Tau pathology epigenetically remodels the neuron-glial cross-talk in Alzheimer's disease.

The neuron-glia cross-talk is critical to brain homeostasis and is particularly affected by neurodegenerative diseases. How neurons manipulate the neuron-astrocyte interaction under pathological conditions, such as hyperphosphorylated tau, a pathological hallmark in Alzheimer's disease (AD), remains elusive. In this study, we identified excessively elevated neuronal expression of adenosine receptor 1 (Adora1 or A1R) in 3×Tg mice, MAPT P301L (rTg4510) mice, patients with AD, and patient-derived neurons. The up-regulation of A1R was found to be tau pathology dependent and posttranscriptionally regulated by Mef2c via miR-133a-3p. Rebuilding the miR-133a-3p/A1R signal effectively rescued synaptic and memory impairments in AD mice. Furthermore, neuronal A1R promoted the release of lipocalin 2 (Lcn2) and resulted in astrocyte activation. Last, silencing neuronal Lcn2 in AD mice ameliorated astrocyte activation and restored synaptic plasticity and learning/memory. Our findings reveal that the tau pathology remodels neuron-glial cross-talk and promotes neurodegenerative progression. Approaches targeting A1R and modulating this signaling pathway might be a potential therapeutic strategy for AD.

Sleep disorders in the acute phase of coronavirus disease 2019: an overview and risk factor study.

BACKGROUND: Sleep disorders are common during the outbreak of pandemic diseases, and similar disorders are noted in hospitalized COVID-19 patients. It is valuable to explore the clinical manifestations and risk factors for sleep disorders in COVID-19 patients. METHODS: Inpatients with COVID-19 were enrolled. Detailed clinical information was collected, and sleep quality was assessed by PSQI. Patients were divided into a sleep disorder group and a normal group based on a PSQI ≥ 7, and the clinical features were compared between the groups. RESULTS: Fifty-three patients were enrolled, and 47.2% presented sleep disorders. Sleep disorders were associated with older age (> 50), anemia and carbon dioxide retention. Furthermore, factors associated with abnormal component scores of the PSQI were: (1) patients with older age were more likely to have decreased sleep quality, prolonged sleep latency, decreased sleep efficiency, sleep disturbances, and daytime dysfunction; (2) decreased sleep quality and prolonged sleep latency were associated with dyspnea, whereas carbon dioxide retention and more lobes involved in chest CT were associated with prolonged sleep latency; (3) decreased sleep efficiency was more prevalent in patients with anemia. CONCLUSIONS: Sleep disorders were prevalent in patients during the acute phase of COVID-19, and many risk factors (older age, anemia, carbon dioxide retention, the number of lobes involved in chest CT, and dyspnea) were identified. It is important to assess the presence of sleep disorders in patients to provide early intervention.

What Is Different about Teratoma-Associated Anti-LGI1 Encephalitis? A Long-Term Clinical and Neuroimaging Case Series.

INTRODUCTION: Anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis is clinically heterogeneous, especially at presentation, and though it is sometimes found in association with tumor, this is by no means the rule. METHODS: Clinical data for 10 patients with anti-LGI1 encephalitis were collected including one case with teratoma and nine cases without and compared for clinical characteristics. Microscopic pathological examination and immunohistochemical assay of the LGI1 antibody were performed on teratoma tissue obtained by laparoscopic oophorocystectomy. RESULTS: In our teratoma-associated anti-LGI1 encephalitis case, teratoma pathology was characterized by mostly thyroid tissue and immunohistochemical assay confirmed positive nuclear staining of LGI1 in some tumor cells. The anti-LGl1 patient with teratoma was similar to the non-teratoma cases in many ways: age at onset (average 47.3 in non-teratoma cases); percent presenting with rapidly progressive dementia (67% of non-teratoma cases) and psychiatric symptoms (33%); hyponatremia (78%); normal cerebrospinal fluid results except for positive LGI1 antibody (78%); bilateral hippocampal hyperintensity on magnetic resonance imaging (44%); diffuse slow waves on electroencephalography (33%); good response to immunotherapy (67%); and mild residual cognitive deficit (22%). Her chronic anxiety and presentation with status epilepticus were the biggest differences compared with the non-teratoma cases. CONCLUSION: In our series, anti-LGI1 encephalitis included common clinical features in our series: rapidly progressive dementia, faciobrachial dystonic seizures, behavioral disorders, hyponatremia, hippocampal hyperintensity on magnetic resonance imaging, and residual cognitive deficit. We observed some differences (chronic anxiety and status epilepticus) in our case with teratoma, but a larger accumulation of cases is needed to improve our knowledge base.

Deep Brain Stimulation in Alzheimer's Disease: Targeting the Nucleus Basalis of Meynert.

Alzheimer's disease (AD) is becoming a prevalent disease in the elderly population. Past decades have witnessed the development of drug therapies with varying targets. However, all drugs with a single molecular target fail to reverse or ameliorate AD progression, which ultimately results in cortical and subcortical network dysregulation. Deep brain stimulation (DBS) has been proven effective for the treatment of Parkinson's disease, essential tremor, and other neurological diseases. As such, DBS has also been gradually acknowledged as a potential therapy for AD. The current review focuses on DBS of the nucleus basalis of Meynert (NBM). As a critical component of the cerebral cholinergic system and the Papez circuit in the basal ganglia, the NBM plays an indispensable role in the subcortical regulation of memory, attention, and arousal state, which makes the NBM a promising target for modulation of neural network dysfunction and AD treatment. We summarized the intricate projection relations and functionality of the NBM, current approaches for stereotactic localization and evaluation of the NBM, and the therapeutic effects of NBM-DBS both in patients and animal models. Furthermore, the current shortcomings of NBM-DBS, such as variations in cortical blood flow, increased temperature in the target area, and stimulation-related neural damage, were presented.

Prodynorphin gene promoter polymorphism and temporal lobe epilepsy: A meta-analysis.

Previous studies have reported the association of prodynorphin (PDYN) promoter polymorphism with temporal lobe epilepsy (TLE) susceptibility, but the results remain inconclusive. To further precisely evaluate this association, we performed a meta-analysis. Published studies of TLE and PDYN polymorphism up to February 2015 were identified. Subgroup analysis by TLE subtype was performed. Moreover, sensitivity, heterogeneity, and publication bias were also analyzed. Seven case-control studies were finally included in this meta-analysis with 875 TLE cases and 1426 controls. We did not find synthetic evidence of association between PDYN promoter polymorphism and TLE susceptibility (OR=1.184, 95% CI: 0.873-1.606, P=0.277). Similar results were also obtained in non-familial-risk TLE subgroup. However, in the familial-risk TLE subgroup analysis, a significant association was observed (OR=1.739, 95% CI: 1.154-2.619, P=0.008). In summary, this meta-analysis suggests that PDYN gene promoter polymorphism might contribute to familial-risk TLE.

Intraclot recombinant tissue-type plasminogen activator reduces perihematomal edema and mortality in patients with spontaneous intracerebral hemorrhage.

The study aimed to investigate the impact of intraclot recombinant tissue-type plasminogen activator (rt-PA) on perihematomal edema (PHE) development in patients with intracerebral hemorrhage (ICH) treated with minimally invasive surgery (MIS) and the effects of intraclot rt-PA on the 30-day survival. We reviewed the medical records of ICH patients undergoing MIS between October 2011 and July 2013. A volumetric analysis was done to assess the change in PHE and ICH volumes at pre-MIS (T1), post-MIS (T2) and day 10-16 (T3) following diagnostic computed tomographic scans (T0). Forty-three patients aged 52.8±11.1 years with (n=30) or without rt-PA (n=13) were enrolled from our institutional ICH database. The median rt-PA dose was 1.5 (1) mg, with a maximum dose of 4.0 mg. The ratio of clot evacuation was significantly increased by intraclot rt-PA as compared with controls (77.9%±20.4% vs. 64%±15%; P=0.046). From T1 to T2, reduction in PHE volume was strongly associated with the percentage of clot evacuation (ρ=0.34; P=0.027). In addition, PHE volume was positively correlated with residual ICH volume at the same day (ρ ranging from 0.39-0.56, P<0.01). There was no correlation between the cumulative dose of rt-PA and early (T2) PHE volume (ρ=0.24; P=0.12) or delayed (T3) PHE volume (ρ=0.19; P=0.16). The 30-day mortality was zero in this cohort. In the selected cohort of ICH patients treated with MIS, intraclot rt-PA accelerated clot removal and had no effects on PHE formation. MIS aspiration and low dose of rt-PA seemed to be feasible to reduce the 30-day mortality in patients with severe ICH. A large, randomized study addressing dose titration and long-term outcome is needed.

αν and ß1 Integrins mediate Aß-induced neurotoxicity in hippocampal neurons via the FAK signaling pathway.

αν and ß1 integrins mediate Aß-induced neurotoxicity in primary hippocampal neurons. We treated hippocampal neurons with 2.5 µg/mL 17E6 and 5 µg/mL ab58524, which are specific αν and ß1 integrin antagonists, respectively, for 42 h prior to 10 µM Aß treatment. Next, we employed small interfering RNA (siRNA) to silence focal adhesion kinase (FAK), a downstream target gene of integrins. The siRNAs were designed with a target sequence, an MOI of 10 and the addition of 5 µg/mL polybrene. Under these conditions, the neurons were transfected and the apoptosis of different cell types was detected. Moreover, we used real-time PCR and Western blotting analyses to detect the expression of FAK and ρFAK genes in different cell types and investigated the underlying mechanism and signal pathway by which αν and ß1 integrins mediate Aß-induced neurotoxicity in hippocampal neurons. An MTT assay showed that both 17E6 and ab58524 significantly increased cell viability compared with the Aß-treated neurons (P<0.01 and P<0.05, respectively). However, this protective effect was markedly attenuated after transfection with silencing FAK (siFAK). Moreover, TUNEL immunostaining and flow cytometry indicated that both 17E6 and ab58524 significantly protected hippocampal neurons against apoptosis induced by Aß (P<0.05) compared with the Aß-treated cells. However, this protective effect was reversed with siFAK treatment. Both the gene and protein expression of FAK increased after Aß treatment. Interestingly, as the gene and protein levels of FAK decreased, the ρFAK protein expression markedly increased. Furthermore, both the gene and protein expression of FAK and ρFAK were significantly diminished. Thus, we concluded that both αν and ß1 integrins interfered with Aß-induced neurotoxicity in hippocampal neurons and that this mechanism partially contributes to the activation of the Integrin-FAK signaling pathway.

Do neuroimaging results impact prognosis of epilepsy surgery? A meta-analysis.

The neuroimaging results of drug-resistant epilepsy patients play an important role in the surgery decision and prognosis. The aim of this study was to evaluate the impact of these results on the efficacy of epilepay surgery, and then to explore surgical benefit for epilepsy patients with negative magnetic resonance (MR) images. Twenty-four subgroups describing the outcomes of 1475 epilepsy patients with positive-neuroimaging results and 696 patients with negative-neuroimaging results were involved in the meta-analysis. Overall, the odds of postoperational seizure-free rate were 2.03 times higher in magnetic resonance imaging-positive (MRI-positive) patients than in MRI-negative patients [odds ratio (OR)=2.03, 95% CI (1.67, 2.47), P<0.00001]. For patients with temporal lobe epilepsy (TLE), the odds were 1.76 times higher in those with MRI-positive results than in those with MRI-negative results [OR=1.76, 95% CI (1.34, 2.32), P<0.0001]. For patients with extra-temporal lobe epilepsy (extra-TLE), the odds were 2.88 times higher in MRI-positive patients than in MRI-negative patients [OR=2.88, 95% CI (1.53, 5.43), P=0.001]. It was concluded that the seizure-free rate of MRI-positive patients after surgery was higher than that of MRI-negative patients. For patients with negative results, an appropriate surgery should be concerned for TLE.

[Efficacy and safety of the combined therapy of valproic acid and lamotrigine for epileptics].

OBJECTIVE: To explore the efficacy and safety of the combined therapy of valproic acid (VPA) and lamotrigine (LTG) for various types of epilepsy. METHODS: The patients were recruited from the epilepsy center at Affiliated Tongji Hospital, Tongji Medical College, Huazhong Science & Technology University from January 2009 to September 2011. They were randomly selected through a number chart and divided into two groups: child group and adult group. The prospective follow-up study lasted for one year to examine the long-term efficacy and safety of combined therapy. Seizure frequency was recorded at Months 3, 6 and 12. The changes of seizure frequency were analyzed to calculate the 50% response rate, 75% response rate and seizure-free rate. All side effects during therapy were recorded. The correlation of efficacy with seizure type was also examined. Statistical analysis was performed through t test, variance analysis and χ(2) test. RESULTS: Among a total of 134 patients, 10 of them withdrew. At Months 3, 6 and 12, as compared with baseline, the average reduction rate of seizure frequency per month was 56%, 62%, 70% in child group versus 74%, 82%, 85% in adult group (P < 0.05). Adult group was better than child group. At Month 3, 50% response rate, 75% response rate and seizure-free rate was 70.97% - 35.48% in child group versus 83.87% - 43.01% in adult group. When compared at Months 3, 6 and 12, 50% response rate, 75% response rate and seizure-free rate showed no statistical difference (P > 0.05). The worse outcomes occurred more frequently in the patients with complex partial seizure (CPS) and than those with simple partial seizure (SPS) and generalized seizure GS (P < 0.05). Rash was the major side effect for withdrawal. CONCLUSION: The co-medication of VPA and LTG is both effective and safe for all epileptic types, especially for SPS and GS. And the efficacy may last for up to one year. Combined therapy shows excellent safety.

A follow-up study on newer anti-epileptic drugs as add-on and monotherapy for partial epilepsy in China.

BACKGROUND: Recently, new anti-epileptic drugs (AEDs) have been more frequently selected to treat epilepsy. In the present study, we evaluated the dynamic changes of efficacy and safety of three newer AEDs for treating partial epilepsy in China. METHODS: Patients were collected sequentially and were divided into three groups which accepted oxcarbazepine (OXC), lamotrigine (LTG) or topiramate (TPM) therapy. Each group included monotherapy and add-on therapy subgroups. We followed all patients for one year and recorded the indexes of efficacy and safety in detail. RESULTS: A total of 909 patients finished the follow-up observation. No significant difference was found in proportion of patients with > or = 50% reduction, > or = 75% reduction and 100% seizure reduction in the LTG and OXC groups between the first and the second six months. In the TPM group there was a statistical difference between the first and the second six months in proportion of patients with > or = 50% reduction (P = 0.002), > or = 75% reduction (P < 0.0001) and 100% seizure reduction (P = 0.009) in the monotherapy subgroup, and about > or = 75% reduction and 100% seizure reduction in the add-on therapy subgroup (P < 0.0001). The efficacy between the add-on and monotherapy subgroups showed a statistical difference. The safety of the three newer AEDs was good. CONCLUSIONS: The three newer AEDs all showed good efficacy and tolerability for partial epilepsy. And the efficacy can be maintained for at least one year.

[Brain injury in adenosine A1 receptor knock-out mice after pentetrazole kindling and its correlation with COX-2].

OBJECTIVE: To investigate the brain injury of neurocytes in hippocampus of adenosine A1 receptor knock-out mice during pentetrazole kindling and detect the correlation of brain injury and the expression of COX-2 so as to evaluate the neuroprotective function of adenosine A1 receptor and its mechanism. METHODS: The animals were divided into two groups: wild type group and KO group. The kindling model was established by injection of pentetrazole into abdominal cavity. The expression of brain injury related protein, caspase-3 and COX-2 in hippocampus was investigated separately at different time points (24 hour, 1 month) post-kindling. RESULTS: The expression of Caspase-3 and COX-2 increased in KO group both during acute and chronic phases post-kindling compared with normal mice. There was statistical difference (P < 0.05). Furthermore, the expression levels of two proteins were higher at 1 month compared with 24 hour (P < 0.01). These results indicated that the increased expression of Caspase-3 and COX-2 post-kindling was earlier and much more in KO mice as compared with wild-type ones. CONCLUSION: Adenosine exerts strong neuroprotective functions through the activation of adenosine A1 receptor. This receptor reduces cell apoptosis during pentetrazole kindling. Cyclooxygenase-2 (COX-2) reflects the extent of brain injury. The neuroprotective function mediated by adenosine A1 receptor might be related with COX-2.