nrf2) mediates activation of the antioxidant responsive element (ARE)-related gene expression, which is crucial to the endogenous antioxidative system. In this case, we used permanent bilateral occlusion of common carotid arteries (2VO) to mimic CCH. The expression of Nrf2 in different regions of the hippocampus as well as the ability of nuclear Nrf2 and ARE binding have been examined. A phenomenon has been observed that the DNA binding activities were down-regulated. Interestingly, the expression of Nrf2 rose significantly in most regions of rat hippocampus within three weeks after the 2VO surgery. The mismatch might attribute to Nrf2 dysfunction and compensatory synthesis. A conclusion can be drawn that Nrf2 dysfunction is an important factor as a cause of CCH-induced oxidative damage and Nrf2 can be treated as a promising target to alleviate oxidative damage, even cognitive impairment caused by CCH.

Changes of c-fos, malondialdehyde and lactate in brain tissue after global cerebral ischemia under different brain temperatures.

Under global cerebral ischemia, the effect of different brain temperature on cerebral ischemic injury was studied. Male Sprague-Dawley rats were divided into normothermic (37-38°C) ischemia, mild hypothermic (31-32°C) ischemia, hyperthermic (41-42°C) ischemia and sham-operated groups. Global cerebral ischemia was established using the Pulsinelli four-vessel occlusion model and brain temperature was maintained at defined level for 60 min after 20-min ischemia. The expression of c-fos protein and the levels of malondialdehyde (MDA) and lactate in brain regions were detected by immunochemistry and spectrophotometrical methods, respectively. C-fos positive neurons were found in the hippocampus and cerebral cortex after cerebral ischemia reperfusion. Mild hypothermia increased the expression of c-fos protein in both areas, whereas hyperthermia decreased the expression of c-fos protein in the hippocampus at 24 h reperfusion, and the cerebral cortex at 48 h reperfusion when compared to normothermic conditions. In normothermic, mild hypothermic and hyperthermic ischemia groups, the levels of MDA and lactate in brain tissue were increased at 24, 48 and 72 h reperfusion following 20-min ischemia as compared with the sham-operated group (P<0.01). The levels of MDA and lactate in mild hypothermic group were significantly lower than those in normothermic group (P<0.01). It is suggested that brain temperature influences the translation of the immunoreactive protein product of c-fos after global cerebral ischemia, and MDA and lactate are also affected by hypothermia and hyperthermia.