Penumbra in acute ischemic stroke

Acute ischemic stroke is one of the leading causes of disability and death worldwide. The brain tissue adjacent to the central necrotic core was first defined as ischemic penumbra characterized by reduced cerebral blood flow (CBF) with electrical failure but maintained ionic homeostasis and transmembrane electrical potentials. Since then, the evolving concepts of the ischemic penumbra have been proposed based on energy metabolism, CBF thresholds and protein synthesis, which provide insight for the diagnosis and treatment of acute ischemic stroke. This paper summarizes the recent advances in the understanding of ischemic penumbra, from its discovery to the diagnosis methods based on imaging techniques and biomarkers, finally some of the treatments developed. In addition, we discussed future perspectives on therapeutic targets beyond ischemic penumbra to develop a treatment for acute ischemic stroke.

P75NTR exacerbates SCI-induced mitochondrial damage and neuronal apoptosis depending on NTRK3

Objective: The aim of the study was to investigate the mechanism by which p75 neurotrophin receptor (p75NTR) affects mitochondrial damage and neuronal apoptosis in spinal cord injury (SCI). Methods: After the establishment of SCI rat models, short hairpin (sh) RNA of p75NTR and control sh-RNA were injected into SCI rats, respectively. On days 1, 7 and 21 after SCI, the severity of SCI and cell apoptosis in SCI rats were determined as well as the recovery of hind limb performance and p75NTR expression. After spinal cord neurons were transfected with p75NTR overexpression plasmid or empty plasmid vector or cotransfected with overexpression plasmids of p75NTR and neurotrophic tyrosine receptor kinase3 (NTRK3), the expression levels of p75NTR and NTRK3 were quantified. Moreover, we detected the apoptosis and proliferation rates of the neurons in addition to the levels of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) in the neurons. The binding between p75NTR and NTRK3 was confirmed via Co-immunoprecipitation (Co-IP). Results: The rat spinal cords in the Model group were notably damaged after SCI accompanied by increased apoptosis and decreased locomotor function. The expression of p75NTR was significantly upregulated after SCI. The aforementioned injuries were remarkably ameliorated in response to injection of sh-p75NTR. p75NTR overexpression induced mitochondrial damage and neuronal apoptosis in spinal cord neurons, while the promotive effects were perturbed by NTRK3 overexpression. Furthermore, p75NTR directly bound to and downregulated NTRK3. Conclusion: Both in vivo and in vitro experiments showed that p75NTR aggravates mitochondrial damage and neuronal apoptosis in SCI through downregulating NTRK3.

White Matter Hyperintensity Burden in Cerebral Small Vessel Disease Patients Is Associated with Nocturnal Heart Rate

Background: Age and hypertension are widely considered to be the main risk factors for white matter hyperintensity (WMH), but they do not account for all the pathophysiological mechanisms of WMH.Therefore, identifying novel risk factors is significant to improve our understanding of the etiology and consequences of WMH. Objective: To examine the association of heart rate(HR) and common vascular risk factors with WMH burden in patients hospitalized for Cerebral Small Vessel Disease(CSVD) Method: The study consisted of 778 patients who underwent 24-hour ambulatory blood pressure and HR monitoring and brain magnetic resonance imaging(MRI). The relationship of HR measures and vascular risk factors with the presence of log WMHV4 was analyzed.Univariable and multivariable analysis was carried out to investigate the relationship of incidence of severe WMH (4th quartile, ≥19.64 ml) and HR measures and common vascular risk factors. Results: Multivariate analysis showed that WMHV was independently predicted by nighttime HR ( OR (95% CI): 1.041（1.02~1.062）, P<0.001),Homocysteine ( OR (95% CI): 1.019（1.005~1.033）, P=0.009), and cerebral infarction ( OR (95% CI): 0.463（0.31~0.691）, P<0.001), No similar association was observed for daytime HR、HR variability and other vascular risk factors . Conclusion: As nighttime HR、Hcy increased, log WMHV increased accordingly; furthermore, patients with cerebral infarction were more likely to have higher levels of WMHV. nighttime HR 、Hcy、cerebral infarction was associated with WMHV, suggesting independent roles of their in WMHV. The influence of HRV on WMHV needs to be addressed by further studies.

Nomogram to Predict Symptomatic Intracranial Hemorrhage after Intravenous Thrombolysis in Acute Ischemic Stroke in an Asian Population.

Background: Symptomatic intracranial hemorrhage (sICH) is a serious hemorrhagic complication after intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) patients. Most existing predictive scoring systems were derived from Western countries Objective: To develop a nomogram to predict the possibility of sICH after IVT in an Asian population. Methods: This retrospective cohort study included AIS patients treated with recombinant tissue plasminogen activator (rt-PA) in a tertiary hospital in Shenzhen, China, from January 2014 to December 2020. The end point was sICH within 36 hours of IVT treatment. Multivariable logistic regression was used to identify risk factors of sICH, and a predictive nomogram was developed. Area under the curve of receiver operating characteristic curves (AUC), calibration curve, and decision curve analyses were performed. The nomogram was validated by bootstrap resampling Results: Data on a total of 462 patients were collected, of whom 20 patients (4.3%) developed sICH. In the multivariate logistic regression model, the National Institute of Health stroke scale scores (NIHSS) (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.06–1.23, P < 0.001), onset to treatment time (OTT) (OR, 1.02; 95% CI, 1.01–1.03, P < 0.001), neutrophil to lymphocyte ratio (NLR) (OR, 1.22; 95% CI, 1.09–1.35, P < 0.001), and cardioembolism (OR, 3.74; 95% CI, 1.23–11.39, P = 0.020) were independent predictors for sICH and were used to construct a nomogram. Our nomogram exhibited favorable discrimination ability [AUC, 0.878; specificity, 87.35%; and sensitivity, 73.81%]. Bootstrapping for 500 repetitions was performed to further validate the nomogram. The AUC of the bootstrap model was 0.877 (95% CI: 0.823–0.922). The calibration curve exhibited good fit and calibration. The decision curve revealed good positive net benefits and clinical effects Conclusion: The nomogram consisted of the predictors NIHSS, OTT, NLR, and cardioembolism could be used as an auxiliary tool to predict the individual risk of sICH in Chinese AIS patients after IVT. Further external verification among more diverse patient populations is needed to demonstrate the accuracy of the model’s predictions.

Protective effects of icariin on traumatic brain injury

Background: Neuroinflammation is central to the pathology of traumatic brain injury (TBI). Icariin (ICA) is a flavonoid derived from the genus Epimedium which is a traditional Chinese herb, a potential therapeutic drug for TBI. This study aims to explore the protective effect of ICA on TBI and its mechanism Methods: Sprague-Dawley rats were exposed to controlled cortical impact to produce a neuroinflammatory response. The treatment groups received ICA (15 mg/kg, 30 mg/kg and 60 mg/kg), while the sham group was gavaged with equal volumes of saline. The beam-balance testing and prehensile traction test were used for neurological scoring. Pathological changes were observed by H&E staining. The protein expression levels of inflammatory factors were measured by Western blot analysis Results: It was found that ICA significantly improved the neuroethology function and alleviated the pathological injury in TBI rats. The protein expression levels of inflammatory factors COX-2, IL-1β, and TNF-α and its regulatory proteins p-NF-κB-p65, p-ERK1/2, p-JNK, and p-p38 were increased in the cerebral cortex injured by TBI. The protein expression levels of inflammatory cytokines were markedly decreased in cerebral cortex of TBI rats when administrated with ICA. Conclusion: The present study demonstrates that ICA may be a promising therapeutic strategy for reducing inflammation in TBI.

Elongated internal carotid arteries in patients with severe carotid artery stenosis.

Objective: To investigate the risk factors and asymptomatic cerebrovascular diseases associated with elongated internal carotid arteries (ICAs), and the relationship between ICA elongation and severe carotid artery (CA) stenosis Methods: We evaluated risk factors for stroke and magnetic resonance imaging (MRI) findings in patients with severe CA stenosis compared with people without neurological disorders who underwent brain screening (controls). On Magnetic resonance angiography (MRA) images we measured the longest distance, defined as the ICA distance, from the most distant anterior wall of the cervical ICA at the site of bending or kinking to the line between the origin of the external CA and the anterior protrusion of the ICA near the petrosal bone. We retrospectively compared various asymptomatic findings, including cerebral microbleeds, lacunar infarctions, and deep white matter hyperintensities (WMHs), between participants with an ICA distance ≥ 1.2 cm vs. < 1.2 cm. The prevalence of findings and stroke risk factors were compared using multivariate logistic regression models. Results: We evaluated 53 patients (70.0 ± 8.1 years old, nine female) with severe CA stenosis treated by CA stenting and 400 controls (63.0 ± 9.2 years old, 227 females). Multivariate analyses showed that ICA distance ≥ 1.2 cm was associated with age ≥ 65 years (odds ratio [OR] = 1.8, p < 0.01), severe deep WMHs (OR = 2.0, p = 0.02), and severe CA stenosis (OR = 0.17, p < 0.01). Conclusion: ICA elongation, measured by ICA distance, was positively associated with age and deep WMHs and negatively associated with severe CA stenosis.

Nonfocal Symptoms in Patients with Transient Ischemic Attack and Association with Stroke Risk

Background and Objective: Patients with transient ischemic attack（TIA）occasionally showed nonfocal symptoms, such as decreased consciousness, amnesia and non-rotatory dizziness. This study intended to evaluate the effect of nonfocal symptoms on the prognosis of patients with TIA. Methods: Data from the prospective hospital-based TIA database of the First Affiliated Hospital of Zhengzhou University were analyzed. The predictive outcome was stroke occurrence at 1 year. Cumulative risks of stroke in patients with and without nonfocal symptoms were estimated with Kaplan-Meier models. Results: We studied 1384 patients with TIA (842 men; mean age, 56±13 years), including 450 (32.5%) with nonfocal symptoms. In the first year after TIA, stroke occurred in 168（12.1%） patients. There was no difference in the risk of stroke between patients with both focal and nonfocal symptoms and patients with focal symptoms alone (11.8% vs 12.4%, log-rank; P=0.691). Conclusions: The occurrence of nonfocal symptoms did not increase the risk of stroke at one-year follow-up compared to the occurrence of focal symptoms alone.

Circulating miR-126 as a Potential Non-invasive Biomarker for Intracranial Aneurysmal Rupture: A Pilot Study

Aim: Intracranial aneurysms (IAs) are characterized by abnormal dilation and thinning of the cerebral vessels wall, leading to rupture and life-threatening aneurysmal subarachnoid hemorrhage (aSAH) condition. This dictates the need to find new biomarkers that predict the presence of IAs and the risk of their rupture. The aim of this study was to measure circulating miR-126 at various time points post-aSAH to identify the timing of peak levels. Methods: Plasma samples from 62 patients with unruptured IAs (UIAs), 80 patients with aSAH at various time points (1, 3, 7, and 14 days post-event), and 47 healthy control were collected and subjected to qRT-PCR analyses for the expression levels of circulating miR-126. ROC curve and AUC were used to evaluate the diagnostic value of circulating miR-126. Results: The expression levels of circulating miR-126 were increased in patients with UIAs than in the healthy control. Furthermore, the expression levels of circulating miR-126 rose substantially from day 1 to day 7, but with a moderate decrease from day 7 to day 14 in plasma of patients with aSAH. The peak was observed on day 7. The AUC for miR-126 was 0.75, 0.75, 0.82, 0.87, and 0.79, respectively, and demonstrated that circulating miR-126 displayed considerable accuracy in discriminating plasma of patients with UIAs and patients after aSAH at various time points from a healthy control. Conclusion: Our results indicated that circulating miR-126 in plasma samples could be served as a potential non-invasive biomarker in IAs detection and prevention IAs with a high risk of rupture.

Combination of Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Agonist and PPAR Gamma Co-Activator 1α (PGC-1α) Activator Ameliorates Cognitive Deficits, Oxidative Stress, and Inflammation in Rodent Model of Parkinson's Disease

Background: PPAR gamma co-activator 1α (PGC-1α) is known as the master regulator of mitochondrial biogenesis. It is also a co-activator of peroxisome proliferator-activated receptor-gamma (PPARγ) and plays a role in preventing mitochondrial dysfunction in several neurodegenerative disorders, including Parkinson’s disease (PD). Depletion in the levels of these proteins has been linked to oxidative stress, inflammation, and DNA damage, all of which are known to contribute to the pathogenesis of PD. Objective: In the present study, combination therapy of PPARγ agonist (GW1929) and PGC-1α activator (alpha-lipoic acid) was employed to ameliorate cognitive deficits, oxidative stress, and inflammation associated with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Results: Our study showed that MPTP-induced PD rats exhibited an increase in oxidative stress and inflammation, leading to cognitive deficits. Furthermore, MPTP-induced PD rats also exhibited reduced mitochondrial biogenesis in comparison to control and sham animals. Intraperitoneal administration of GW 1929 and alpha-lipoic acid in doses lower than those earlier reported individually in literature led to an improvement in the cognitive deficits in comparison to MPTP-induced PD rats. These improvements were accompanied by a reduction in the levels of oxidative stress and inflammation. In addition, an increase in mitochondrial biogenesis was also observed after the combination of these pharmacological agents. Conclusion: Our results provide a rationale for the development of agents targeting PPARγ and PGC-1α as potent therapeutics for the treatment of neurological diseases like PD.