Ectopic expression of neuronal adenosine kinase, a biomarker in mesial temporal lobe epilepsy without hippocampal sclerosis.

AIMS: Mesial temporal lobe epilepsy without hippocampal sclerosis (no-HS MTLE) refers to those MTLE patients who have neither magnetic resonance imaging (MRI) lesions nor definite pathological evidence of hippocampal sclerosis. They usually have resistance to antiepileptic drugs, difficulties in precise seizure location and poor surgical outcomes. Adenosine is a neuroprotective neuromodulator that acts as a seizure terminator in the brain. The role of adenosine in no-HS MTLE is still unclear. Further research to explore the aetiology and pathogenesis of no-HS MTLE may help to find new therapeutic targets. METHODS: In surgically resected hippocampal specimens, we examined the maladaptive changes of the adenosine system of patients with no-HS MTLE. In order to better understand the dysregulation of the adenosine pathway in no-HS MTLE, we developed a rat model based on the induction of focal cortical lesions through a prenatal freeze injury. RESULTS: We first examined the adenosine system in no-HS MTLE patients who lack hippocampal neuronal loss and found ectopic expression of the astrocytic adenosine metabolising enzyme adenosine kinase (ADK) in hippocampal pyramidal neurons, as well as downregulation of neuronal A1 receptors (A1 Rs) in the hippocampus. In the no-HS MTLE model rats, the transition of ADK from neuronal expression to an adult pattern of glial expression in the hippocampus was significantly delayed. CONCLUSIONS: Ectopic expression of neuronal ADK might be a pathological hallmark of no-HS MTLE. Maladaptive changes in adenosine metabolism might be a novel target for therapeutic intervention in no-HS MTLE.

Synthesis of Substituted of Benzo[4,5]imidazo[1,2-a]pyrimidines through (3 + 2+1) Cyclization of 2-Aminobenzimidazole, Acetophenone, and N,N-Dimethylformamide as One-Carbon Synthon.

An efficient method for the construction of benzo[4,5]imidazo[1,2-a]pyrimidines using N,N-dimethylformamide as a one-carbon source and 2-aminobenzimidazoles and acetophenone as substrates through a one-pot, three-component cascade reaction is described. Spectra investigations indicated the fluorescent properties of selected products, exhibiting quantum yields 0.07-0.16 with maxima absorption at 266-294 nm and emission at 472-546 nm.

Association of ß-cell function and cognitive impairment in patients with abnormal glucose metabolism.

BACKGROUND: Insulin has been demonstrated to play an important role in the occurrence and development of Alzheimer's disease, especially in those with diabetes. ß cells are important insulin-producing cells in human pancreas. This study aimed to investigate the association between ß-cell dysfunction and cognitive impairment among patients over 40-year-old with abnormal glucose metabolism in Chinese rural communities. METHODS: A sample of 592 participants aged 40 years or older from the China National Stroke Prevention Project (CSPP) between 2015 and 2017 were enrolled in this study. Abnormal glucose metabolism was defined when hemoglobin Alc ≥ 5.7%. Cognitive function was assessed by the Beijing edition of the Montreal Cognitive Assessment scale. Homeostasis assessment of ß-cell function was performed and classified into 4 groups according to the quartiles. A lower value of HOMA-ß indicated a worse condition of ß-cell function. Multivariate logistic regression was used to analyze the association between ß-cell function and cognitive impairment. RESULTS: In a total of 592 patients with abnormal glucose metabolism, the average age was 60.20 ± 7.63 years and 60.1% patients had cognitive impairment. After adjusting for all potential risk factors, we found the first quartile of ß-cell function was significantly associated with cognitive impairment (OR: 2.27, 95%CI: 1.32-3.92), especially at the domains of language (OR: 1.64, 95%CI: 1.01-2.65) and abstraction (OR: 2.29, 95%CI: 1.46-3.58). CONCLUSIONS: Our study showed that worse ß-cell function is associated with cognitive impairment of people over 40-year-old with abnormal glucose metabolism in Chinese rural communities, especially in the cognitive domains of abstraction and language.

Association between hemoglobin A1c and asymptomatic carotid intima-media thickness in middle-aged and elderly populations without diabetes.

BACKGROUND AND AIMS: Carotid atherosclerosis, including carotid artery intima-media thickness, plaques, and stenosis, is an important risk factor for stroke. However, the association between hemoglobin A1c (HbA1c) and carotid intima-media thickness (cIMT) was inconsistent. The aim of this study was to explore the association between HbA1c and the risk of increased cIMT among the Chinese population aged ≥40 years without diabetes. METHODS AND RESULTS: A total of 3528 participants without diabetes from the China National Stroke Screen Survey program were enrolled in this study. cIMT was measured using duplex ultrasound examination. Logistic regression models were used to assess the association between HbA1c level and the risk of increased cIMT. A total of 565 (16.0%) participants had increased cIMT. After adjustment for other potential confounding factors, higher levels of HbA1c increased the risk of increased cIMT compared with the lowest level, and the odds ratios for quartile 2, quartile 3, and quartile 4 were 1.58, 1.67, and 1.98, respectively. Age had an interaction impact on the association between HbA1c level and the risk of increased cIMT. CONCLUSION: In this large-scale and cross-sectional study, high-normal HbA1c was associated with the risk of increased asymptomatic cIMT in a rural Chinese population without diabetes, especially in individuals aged <60 years.

Epilepsy and Autism Spectrum Disorder (ASD): The Underlying Mechanisms and Therapy Targets Related to Adenosine.

Epilepsy and autism spectrum disorder (ASD) are highly mutually comorbid, suggesting potential overlaps in genetic etiology, pathophysiology, and neurodevelopmental abnormalities. Adenosine, an endogenous anticonvulsant and neuroprotective neuromodulator of the brain, has been proved to affect the process of epilepsy and ASD. On the one hand, adenosine plays a crucial role in preventing the progression and development of epilepsy through adenosine receptordependent and -independent ways. On the other hand, adenosine signaling can not only regulate core symptoms but also improve comorbid disorders in ASD. Given the important role of adenosine in epilepsy and ASD, therapeutic strategies related to adenosine, including the ketogenic diet, neuromodulation therapy, and adenosine augmentation therapy, have been suggested for the arrangement of epilepsy and ASD. There are several proposals in this review. Firstly, it is necessary to further discuss the relationship between both diseases based on the comorbid symptoms and mechanisms of epilepsy and ASD. Secondly, it is important to explore the role of adenosine involved in epilepsy and ASD. Lastly, potential therapeutic value and clinical approaches of adenosine-related therapies in treating epilepsy and ASD need to be emphasized.

A one-pot synthesis of 2,3-disubstituted-4(3H)-quinazolinone from o-aminobenzoic acid and DMF derivatives using imidazole hydrochloride as a promoter.

As a novel and environmentally friendly Brönsted acid, imidazole hydrochloride was used to promote the synthesis of 2,3-disubstituted-4(3H)-quinazolinone from o-aminobenzoic acid and DMF derivatives. The essence of this reaction is a multicomponent reaction, which constructs multiple chemical bonds between different components through the transamidation of imidazole hydrochloride. This protocol showed a wide range of functional group tolerance, and a series of quinazolinones were synthesized in low to moderate yields without metal catalysts, oxidants or other additives.

Aberrant adenosine signaling in patients with focal cortical dysplasia.

Focal cortical dysplasia (FCD), a common malformation of cortical development, is frequently associated with pharmacoresistant epilepsy in both children and adults. Adenosine is an inhibitory modulator of brain activity and a prospective anti-seizure agent with potential for clinical translation. Our previous results demonstrated that the major adenosine-metabolizing enzyme adenosine kinase (ADK) was upregulated in balloon cells (BCs) within FCD type IIB lesions, suggesting that dysfunction of the adenosine system is implicated in the pathophysiology of FCD. In our current study, we therefore performed a comprehensive analysis of adenosine signaling in surgically resected cortical specimens from patients with FCD type I and type II via immunohistochemistry and immunoblot analysis. Adenosine enzyme signaling was assessed by quantifying the levels of the key enzymes of adenosine metabolism, i.e., ADK, adenosine deaminase (ADA), and ecto-5'-nucleotidase (CD73). Adenosine receptor signaling was assessed by quantifying the levels of adenosine A2A receptor (A2AR) and putative downstream mediators of adenosine, namely, glutamate transporter-1 (GLT-1) and mammalian target of rapamycin (mTOR). Within lesions in FCD specimens, we found that the adenosine-metabolizing enzymes ADK and ADA, as well as the adenosine-producing enzyme CD73, were upregulated. We also observed an increase in A2AR density, as well as a decrease in GLT-1 levels and an increase in mTOR levels, in FCD specimens compared with control tissue. These results suggest that dysregulation of the adenosine system is a common pathologic feature of both FCD type I and type II. The adenosine system might therefore be a therapeutic target for the treatment of epilepsy associated with FCD.

Adenosine Dysfunction in Epilepsy and Associated Comorbidities.

Epilepsy, a complex neurological syndrome with dominant symptoms and various comorbidities, affects over 70 million people worldwide. Epilepsy-related comorbidities, including cognitive and psychiatric disorders, can impede therapy for epilepsy patients, leading to heavy burdens on patients and society. Adenosine has an anti-epileptic and anticonvulsive function in the brain. Several studies have shown that, through adenosine receptor-dependent and -independent mechanisms, adenosine can influence the development and progression (epileptogenesis) of epilepsy and its associated comorbidities. As the key enzyme for adenosine clearance, adenosine kinase (ADK) can exacerbate epileptic seizures not only by accelerating adenosine clearance, but also by increasing global DNA methylation through the transmethylation pathway. Therefore, adenosine augmentation therapies for epilepsy can have dual functions in the inhibition of epileptic seizures and the prevention of its overall progress. This review has three main purposes. First, we discuss how maladaptive changes in the adenosine pathway affect the development and progress of epilepsy in both receptor-dependent and receptor-independent ways. Second, we highlight the important influence of associated comorbidities on the prognosis of epilepsy and explore the role of adenosine in these comorbidities. Finally, we emphasize the potential of adenosine augmentation therapies in restoring normal adenosine signaling in the epileptic brain. Such treatments could effectively improve the prognosis of patients who are resistant to most antiepileptic drugs (AEDs), and thus bring new challenges and opportunities in the treatment of epilepsy patients.

Effectiveness of vagus nerve stimulation therapy in refractory hypoxic-ischemic encephalopathy-induced epilepsy.

Background: Epilepsy is one of the important long-term sequelae of neonatal hypoxic-ischemic encephalopathy (HIE) and is typically characterized by drug resistance and poor surgical outcomes. Vagus nerve stimulation (VNS) is a promising neuromodulation therapy for refractory epilepsy. Objectives: The present study aimed to first evaluate the effectiveness of VNS in patients with refractory HIE-induced epilepsy and scrutinize potential clinical predictors. Methods: We retrospectively collected the outcomes of VNS in all patients with refractory HIE-induced epilepsy and at least 2 years of follow-up. Subgroups were classified as responders and nonresponders according to the effectiveness of VNS (⩾50% or <50% reduction in seizure frequency). Preoperative data were analyzed to screen for potential predictors of VNS effectiveness. Results: A total of 55 patients with refractory HIE-induced epilepsy who underwent VNS therapy were enrolled. Responders represented 56.4% of patients, and 12.7% of patients achieved seizure freedom at the last follow-up. In addition, the responder rate increased over time with rates of 23.6%, 38.2%, 50.9%, and 56.4% at the 3-, 6-, 12- and 24-month follow-ups, respectively. After multivariate analysis, neonatal seizure was identified as a negative predictor (OR: 4.640, 95% CI: 1.129-19.066), and a predominant seizure type of generalized onset was identified as a positive predictor (OR: 0.261, 95% CI: 0.078-0.873) of VNS effectiveness. Conclusion: VNS therapy was effective in patients with refractory HIE-induced epilepsy and was well tolerated over a 2-year follow-up period. VNS therapy demonstrated better effectiveness in patients without neonatal seizures or with a predominant seizure type of generalized onset.

Efficacy and potential predictors of vagus nerve stimulation therapy in refractory postencephalitic epilepsy.

BACKGROUND: Vagus nerve stimulation (VNS) is a therapeutic approach for patients with refractory postencephalitic epilepsy (PEE), which is characterized by drug resistance and disappointing surgical outcomes. However, the efficacy of VNS has not yet been studied in patients with refractory PEE. The present study aimed to demonstrate the efficacy of VNS and evaluate potential clinical predictors in patients with refractory PEE. METHODS: We retrospectively collected the outcomes of VNS with at least a 1-year follow-up in all patients with refractory PEE. Subgroups were classified as responders and non-responders according to the efficacy of VNS (⩾50% or < 50% reduction in seizure frequency). Preoperative data were analyzed to screen for potential predictors of VNS responsiveness. RESULTS: A total of 42 refractory PEE patients who underwent VNS therapy were enrolled, with an average age of 21.13 ± 9.70 years. Seizure frequency was reduced by more than 50% in 64.25% of patients, and 7.14% of patients achieved seizure-free events after VNS therapy. In addition, the response rates increased over time, with 40.5%, 50.0% and 57.1%, respectively at 6 months, 12 months, and 24 months after VNS therapy. Preoperative duration of epilepsy, monthly seizure frequency, and spatial distribution of interictal epileptic discharges (IEDs) were correlated with responders (p < 0.05) in the univariate analysis. Further multivariate regression analysis demonstrated that refractory PEE patients with high monthly seizure frequency or Focal IEDs (focal or multifocal epileptiform discharges) achieved better efficacy on VNS (p = 0.010, p = 0.003, respectively). CONCLUSION: VNS is an effective palliative therapy for patients with refractory PEE. Focal IEDs (focal or multifocal epileptiform discharges) and high seizure frequency were potential preoperative predictors of effectiveness after VNS therapy.

Vagus nerve stimulation for refractory posttraumatic epilepsy: Efficacy and predictors of seizure outcome.

Background: Traumatic brain injury (TBI) has been recognized as an important and common cause of epilepsy since antiquity. Posttraumatic epilepsy (PTE) is usually associated with drug resistance and poor surgical outcomes, thereby increasing the burden of the illness on patients and their families. Vagus nerve stimulation (VNS) is an adjunctive treatment for medically refractory epilepsy. This study aimed to determine the efficacy of VNS for refractory PTE and to initially evaluate the potential predictors of efficacy. Methods: We retrospectively collected the outcomes of VNS with at least a 1-year follow-up in all patients with refractory PTE. Subgroups were classified as responders and non-responders according to the efficacy of VNS (≥50% or <50% reduction in seizure frequency). Preoperative data were analyzed to screen for potential predictors of VNS efficacy. Results: In total, forty-five patients with refractory PTE who underwent VNS therapy were enrolled. Responders were found in 64.4% of patients, and 15.6% of patients achieved seizure freedom at the last follow-up. In addition, the responder rate increased over time, with 37.8, 44.4, 60, and 67.6% at the 3-, 6-, 12-, and 24-month follow-ups, respectively. After multivariate analysis, generalized interictal epileptic discharges (IEDs) were found to be a negative predictor (OR: 4.861, 95% CI: 1.145-20.632) of VNS efficacy. Conclusion: The results indicated that VNS therapy was effective in refractory PTE patients and was well tolerated over a 1-year follow-up period. Patients with focal or multifocal IEDs were recognized to have better efficacy after VNS therapy.

Vagus nerve stimulation for pharmacoresistant epilepsy secondary to encephalomalacia: A single-center retrospective study.

Objective: Vagus nerve stimulation (VNS) is an adjunctive treatment for pharmacoresistant epilepsy. Encephalomalacia is one of the most common MRI findings in the preoperative evaluation of patients with pharmacoresistant epilepsy. This is the first study that aimed to determine the effectiveness of VNS for pharmacoresistant epilepsy secondary to encephalomalacia and evaluate the potential predictors of VNS effectiveness. Methods: We retrospectively analyzed the seizure outcomes of VNS with at least 1 year of follow-up in all patients with pharmacoresistant epilepsy secondary to encephalomalacia. Based on the effectiveness of VNS (≥50% or <50% reduction in seizure frequency), patients were divided into two subgroups: responders and non-responders. Preoperative data were analyzed to screen for potential predictors of VNS effectiveness. Results: A total of 93 patients with epilepsy secondary to encephalomalacia who underwent VNS therapy were recruited. Responders were found in 64.5% of patients, and 16.1% of patients achieved seizure freedom at the last follow-up. In addition, the responder rate increased over time, with 36.6, 50.5, 64.5, and 65.4% at the 3-, 6-, 12-, and 24-month follow-ups, respectively. After multivariate analysis, seizure onset in adults (>18 years old) (OR: 0.236, 95%CI: 0.059-0.949) was found to be a positive predictor, and the bilateral interictal epileptic discharges (IEDs) (OR: 3.397, 95%CI: 1.148-10.054) and the bilateral encephalomalacia on MRI (OR: 3.193, 95%CI: 1.217-8.381) were found to be negative predictors of VNS effectiveness. Conclusion: The results demonstrated the effectiveness and safety of VNS therapy in patients with pharmacoresistant epilepsy secondary to encephalomalacia. Patients with seizure onset in adults (>18 years old), unilateral IEDs, or unilateral encephalomalacia on MRI were found to have better seizure outcomes after VNS therapy.

Association Between Asymptomatic Vulnerable Carotid Plaques and Cognitive Impairment in Rural Adults.

Background: The prevalence of cognitive impairment is growing and higher in rural areas. The association between carotid plaque and cognitive impairment remains uncertain, and few studies focused on the cognitive function of the rural population. We designed this study to investigate the association between carotid plaque and cognitive impairment in a rural community. Methods: We enrolled 3,336 participants who underwent carotid ultrasound and cognitive function measurements, free of cerebrovascular diseases, and without neurological deficits, from the China National Stroke Screen Survey program. Cognitive function was evaluated by the Montreal Cognitive Assessment (Beijing version). We used multivariable logistic regression to assess the association between asymptomatic carotid plaques and the presence of cognitive impairment. Results: Nine hundred seventy-six participants had cognitive impairment in this study. After adjustment for potential confounding factors, asymptomatic carotid plaques (odds ratio was 1.35; 95% confidence interval, 1.15-1.58), especially vulnerable carotid plaques (odds ratio was 1.54; 95% confidence interval, 1.28-1.85), were associated with cognitive impairment. Conclusion: In this community-based and observational study, asymptomatic vulnerable carotid plaque is an independent and significant risk factor for cognitive impairment in rural residents.

Association of diabetes status with cognitive impairment in two Chinese rural communities.

BACKGROUND AND PURPOSE: Diabetes may be one of the risk factors of cognitive impairment. In this study, we aimed to investigate the relationship between diabetes status and cognitive impairment among the middle-aged and elderly population (≥40 years) in Chinese rural communities. METHODS: A sample of 3392 participants aged 40 years or older from the China National Stroke Prevention Project (CSPP) between 2015 and 2017 were enrolled in this study. Cognitive function was assessed by the Beijing edition of the Montreal cognitive assessment (MoCA) scale. Cognitive impairment was diagnosed as a MoCA score < 26. Diabetes status was divided into three groups------Normal: fasting plasma glucose (FPG) ≤ 5.5 mmol/L, Prediabetes: 5.6 ≤ FPG ≤ 6.9 mmol/L, Diabetes: FPG ≥ 7.0 mmol/L or with a history of diabetes. Multivariate logistic regression was used to analyze the association between diabetes status and cognitive impairment. RESULTS: Out of the 3392 enrolled participants, 2023(59.6%) had cognitive impairment, 1586(46.8%) had abnormal fasting plasma glucose including 867(25.6%) prediabetes and 719(21.2%) diabetes. After adjusting for potential risk factors, we found prediabetes (OR: 1.22, 95%CI: 1.03-1.45) and diabetes (OR: 1.28, 95%CI: 1.06-1.55) are all associated with cognitive impairment, especially in the domains of language (prediabetes: OR: 1.14, 95%CI: 1.05-1.25; diabetes: OR:1.13, 95%CI: 1.03-1.24), visuospatial/executive functions (diabetes: OR: 1.50, 95%CI: 1.22-1.84) and attention (diabetes: OR: 1.15, 95%CI: 1.02-1.31). CONCLUSIONS: In this large community-based study, we found diabetes status may be an independent risk factor for cognitive impairment, particularly in domains of language, visuospatial/executive functions, and attention.