Genetic variation in targets of lipid-lowering drugs and amyotrophic lateral sclerosis risk: a Mendelian randomization study.

BACKGROUND: The use of lipid-lowering drugs is still highly controversial in patients with amyotrophic lateral sclerosis (ALS). We performed a drug-target Mendelian randomization (MR) analysis to investigate the effect of targeted lipid-lowering drugs on the risk of ALS. METHODS: First, we evaluated the causal relationship between HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase (HMGCR) inhibitors-taking trait and ALS using a bidirectional two-sample MR study. Second, we investigated the causal relationship between lipid-lowering drugs and ALS through a drug-target MR approach. The summary data for HMGCR inhibitors-taking traits were extracted from a genome-wide association study (GWAS) of medication use and associated disease in the UK Biobank. The summary data for low-density lipoprotein cholesterol and apolipoprotein B (apoB) were extracted from a meta-analysis of GWAS in individuals of European ancestry in the UKB. The GWAS summary data of ALS were obtained from the Project MinE. RESULTS: Our bidirectional two-sample MR showed that genetically determined increased HMGCR inhibitors-taking trait was an independent risk factor for ALS (odds ratio [OR] = 1.090, 95% confidence interval [CI] = 1.035-1.150, p = 0.001). The results of drug-target MR showed that the increased expression of the HMGCR gene in blood with the higher risk of ALS (OR = 1.21, 95% CI = 1.01-1.46; p = 0.042) through SMR method and the apoB level mediated by the APOB gene increased the risk of ALS (OR = 1.15; 95% CI =1.05-1.25; p = 0.001) through inverse-variance weighted MR method. CONCLUSION: This present study provides genetic support for a positive causal effect of HMGCR inhibitors-taking trait and ALS. The reason for this may be due to the underlying disease condition behind the medication, rather than the medication itself. Our findings also suggested that HMGCR and apoB inhibitors may have potential protective effects on ALS.

The Beaumont behavioral intervention in a Chinese amyotrophic lateral sclerosis cohort.

OBJECTIVE: The prevalence of behavior impairment (27.38%) in the Chinese amyotrophic lateral sclerosis (ALS) cohort is lower. We hypothesize that the screening scales used among studies might not be appropriate to diagnose behavioral disorders in ALS patients. So, we urgently need to find a behavior scale with a high detection rate designed specifically for ALS. This study aims to verify the Chinese translation of the Beaumont Behavioral Inventory (BBI) as an effective assessment in a Chinese ALS cohort. METHODS: Ninety-eighty ALS patients and ninety-three healthy controls were included in this cross-sectional study. All participants took emotional state, overall cognitive, sleep quality and gastroenteric function, and behavioral evaluation. RESULTS: The BBI scores showed a strong association with the amyotrophic lateral sclerosis-Frontotemporal Dementia-Questionnaire (ALS-FTD-Q) (rs = 0.71, p < 0.001) as well as a moderate correlation with the Frontal Behavioral Inventory (FBI) (rs = 0.55, p < 0.001). High internal consistency was demonstrated in patients using BBI-after items (Cronbach's a = 0.89). When tested against clinical diagnoses, the optimal cutoff of total BBI score was identified at 5.5 (AUC = 0.95; SE = 0.02; 95% CI [0.91, 0.99]), the BBI reached optimal sensitivity and specificity values (91.5% and 87.2%). The BBI turned out to be more precise than the FBI (AUC = 0.76; SE = 0.05; 95% CI [0.66, 0.86]) and the ALS-FTD-Q (AUC = 0.84; SE = 0.04; 95% CI [0.77, 0.92]). CONCLUSION: The Chinese version of BBI is a quicker and more efficient instrument for assessing behavioral impairment in the ALS population in China.

Cortical structure and the risk of amyotrophic lateral sclerosis: A bidirectional Mendelian randomization study.

BACKGROUND: Current observational studies indicate progressive brain atrophy is closely associated with the clinical feature of amyotrophic lateral sclerosis. However, it is unclear whether the changes in cortical structure are the cause or result of ALS. Our study aimed to investigate the causal relationship between cortical structure and ALS risk using a bidirectional two-sample MR study. METHODS: We collected publicly available genome-wide association studies' summary statistics for cortical structure from UK Biobank and ENIGMA consortium (n = 33,992) and ALS from the Project MinE (n = 138,086). We used the inverse variance weighted method (IVW) as primary analysis in order to evaluate the causal effects. In addition, the weighted median and MR Egger methods were performed to ensure the robustness and reliability of the IVW results. RESULTS: We found the decreased surface of the paracentral lobule and thickness of the frontal pole and middle temporal lobe were suggestively associated with an increased risk of ALS as well as the increased surface of medial orbitofrontal and middle temporal lobe. In another aspect, the causalities between the susceptibility to ALS and the volume of the transverse temporal gyrus and superior temporal gyrus were negative. Besides, the susceptibility to ALS might also contribute to an increased thickness of the postcentral gyrus and superior parietal gyrus. CONCLUSION: In this two-sample MR analysis, we observed that multiple cortical brain regions are associated with a higher ALS risk. Further research into the underlying mechanisms is required to back up our findings.

Sleep Disturbances as a Potential Risk Factor for Deterioration of Respiratory Function in Patients with Amyotrophic Lateral Sclerosis.

Objectives: Sleep disturbances are common in amyotrophic lateral sclerosis (ALS). However, previous studies have explored sleep quality at the cross-sectional level and the longitudinal variability characteristics are currently unknown. Our study aimed to longitudinally explore the effect of sleep quality on disease progression in patients with ALS. Methods: All enrolled patients with ALS were first diagnosed and completed the 6- and 12-month follow-ups. Subjective sleep disturbance was assessed using the Pittsburgh Sleep Quality Index (PSQI). Based on the PSQI score at baseline, patients with ALS were classified as poor sleepers (PSQI >5) and good sleepers (PSQI ≤5). Disease progression was assessed using the rate of disease progression, the absolute change from baseline forced vital capacity (ΔFVC) and the percentage change from baseline FVC (ΔFVC%) over the follow-up period. Results: Sixty-three patients were included in the study, 24 (38.1%) were poor sleepers and 39 were good sleepers. The percentage of patients with poor sleep quality was 38.1% at baseline, increasing to 60.3% and 74.6% at 6- and 12-month, respectively. Compared to good sleepers, ΔFVC and ΔFVC% values were greater in poor sleepers (P < 0.001 and P = 0.001, respectively). Poor sleep quality at diagnosis is associated with rapid deterioration of respiratory function during disease progression. Conclusions: Sleep disturbances maybe a potential risk factor for deterioration of respiratory function in patients with ALS. The role of sleep disturbances in disease progression deserves attention, and early assessment and intervention may slow disease progression and improve life quality of patients with ALS.

Danshensu Enhances Cerebral Angiogenesis in Mice by Regulating the PI3K/Akt/Mtor/VEGF Signaling Axis.

BACKGROUND: Cerebral infraction seriously affects the life quality of patients. Danshensu has been reported to exhibit anti-inflammatory and vascular protective effects. However, the therapeutic function of Danshensu in cerebral vascular injury is still unclear. METHODS: Middle cerebral artery occlusion (MCAO) was used to construct the cerebral infraction model. Wound healing and tube formation assays were used to evaluate angiogenesis in vitro. Western blot assay was used to evaluate the activation of the PI3K/Akt/mTOR signaling pathway. The laser Doppler scanner was used to measure the regional cerebral blood flow (rCBF) in the area around the infarction, and the adhesion removal test was used to measure the sensorimotor function. The Modified Neurological Severity Score was performed to evaluate the cognitive functions of mice. RESULTS: Danshensu promoted the proliferation of bEnd.3 cells and angiogenesis in vitro. Danshensu upregulated the expression of VEGF through PI3K/Akt/mTOR signaling pathway in bEnd.3 cells. Danshensu improved rCBF restoration and attenuated the behavioral deficits in mice post-MCAO/R. CONCLUSION: Danshensu enhances angiogenesis through the PI3K/Akt/mTOR/VEGF signaling pathway in a mouse model of cerebral ischemic injury.

NLRP3 inflammasome inhibitor ameliorates ischemic stroke by reprogramming the phenotype of microglia/macrophage in a murine model of distal middle cerebral artery occlusion.

Stroke is one of the leading causes of death and disability worldwide. NLRP3 inflammasome has an essential role in the neuropathology of stroke. Recent studies report that shifting the microglial M1 phenotype to the M2 phenotype protects against ischemic stroke. In the present study, the precise effects of Tranilast, a NLPR3 inflammasome inhibitor, on stroke were evaluated. We established a murine model of distal middle cerebral artery occlusion (dMCAO) and administered Tranilast to dMCAO-induced stroke mice. The NLRP3 level, caspase 1 activity, and infarct volume stroke mice were measured. The sensorimotor function, pro-inflammatory cytokine production, and M1/M2 marker expression were measured. The M1 phenotype was induced by treatment of BV2 microglia with lipopolysacharide and interferon γ, and these BV-2 cells were further treated with Tranilast. The expression of CD16 and CD206 was monitored. dMCAO increased the NLRP3 expression and enhanced caspase 1 activity. Tranilast treatment significantly decreased the infarct volume, improved sensorimotor function, and suppressed the production of inflammatory cytokines in stroke mice. Moreover, Tranilast decreased the M1 marker level while promoting the expression of M2 markers. In summary, our findings suggest that Tranilast ameliorates ischemic stroke through stimulating M2 polarization of microglia.

cVEMP and VAT for the diagnosis of vestibular migraine.

BACKGROUND: Although the diagnostic criteria of vestibular migraine (VM) have already been defined, various clinical manifestations of VM and the lack of pathognomonic biomarker result in high rate of misdiagnosis and mismanagement. A timely and accurate diagnosis tool for the evaluation of VM is highly needed. OBJECTIVE: The current study aims to investigate the potential feasibility of cervical vestibular evoked myogenic potential (cVEMP) and vestibular autorotation test (VAT) as a diagnosis tool for VM. METHODS: A total of 211 subjects were recruited into the current study with all subjects meeting the inclusion and exclusion criteria. The subjects were divided into 3 groups: healthy control group, general migraine group and VM group. Test of cVEMP and VAT was conducted in all the groups, and the generated data were statistically compared. RESULTS: Compared with the other two groups, cVEMP P13-N23 amplitudes of VM patients showed a significant decline. Mean latency values of the VM group had no significant difference in comparison with other groups. Asymmetry ratios showed increased level in VM patients compared to the control groups, without significant difference. VAT results showed that all the horizontal gain, horizontal phase, vertical gain and vertical phase differ from the other two groups to varying degrees at higher frequency. CONCLUSION: cVEMP and VAT have potential usage in the assessment of VM and can serve as powerful tool in diagnosis of VM.

miR-499-5p suppresses C-reactive protein and provides neuroprotection in hypoxic-ischemic encephalopathy in neonatal rat.

Perinatal hypoxic-ischemic encephalopathy (HIE) is associated with high neonatal mortality and permanent neurologic deficit. Recent data suggested microRNAs (miRNAs) may have essential functions in the regulation of HIE. This study aims to investigate the functional role of miR-499-5p and the underlying mechanism in regulating neonatal hypoxia-ischemia (HI)-induced brain injury. Dual-luciferase reporter assay and western blotting assay were performed to investigate the relationship between miR-499-5p and C-reactive protein (CRP). TUNEL staining assay was applied to evaluate neuronal cell apoptosis in the hippocampus after administration of miR-499-5p in HIE rat model. Neurobehavioral assays were conducted to evaluate the effect of miR-499-5p on the neurological functions of rat pups with HI-induced brain injury. Our study showed that miR-499-5p regulated CRP expression in L-02 cells and rat HIE model. The miR-499-5p treatment resulted in significant reduction of neuronal cell apoptosis and the infarct size of the brain. Furthermore, administration of miR-499-5p significantly improved spatial learning ability, spatial memory, and locomotor function of rat pups with HIE. Our data demonstrated that miR-499-5p have a neuroprotective effect in HI-induced brain injury in rat pups, which suggests a potential therapeutic application of miR-499-5p in the treatment of neonatal HIE.

Fisetin Prolongs Therapy Window of Brain Ischemic Stroke Using Tissue Plasminogen Activator: A Double-Blind Randomized Placebo-Controlled Clinical Trial.

Recombinant tissue plasminogen activator (rt-PA) can be utilized to treat ischemic stroke with safety and effectiveness but limited by a narrow therapeutic window. In the present clinical trial among patients with stroke, we sought to evaluate the potential of fisetin to extend the therapeutic window of rt-PA treatment. Patients with stroke were divided based on their onset-to-treatment time (OTT) and then randomly assigned to receive the rt-PA treatment combined with fisetin or placebo. Primary outcome was evaluated using the National Institutes of Health Stroke scale (NIHSS), and secondary outcome was assessed by serum levels of matrix metalloproteinase (MMP) 2, MMP 9, and C-reactive protein (CRP). Fisetin dramatically improved the treatment outcomes of the patients with stroke in the delayed OTT strata, as revealed by lower NIHSS scores. The beneficial effect of fisetin was likely attributable to reduced levels of MMP-2, MMP-9, and CRP in the serum, as evidenced by strong linear correlations between serum levels of such markers with the NIHSS scores in all enrolled patients. Fisetin may possess the potential to supplement traditional rt-PA treatments among patients with stroke, particularly for those with delayed OTT, and thereby extend the otherwise narrow therapeutic window and improve the treatment outcomes.

[Abnormal automatic processing of facial expression in generalized anxiety disorder patients: an event-related potential study].

OBJECTIVE: To examine the automatic processing of facial expression and explore the pathogenesis in generalized anxiety disorder (GAD) patients. METHODS: Fifteen GAD patients and 15 gender-, age- and education-matched healthy volunteers were recruited from First Affiliated Hospital, Dalian Medical University. The expression-related mismatch negativity (MMN) was recorded to explore the automatic processing mechanism into emotional faces with task-irrelevant emotional faces as effective media. RESULTS: The MMNs elicited by emotional faces were significantly lower in GAD participants than those in healthy participants [MMN1:case group (-0.30 ± 0.09) µV, control group (-0.68 ± 0.13) µV, P = 0.0003; MMN2: case group (-0.22 ± 0.13) µV, control group (-0.72 ± 0.13) µV, P = 0.011] (Ps < 0.05) analyzing. For the effect of expression, it was found that the MMNs elicited by negative expression were lower in GAD participants than those in healthy participants mainly in right hemisphere while positive expression mainly in left hemisphere [MMN1:case group (-0.45 ± 0.15) µV, control group (-0.99 ± 0.15) µV, P = 0.017; MMN2:case group (0.23 ± 0.22) µV, control group (-1.23 ± 0.22) µV, P = 0.003; (MMN1:case group (-0.12 ± 0.14) µV, control group (-0.65 ± 0.14) µV, P = 0.015; MMN2:case group (0.14 ± 0.18) µV, control group (-0.42 ± 0.18) µV, P = 0.039]. CONCLUSION: There is an impairment of automatic processing of emotional faces.

Electrophysiological correlates of emotional processing in sensation seeking.

Previous studies have consistently reported a relationship between sensation seeking and emotional reactivity. However, little is known about the neural correlates and the time course of emotional processing in sensation seeking. The present study addressed these issues by recording event-related potentials (ERPs) during an emotional oddball task. Valence effect was significant at N2, P3 and LPP whereas arousal effect was significant at P3 and LPP. More importantly, low sensation seekers (LSSs) exhibited an increased emotional N2 whereas high sensation seekers (HSSs) showed an enhanced emotional P3. Furthermore, the arousal effect was similar across the two groups, but the valence effect at N2 stage was significant in LSSs instead of HSSs. These findings suggest that LSSs tend to show a more active general alerting system toward emotional stimuli, particularly for negative stimuli, whereas HSSs tend to display a stronger preference for intense stimulation irrespective of the emotional valence.