A High Resolution MRI Study of the Relationship Between Plaque Enhancement and Perforator Stroke after Stenting for Symptomatic Vertebrobasilar Artery Stenosis.

BACKGROUND AND PURPOSE: Perforator stroke is one of the most common complications of vertebrobasilar arterial stenting. We investigated whether perforator stroke after vertebrobasilar arterial stenting is associated with plaque enhancement in patients with severe vertebrobasilar artery stenosis. METHODS: We studied patients with symptomatic vertebrobasilar arterial stenosis who underwent stenting from January 2017 to July 2020. Patients who underwent high resolution magnetic resonance imaging were recruited among them. Demographic data, risk factors of atherosclerosis, procedure details, and characteristics of imaging were extracted from electronic health records and imaging data. Plaque features were investigated by high resolution magnetic resonance imaging. RESULTS: 136 patients were enrolled in this study, 39 of whom fulfilled the inclusion criteria. 18 patients (46.2%) had obvious plaque enhancement among the 39 patients, and 21 (53.8%) had plaque non-enhancement. 21 patients (53.8%) had diffuse distribution, and 22 patients (56.4%) had irregular plaques surface. Patients were divided into plaque enhanced and plaque non-enhanced groups according to the degree of plaque enhancement. Clinical characteristics and other plaque features were similar between two groups. Procedure-related perforator stroke was identified in 4 patients (10.3%). Patients with plaque enhancement were more likely to have perforator stroke after stenting compared with those with plaque non-enhancement (22.2% versus 0%, P = 0.037). CONCLUSIONS: Plaque enhancement in high resolution magnetic resonance imaging may be associated with perforator stroke after vertebrobasilar artery stenting.

Association between LRH-1 single nucleotide polymorphisms and unexplained recurrent spontaneous abortion in Chinese Han couples.

To explore the genetic relationships between LRH-1 (rs2816948), CYP19 (rs727479 and rs700518), and P450scc (rs4077582) as a potential mechanism behind unexplained recurrent spontaneous abortions in a Chinese Han population. A case-control study was used and featured two groups: Patients with unexplained recurrent miscarriage (n = 82, abortion group) and those who voluntary surrendered of a normal early pregnancy (n = 97, control group). Abortion villi samples were obtained from all patients. Genomic DNA was later extracted and sequenced, after which statistical analyses performed to assess the relationship between single nucleotide polymorphisms and unexplained recurrent spontaneous abortions. There were significant differences in the genotypic and allelic distribution (p < .05) for CYP19 (rs727479) between the abortion and the control groups. There were no significant differences in the genotypic or allelic distributions (p > .05) for either the LRH-1 (rs2816948) or CYP19 (rs700518). There were also significant genotypic differences (p < .05) for P450scc (rs4077582), but no significant differences for its allelic distribution (p > .05). There was a significant correlation between the occurrence of unexplained recurrent spontaneous abortion and CYP19 (rs727479) single nucleotide polymorphisms.

White matter hyperintensities mediate the association between frailty and cognitive impairment in moyamoya disease.

OBJECTIVES: The relationship between cognitive function and frailty in moyamoya disease (MMD) remains unclear, and the underlying mechanism is poorly understood. This study aims to investigate whether white matter hyperintensities (WMHs) mediate the association between frailty and cognitive impairment in MMD. METHODS: Patients with MMD were consecutively enrolled in our study from January 2021 to May 2023. Pre-admission frailty and cognition were assessed using the Clinical Frailty Scale (CFS) and cognitive tests, respectively. Regional deep WMH (DWMH) and periventricular WMH (PWMH) volumes were calculated using the Brain Anatomical Analysis using Diffeomorphic deformation toolbox based on SPM 12 software. Multivariate logistic regression analysis was conducted to evaluate the association between frailty and cognitive function in MMD. Mediation analysis was performed to assess whether WMHs explained the association between frailty and cognition. RESULTS: A total of 85 patients with MMD were enrolled in this study. On the basis of the CFS scores, 24 patients were classified as frail, 38 as pre-frail, and 23 as robust. Significant differences were observed in learning, memory, processing speed, executive functions, and semantic memory among the three groups (p < 0.001). Frailty was independently associated with memory and executive functions (p < 0.05); even after controlling for WMH. Mediation analysis indicated that the associations of frailty with memory and executive functions were partially mediated by WMH, DWMH, and PWMH (p < 0.05). CONCLUSION: Frailty is significantly correlated with a higher risk of cognitive impairment in MMD, even after adjusting for other covariates. WMHs partially mediate the association between frailty and cognitive impairment.

The environmental enrichment ameliorates chronic cerebral hypoperfusion-induced cognitive impairment by activating autophagy signaling pathway and improving synaptic function in hippocampus.

BACKGROUND: Chronic cerebral hypoperfusion (CCH) is a frequently observed underlying pathology of both Alzheimer's disease (AD) and vascular dementia (VD), which is a common consequence of cerebral blood flow (CBF) dysregulation. Synaptic damage has been proven as a crucial causative factor for CCH-related cognitive impairment. This study aimed to investigate the neuroprotective impact of environmental enrichment (EE) intervention on CCH-induced synaptic destruction and the consequent cognitive impairment. Furthermore, the underlying mechanism of this neuroprotective effect was explored to provide new insights into therapeutic interventions for individuals suffering from AD or VD. METHODS: In this experiment, all rats were initially acclimatized to a standard environment (SE) for a period of one week. On the seventh day, rats underwent either bilateral common carotid artery occlusion (2VO) surgery or sham surgery (Sham) before being subjected to a four-week procedure of exposure to an EE, except for the control group. During the EE or SE procedure, intraperitoneal injection of chloroquine (CQ) into rats was performed once daily for four weeks. Following this, cognitive function was assessed using the Morris water maze (MWM) test. The synapse ultrastructure was subsequently observed using transmission electron microscopy. Expression levels of autophagy-related proteins (LC3, LAMP1, and P62) and synapse-related proteins (Synapsin I and PSD-95) were detected through Western blotting. Finally, immunofluorescence was used to examine the expression levels of Synapsin I and PSD-95 and the colocalization of LAMP-1 and LC3 in the hippocampus. RESULTS: After undergoing 2VO, rats exposed to SE exhibited cognitive impairment, autophagic dysfunction, and synapse damage. The synapse damage was evidenced by ultrastructural damage and degradation of synapse-related proteins. However, these effects were significantly mitigated by exposure to an EE intervention. Moreover, the intervention led to an improvement in autophagic dysfunction. CONCLUSION: The study found that EE had a positive impact on CCH-induced synaptic damage. Specifically, EE was found to increase synaptic plasticity-associated proteins and postsynaptic density thickness, while decreasing synaptic space. This multifaceted effect resulted in an amelioration of CCH-induced cognitive impairment. It was shown that this beneficial outcome was mediated via the activation of the autophagy-lysosomal pathway. Overall, the findings suggest that EE may have a therapeutic potential for cognitive impairments associated with CCH through autophagy-mediated synaptic improvement.

Enriched environment priors to TET1 hippocampal administration for regulating psychiatric behaviors via glial reactivity in chronic cerebral hypoperfusion models.

BACKGROUND: Chronic cerebral hypoperfusion (CCH) has been gradually regarded as a common etiologic mechanism for cognitive and psychiatric disturbances. Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) played an important role in adult hippocampal neurogenesis (AHN), neuronal circuits formation, cognition and psychiatric disorders. Enriched environment (EE) showed a beneficial effect on cognition and depression via effectively regulating AHN and glial reactivity. This study aimed to assess which strategy was feasible to improve cognition and psychiatric disturbances by comparing the TET1 hippocampal microinjection and EE in CCH models and to investigate the possible mechanisms. METHOD: CCH rats were established via permanent bilateral common carotid artery occlusion (2-VO). Rats were stereotaxically injected with the human catalytic domain of TET1 (hTET1) to overexpress the hTET1 in the hippocampus 10 days before 2-VO. 3 days after 2-VO, rats were subjected to standard environment or EE with free access to food and water. Behavioral tests were used to appraise depression and cognition before sacrifice. Epigenetic molecules, adult neurogenesis, synaptic proteins expression, and glial activation were analyzed using immunofluorescent staining, qRT-PCR and western blot. RESULTS: In the present study, we found both EE and genetical treatment with overexpressing hTET1 were sufficient for stimulating AHN. However, promoting ANH could not deal with the cognitive dysfunction and depressive-like behaviors in CCH rats. Notably, a healthy local brain environment with elevated BDNF and astrocytes was conducive to improving cognitive dysfunction. Meanwhile, astrocytes were involved in the cognitive regulating process of neurons, presynaptic function and microglia. In general, we held that depressive disturbances were determined by BDNF levels, neuronal and presynaptic function, as well as glial activation containing astrocytes and microglia. To further support this point, we investigated severe depressive symptoms that were strongly correlated with the activation of astroglia and microglia. Importantly, causal mediation analysis showed significant mediation by the presence of reactive glial cells in the relation between neural plasticity and depressive symptoms. Finally, we showed EE performed better than hTET1 treatment for cognitive deficits and depression. EE with less glial reactivity was much more resistant to depression, while hTET1 with more glial activation was more vulnerable to depressive disorders. CONCLUSIONS: EE was likely to be superior to TET1 hippocampal administration for cognition and psychiatric behaviors in CCH rats. Furthermore, a healthy local brain environment with elevated BDNF and astrocytes was conducive to improving cognitive dysfunction. More glial activation, and more vulnerable to depressive disorders. These results were important for our understanding of disease mechanisms and provided valuable tools for the overall management of CCH patients.

The environmental enrichment ameliorates chronic unpredictable mild stress-induced depressive-like behaviors and cognitive decline by inducing autophagy-mediated inflammation inhibition.

BACKGROUND: People exposed to prolonged chronic unpredictable mild stress (CUMS) are easy to suffer from depression and cognitive impairment. Environmental enrichment (EE) had a beneficial effect on depressive-like and cognition-like behaviors by inhibiting inflammation. However, the specific mechanism involved in the inflammation inhibition that occurs after EE treatment for the depression and cognitive decline induced by CUMS remains unclear. In this study, we evaluated the possible mechanism of the beneficial effects on depression and cognition by EE. METHODS: Rats were randomly divided into 5 groups as follows: (1) Control + standard environment (SE), (2) CUMS + SE, (3) CUMS + EE, (4) CUMS + EE+ 3-methiladenine (3-MA), (5) CUMS + SE + 3-MA. They were exposed to CUMS procedure for 5 weeks except the control group. After CUMS procedure, rats were housed in the EE or SE for 3 weeks. During EE or SE treatment, rats were injected with normal saline or 3-MA every day. 3-MA as an autophagy inhibitor suppresses autophagy via inhibition of class III PI3K. Behavioral tests were used to investigate depressive-like and cognition-like behaviors after EE treatment. Then, autophagy-related proteins, inflammation-related molecules, transmission electron microscopy (TEM) and immunofluoresence were determined. RESULTS: We found that CUMS induced depressive-like behaviors and cognitive impairment, reflected in worse behavioral test, such as reduced sucrose preference ratio, decreased locomotor and exploratory activity, prolonged immobility and spatial learning and memory impairment. In addition, CUMS rats exhibited the reduced expression of autophagy related proteins including LC3 and Beclin-1 and the increased inflammation activation including microglia cells, NLRP3 inflammasome and proinflammatory cytokines (IL-1ß, IL-6 and TNF-α). After EE treatment, these changes were reversed. However, 3-MA, the inhibitor of autophagy, eliminated the neuroprotective effects of EE on depressive-like behaviors and cognitive decline. CONCLUSION: This study demonstrates that EE can play neuroprotective effects on depression and cognitive impairment by inducing autophagy-mediated inflammation inhibition, which accounts for the reduction of proinflammatory cytokines, including IL-1ß, IL-6 and TNF-α.

Dimethyl fumarate improves cognitive deficits in chronic cerebral hypoperfusion rats by alleviating inflammation, oxidative stress, and ferroptosis via NRF2/ARE/NF-κB signal pathway.

Cerebrovascular disease and its risk factors cause persistent decrease of cerebral blood flow, chronic cerebral hypoperfusion (CCH) is the major foundation of vascular cognitive impairment (VCI). The hippocampus is extremely vulnerable to cerebral ischemia and hypoxia. Oxidative stress and neuroinflammation injury are important pathophysiological mechanisms of this process, which is closely related to hippocampal neurons damage and loss. Dimethyl fumarate (DMF), an FDA-approved therapeutic for multiple sclerosis (MS), plays a protective role in multiple neurological disorders. Studies have shown that DMF exerts anti-inflammatory and antioxidant effects via the NRF2/ARE/NF-κB signaling pathway. Thus, this study aimed to evaluate the neuroprotective effect of DMF in the CCH rat model. Ferroptosis, a novel defined iron-dependent cell death form, were found to be strongly associated with the pathophysiology of CCH. Emerging evidences have shown that inhibition of ferroptosis by targeting NRF2 exerted neuroprotective effect in neurodegeneration diseases. We also investigated whether DMF can alleviate cognitive deficits through inhibition of ferroptosis by the NRF2 signaling pathway in this study. DMF was intragastric for consecutive five weeks (100 mg/kg/day). Then behavior test and histological, molecular, and biochemical analysis were performed. We found that DMF treatment significantly improved cognitive deficits and partially reversed hippocampus neuronal damage and loss caused by CCH. And DMF treatment decreased hippocampus IL-1ß, TNF-α, and IL-6 pro-inflammatory cytokines concentration, and mediated the NF-κB signaling pathway. And DMF also alleviated hippocampus oxidative stress through reducing MDA, and increasing GSH and SOD levels, which are also closely associated with ferroptosis. Besides, DMF treatment reduced the expression of PTGS2, and increased the expression of FTH1 and xCT, and the iron content is also reduced, which were the important features related to ferroptosis. Furthermore, DMF activated the NRF2/ARE signaling pathway and upregulated the expression of HO-1, NQO1 and GPX4. These outcomes indicated that DMF can improve cognitive impairment in rats with CCH, possibly through alleviating neuroinflammation, oxidative stress damage and inhibiting ferroptosis of hippocampal neurons. Overall, our results provide new evidence for the neuroprotective role of DMF.

Nuclear receptor TLX may be through regulating the SIRT1/NF-κB pathway to ameliorate cognitive impairment in chronic cerebral hypoperfusion.

BACKGROUND: Chronic cerebral hypoperfusion (CCH) is a common pathophysiological mechanism in neurodegenerative diseases, such as Alzheimer's disease and vascular dementia. The orphan nuclear receptor TLX plays an important role in neural development, adult neurogenesis and cognition. The aim of this study was to investigate the neuroprotective effects of TLX on cognitive dysfunction, hippocampal neurogenesis and neuroinflammation in a rat model of CCH and to assess the possible mechanisms. METHODS: Permanent bilateral common carotid artery occlusion (2-VO) was used to establish a model of CCH. Stereotaxic injection of an adeno-associated virus vector expressing TLX was used to overexpress TLX in the hippocampus. Cognitive function was evaluated by the Morris Water Maze test. Immunofluorescent staining was used to assess hippocampal neurogenesis. The effects of overexpression of TLX on SIRT1 and inflammatory cytokines were analyzed with qRT-PCR and western blot. RESULT: After 2-VO, CCH rats exhibited cognitive impairment and reduction of hippocampal TLX levels. Overexpression of TLX ameliorated cognitive impairments with increasing number of BrdU + cells and BrdU + NeuN + cells in DG. Furthermore, TLX rescued the reduced SIRT1 usually induced by CCH. Additionally, TLX also inhibited the expression of inflammatory cytokines such as NF-κB and IL-1ß. CONCLUSIONS: The present findings suggested that TLX exerted protective effects against cognitive deficits induced by CCH. The possible mechanisms of TLX may be through regulating the SIRT1/NF-κB pathway, promoting hippocampal neurogenesis and inhibiting the neuroinflammatory response.

Protection of blood-brain barrier as a potential mechanism for enriched environments to improve cognitive impairment caused by chronic cerebral hypoperfusion.

BACKGROUND: Chronic cerebral hypoperfusion (CCH) is a common pathophysiological basis for Alzheimer's Disease and vascular dementia in the early stages. It has been confirmed that blood-brain barrier (BBB) destruction is a key factor in CCH-related cognitive impairment. Here we explored the effects of an enriched environment (EE) intervention on CCH-induced BBB destruction and cognitive impairment, and the underlying mechanism. METHODS: Rats in the EE group were exposed to an EE, while the standard environment (SE) group was maintained in a standard cage with bedding but no other objects. On day 14, CCH was induced via permanent bilateral common carotid artery occlusion (2VO). Next, Evans blue (EB) leakage in the hippocampus was measured by chemical colorimetry to dynamically evaluate BBB permeability. On day 28, the BBB ultrastructure was observed using transmission electron microscopy. The expression levels of BBB integrity-related proteins, matrix metalloproteinases-2/-9 (MMP-2/-9), and the classical Wnt/ß-catenin signaling pathway-related proteins were detected using western-blotting techniques. On day 43, cognitive function was assessed using the Morris water maze. RESULTS: After 2VO, CCH rats exposed to the SE developed obvious cognitive impairment and BBB destruction. BBB damage was manifested through increased EB leakage, ultrastructural destruction, degradation of BBB integrity-related proteins, and up-regulation of MMP-2/-9. These changes were significantly alleviated after the EE intervention. In addition, EEs activated the Wnt/ß-catenin signaling pathway in the hippocampus of rats. CONCLUSIONS: These results suggest that protection of the BBB may be a novel mechanism by which EEs ameliorate CCH-induced cognitive impairment, and this effect may be related to the activation of the Wnt/ß-catenin pathway.

Mfsd2a Reverses Spatial Learning and Memory Impairment Caused by Chronic Cerebral Hypoperfusion via Protection of the Blood-Brain Barrier.

Disruption of the blood-brain barrier (BBB) can lead to cognitive impairment. Major facilitator superfamily domain-containing protein 2a (Mfsd2a) is a newly discovered protein that is essential for maintaining BBB integrity. However, the role of Mfsd2a in vascular cognitive impairment has not been explored yet. In this study, a rat model of chronic cerebral hypoperfusion (CCH) was established by producing permanent bilateral common carotid artery occlusion (2VO) in rats. We found that after the 2VO procedure, the rats exhibited cognitive impairment, showed increased BBB leakage within the hippocampus, and had reduced expression of the Mfsd2a protein. The overexpression of Mfsd2a in the rat hippocampus reversed these changes. Further investigations using transmission electron microscopy revealed a significantly increased rate of vesicular transcytosis in the BBB of the hippocampus of the CCH rats; the rate reduced after overexpression of Mfsd2a. Moreover, Mfsd2a overexpression did not cause changes in the expression of tight junction-associated proteins and in the ultrastructures of the tight junctions. In conclusion, Mfsd2a attenuated BBB damage and ameliorated cognitive impairment in CCH rats, and its protective effect on the BBB was achieved via inhibition of vesicular transcytosis.

Improvement of autophagy dysfunction as a potential mechanism for environmental enrichment to protect blood-brain barrier in rats with vascular cognitive impairment.

Vascular cognitive impairment (VCI) is the second most common cause of dementia after Alzheimer's disease, and the cognitive impairment is one of the common effects of VCI. Unfortunately, it lacks effective therapeutic treatments at present. In our previous study, environmental enrichment (EE), as an early intervention for lifestyle modification, can ameliorate cognitive impairment by attenuating hippocampal blood-brain barrier (BBB) injury in chronic cerebral hypoperfusion (CCH) rats. However, the underlying mechanism remains unclear. Here, we found CCH rats in the standard environment (SE) developed cognitive impairment and BBB damage, which were significantly alleviated with the EE intervention. Meantime, EE improved the autophagy dysfunction caused by CCH in the hippocampus of rats, suggesting that the effect of EE on cognitive function and BBB may be related to the improvement of autophagy pathway.

Value of combined detection of anti-nuclear antibody, anti-double-stranded DNA antibody and C3, C4 complements in the clinical diagnosis of systemic lupus erythematosus.

Combined detection of antinuclear antibody (ANA), anti-double-stranded DNA (ds-DNA) antibody and complements C3 and C4 in the diagnosis of systemic lupus erythematosus (SLE) was analyzed. One hundred and ninety-four patients with SLE admitted to Yantaishan Hospital of Yantai from January 2012 to December 2017 were selected as SLE group. A total of 106 patients with non-SLE rheumatic disease were selected as disease control group and 120 healthy subjects as healthy control group. The ANA and anti-ds-DNA antibodies were detected by ELISA and complement C3 and C4 were detected by rate nephelometry. The sensitivity and specificity of these four factors were also analyzed for the diagnosis of SLE. The sensitivity and specificity of ANA in diagnosing SLE were 91.75 and 79.65%, respectively; of anti-ds-DNA antibody were 67.01 and 98.23%, respectively; of complement C3 were 87.11 and 82.74%, respectively; and of complement C4 were 88.66 and 77.43%, respectively. The sensitivity and specificity of ANA and anti-ds-DNA antibody in the diagnosis of SLE were 95.36 and 96.90%, respectively; of C3 and C4 were 92.78 and 79.20%, respectively; and the sensitivity and specificity of the combination of all four indicators were 97.42 and 80.97%, respectively. The combined diagnosis of SLE with ANA, anti-ds-DNA antibody, complement C3 and C4 can play a complementary role in the diagnosis and treatment of SLE patients, and it is of great significance to the diagnosis and treatment planning of SLE patients.

Pharmacological Activation of Peroxisome Proliferator-Activated Receptor {Delta} Increases Sphingomyelin Synthase Activity in THP-1 Macrophage-Derived Foam Cell.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which mediate glucose and lipid homeostasis by regulating the expression of a large number of transcription factors. Sphingomyelin synthase (SMS) is a key enzyme in the synthesis of sphingomyelin (SM), and its expression and activity have been reported to be associated with atherosclerosis (AS). Although there have been many functional PPAR and SMS studies on atherosclerosis in recent years, few have investigated the correlation between the activation of PPARδ and the activity of SMS. In his study, macrophage-induced foam cells were utilized to model important pathological changes that occur in AS. The influence of PPARδ agonism by GW501516 on SMS and its product molecule SM were measured. Results indicated that the activation of PPARδ was correlated in a positive manner with the activity of SMS2, and the content of SM was dose dependently increased by GW501516. Together, this study represents the first to suggest that PPARδ activation may be a potential risk of AS through enhancing activity of SMS2.