Characteristics of non-stenotic carotid plaque in embolic stroke of undetermined source compared with cardiogenic embolism: a retrospective cross-sectional observational study.

BACKGROUND: Non-stenotic carotid plaque is considered an important etiology of embolic stroke of undetermined source (ESUS). However, only a few previous studies included a negative control group, and the characteristics of non-stenotic carotid plaque in ESUS have yet to be investigated. The objective of this study is to explore the clinical characteristics of ESUS and the correlation between non-stenotic carotid plaque and ESUS. METHODS: This is a single-center, retrospective cross-sectional observational study conducted to compare differences in clinical information among ESUS, CE, and large-artery atherosclerosis (LAA), as well as the prevalence of non-stenotic carotid plaque and non-stenotic carotid plaque with low echo between patients with ESUS and CE in Changzhou No.2 People's Hospital from January 2020 to January 2022. Ultrasound was used to evaluate the characteristics of non-stenotic carotid plaque and vulnerable carotid plaque was defined as plaque with low echo. The binary logistic regression model was used to analyze the relationship between the characteristics of non-stenotic carotid plaque and ESUS. The receiver-operating characteristic curve was used to evaluate the diagnostic efficiency of the characteristics of non-stenotic carotid plaque for ESUS. RESULTS: We had a final studying population of 280 patients including 81 with ESUS, 37 with CE, and 162 with LAA. There were no differences in clinical features between ESUS and LAA, but in the comparison of CE and ESUS, there were differences in age, smoking, hypertension, levels of triglyceride, total cholesterol, and low density lipoprotein cholesterol. In ESUS, the prevalence of non-stenotic carotid plaque was more common on the ipsilateral side of stroke than in CE [55 (67.90%) vs. 18 (48.65%), p = 0.046], so was the prevalence of non-stenotic carotid plaque with low echo [38 (46.91%) vs. 5 (13.51%), p < 0.001]. Logistic regression analysis showed that the prevalence of non-stenotic carotid plaque (OR: 4.19; 95% CI: 1.45-12.11; p = 0.008) and the prevalence of non-stenotic carotid plaque with low echo (OR: 5.12; 95% CI: 1.55-16.93; p = 0.007) were, respectively, the independent predictors of ESUS. The results receiver-operating characteristic (ROC) curve showed that the combination of age, hypertension, and ipsilateral non-stenotic carotid plaque with low echo had the best diagnostic efficiency for ESUS (0.811; 95%CI: 0.727-0.896; p < 0.001). CONCLUSION: Our results suggest that ipsilateral vulnerable non-stenotic carotid plaque is associated with ESUS in anterior circulation infarction.

Influence of white matter lesions on the prognosis of acute cardioembolic stroke without reperfusion therapy.

BACKGROUND: Few studies have investigated the influence of white matter lesions (WMLs) on the prognosis of acute cardioembolic stroke (CES). We aimed to explore the role of WMLs in predicting 3-month prognosis of CES without reperfusion therapy. METHODS: A number of 251 acute CES patients without reperfusion therapy at a single center were retrospectively recruited. The severity of WMLs was evaluated by Fazekas scale and patients were divided into mild WMLs group (188 cases, Fazekas ≤ 2 points) and moderate to severe WMLs group (63 cases, Fazekas ≥ 3 points) accordingly. General data and clinical features of the two groups were compared. Functional outcomes of patients were followed up for 3 months using the modified Rankin scale (mRS) and patients were divided into poor outcome group (mRS ≥ 3) and favorable outcome group (mRS ≤ 2). The effect of WMLs on the prognosis was identified by binary logistic regression. RESULTS: Patients in moderate to severe WMLs group were older (P < 0.001). Also, they had higher baseline National Institutes of Health Stroke Scale (NIHSS) score (P < 0.001) and elevated incidence of asymptomatic cerebral hemorrhage (P = 0.040) and stroke associated pneumonia (P = 0.001) than those in mild WMLs group. At 3 months, there were 100 cases in the poor outcome group. Patients in poor outcome group had higher baseline NIHSS score, increased proportion of moderate to severe WMLs, and elevated incidence of stroke associated pneumonia than those in favorable outcome group (P < 0.001). Binary logistic regression analysis showed that moderate to severe WMLs (odds ratio [OR] = 4.105, 95 % confidence interval [CI] = 1.447-11.646), baseline NIHSS score (OR = 1.368, 95 % CI = 1.240-1.511), and stroke-associated pneumonia (OR = 4.840, 95 %CI = 1.889-12.400) were independent risk factors for poor outcome. CONCLUSIONS: Moderate to severe WMLs is an independent risk factor for prognosis of CES patients without reperfusion therapy.

Involvement of the GluN2A and GluN2B subunits in synaptic and extrasynaptic N-methyl-D-aspartate receptor function and neuronal excitotoxicity.

GluN2A and GluN2B are the major subunits of functional NMDA receptors (NMDAR). Previous studies have suggested that GluN2A and GluN2B may differentially mediate NMDAR function at synaptic and extrasynaptic locations and play opposing roles in excitotoxicity, such as neurodegeneration triggered by ischemic stroke and brain injury. By using pharmacological and molecular approaches to suppress or enhance the function of GluN2A and GluN2B in cultured cortical neurons, we examined NMDAR-mediated, bidirectional regulation of prosurvival signaling (i.e. the cAMP response element-binding protein (CREB)-Bdnf cascade) and cell death. Inhibition of GluN2A or GluN2B attenuated the up-regulation of prosurvival signaling triggered by the activation of either synaptic or extrasynaptic NMDAR. Inhibition of GluN2A or GluN2B also attenuated the down-regulation of prosurvival signaling triggered by the coactivation of synaptic and extrasynaptic receptors. The effects of GluN2B on CREB-Bdnf signaling were larger than those of GluN2A. Consistently, compared with suppression of GluN2A, suppression of GluN2B resulted in more reduction of NMDA- and oxygen glucose deprivation-induced excitotoxicity as well as NMDAR-mediated elevation of intracellular calcium. Moreover, excitotoxicity and down-regulation of CREB were exaggerated in neurons overexpressing GluN2A or GluN2B. Together, we found that GluN2A and GluN2B are involved in the function of both synaptic and extrasynaptic NMDAR, demonstrating that they play similar rather than opposing roles in NMDAR-mediated bidirectional regulation of prosurvival signaling and neuronal death.

Unveiling the Complex Role of Exosomes in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative illness, characterized by memory loss and cognitive decline, accounting for 60-80% of dementia cases. AD is characterized by senile plaques made up of amyloid ß (Aß) protein, intracellular neurofibrillary tangles caused by hyperphosphorylation of tau protein linked with microtubules, and neuronal loss. Currently, therapeutic treatments and nanotechnological developments are effective in treating the symptoms of AD, but a cure for the illness has not yet been found. Recently, the increased study of extracellular vesicles (EVs) has led to a growing awareness of their significant involvement in neurodegenerative disorders, including AD. Exosomes are small extracellular vesicles that transport various components including messenger RNAs, non-coding RNAs, proteins, lipids, DNA, and other bioactive compounds from one cell to another, facilitating information transmission and material movement. There is growing evidence indicating that exosomes have complex functions in AD. Exosomes may have a dual role in Alzheimer's disease by contributing to neuronal death and also helping to alleviate the pathological progression of the disease. Therefore, the primary aim of this review is to outline the updated understandings on exosomes biogenesis and many functions of exosomes in the generation, conveyance, distribution, and elimination of hazardous proteins related to Alzheimer's disease. This review is intended to provide novel insights for understanding the development, specific treatment, and early detection of Alzheimer's disease.

Piperine potentiates the antidepressant-like effect of trans-resveratrol: involvement of monoaminergic system.

Major depression is characterized by dysfunction of neuroendocrine and immune networks. Trans-resveratrol, a phenolic compound presented in polygonum cuspidatum, was demonstrated previously to exert antidepressant-like effects through regulating monoaminergic system, oxidative/antioxidant defense and inflammatory response. The present study investigated the synergistic antidepressant-like effect of trans-resveratrol and piperine, a bioavailability enhancer, in mice and explored the possible mechanism. Trans-resveratrol was shown to reduce the immobility time both in the tail suspension and forced swimming tests (TST and FST). But the maximal inhibition was nearly 60% even if the doses were increased by 160 mg/kg; while piperine produced weak antidepressant-like effects in these two models. The interaction between trans-resveratrol and piperine was shown a clear-cut synergistic effect as evidenced by an isobolographic analysis. The further study suggested that the anti-immobility response from the subthreshold dose of piperine (2.5 mg/kg) and low doses of trans-resveratrol (10 and 20 mg/kg) was abolished by pretreatment with para-chlorophenylalanine (PCPA, 300 mg/kg, i.p.) in TST and FST, indicating the involvement of serotonergic system. Moreover, treatment with the subthreshold dose of piperine and low doses of trans-resveratrol attenuated reserpine-induced hypothermia and ptosis arguing for the relevance of noradrenaline. Additional evidence from neurochemical (monoamines in the frontal cortex, hippocampus, and hypothalamus) and biochemical (monoamine oxidase, MAO activity) assays corroborated the synergistically elevated monoaminergic system after co-treatment with trans-resveratrol and piperine. The present results indicate the effect of trans-resveratrol combined with piperine on depressive-like behaviors may be partly due to the potentiated activation of monoaminergic system in the brain. Further studies are necessary to elucidate the involvement of the oxidative/nitrosative stress, inflammatory and neuroprotective pathway in the antidepressant-like effect of this combination. The synergistic effect obtained from the combination may provide innovative clues for designing novel antidepressants with high efficacy and low side effects.

Correlation of atherosclerotic renal artery stenosis with extracranial carotid and intracranial cerebral artery atherosclerosis in patients with ischemic stroke.

OBJECTIVE: This study was to evaluate the relationship of atherosclerotic renal artery stenosis (ARAS) with extracranial carotid arteries atherosclerosis (ECAS) and intracranial cerebral atherosclerosis (ICAS) in ischemic stroke (IS) patients. METHODS: This study was a prospective cohort analysis of consecutive patients with IS who had not a history of renal artery stenosis (RAS). Abdominal aortography was performed to screen for RAS after the cerebrovascular diagnostic procedure. Multivariate logistic regression analysis was performed to investigate the association of the clinical variables with significant ARAS (≥ 50%). RESULTS: ARAS was identified in 61 (23.1%) of all patients and 34 patients (12.9%) had significant ARAS (≥ 50%). ECAS (≥ 70%) and ICAS (≥ 50%) was found in 66 (25%) and 48 (18.2%) respectively. Patients with ECAS (≥ 70%) were more likely to have significant ARAS than patients without ECAS (28.8% vs 6.2%, p < 0.001). In multivariate analysis, only advanced age (≥ 60 years) (OR = 2.84, 95% CI 1.01-7.91) and ECAS (≥ 70%) (OR = 5.27, 95% CI 2.396-11.60) were independent risk factors for significant ARAS. CONCLUSION: Incidental ARAS is a relatively common finding among patients with IS, and there is a close relationship between ARAS and ECAS. Abdominal aortography should be performed to identify ARAS in elderly patients with IS, especially combined with severe ECAS.

Influence of Pre-Existing Cerebral Small Vessel Disease on the Outcome of Acute Cardioembolic Stroke: A Retrospective Study.

Purpose: This study was to explore the role of pre-existing small vessel disease (SVD) on the 3-month outcomes of acute cardioembolic stroke (CES) patients. Patients and Methods: Data of 189 consecutive acute CES patients at a single center were retrospectively enrolled. SVD imaging markers of lacunes, white matter hyperintensities (WMH) and enlarged perivascular spaces (EPVS) were evaluated and their total burden score (0-3 points) was calculated. Patients were divided into the good functional outcome group (modified Rankin scale, mRS ≤ 2) and the poor functional outcome group (mRS ≥ 3) at 3 months after stroke onset. The effect of each single SVD marker and its total burden score on the outcome was identified using binary logistic regression. Results: Overall, 100 (52.9%), 52 (27.1%), 28 (14.8%) and 9 (4.8%) patients had 0, 1, 2 and 3 SVD imaging markers. Patients with a total SVD burden score of 2 and 3 were significantly older and had higher baseline National Institutes of Health Stroke Scale (NIHSS) score than those with a score of 0 and 1 (P<0.01). Forty-seven (24.9%) patients had a poor outcome. Patients in the poor outcome group had significantly higher baseline NIHSS score, increased incidence of stroke associated pneumonia, and heavier burden of lacunes, WMH and EPVS, and thus had elevated total SVD burden score than those in good outcome group (P<0.05). After adjusting for potential confounders, the WMH (odds ratio [OR] = 2.6777, 95% confidence interval [CI] = 1.052-6.812, P = 0.039) and the total SVD burden score (OR = 1.717, 95% CI = 1.072-2.749, P = 0.024) were, respectively, independent risk factors for a poor outcome. Conclusion: The pre-existing SVD may be associated with the 3-month prognosis of CES.

Perceived Stress and Psychological Impact Among Healthcare Workers at a Tertiaty Hospital in China During the COVID-19 Outbreak: The Moderating Role of Resilience and Social Support.

Aims: To investigate the psychological distress experienced by healthcare workers (HCWs) at a tertiary hospital in Changzhou, China, outside Wuhan, during the early stage of COVID-19 and evaluate the moderating effects of resilience and social support on the relationship between stress and psychological distress. Methods: The study was conducted between February 10 and 15, 2020, in a non-probabilistic way. The survey included questions regarding the risk of exposure, sociodemographics, perceived stress [10-item Perceived Stress Scale (PSS-10)], resilience [10-item Connor-Davidson Psychological Resilience (CD-RISC-10)], social support [Multidimensional Scale of Perceived Social Support (MSPSS)], and psychological distress [12-item General Health Questionnaire (GHQ-12)]. We applied the PROCESS macro for SPSS to test the hypotheses that resilience and social support moderated the stress response. In addition, a simple slope analysis was conducted when the interaction effect was statistically significant. Results: Some 33.6% of participants suffered from psychological distress (GHQ-12 ≥ 12). Perceived stress was positively related to psychological distress (r = 0.42, p < 0.001). In addition, resilience (ΔR2 = 0.03, p for interaction < 0.001) and social support (ΔR2 = 0.01, p for interaction <0.01) moderated the stress response. The impact of perceived stress on psychological distress was attenuated when subjects who were resilient (high ß = 0.15, p < 0.001; low ß = 0.36, p < 0.001), and perceived stress had less impact on psychological distress when social support was high (ß = 0.24, p < 0.001) rather than low (ß = 0.34, p < 0.001). Limitations: The cross-sectional design led to a lack of causal relationships between variables. Conclusions: Our data showed that resilience and social support moderated the stress response among HCWs in the pandemic, suggesting that improving resilience and social support could be appropriate targets to improve HCWs' mental health in the pandemic.

Association between BDNF G196A (Val66Met) polymorphism and cognitive impairment in patients with Parkinson's disease: a meta-analysis.

Brain-derived neurotrophic factor (BDNF) is widely expressed in the central nervous system and prolongs the survival of dopaminergic neurons in the substantia nigra. Several studies have recently investigated the association between BDNF G196A (Val66Met), a single nucleotide polymorphism influencing cognitive processes, and cognitive impairment in Parkinson's disease (PD), but with contradictory findings. Thus, this meta-analysis was performed to clarify the possible association. Relevant studies were identified by a systematic search of PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases. The strength of the association was evaluated using crude odds ratios and 95% confidence interval. Finally, six studies involving 532 cases and 802 controls were included. Our analyses suggested the G196A (Val66Met) polymorphism was significantly associated with cognitive impairment in PD, especially in Caucasian populations. In conclusion, BDNF G196A (Val66Met) is confirmed to be a risk factor for cognitive impairment in PD.

Inhibition of PDE2 reverses beta amyloid induced memory impairment through regulation of PKA/PKG-dependent neuro-inflammatory and apoptotic pathways.

Beta amyloid peptides (Aß) are known risk factors involved in cognitive impairment, neuroinflammatory and apoptotic processes in Alzheimer's disease (AD). Phosphodiesterase 2 (PDE2) inhibitors increase the intracellular cAMP and/or cGMP activities, which may ameliorate cognitive deficits associated with AD. However, it remains unclear whether PDE2 mediated neuroapoptotic and neuroinflammatory events, as well as cognitive performance in AD are related to cAMP/cGMP-dependent pathways. The present study investigated how the selective PDE2 inhibitor BAY60-7550 (BAY) affected Aß-induced learning and memory impairment in two classic rodent models. IL-22 and IL-17, Bax and Bcl-2, PKA/PKG and the brain derived neurotropic factor (BDNF) levels in hippocampus and cortex were detected with immunoblotting assay. The results showed that BAY reversed Aß-induced cognitive impairment as shown in the water maze test and step-down test. Moreover, BAY treatment reversed the Aß-induced changes in IL-22 and IL-17 and the ratio of Bax/Bcl-2. Changes in cAMP/cGMP levels, PKA/PKG and BDNF expression were also prevented by BAY. These effects of BAY on memory performance and related neurochemical changes were partially blocked by the PKG inhibitor KT 5823. These findings indicated that the protective effects of BAY against Aß-induced memory deficits might involve the regulation of neuroinflammation and neuronal apoptotic events.

Extrasynaptic NMDA Receptor in Excitotoxicity: Function Revisited.

It is generally accepted that proper activation of N-methyl-d-aspartate receptors (NMDARs) promotes neuronal survival and supports neuroplasticity, and excessive NMDAR activation leads to pathological outcomes and neurodegeneration. As NMDARs are found at both synaptic and extrasynaptic sites, there is significant interest in determining how NMDARs at different subcellular locations differentially regulate physiological as well as pathological functions. Better understanding of this issue may support the development of therapeutic strategies to attenuate neuronal death or promote normal brain function. Although the current prevailing theory emphasizes the major role of extrasynaptic NMDARs in neurodegeneration, there is growing evidence indicating the involvement of synaptic receptors. It is also evident that physiological functions of the brain also involve extrasynaptic NMDARs. Our recent studies demonstrate that the degree of cell death following neuronal insults depends on the magnitude and duration of synaptic and extrasynaptic receptor co-activation. These new results underscore the importance of revisiting the function of extrasynaptic NMDARs in cell fate. Furthermore, the development of antagonists that preferentially inhibit synaptic or extrasynaptic receptors may better clarify the role of NMDARs in neurodegeneration.

Co-activation of synaptic and extrasynaptic NMDA receptors by neuronal insults determines cell death in acute brain slice.

Overactivation of NMDA receptors is linked to cell death during neuronal insults. However the precise role of synaptic and extrasynaptic NMDA receptors remains to be further determined. In this study, we used the acute brain slice to examine the contributions of synaptic and extrasynaptic NMDA receptors to neuronal death. By activation of synaptic NMDA receptors with bath application of 100 µM bicuculline in acute brain slices, we observed a significant up-regulation in activation of neuronal survival-related signaling (p-CREB, p-ERK1/2 and p-AKT), without an obvious increase of LDH release and neuronal death. Interestingly, activation of extrasynaptic NMDA receptors alone by high dose of glutamate (200 µM) following blockade of synaptic NMDA receptors with co-application of 20 µM MK801 and 100 µM bicuculline, we failed to observe inhibition of neuronal survival signaling and neuronal damage. In contrast, co-activation of synaptic and extrasynaptic NMDA receptors by applying 200 µM glutamate or oxygen-glucose deprivation (OGD) to acute brain slices for 30 min, we observed a significant inhibition of CREB, ERK1/2 and AKT activation, an increase of LDH release and neuronal condensation. Together, co-activation of synaptic and extrasynaptic NMDA receptors by neuronal insults contributes to cell death in acute brain slice.

Association between BDNF G196A (Val66Met) polymorphism and cognitive impairment in patients with Parkinson's disease: a meta-analysis

Brain-derived neurotrophic factor (BDNF) is widely expressed in the central nervous system and prolongs the survival of dopaminergic neurons in the substantia nigra. Several studies have recently investigated the association between BDNF G196A (Val66Met), a single nucleotide polymorphism influencing cognitive processes, and cognitive impairment in Parkinson's disease (PD), but with contradictory findings. Thus, this meta-analysis was performed to clarify the possible association. Relevant studies were identified by a systematic search of PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases. The strength of the association was evaluated using crude odds ratios and 95% confidence interval. Finally, six studies involving 532 cases and 802 controls were included. Our analyses suggested the G196A (Val66Met) polymorphism was significantly associated with cognitive impairment in PD, especially in Caucasian populations. In conclusion, BDNF G196A (Val66Met) is confirmed to be a risk factor for cognitive impairment in PD.

Phosphodiesterase-5 inhibitor sildenafil prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in APP/PS1 transgenic mice.

Memory deficit is a marker of Alzheimer's disease (AD) that has been highly associated with the dysfunction of cyclic GMP (cGMP) signaling and an ongoing inflammatory process. Phosphodiesterase-5 (PDE5) inhibitors prevent the breakdown of cGMP and are currently studied as a possible target for cognitive enhancement. However, it is still unknown whether inhibition of PDE5 reversed ß-amyloid peptide (Aß)-induced neuroinflammation in APP/PS1 transgenic (Tg APP/PS1) mice. The present study evaluated the cognitive behaviors, inflammatory mediators, and cGMP/PKG/pCREB signaling in 15-month-old Tg APP/PS1 mice and age-matched wild-type (WT) mice that were treated with PDE5 inhibitor sildenafil and the inhibitor of cGMP-dependent protein kinase Rp-8-Br-PET-cGMPS. In comparison with WT mice, Tg APP/PS1 mice were characterized by impaired cognitive ability, neuroinflammatory response, and down-regulated cGMP signaling. Sildenafil reversed these memory deficits and cGMP/PKG/pCREB signaling dysfunction; it also reduced both the soluble Aß1-40 and Aß1-42 levels in the hippocampus. These effects of sildenafil were prevented by intra-hippocampal infusion of the Rp-8-Br-PET-cGMPS. These results suggest that sildenafil could restore cognitive deficits in Tg APP/PS1 mice by the regulation of PKG/pCREB signaling, anti-inflammatory response and reduction of Aß levels.

SNP rs356219 of the α-synuclein (SNCA) gene is associated with Parkinson's disease in a Chinese Han population.

BACKGROUND: Over the last decades, increasing knowledge about the genetic architecture of Parkinson's disease(PD) has provided novel insights into the pathogenesis of the disorder. Recently, several studies in different populations have found a strong association between idiopathic PD and the single-nucleotide polymorphism (SNP) rs356219, which is located in the 3'UTR of the SNCA gene. In this study, we aimed to verify these findings and to explore further the nature of the association in a subset of Chinese Han PD patients. METHODS: Four hundred and three unrelated patients with sporadic PD and 315 healthy ethnically matched control subjects were recruited consecutively for the study. Patients and normal controls were genotyped for SNCA rs356219 variant by ligase detection reaction (LDR). RESULTS: A statistically significant difference was found in the frequencies of the single alleles of rs356219 (χ(2) = 12.986,P = 0.002) between PD patients and normal subjects. The distribution of A > G genotypes was different between patients and controls (χ(2) = 13.243, P < 0.001). The OR for subjects with the variant genotypes (AG and GG) was 1.88 (95%CI = 1.27-2.78, P = 0.001). The frequencies of the homozygous genotype for this variant was 42.2% (170 patients), which was significantly higher than that in controls (32.4%, P < 0.001). CONCLUSION: The results suggested that SNCA rs356219 variant might have an increased risk of susceptibility to PD in a Chinese Han population. Further studies are needed to replicate the association that we found.