Potential Pleiotropic Genes and Shared Biological Pathways in Epilepsy and Depression Based on GWAS Summary Statistics.

Current epidemiological and experimental studies have indicated the overlapping genetic foundation of epilepsy and depression. However, the detailed pleiotropic genetic etiology and neurobiological pathways have not been well understood, and there are many variants with underestimated effect on the comorbidity of the two diseases. Utilizing genome-wide association study (GWAS) summary statistics of epilepsy (15,212 cases and 29,677 controls) and depression (170,756 cases and 329,443 controls) from large consortia, we assessed the integrated gene-based association with both diseases by Multimarker Analysis of Genomic Annotation (MAGMA) and Fisher's meta-analysis. On the one hand, shared genes with significantly altered transcripts in Gene Expression Omnibus (GEO) data sets were considered as possible pleiotropic genes. On the other hand, the pathway enrichment analysis was conducted based on the gene lists with nominal significance in the gene-based association test of each disease. We identified a total of two pleiotropic genes (CD3G and SLCO3A1) with gene expression analysis validated and interpreted twenty-five common biological process supported with literature mining. This study indicates the potentially shared genes associated with both epilepsy and depression based on gene expression, meta-data analysis, and pathway enrichment strategy along with traditional GWAS and provides insights into the possible intersecting pathways that were not previously reported.

Novel Intronic Mutations of TBK1 Promote Aberrant Splicing Modes in Amyotrophic Lateral Sclerosis.

TANK-binding kinase 1 (TBK1) has been identified as a causative gene of amyotrophic lateral sclerosis (ALS) in the Caucasian population in 2015. Here, we sequenced for TBK1 variants in a cohort of 15 familial ALS (fALS) and 275 sporadic ALS (sALS) of Chinese origin by targeted next-generation sequencing. We identified one likely benign missense variant (p. Ser398Pro), two missense variants of uncertain significance (p. Ile37Leu and p. Tyr677Asn), and two novel heterozygous variants in introns of TBK1, c.1522-3T > G and c.2066 + 4A > G. We performed splicing assays through minigene plasmids and RNA pull-down assay to determine that the two substitutions of nucleotides disrupted the binding of the important splicing regulator hnRNPA1 and promoted aberrant pre-mRNA splicing modes. The c.1522-3T > G variant promoted nearly 50.0% of abnormal transcripts (3 different types of insertions and deletions (indels) in junction of intron 13-exon 14) and the c.2066 + 4A > G variant inhibited about 75.0% inclusion of exon 19, both causing premature stop codon and producing TBK1 protein without CCD2. Immunofluorescence analysis showed that the expression of TBK1 with intronic variants was lower since less TBK1 distribution was observed in HEK293T cells. Both patients carrying TBK1 c.1522-3T > G and c.2066 + 4A > G variants developed a rapidly progressive ALS, with a survival of 31 and 10 months, respectively. The frequency of loss of function (LoF) variants in TBK1 was 0.73% in sALS in our cohort. We emphasize that intronic sequencing and pre-mRNA splicing analysis cannot be ignored to demonstrate the complex mutational spectrum and pathogenesis of ALS.

Phenotype of VCP Mutations in Chinese Amyotrophic Lateral Sclerosis Patients.

Mutations in the valosin-containing protein (VCP) gene have been linked to amyotrophic lateral sclerosis (ALS) in the Caucasian populations. However, the phenotype of VCP mutations in Chinese patients with (ALS) remains unclear. Targeted next-generation sequencing covered 28 ALS-related genes including the VCP gene was undertaken to screen in a Chinese cohort of 275 sporadic ALS cases and 15 familial ALS pedigrees. An extensive literature review was performed to identify all patients with ALS carrying VCP mutations previously reported. The clinical characteristics and genetic features of ALS patients with VCP mutations were reviewed. One known p.R155C mutation in the VCP gene was detected in two siblings from a familial ALS pedigree and two sporadic individuals. In addition, the same VCP p.R155C mutation was detected in an additional patient with ALS referred in 2021. Three patients with VCP p.R155C mutation presented with muscular weakness starting from proximal extremities to distal extremities. The other patient developed a phenotype of Paget's disease of bone in addition to the progressive muscular atrophy. We reported the first VCP mutation carrier manifesting ALS with Paget's disease of bone in the Chinese population. Our findings expand the phenotypic spectrum of the VCP mutations in Chinese patients with ALS and suggest that ALS patients with VCP p.R155C mutations tend to present with relatively young onset, symmetrical involvement of proximal muscles weakness of arms or legs, and then progressed to distal muscles of limbs.

Novel Variants in the FIG4 Gene Associated With Chinese Sporadic Amyotrophic Lateral Sclerosis With Slow Progression.

BACKGROUND AND PURPOSE: Mutations in the FIG4 gene have been linked to amyotrophic lateral sclerosis (ALS) type 11 in Caucasian populations. The purpose of this study was to identify FIG4 variants in a cohort of 15 familial ALS (FALS) indexes and 275 sporadic ALS (SALS) patients of Han Chinese origin. METHODS: All 23 exons of FIG4 were sequenced using targeted next-generation sequencing. An extensive literature review was performed to detect genotype-phenotype associations of FIG4 mutations. RESULTS: No FIG4 variants were identified in the FALS patients. One novel heterozygous missense variant (c.352G>T [p.D118Y]) and one novel heterozygous nonsense variant (c.2158G>T [p.E720X]) in FIG4 were identified in two SALS patients. The p.E720X variant is interpreted as likely pathogenic while the p.D118Y variant is a variant of uncertain significance. The patient carrying the p.E720X mutation developed lower-limb-onset slowly progressive ALS, and survived for 11.5 years. The patient harboring the FIG4 p.D118Y variant also presented with progressive ALS, with the score on the ALS Functional Rating Scale-Revised (ALSFRS-R) decreasing by 0.4 per month. The rate of decrease in the ALSFRS-R scores from symptom onset to diagnosis seemed to be lower in the patients carrying FIG4 variants than the no-FIG4-mutation ALS patients in this study. CONCLUSIONS: Our findings suggest that ALS patients carrying FIG4 mutations are not common in the Chinese population and are more likely to exhibit slow progression.

Novel TARDBP missense mutation caused familial amyotrophic lateral sclerosis with frontotemporal dementia and parkinsonism.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that predominately involves the motor neurons in the brain and spinal cord. The TARDBP gene, encoding TAR DNA-binding protein 43 (TDP-43) protein, has been identified as a major causative gene in ALS. In this study, we screened 275 SALS patients and 20 unrelated FALS probands for TARDBP mutations. We identified three TARDBP mutations in three SALS patients and two TARDBP mutations in two FALS probands, including a previously unreported mutation, p.K176I, in FALS patients consistent with frontotemporal dementia (FTD) and parkinsonism. The p.K176I mutation is the first mutation outside exon 6 of the TARDBP gene manifesting parkinsonism and the first TARDBP mutation manifesting parkinsonism identified in the Chinese population. Our results support that TARDBP mutations are one of the most common changes in both FALS and SALS in China. Patients with TARDBP mutations may have a broad phenotype spectrum of ALS, FTD, and parkinsonism. The TARDBP gene should be included in genetic screening for ALS with FTD, and/or parkinsonism.

Novel FUS mutation Y526F causing rapidly progressive familial amyotrophic lateral sclerosis.

FUS gene is one of the most common mutated genes in amyotrophic lateral sclerosis (ALS). We sequenced for FUS mutations in a cohort of 15 familial ALS and 275 sporadic ALS of Chinese origin. All 15 exons of the FUS gene were sequenced by targeted next-generation sequencing in a cohort of 15 familial ALS indexes and 275 sporadic ALS patients of Chinese origin. One novel p.Y526F mutation in FUS was detected in one familial ALS proband. Another novel FUS p.Q140R variant and two known FUS mutations (p.R495Efs*33 and p.R521C) were identified in four sporadic ALS cases. The frequency of FUS mutation in our cohort is 6.7% in familial ALS and 1.5% in sporadic ALS. The familial ALS proband carrying the FUS p.Y526F mutation presented with juvenile-onset lower limbs weakness and demonstrated an aggressive course, with respiratory muscles involvement 6 months after onset. The other patients in the family all had limbs weakness and died 1-2 years after disease onset. Our results strengthen that FUS mutations are the most frequent genetic causes of young-onset aggressive ALS. Genetic testing of the FUS gene should be performed in early-onset ALS patients especially those with a rapid progression.

Novel mutation in optineurin causing aggressive ALS+/-frontotemporal dementia.

OBJECTIVE: Mutations in optineurin (OPTN) have been identified in familial and sporadic amyotrophic lateral sclerosis (ALS). We screened a cohort of Chinese patients for mutations in optineurin. We also performed an extensive literatures review of all mutations in optineurin identified previously to detect genotype-phenotype associations. METHODS: All 16 exons of the OPTN gene in a cohort of 15 familial ALS indexes and 275 sporadic ALS patients of Chinese origin were sequenced by targeted next generation sequencing. RESULTS: Two known heterozygous missense mutations in the OPTN, c.1481T> G (p.L494W), and c.1546G> C (p.E516Q), as well as one novel heterozygous missense mutation c.1690G> C (p.D564H) were each detected in one sporadic ALS patient. The patient carrying the p.E516Q mutation developed clinical features of ALS-frontotemporal dementia (FTD) and the patient carrying the p.D564H mutation showed a phenotype of ALS. They both had an aggressive course, with a survival of 18 and 14 months respectively. Literature review showed that the clinical phenotypes in OPTN mutated ALS were not homogeneous, although some individuals showed a relatively slow progression and a long duration, some mutations carriers developed an aggressive progression and a short survival. INTERPRETATION: OPTN mutations contribute to ALS in Chinese population and account for 0.8% of sporadic ALS patients and 1.5% of familial ALS in the pooled Chinese ALS cohorts. Mutations in optineurin can cause aggressive ALS+/-FTD.

Diffusion Tensor Imaging With Tract-Based Spatial Statistics Reveals White Matter Abnormalities in Patients With Vascular Cognitive Impairment.

Purpose: The aim of this study was to evaluate microstructural changes of major white matter (WM) tracts in patients with vascular cognitive impairment (VCI). Method: Diffusion tensor imaging (DTI) data were obtained from 24 subjects with subcortical ischemic vascular disease (SIVD), including 13 subjects with VCI-no dementia (VCIND) and 11 subjects with normal cognition (as a control group). A tract-based spatial statistics approach was performed to investigate WM microstructure in VCIND by integrating multiple indices including fractional anisotropy (FA) and mean diffusivity (MD), which are intra-voxel metrics, and local diffusion homogeneity (LDH), which is an inter-voxel metric. Results: The VCIND group had decreased FA and increased MD values throughout widespread WM areas predominately in the corpus callosum, bilateral internal capsule/corona radiata/posterior thalamic radiation/inferior fronto-occipital fasciculus and right inferior/superior longitudinal fasciculus. There was a slight discrepancy between the distribution of areas with decreased FA and LDH. The FA, MD and LDH values were significantly correlated with cognitive test results. According to a WM tract atlas, 10 major tracts were identified as tracts of interest in which three diffusion metrics simultaneously differed between groups, including bilateral anterior thalamic radiation, forceps minor, right corticospinal tract, bilateral inferior fronto-occipital fasciculus, left inferior and superior longitudinal fasciculus, and bilateral uncinate fasciculus. Receiver operating characteristic (ROC) analysis demonstrated the feasibility of using diffusion metrics along the forceps minor and left anterior thalamic radiation for separating two groups. Conclusion: The results suggest WM microstructural abnormalities contribute to cognitive impairments in SIVD patients. DTI parameters may be potential biomarkers for detecting VCIND from SIVD.

DL-3-n-butylphthalide protects endothelial cells against advanced glycation end product-induced injury by attenuating oxidative stress and inflammation responses.

Endothelial dysfunction, regarded as a key step in the pathophysiological course of diabetic vascular complications, is initiated and deteriorated by advanced glycation end products (AGEs). DL-3-n-butylphthalide (DL-NBP) has been proven to have protective effects on neurons and vascular endothelial cells against ischemic and anoxic damage. The aim of the present study was to investigate whether NBP is able to attenuate AGE-induced endothelial dysfunction in vitro, and also elucidate the possible underlying mechanism. An injury model of human umbilical vein endothelial cells (HUVECs) induced by AGEs (200 µg/ml) was established. The results demonstrated that pretreatment with NBP (1-100 µM) significantly increased HUVEC viability and inhibited the apoptosis induced by AGEs. In addition, AGEs stimulated the expression levels of the receptor for AGEs protein and the downstream protein nuclear factor-κB in HUVECs, which were inhibited by pretreatment with NBP. Furthermore, it significantly reduced reactive oxygen species generation and the level of the inflammatory cytokines, intercellular cell adhesion molecule-1 and monocyte chemotactic protein-1, in HUVECs mediated by AGEs. The current findings indicated that NBP attenuated AGE-induced endothelial dysfunction by ameliorating inflammation and oxidative stress responses.

Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis.

BACKGROUND: Genetic studies have shown that C9orf72, SOD1, TARDBP and FUS are the most common mutated genes in amyotrophic lateral sclerosis (ALS). Here, we performed a meta-analysis to determine the mutation frequencies of these major ALS-related genes in patients with ALS. METHODS: We performed an extensive literature research to identify all original articles reporting frequencies of C9orf72, SOD1, TARDBP and FUS mutations in ALS. The mutation frequency and effect size of each study were combined. Possible sources of heterogeneity across studies were determined by meta-regression, sensitivity analysis and subgroup analysis. RESULTS: 111 studies were included in the meta-analysis. The overall pooled mutation frequencies of these major ALS-related genes were 47.7% in familial amyotrophic lateral sclerosis (FALS) and 5.2% in sporadic ALS (SALS). A significant difference was identified regarding the frequencies of mutations in major ALS genes between European and Asian patients. In European populations, the most common mutations were the C9orf72 repeat expansions (FALS 33.7%, SALS 5.1%), followed by SOD1 (FALS 14.8%, SALS 1.2%), TARDBP (FALS 4.2%, SALS 0.8%) and FUS mutations (FALS 2.8%, SALS 0.3%), while in Asian populations the most common mutations were SOD1 mutations (FALS 30.0%, SALS 1.5%), followed by FUS (FALS 6.4%, SALS 0.9%), C9orf72 (FALS 2.3%, SALS 0.3%) and TARDBP (FALS 1.5%, SALS 0.2%) mutations. CONCLUSIONS: These findings demonstrated that the genetic architecture of ALS in Asian populations is distinct from that in European populations, which need to be given appropriate consideration when performing genetic testing of patients with ALS.

Comparative Efficacy and Safety of Nine Anti-Platelet Therapies for Patients with Ischemic Stroke or Transient Ischemic Attack: a Mixed Treatment Comparisons.

Anti-platelet treatments, an effective anti-thrombotic therapy, are widely used in non-cardioembolic ischemic stroke or transient ischemic attack (TIA), including aspirin, cilostazol, clopidogrel, and other mono or dual therapies, while the optimal choice remains uncertain. All the literatures of 38 eligible randomized control trials were searched in PubMed, Embase, and China National Knowledge Internet (CNKI) without language limitation. And, nine anti-platelet therapies were assessed, including aspirin, clopidogrel, cilostazol, ticlopidine, triflusal, terutroban, sarpogrelate, dipyridamole plus aspirin, and clopidogrel plus aspirin. Additionally, we extract data of composite vascular events, major bleeding, ischemic stroke, intracranial hemorrhage, and all-cause death, as indicators of efficacy and safety. And among them, composite vascular events were the primary outcome. The binary outcomes were expressed as odds ratios (ORs) with corresponding 95 % confidence intervals (CIs). Both traditional meta-analysis and network meta-analysis were performed. Besides, for each outcome, the rank order was applied to reflect the superiority of every therapy compared with others, using the surface under the cumulative ranking curve (SUCRA). A cluster analysis was also conducted. Through the network meta-analysis, the synthesized data shows that cilostazol performed best on composite vascular events compared with placebo (OR = 0.62, 95 % CI 0.46-0.83) and aspirin (OR = 0.71, 95 % CI 0.53-0.95). In terms of ischemic stroke, clopidogrel plus aspirin seems the optimal, and it has significant difference between placebo (OR = 0.53, 95 % CI 0.35-0.74) and aspirin (OR = 0.75, 95 % CI 0.61-0.95). Meanwhile, cilostazol is also the first rank in major bleeding, especially when it is in contrast to aspirin (OR = 0.13, 95 % CI 0.02-0.70) and clopidogrel plus aspirin (OR = 0.09, 95 % CI 0.01-0.50). There is no significant difference among these nine treatments and placebo, as to all-cause death and intracranial hemorrhage. According to the cluster analysis, cilostazol can be the best choice with comprehensive assessment of composite vascular events, ischemic stroke and major bleeding. Based on this network meta-analysis, cilostazol was recommended as the optimal choice with good performance in both efficacy and safety for patient with ischemic stroke or TIA among nine anti-platelet therapies.

Toward precision medicine in amyotrophic lateral sclerosis.

Precision medicine is an innovative approach that uses emerging biomedical technologies to deliver optimally targeted and timed interventions, customized to the molecular drivers of an individual's disease. This approach is only just beginning to be considered for treating amyotrophic lateral sclerosis (ALS). The clinical and biological complexities of ALS have hindered development of effective therapeutic strategies. In this review we consider applying the key elements of precision medicine to ALS: phenotypic classification, comprehensive risk assessment, presymptomatic period detection, potential molecular pathways, disease model development, biomarker discovery and molecularly tailored interventions. Together, these would embody a precision medicine approach, which may provide strategies for optimal targeting and timing of efforts to prevent, stop or slow progression of ALS.

Surgical treatment of pituitary apoplexy in association with hemispheric infarction.

We report a patient with pituitary apoplexy in whom cerebral infarction developed, possibly secondary to vasospasm. Pituitary apoplexy is a clinical syndrome caused by acute hemorrhage or infarction of the pituitary gland. Our patient's clinical symptoms and radiographic findings greatly improved after surgical resection of the apoplectic pituitary gland. An extensive literature review was performed, including all previously reported cases of pituitary apoplexy leading to cerebral infarction. The clinical features, pathophysiological mechanisms, management and outcome of cerebral infarction following pituitary apoplexy are discussed. We show that cerebral infarction following pituitary apoplexy is associated with much poor prognosis. Early surgical decompression of the tumor and hemisphere should be performed in patients with severe or progressive neurological deficits, however, those with less severe presentations may be treated conservatively or with delayed elective surgery.

Clinical genetics of Alzheimer's disease.

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease and the most common form of dementia in the elderly. It is a complex disorder with environmental and genetic components. There are two major types of AD, early onset and the more common late onset. The genetics of early-onset AD are largely understood with mutations in three different genes leading to the disease. In contrast, while susceptibility loci and alleles associated with late-onset AD have been identified using genetic association studies, the genetics of late-onset Alzheimer's disease are not fully understood. Here we review the known genetics of early- and late-onset AD, the clinical features of EOAD according to genotypes, and the clinical implications of the genetics of AD.

Seizure-induced 5-HT release and chronic impairment of serotonergic function in rats.

We analyzed the dynamic concentration change of serotonin (5-HT) and its main metabolite 5-hydroxyindoleacetic acid (5-HIAA) within the epileptic hippocampus in rats. Seizure was induced by systemic injection of pilocarpine (320mg/kg, i.p.). Using electroencephalography (EEG) recordings, we found that primary seizure discharge was induced 30min after pilocarpine administration and that recurrent discharge peaked 14d after the onset of status epilepticus (SE). The extracellular fluid in the hippocampus was sampled by microdialysis from conscious animals at various time points before and after SE. The concentrations of 5-HT and 5-HIAA in the samples were measured by high-performance liquid chromatography and electrochemical detection (HPLC-ECD). Interestingly, 5-HT levels in the hippocampus were dramatically increased within the 30min following SE. This reversed to basal level by 4d after SE and continued to drop to 48% at 7d and 28% of basal level 14d after SE. Accordingly, a marked increase of 5-HIAA in the hippocampus appeared at 2d after SE, then gradually declined to levels below baseline. To identify serotonergic neurons in the raphe nuclei (a major source of 5-HT release in the brain), brain sections were immunostained for tryptophan hydroxylase (TPH). The number of TPH positive neurons and the intensity of TPH staining significantly decreased at 28d after SE. These data suggest that pilocarpine induces depletion of 5-HT in the hippocampus and significantly compromise serotonergic neurons in the raphe nuclei. The loss of serotonergic function may play a significant role in the pathophysiology of epilepsy.

Factors associated with generic and disease-specific quality of life in epilepsy.

OBJECTIVE: To investigate the association between quality of life (QOL) and sociodemographic factors, clinical seizure factors, depression and anxiety in patients suffering from epilepsy. METHODS: We examined 141 consecutive patients with epilepsy (mean age 25.8±9.6, 61.7% male). All patients completed the Self-Rating Depression Scale, Self-Rating Anxiety Scale, WHOQOL-BREF and QOLIE-31(Chinese version). Multiple linear regression analyses were applied to investigate factors impact on QOL. RESULTS: The results revealed that scores on two domains of the WHOQOL-BREF (i.e., physical and psychological domains, P<0.05) were significantly lower in the epilepsy group compared with the control group. Multiple regression analyses showed that anxiety, depression and course explained approximately 40% of the variance in patients' QOL. Anxiety was consistently the strongest predictor of lower scores on almost all QOL domains. In addition, the severity of depressive symptoms was significantly associated with lower scores across many QOL domains. CONCLUSION: Our findings suggest that QOLIE scores might be substantially affected by the presence and severity of anxiety symptoms and, to a lesser degree, of depressive symptoms and prolonged course of illness. In contrast, clinical seizure variables had a weaker association with QOL. Healthcare professionals should be aware of the significance of patients' emotional state and of the role it plays in their QOL.

A neurofibromatosis type 1 patient with thoracic encapsulated fluid and intracranial hypotension syndrome: a case report.

INTRODUCTION: Spinal meningoceles are uncommon entities, mostly associated with neurofibromatosis type 1 (NF-1). Their intrusion into the thoracic cavity, which compresses lung tissue, is quite often mistaken as a "pleural effusion." The withdrawal of a large amount of "pleural effusion" can lead to the intracranial hypotension syndrome (IHS), herniation, or even death. CASE REPORT: A 43-year-old woman, with NF-1 and a large "pleural effusion" which compressed lung tissue, was admitted to the Thoracic Department due to the patient's shortness of breath during her physical activities. The patient complained of headache shortly after withdrawal of about 250 mL of "pleural effusion." She was diagnosed with IHS according to the typical symptoms of postural headache, low cerebrospinal fluid (CSF) pressure and magnetic resonance imaging findings of diffuse pachymeningeal gadolinium enhancement. The "pleural effusion" was examined and found to be CSF. CONCLUSION: The reported case is the first 1 in the literature in which the intrusion of the NF-1 patient's spinal meningoceles into the thoracic cavity was diagnosed as a "pleural effusion" and large CSF withdrawal led to IHS. We highlight the possibility that thoracic meningoceles can coexist with a thoracic spinal deformity and the caution that needs to be taken when cases with similar symptoms are subjected to withdrawal of fluid.

[Evaluation of brain dysfunction in chronic anoxic encephalopathy with evoked potentials].

AIM: To explore the relationship between evoked potentials (EPs) and chronic anoxic brain damage by chronic intermittent hypoxia (CIH), and provide theory evidence for diagnosis and treatment of anoxic encephalopathy. METHODS: BAEP and SLSEP were recorded in rat model with CIH (hypoxia group) and rat with normoxia (normal group). Morris water maze was used to observe learning and memory ability. Immunohistochemical method was used to investigate the expression levels of caspase-3 in brain tissue. RESULTS: The peak latency (PL) of wave I, III, V and the interpeak latency (IPL) of wave III - V, I - V in BAEP in hypoxia group were much longer than that of in normal group (P < 0.05). The PL of wave N1, P1 of SEP in hypoxia group were much longer than that of in normal group (P < 0.05). In the water mase test, the escape latency (EL) of hypoxia group was much longer than normal group (P < 0.01). The number of caspase-3 positive cells in hypoxia group was much larger than that of in normal group (P < 0.05). There was a positive correlation among BAEP, SLSEP, the number of caspase-3 positive neuron and EL of water mase. CONCLUSION: The alteration of BAEP and SLSEP has an apparent correlation with chronic anoxic brain damage. This provides theory evidence for diagnosis and treatment of anoxic encephalopathy.