The effects of P2 segment of posterior cerebral artery to thalamus blood supply pattern on gait in cerebral small vessel disease: A 7 T MRI based study.

Gait disturbance is a manifestation of cerebral small vessel disease (CSVD). The posterolateral thalamus (PL), whose blood is mainly supplied by the P2 segment of posterior cerebral artery (P2-PCA), plays pivotal roles in gait regulation. We investigated the influence of the distance between P2-PCA and PL on gait with varying CSVD burden. 71 participants were divided into low and high CSVD burden groups. The distance from P2-PCA to PL was measured using 7 T TOF-MRA and categorized into an immediate or distant PCA-to-thalamus pattern. Functional connectivity (FC) and voxel-based morphometry were assessed to evaluate functional and structural alterations. In the low CSVD burden group, immediate PCA-to-thalamus supply strongly correlates with longer step length and higher wave phase time percent, and exhibited enhanced FCs in left supplementary motor area, right precentral cortex (PreCG.R). While in the high CSVD burden group, no association between PCA-to-thalamus pattern and gait was found, and we observed reduced FC in PreCG.R with immediate PCA-to-thalamus pattern. Higher CSVD burden was associated with decreased gray matter density in bilateral thalamus. However, no significant structural thalamic change was observed between the two types of PCA-to-thalamus patterns in all patients. Our study demonstrated patients with immediate PCA-to-thalamus supply exhibited better gait performance in low CSVD burden populations, which also correlated with enhanced FCs in motor-related cortex, indicating the beneficial effects of the immediate PCA-to-thalamus supply pattern. In the higher burden CSVD populations, the effects of PCA-to-thalamus pattern on gait are void, attributable to the CSVD-related thalamic destruction and impairment of thalamus-related FC.

Antiplatelet effect of ginkgo diterpene lactone meglumine injection in acute ischemic stroke: A randomized, double-blind, placebo-controlled clinical trial.

This study was designed to evaluate antiplatelet effect and therapeutic effect of ginkgo diterpene lactone meglumine injection (GDLI) in acute ischemic stroke (AIS) patients. In this randomized, double-blind, placebo-controlled trial, we randomly assigned 70 inpatients within 48 hr after the onset of AIS to combination therapy with GDLI and aspirin (GDLI at a dose of 25 mg/d for 14 days plus aspirin at a dose of 100 mg/d for 90 days) or to placebo plus aspirin in a ratio of 1:1. Platelet function, the National Institute of Health Stroke Scale (NIHSS), and the modified Rankin Scale (mRS) were evaluated. A good outcome was defined as NIHSS scores decrease ≥5 or mRS scores decrease ≥2. Results showed that arachidonic acid induced maximum platelet aggregation rate (AA-MAR) and mean platelet volume (MPV) of the GDLI-aspirin group were much lower than that of the aspirin group (p = 0.013 and p = 0.034, respectively) after the 14-day therapy. The combination of GDLI and aspirin was superior to aspirin alone, and had significant impact on the good outcome at day 90 (ORadj 7.21 [95%CI, 1.03-50.68], p = 0.047). In summary, GDLI has antiplatelet effect and can improve the prognosis of AIS patients.

Deep white matter hyperintensity is spatially correlated to MRI-visible perivascular spaces in cerebral small vessel disease on 7 Tesla MRI.

BACKGROUND: The association between perivascular space (PVS) and white matter hyperintensity (WMH) has been unclear. Normal-appearing white matter (NAWM) around WMH is also found correlated with the development of focal WMH. This study aims to investigate the topological connections among PVS, deep WMH (dWMH) and NAWM around WMH using 7 Tesla (7T) MRI. METHODS: Thirty-two patients with non-confluent WMHs and 16 subjects without WMHs were recruited from our department and clinic. We compared the PVS burden between patients with and without WMHs using a 5-point scale. Then, the dilatation and the number of PVS within a radius of 1 cm around each dWMH were compared with those of a reference site (without WMH) in the contralateral hemisphere. In this study, we define NAWM as an area within the radius of 1 cm around each dWMH. Furthermore, we assessed the spatial relationship between dWMH and PVS. RESULTS: Higher PVS scores in the centrum semiovale were found in patients with >5 dWMHs (median 3) than subjects without dWMH (median 2, p = 0.014). We found there was a greater dilatation and a higher number of PVS in NAWM around dWMH than at the reference sites (p<0.001, p<0.001). In addition, 79.59% of the dWMHs were spatially connected with PVS. CONCLUSION: dWMH, NAWM surrounding WMH and MRI-visible PVS are spatially correlated in the early stage of cerebral small vessel disease. Future study of WMH and NAWM should not overlook MRI-visible PVS.

Association of Serum Interleukin-8 and Serum Amyloid A With Anxiety Symptoms in Patients With Cerebral Small Vessel Disease.

Objective: Cerebral small vessel disease (CSVD) is a clinical syndrome caused by pathological changes in small vessels. Anxiety is a common symptom of CSVD. Previous studies have reported the association between inflammatory factors and anxiety in other diseases, but this association in patients with CSVD remains uncovered. Our study aimed to investigate whether serum inflammatory factors correlated with anxiety in patients with CSVD. Methods: A total of 245 CSVD patients confirmed using brain magnetic resonance imaging (MRI) were recruited from December 2019 to December 2021. Hamilton Anxiety Rating Scale (HAMA) was used to assess the anxiety symptoms of CSVD patients. Patients with HAMA scores ≥7 were considered to have anxiety symptoms. The serum levels of interleukin-1ß (IL-1ß), IL-2R, IL-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α), serum amyloid A (SAA), C-reactive protein (CRP), high-sensitivity C-reactive protein (hs-CRP) and erythrocyte sedimentation rate (ESR) were detected. We compared levels of inflammatory factors between the anxiety and non-anxiety groups. Logistic regression analyses examined the correlation between inflammatory factors and anxiety symptoms. We further performed a gender subgroup analysis to investigate whether this association differed by gender. Results: In the fully adjusted multivariate logistic regression analysis model, we found that lower levels of IL-8 were linked to a higher risk of anxiety symptoms. Moreover, higher levels of SAA were linked to a lower risk of anxiety symptoms. Our study identified sex-specific effects, and the correlation between IL-8 and anxiety symptoms remained significant among males, while the correlation between SAA and anxiety symptoms remained significant among females. Conclusions: In this study, we found a suggestive association between IL-8, SAA, and anxiety symptoms in CSVD participants. Furthermore, IL-8 and SAA may have a sex-specific relationship with anxiety symptoms.

Day to Day Blood Pressure Variability Associated With Cerebral Arterial Dilation and White Matter Hyperintensity.

BACKGROUND: Previous studies suggested blood pressure variability (BPV) might help reveal interactions between blood pressure fluctuation and white matter lesions, and the impact of elevated BPV on white matter hyperintensity (WMH) or cerebral arterial dilation is unclear. METHODS: This retrospective observational study involved 2634 stroke-free individuals (68.6±11.1 years, 50.3% female), who underwent magnetic resonance imaging and magnetic resonance angiography scans, from a single center in Shanghai, China. Measurements for variability of blood pressure were made based on 7 days blood pressure recordings. WMHs were quantified from T2-FLAIR images and further classified as periventricular WMH or deep WMH. M1 segment of middle cerebral artery dilation was assessed from magnetic resonance angiography images. General linear model was used to examine the associations. RESULTS: Both increased systolic and diastolic BPV were associated with increased WMH volume (systolic: ß=0.02 [95% CI, 0.004-0.03], P=0.01; diastolic: ß=0.05 [95% CI, 0.03-0.08], P<0.001). Only periventricular WMH was associated with BPV (systolic: ß=0.02 [95% CI, 0.005-0.04], P=0.01; diastolic: ß=0.06 [95% CI, 0.04-0.09], P<0.001). MCA dilation was found in 125 individuals (4.75%). Systolic BPV was associated with MCA dilation only in the hypertensive individuals (ß=0.11 [95% CI, 0.06-0.17], P<0.001). Increased WMH volume was found associated with dilated MCA (ß=0.17 [95% CI, 0.11-0.23], P<0.001). CONCLUSIONS: Increased BPV might be one of the pathophysiological phenomena involving in the small vessel disease independent of hypertension. Increased BPV might independently contribute to intracranial arterial dilation. Management of BPV might be a target to preserve cerebrovascular wellness.

Gut-brain axis: Focus on gut metabolites short-chain fatty acids.

Emerging evidence supports that the gut microbiome, reconsidered as a new organ in the human body, can not only affect the local gut, but also communicate with the brain via multiple pathways related to neuroendocrine, immune, and neural pathways, thereby proposing the new concept of the microbiome-gut-brain (MGB) axis. Recently, the role of short-chain fatty acids (SCFAs), which are the main anaerobic fermented metabolites of the gut microbiota in the MGB axis, has garnered significant attention. SCFAs are involved in a broad range of central neurological diseases, including neurodegenerative diseases, cerebral vascular diseases, epilepsy, neuroimmune inflammatory diseases, and mood disorders. However, the underlying mechanism of SCFA-related distant organ crosstalk is yet to be elucidated. Herein, we summarize current knowledge regarding interactions between SCFAs and the MGB axis, as well as their protective effects against central neurological diseases.

The Protective Effect of Quercetin on Endothelial Cells Injured by Hypoxia and Reoxygenation.

Background: Cerebral small vessel disease (CSVD) is a group of clinical syndromes covering all pathological processes of small vessels in the brain, which can cause stroke and serious dementia. However, as the pathogenesis of CSVD is not clear, so the treatment is limited. Endothelial cell dysfunction is earlier than clinical symptoms, such as hypertension and leukosis. Therefore, the treatment of endothelial cells is expected to be a new breakthrough. Quercetin, a flavonoid present in a variety of plants, has the function of anti-inflammation and anti-oxidation. This study aimed to investigate the protective effect of quercetin on endothelial cell injury and provide a basic theory for subsequent application in the clinic. Methods: Human brain microvascular endothelial cells (HBMECs) were cultured in vitro, and the injury model of endothelial cells was established by hypoxia and reoxygenation (H/R). The protective effects of quercetin on HBMECs were studied from the perspectives of cell viability, cell migration, angiogenesis and apoptosis. In order to further study the mechanism of quercetin, oxidative stress and endoplasmic reticulum stress were analyzed. What's more, blood-brain barrier (BBB) integrity was also studied. Results: Quercetin can promote the viability, migration and angiogenesis of HBMECs, and inhibit the apoptosis. In addition, quercetin can also activate Keap1/Nrf2 signaling pathway, reduce ATF6/GRP78 protein expression. Further study showed that quercetin could increase the expression of Claudin-5 and Zonula occludens-1. Conclusions: Our experiments show that quercetin can protect HBMECs from H/R, which contains promoting cell proliferation, cell migration and angiogenesis, reducing mitochondrial membrane potential damage and inhibiting cell apoptosis. This may be related to its antioxidation and inhibition of endoplasmic reticulum stress. At the same time, quercetin can increase the level of BBB connexin, suggesting that quercetin can maintain BBB integrity.

The Synergistic Effect of Ginkgo biloba Extract 50 and Aspirin Against Platelet Aggregation.

PURPOSE: We aimed to investigate potential synergistic antiplatelet effects of Ginkgo biloba extract (GBE50) in combination with aspirin using in vitro models. METHODS: Arachidonic acid (AA), platelet activating factor (PAF), adenosine 5'-diphosphate (ADP) and collagen were used as inducers. The antiplatelet effects of GBE50, aspirin and 1:1 combination of GBE50 and aspirin were detected by microplate method using rabbit platelets. Synergy finder 2.0 was used to analyze the synergistic antiplatelet effect. The compounds in GBE50 were identified by UPLC-Q/TOF-MS analysis and the candidate compounds were screened by TCMSP database. The targets of candidate compounds and aspirin were obtained in TCMSP, CCGs, Swiss target prediction database and drugbank. Targets involving platelet aggregation were obtained from GenCLiP database. Compound-target network was constructed and GO and KEGG enrichment analyses were performed to identify the critical biological processes and signaling pathways. The levels of thromboxane B2 (TXB2), cyclic adenosine monophosphate (cAMP) and PAF receptor (PAFR) were detected by ELISA to determine the effects of GBE50, aspirin and their combination on these pathways. RESULTS: GBE50 combined with aspirin inhibited platelet aggregation more effectively. The combination displayed synergistic antiplatelet effects in AA-induced platelet aggregation, and additive antiplatelet effects occurred in PAF, ADP and collagen induced platelet aggregation. Seven compounds were identified as candidate compounds in GBE50. Enrichment analyses revealed that GBE50 could interfere with platelet aggregation via cAMP pathway, AA metabolism and calcium signaling pathway, and aspirin could regulate platelet aggregation through AA metabolism and platelet activation. ELISA experiments showed that GBE50 combined with aspirin could increase cAMP levels in resting platelets, and decreased the levels of TXB2 and PAFR. CONCLUSION: Our study indicated that GBE50 combined with aspirin could enhance the antiplatelet effects. They exerted both synergistic and additive effects in restraining platelet aggregation. The study highlighted the potential application of GBE50 as a supplementary therapy to treat thrombosis-related diseases.

Mild hypothermia alleviates diabetes aggravated cerebral ischemic injury via activating autophagy and inhibiting pyroptosis.

Diabetic patients manifest with more severe neurological deficits than non-diabetes after ischemic stroke. It has been shown that hypothermia has neuroprotective effects on cerebral ischemia, but whether it is effective for cerebral ischemia in diabetic patients remains unknown. The aim of this study was to investigate whether hypothermia can alleviate cerebral ischemic injury in diabetic rats and the regulation of autophagy and pyroptosis of the treatment. We introduced permanent middle cerebral artery occlusion (pMCAO) in a model of type 2 diabetic rats prepared by high-fat diet combined with intraperitoneal injection of STZ in vivo and mimicked cerebral ischemia with diabetes by employing high glucose stimulation and oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro. Moreover, 3-methyladenine and bafilomycin A1 were used to evaluate the association between autophagy and pyroptosis in vitro. Our results showed that diabetes aggravated neurological deficits, increased the volume of cerebral infarction and brain edema as well as the blood brain barrier permeability after cerebral ischemia, which were alleviated by mild hypothermia. Compared with the pMCAO model in non-diabetic rats and OGD/R model without high glucose stimulation in vitro, the expression of P62, NOD-like receptor protein 3 (NLRP3), cleaved caspase-1 and Gasdermin-N increased and the ratio of microtubule-associated protein 1 light chain 3B (LC3B) Ⅱ/Ⅰ decreased in the pMCAO model in diabetic rats and OGD/R model with high glucose stimulation, which could be reversed by mild hypothermia. In conclusion, mild hypothermia alleviated diabetes aggravated cerebral ischemic injury via activating autophagy and inhibiting pyroptosis.

Vascular Remodeling, Oxidative Stress, and Disrupted PPARγ Expression in Rats of Long-Term Hyperhomocysteinemia with Metabolic Disturbance.

Hyperhomocysteinemia, a risk factor for vascular disease, is associated with metabolic syndrome. Our study was aimed at exploring the effect of long-term hyperhomocysteinemia with metabolic disturbances on vascular remodeling. We also studied oxidative stress and expression of PPARγ in the coronary arteriole as a possible mechanism underlying vascular remodeling. Rats were treated with standard rodent chow (Control) or diet enriched in methionine (Met) for 48 weeks. Plasma homocysteine, blood glucose, serum lipids, malondialdehyde (MDA), superoxide dismutase (SOD), and nitric oxide (NO) levels were measured. Coronary arteriolar and carotid arterial remodeling was assessed by histomorphometric techniques and the expression of PPARγ in vessel wall was investigated. In Met group, an increase in the level of fasting blood glucose, serum triglyceride, total cholesterol, MDA, and NO, a decline in the serum SOD level, and increased collagen deposition in coronary and carotid arteries were found. Moreover, we detected decreased expression of PPARγ in the coronary arterioles in Met group. In summary, our study revealed metabolic disturbances in this model of long-term hyperhomocysteinemia together with vascular remodeling and suggested that impaired oxidative stress, endothelium dysfunction, and decreased PPARγ expression in the vessel wall could be underlying mechanisms.

Mild hypothermia protects rat neuronal injury after intracerebral hemorrhage via attenuating endoplasmic reticulum response induced neuron apoptosis.

BACKGROUND AND PURPOSE: Mild hypothermia has been proved to reduce global and focal cerebral ischemic injury in rodents by preventing cellular apoptosis through several pathways. However, whether hypothermia will be beneficial for intracerebral hemorrhage (ICH) and its underlying mechanisms haven't reached a consensus. It has been implicated that endoplasmic reticulum (ER) stress plays a role in the secondary injury after ICH in rats. In this study, we aimed to investigate whether mild hypothermia would attenuate ICH induced neuronal injury via regulating ER stress. METHODS: The model of ICH was induced by injecting autologous blood (120µl) into the rat striatum. Rats were divided into sham, normothermic (NT) and hypothermic (HT) groups. HT group were subjected to mild hypothermia (33°C-35°C) for 2days starting from 6h after ICH. Neurological deficits were evaluated. The ER stress related proteins (GRP78, CHOP and p-eIF2α) and the apoptosis associated indicators (cleaved caspase3, Bcl-2 and Bim) around hematoma were assessed by western blot, qRT-PCR (quantificational real-time polymerase chain reaction), immunofluorescence and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling) assay. RESULTS: Neurological deficits following ICH were reduced in HT group compared to NT group. Protein levels of GRP78, CHOP and p-eIF2α significantly increased after ICH in both NT and HT group compared to sham group, which was consistent with the trend of cleaved-caspase3 at protein level, and Bim, Bcl-2 at gene level. In comparison to NT group, GRP78, CHOP, p-eIF2α, cleaved caspase-3 and Bim all decreased, while Bcl-2 increased in HT group. Additionally, apoptotic cells detected by TUNEL staining significantly decreased in the HT group. CONCLUSION: Mild hypothermia could attenuate ICH caused neuron injury by decreasing ER response-induced neuron apoptosis.