Normal Control Individuals Research Articles

Accumulation of network redundancy marks the early stage of Alzheimer's disease.

Brain wiring redundancy counteracts aging-related cognitive decline by reserving additional communication channels as a neuroprotective mechanism. Such a mechanism plays a potentially important role in maintaining cognitive function during the early stages of neurodegenerative disorders such as Alzheimer's disease (AD). AD is characterized by severe cognitive decline and involves a long prodromal stage of mild cognitive impairment (MCI). Since MCI subjects are at high risk of converting to AD, identifying MCI individuals is essential for early intervention. To delineate the redundancy profile during AD progression and enable better MCI diagnosis, we define a metric that reflects redundant disjoint connections between brain regions and extract redundancy features in three high-order brain networks-medial frontal, frontoparietal, and default mode networks-based on dynamic functional connectivity (dFC) captured by resting-state functional magnetic resonance imaging (rs-fMRI). We show that redundancy increases significantly from normal control (NC) to MCI individuals and decreases slightly from MCI to AD individuals. We further demonstrate that statistical features of redundancy are highly discriminative and yield state-of-the-art accuracy of up to 96.8 ± 1.0% in support vector machine (SVM) classification between NC and MCI individuals. This study provides evidence supporting the notion that redundancy serves as a crucial neuroprotective mechanism in MCI.

Could serum serotonin be used as a marker for portal vein invasion in patients with hepatocellular carcinoma?

Introduction: Hepatocellular carcinoma represents the sixth and the fourth cause of cancer in the world and Egypt, respectively. In Egypt, HCC mortality and morbidity is high. Serotonin is a precious neurotransmitter and vascular viable molecule. Serotonin plays an important role in hepatocytes mitosis and tumor genesis leading to hepatocellular carcinoma. Aim of Work: To investigate if serum serotonin can be used as a marker for portal vein invasion in patient with hepatocellular carcinoma. Methods: Cross-sectionla analytic study was performed in Suez Canal University Hospitals. The study included 90 participants; 10 normal healthy control individuals and 80 chronic liver disease patients divided into four groups ( 20 cirrhotic; 20 early HCC; 20 advanced HCC and 20 ablated HCC). All study groups were subjected to the following; history, clinical examination, and investigations including hematological, biochemical, serum Alpha fetoprotein and Serotonin levels) with pelviabdominal ultrasound and Triphasic computerized tomography. Results: Portal Vein Thrombosis (PVT), abnormal liver function tests, and AFP were positively correlate with serum serotonin level. In comparison between study groups, mean serum serotonin level was (117±84, 693±65,1613±37) for patients with normal, dilated, and portal vein invasion respectively with a statistically significant difference ( p value <0.001).

Identification of bi-allelic KIF9 loss-of-function variants contributing to asthenospermia and male infertility in two Chinese families.

Asthenozoospermia (AZS) is a leading cause of male infertility, affecting an estimated 18% of infertile patients. Kinesin proteins function as molecular motors capable of moving along microtubules. The highly conserved kinesin family member 9 (KIF9) localizes to the central microtubule pair in the flagella of Chlamydomonas cells. The loss of KIF9 expression in mice has been linked to AZS phenotypes. Variant screening was performed by whole exome sequencing from 92 Chinese infertile patients with AZS. Western blot was used to was used for analyzing of candidate proteins expression. Patients' sperm samples were stained with immunofluorescent to visualise proteins localization and were visualised by transmission electron microscopy (TEM) to determine axoneme structures. Co-immunoprecipitation assay was used to verify the binding proteins of KIF9. In vitro fertilization (IVF) was used to evaluate the efficiency of clinical treatment. Bi-allelic KIF9 loss-of-function variants were identified in two unrelated Chinese males exhibiting atypical sperm motility phenotypes. Both of these men exhibited typical AZS and suffered from infertility together with the complete absence of KIF9 expression. In contrast to these KIF9-deficient patients, positive KIF9 staining was evident throughout the flagella of sperm from normal control individuals. KIF9 was able to interact with the microtubule central pair (CP) component hydrocephalus-inducing protein homolog (HYDIN) in human samples. And KIF9 was undetectable in spermatozoa harboring CP deletions. The morphologicy of KIF9-deficient spermatozoa appeared normal under gross examination and TEM. Like in mice, in vitro fertilization was sufficient to overcome the fertility issues for these two patients. These findings indicate that KIF9 associates with the central microtubules in human sperm and that it functions to specifically regulate flagellar swinging. Overall, these results offer greater insight into the biological functions of KIF9 in the assembly of the human flagella and its role in male fertility.

Neurodegenerative Pathways in Alzheimer's Disease Subtypes

AbstractBackgroundBiological heterogeneity in Alzheimer’s disease (AD) has been observed and described as subtypes in measures of neurodegeneration (e.g., hypometabolism and atrophy). However, the relationship between these AD subtypes have not been studied. Thus, we aimed to compare and identify pathways associated with hypometabolism‐based and atrophy‐based subtypes.MethodCross‐sectional FDG‐PET and MRI scans from 173 amyloid‐positive AD individuals and 120 amyloid‐negative cognitively normal control individuals from the ADNI were included. Subtypes were identified in each neuroimaging modality by random forest hierarchical clustering using FDG‐PET uptake (measuring hypometabolism) and MRI volumes (measuring atrophy) in cortical and subcortical regions. We performed cross‐modal comparisons of atrophy patterns in hypometabolism‐based subtypes and hypometabolism patterns in atrophy‐based subtypes. To identify neurodegenerative pathways corresponding to each subtype, we used event‐based modelling to predict sequential progression of abnormality in hypometabolism and atrophy across brain regions (hippocampus, AD signature, frontal, posterior areas).ResultClustering revealed four hypometabolism‐based (two relatively limbic‐predominant: 25.7%, 19.8% and two relatively cortical‐predominant: 25.7%, 28.6%) and three atrophy‐based (diffuse: 18.7%, relatively limbic‐predominant: 28.6%, minimal: 52.6%) subtypes of AD with distinct spatial patterns and demographic and clinical characteristics. Cross‐modally, we found comparable AD‐typical atrophy patterns (involving the hippocampus and temporal regions) across the four hypometabolism‐based subtypes and comparable AD‐typical hypometabolism patterns (involving the retrosplenial cortex) across the three atrophy‐based subtypes. Event‐based modelling showed that each hypometabolism‐based subtype was associated with a unique sequential progression of regional hypometabolism, but not regional atrophy (sequence always initiated with frontal atrophy across all subtypes). Similarly, each atrophy‐based subtype was associated with a unique sequential progression of regional atrophy, but not regional hypometabolism (sequence always initiated with hypometabolism in AD signature areas across all subtypes).ConclusionOur findings suggest that hypometabolism‐based and atrophy‐based AD subtypes are not interchangeable. We identified unique metabolic and atrophy pathways specific to each subtype, which supports the notion that neurodegeneration manifests and progresses differentially across subtypes of AD. Despite being measures of neurodegeneration, hypometabolism and atrophy may not share the same extent of heterogeneity, bearing a complex multimodal relationship. Disentangling such relationships and combining complementary biomarkers to investigate heterogeneity could aid personalized treatment of AD.

Polygenic hazard score modified the relationship between hippocampal subfield atrophy and episodic memory in older adults

Understanding genetic influences on Alzheimer's disease (AD) may improve early identification. Polygenic hazard score (PHS) is associated with the age of AD onset and cognitive decline. It interacts with other risk factors, but the nature of such combined effects remains poorly understood. We examined the effect of genetic risk and hippocampal atrophy pattern on episodic memory in a sample of older adults ranging from cognitively normal to those diagnosed with AD using structural MRI. Participants included 51 memory unimpaired normal control (NC), 69 mild cognitive impairment (MCI), and 43 AD adults enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Hierarchical linear regression analyses examined the main and interaction effects of hippocampal subfield volumes and PHS, indicating genetic risk for AD, on a validated episodic memory composite score. Diagnosis-stratified models further assessed the role of PHS. Polygenic hazard score moderated the relationship between right fimbria/hippocampus volume ratio and episodic memory, such that patients with high PHS and lower volume ratio had lower episodic memory composite scores [ΔF = 6.730, p = 0.011, ΔR 2 = 0.059]. This effect was also found among individuals with MCI [ΔF = 4.519, p = 0.038, ΔR 2 = 0.050]. In contrast, no interaction effects were present for those NC or AD individuals. A follow-up mediation analysis also indicated that the right fimbria/hippocampus volume ratio might mediate the link between PHS and episodic memory performance in the MCI group, whereas no mediation effects were present for those NC or AD individuals. These findings suggest that the interaction between AD genetic risk and hippocampal subfield volume ratio increases memory impairment among older adults. Also, the results highlighted a potential pathway in which genetic risk affects memory by degrading hippocampal subfield volume ratio in cognitive decline subjects.

Screening of plasma exosomal lncRNAs to identify potential biomarkers for obstructive sleep apnea

BackgroundObstructive sleep apnea (OSA) is highly prevalent, but frequently undiagnosed. The existing biomarkers of OSA are relatively insensitive and inaccurate. Long non-coding RNAs (lncRNAs) have no protein-coding ability but have a role in regulating gene expression. They are stably expressed in exosomes, easily and rapidly measurable. Changes in expression of exosomal lncRNAs can be useful for disease diagnoses. However, there are few reports on the association of exosomal lncRNAs with OSA. We aimed to investigate the exosomal lncRNA profiles to establish the differences between non-OSA, OSA with or without hypertension (HTN) and serve as a potential diagnostic biomarker.MethodsThis diagnostic test included 63 participants: [normal control (NC) =25], (OSA =23), and (HTN-OSA =15). Expression profiling of lncRNAs in isolated exosomes was performed through high-throughput sequencing in 9 participants. Subsequently, OSA/HTN-OSA related lncRNAs were selected for validation by droplet digital polymerase chain reaction (ddPCR), receiver operating characteristic (ROC) curves were used to determine the diagnostic value. The reliabilities of the screened gene were further validated in another independent cohort: (NC =10), (OSA mild =10), (OSA moderate =11), and (OSA severe =10), the correlation between clinical features and its expression was analyzed. The MiRanda software was used to predict the binding sites of interaction between microRNA (miRNA) and target genes regulated by screened lncRNA.ResultsWe identified the differentially expressed lncRNAs and mRNAs in plasma exosomes of the NC, OSA, HTN-OSA groups. Most pathways enriched in differentially expressed lncRNAs and mRNAs had previously been linked to OSA. Among them, ENST00000592016 enables discrimination between NC and OSA individuals [area under curve (AUC) =0.846, 95% confidence interval (CI): 0.72–0.97]. The severity of OSA was associated with changes in the ENST00000592016 expression. Furthermore, ENST00000592016 affected the PI3K-Akt, MAPK, and TNF pathways by regulating miRNA expressions.ConclusionsThis is the first report about differential expression of lncRNA in OSA and HTN-OSA exosomes. ENST00000592016 enables discrimination between NC and OSA individuals. This work enabled characterization of OSA and provided the preliminary work for the study of biomarker of OSA.

An insight into the value of circular RNA in psoriasis pathogenesis and its correlation with PASI score

Background Psoriasis is a chronic hyperproliferative inflammatory disease, in which genetic and environmental factors have an important role, but the exact cause is yet unknown. Circular RNAs (circRNAs) are regulatory noncoding RNAs. They play an important role in multiple physiological and pathological processes, such as cancer, cardiovascular diseases, and neuronal diseases. Some circRNAs are involved in regulating immunity, inflammation, and cell proliferation in many types of cells. Aim To detect the expression of circRNA (Circ0061012) in psoriatic skin of diseased patients as compared with normal control persons to investigate the possible role of circRNA in psoriasis pathogenesis and its correlation with disease severity. Patients and methods The present study included 30 psoriatic patients and 30 healthy controls. A 4-mm punch skin biopsy was taken from patients (psoriatic lesion) and controls, and it was kept in the lysis solution for the stability of the studied parameters and was kept frozen at -80°Celsius till analysis of circRNA by real-time polymerase chain reaction. Results The tissue level of circRNA (Circ0061012) was significantly higher among patients with psoriasis as compared with normal control individuals. Conclusion circRNA could contribute to psoriasis pathogenesis through its immunomodulatory role, so it might be a therapeutic target in the future.

Development of a Machine Learning Model to Discriminate Mild Cognitive Impairment Subjects from Normal Controls in Community Screening.

Background: Mild cognitive impairment (MCI) is a transitional stage between normal aging and probable Alzheimer’s disease. It is of great value to screen for MCI in the community. A novel machine learning (ML) model is composed of electroencephalography (EEG), eye tracking (ET), and neuropsychological assessments. This study has been proposed to identify MCI subjects from normal controls (NC). Methods: Two cohorts were used in this study. Cohort 1 as the training and validation group, includes184 MCI patients and 152 NC subjects. Cohort 2 as an independent test group, includes 44 MCI and 48 NC individuals. EEG, ET, Neuropsychological Tests Battery (NTB), and clinical variables with age, gender, educational level, MoCA-B, and ACE-R were selected for all subjects. Receiver operating characteristic (ROC) curves were adopted to evaluate the capabilities of this tool to classify MCI from NC. The clinical model, the EEG and ET model, and the neuropsychological model were compared. Results: We found that the classification accuracy of the proposed model achieved 84.5 ± 4.43% and 88.8 ± 3.59% in Cohort 1 and Cohort 2, respectively. The area under curve (AUC) of the proposed tool achieved 0.941 (0.893–0.982) in Cohort 1 and 0.966 (0.921–0.988) in Cohort 2, respectively. Conclusions: The proposed model incorporation of EEG, ET, and neuropsychological assessments yielded excellent classification performances, suggesting its potential for future application in cognitive decline prediction.

Plasma β-amyloid, tau, neurodegeneration biomarkers and inflammatory factors of probable Alzheimer's disease dementia in Chinese individuals.

BackgroundPlasma-derived β-amyloid, tau, and neurodegeneration (ATN) biomarkers can accurately diagnose Alzheimer’s disease (AD) and predict its progression. Few studies have investigated the relationship between plasma biomarkers and changes in plasma inflammatory markers in clinically diagnosed AD.MethodsSeventy-four participants were recruited, including 30 mild-to-moderate AD dementia patients and 44 normal controls (NC). All participants underwent neuropsychological testing and blood sampling for biomarker testing. AD was clinically diagnosed according to the National Institute on Aging-Alzheimer’s Association (NIA-AA) core criteria and required age-mismatched hippocampal atrophy. We performed Single Molecule Array (Simoa), an ultra-sensitive enzyme-linked immunosorbent assay (ELISA), to examine plasma ATN markers, including β-amyloid (Aβ) 40, Aβ42, p-tau181, total (t)-tau, neurofilament protein light chain (NfL), and inflammatory factors (TNF-α, IL-1β, IL-6, and IL-8).ResultsThe level of the plasma Aβ42/Aβ40 ratio was significantly declined and the levels of the plasma p-tau181, NfL and TNF-α were significantly higher in the AD group than the NC group, but there was no significant difference in the levels of plasma t-tau, IL-1β, IL-6, and IL-8 between the AD and NC groups. The levels of plasma p-tau181, NfL, Aβ42/Aβ40 ratio, and TNF-α were all associated with impairments in multiple cognitive domains. Among them, the plasma Aβ42/Aβ40 ratio, and the p-tau181 and TNF-α levels were associated with impairments in global cognition, memory, and visuospatial abilities, but not with executive function, only plasma NfL level was associated with executive function. Plasma NfL showed higher diagnostic performance in AD than in NC individuals (AUC = 0.833). A combined diagnostic prediction model of plasma Aβ42/Aβ40 ratio, p-tau 181, and NfL had the highest value than each factor alone (AUC = 0.902),with a sensitivity and specificity of 0.867 and 0.886, respectively.ConclusionThe levels of plasma ATN biomarkers (Aβ42/Aβ40 ratio, p-tua181, and NfL) were significantly changed in clinically diagnosed AD patients and they all associated with different domains of cognitive impairment. Plasma ATN biomarkers better differentiate mild-to-moderate AD dementia from NC when they are incorporated into diagnostic models together rather than individually. Plasma ATN biomarkers have the potential to be a screening tool for AD. However, the expression of inflammatory factors in AD patients requires further research.

Crosstalk between mucosal microbiota, host gene expression, and sociomedical factors in the progression of colorectal cancer

Various omics-based biomarkers related to the occurrence, progression, and prognosis of colorectal cancer (CRC) have been identified. In this study, we attempted to identify gut microbiome-based biomarkers and detect their association with host gene expression in the initiation and progression of CRC by integrating analysis of the gut mucosal metagenome, RNA sequencing, and sociomedical factors. We performed metagenome and RNA sequencing on colonic mucosa samples from 13 patients with advanced CRC (ACRC), 10 patients with high-risk adenoma (HRA), and 7 normal control (NC) individuals. All participants completed a questionnaire on sociomedical factors. The interaction and correlation between changes in the microbiome and gene expression were assessed using bioinformatic analysis. When comparing HRA and NC samples, which can be considered to represent the process of tumor initiation, 28 genes and five microbiome species were analyzed with correlation plots. When comparing ACRC and HRA samples, which can be considered to represent the progression of CRC, seven bacterial species and 21 genes were analyzed. When comparing ACRC and NC samples, 16 genes and five bacterial species were analyzed, and four correlation plots were generated. A network visualizing the relationship between bacterial and host gene expression in the initiation and progression of CRC indicated that Clostridium spiroforme and Tyzzerella nexilis were hub bacteria in the development and progression of CRC. Our study revealed the interactions of and correlation between the colonic mucosal microbiome and host gene expression to identify potential roles of the microbiome in the initiation and progression of CRC. Our results provide gut microbiome-based biomarkers that may be potential diagnostic markers and therapeutic targets in patients with CRC.

Reduced inter-hemispheric auditory and memory-related network interactions in patients with schizophrenia experiencing auditory verbal hallucinations.

BackgroundInter-hemispheric disconnection is a primary pathological finding in schizophrenia. However, given the inherent complexity of this disease and its development, it remains unclear as to whether associated inter-hemispheric changes play an important role in auditory verbal hallucination (AVH) development. As such, this study was developed to explore inter-hemispheric connectivity in the context of schizophrenia with AVH while excluding positive symptoms and other factors with the potential to confound these results.MethodIn total, resting-state functional magnetic resonance imaging (fMRI) was used to assess 42 patients with AVH (APG), 26 without AVH (NPG), and 82 normal control (NC) individuals. Inter-hemispheric connectivity in these subjects was then assessed through the use of voxel-mirrored homotopic connectivity (VMHC) and Pearson correlation analyses.ResultRelative to HC and NPG subjects, APG individuals exhibited a decrease in VMHC in the superior temporal gyrus (STG) extending into Heschl's gyrus, the insula, and the Rolandic operculum as well as in the fusiform gyrus extending into the para-hippocampus (Corrected p < 0.005, cluster size = 52). Among APG individuals, these observed impairments of inter-hemispheric connectivity were negatively correlated with Hoffman auditory hallucination scores.ConclusionThese results support the schizophrenia hemitropic disconnection hypothesis, and provide novel evidence suggesting that there may be a relationship between reductions in inter-hemispheric connectivity in auditory and memory-related networks and the pathogenesis of AVH in patients with schizophrenia following the exclusion of confounding factors from other positive symptoms.

Bone morphogenetic protein-9 maybe an important factor which improves insulin resistance in PCOS

Background Polycystic ovary syndrome (PCOS) is closely related to insulin resistance (IR). Bone morphogenetic protein-9 (BMP-9) plays an important role in maintaining glucose homeostasis, but an association between BMP-9 and PCOS has not been reported. Here, we report the changes in BMP-9 and the influence of this protein on IR in PCOS. Methods 57 PCOS patients were selected (among them 25 received interventional treatment with exenatide (EX) for 3 months, and 32 received no treatment). 22 normal control individuals and 30 IR patients were also recruited. We evaluated IR with the euglycaemic-hyperinsulinaemic clamp (EHC) technique. IR and the glucose metabolism rate were assessed by EHC and [3-3H]glucose tracer experiments. We determined the protein expression levels of BMP-9, p-AKT (protein kinase B) and androgen receptor in the ovaries and liver by Western blotting. Results We found that circulating BMP-9 levels were significantly decreased in PCOS with IR patients. Circulating BMP-9 levels and p-AKT levels were decreased in HFD and PCOS rats and increased after MF and EX treatment. The glucose infusion rate, glucose disappearance rate and suppression of hepatic glucose production decreased in the HFD and PCOS groups, the opposite results were found for HGP. AR protein expression levels increased in the HFD and PCOS groups and decreased in the MF and EX groups. Conclusions Our study results suggest that BMP-9 is an independent factor that influences IR in PCOS patients. The decrease in BMP-9 levels in the liver and ovaries may be involved in IR through the PI3K/AKT signaling pathway in PCOS rats.

Analyzing the gene regulatory network in hepatitis B patients by single-cell ATAC sequencing.

This study aims to provide a new perspective of determining the pathophysiology of chronic hepatitis B (CHB) development by analyzing the gene regulatory network in CHB patients using single-cell ATAC sequencing. Hepatitis B virus (HBV)-related liver disease induces liver damage by hepatic immune and inflammatory responses. The exact mechanism is unknown. As such, there is an urgent need to address this problem and study the relationship between aberrant peripheral blood mononuclear cell (PBMC) immune response and progression of liver disease. The sequencing of the chromatin accessibility of 8016 cells from the whole venous blood of normal control (NC) individuals and CHB patients was performed through assay for transposase-accessible chromatin in single-cell sequencing (ScATAC-seq). Unsupervised clustering and annotation analyses were performed by Signac (version 1.7.0) and Seurat clustering to identify different cell types. Then, TF motif enrichment analysis and differentially expressed peak analysis were performed to identify cell-type-specific candidate open chromatins related to CHB. We identified 12 leukocytic clusters corresponding to five cell types. The specific cell types associated with CHB were found to be located in B-0 and T-3. We have drawn the regulatory network of the hepatitis B signal pathway composed of genes linked to the differentially expressed peaks of these two CHB disease-specific cell types. Further, we profoundly explored the potential mechanisms of B-0-associated TF motif IRF2 and T-3-associated TF motif FOXC2 in the occurrence of CHB. We have drawn a systematic and distinguishing gene regulatory network of CHB-related PBMCs. Key Points • Peripheral blood mononuclear cells were robustly clustered based on their types without using antibodies. • We draw a systematic and distinctive gene regulatory network of CHB-related PBMC through ScATAC-seq.

Altered voxel-mirrored homotopic connectivity in right temporal lobe epilepsy as measured using resting-state fMRI and support vector machine analyses.

BackgroundPrior reports revealed abnormalities in voxel-mirrored homotopic connectivity (VMHC) when analyzing neuroimaging data from patients with various psychiatric conditions, including temporal lobe epilepsy (TLE). Whether these VHMC changes can be leveraged to aid in the diagnosis of right TLE (rTLE), however, remains to be established. This study was thus developed to examine abnormal VMHC findings associated with rTLE to determine whether these changes can be used to guide rTLE diagnosis.MethodsThe resultant imaging data of resting-state functional MRI (rs-fMRI) analyses of 59 patients with rTLE and 60 normal control individuals were analyzed using VMHC and support vector machine (SVM) approaches.ResultsRelative to normal controls, patients with rTLE were found to exhibit decreased VMHC values in the bilateral superior and the middle temporal pole (STP and MTP), the bilateral middle and inferior temporal gyri (MTG and ITG), and the bilateral orbital portion of the inferior frontal gyrus (OrbIFG). These patients further exhibited increases in VMHC values in the bilateral precentral gyrus (PreCG), the postcentral gyrus (PoCG), and the supplemental motor area (SMA). The ROC curve of MTG VMHC values showed a great diagnostic efficacy in the diagnosis of rTLE with AUCs, sensitivity, specificity, and optimum cutoff values of 0.819, 0.831, 0.717, and 0.465. These findings highlight the value of the right middle temporal gyrus (rMTG) when differentiating between rTLE and control individuals, with a corresponding SVM analysis yielding respective accuracy, sensitivity, and specificity values of 70.59% (84/119), 78.33% (47/60), and 69.49% (41/59).ConclusionIn summary, patients with rTLE exhibit various forms of abnormal functional connectivity, and SVM analyses support the potential value of abnormal VMHC values as a neuroimaging biomarker that can aid in the diagnosis of this condition.

Extracellular vesicle biomarkers for cognitive impairment in Parkinson's disease.

Besides motor symptoms, many individuals with Parkinson's disease develop cognitive impairment perhaps due to coexisting α-synuclein and Alzheimer's disease pathologies and impaired brain insulin signalling. Discovering biomarkers for cognitive impairment in Parkinson's disease could help clarify the underlying pathogenic processes and improve Parkinson's disease diagnosis and prognosis. This study used plasma samples from 273 participants: 103 Parkinson's disease individuals with normal cognition, 121 Parkinson's disease individuals with cognitive impairment (81 with mild cognitive impairment, 40 with dementia) and 49 age- and sex-matched controls. Plasma extracellular vesicles enriched for neuronal origin were immunocaptured by targeting the L1 cell adhesion molecule, then biomarkers were quantified using immunoassays. α-Synuclein was lower in Parkinson's disease compared to control individuals (P = 0.004) and in cognitively impaired Parkinson's disease individuals compared to Parkinson's disease with normal cognition (P < 0.001) and control (P < 0.001) individuals. Amyloid-β42 did not differ between groups. Phosphorylated tau (T181) was higher in Parkinson's disease than control individuals (P = 0.003) and in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P < 0.001) and controls (P < 0.001). Total tau was not different between groups. Tyrosine-phosphorylated insulin receptor substrate-1 was lower in Parkinson's disease compared to control individuals (P = 0.03) and in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P = 0.02) and controls (P = 0.01), and also decreased with increasing motor symptom severity (P = 0.005); serine312-phosphorylated insulin receptor substrate-1 was not different between groups. Mechanistic target of rapamycin was not different between groups, whereas phosphorylated mechanistic target of rapamycin trended lower in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P = 0.05). The ratio of α-synuclein to phosphorylated tau181 was lower in Parkinson's disease compared to controls (P = 0.001), in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P < 0.001) and decreased with increasing motor symptom severity (P < 0.001). The ratio of insulin receptor substrate-1 phosphorylated serine312 to insulin receptor substrate-1 phosphorylated tyrosine was higher in Parkinson's disease compared to control individuals (P = 0.01), in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P = 0.02) and increased with increasing motor symptom severity (P = 0.003). α-Synuclein, phosphorylated tau181 and insulin receptor substrate-1 phosphorylated tyrosine contributed in diagnostic classification between groups. These findings suggest that both α-synuclein and tau pathologies and impaired insulin signalling underlie Parkinson's disease with cognitive impairment. Plasma neuronal extracellular vesicles biomarkers may inform cognitive prognosis in Parkinson's disease.

Whole exome sequencing identified a homozygous novel mutation in SUOX gene causes extremely rare autosomal recessive isolated sulfite oxidase deficiency

BackgroundIsolated sulfite oxidase deficiency (ISOD) is a rare type of life-threatening neurometabolic disorders characterized by neonatal intractable seizures and severe developmental delay with an autosomal recessive mode of inheritance. Germline mutation in SUOX gene causes ISOD. Till date, only 32 mutations of SUOX gene have been identified and reported to be associated with ISOD. MethodsHere, we investigated a 5-days old Chinese female child, presented with intermittent tremor or seizures of limbs, neonatal encephalopathy, subarachnoid cyst and haemorrhage, dysplasia of corpus callosum, neonatal convulsion, hyperlactatemia, severe metabolic acidosis, hyperglycemia, and hyperkalemia. ResultsWhole exome sequencing identified a novel homozygous transition (c.1227G > A) in exon 6 of the SUOX gene in the proband. This novel homozygous variant leads to the formation of a truncated sulfite oxidase (p.Trp409*) of 408 amino acids. This variant causes partial loss of the dimerization domain of sulfite oxidase. Hence, it is a loss-of-function variant. Proband’s father and mother is carrying this novel variant in a heterozygous state. This variant was not found in 200 ethnically matched normal healthy control individuals. ConclusionsOur study not only expanded the mutational spectrum of SUOX gene associated with ISOD, but also strongly suggested the significance of whole exome sequencing for identifying candidate genes and novel disease-causing variants.

LCN2 is a new diagnostic biomarker and potential therapeutic target in idiopathic short stature.

Idiopathic short stature (ISS) is the most common paediatric endocrine disease. However, the underlying pathology of ISS remains unclear. Currently, there are no effective diagnostic markers or therapeutic strategies available for ISS. In this study, we aimed to identify differential plasma protein expression and novel biomarkers in patients with ISS, and elucidate the biological functions of candidate proteins in ISS pathogenesis. Four specimen pairs from four ISS children and age‐/sex‐matched control individuals were subjected to proteomics analysis, and 340 samples of children with a mean age 9.73 ± 0.24 years were utilized to further verify the differentially expressed proteins by enzyme‐linked immunosorbent assay (ELISA). The receiver‐operating characteristic (ROC) curve and the area under the ROC curve (AUC) were plotted. A total of 2040 proteins were identified, of which 84 were differentially expressed. In vitro and in vivo experiments confirmed the biological functions of these candidate proteins. LCN2 overexpression in ISS was verified using ELISA. Meanwhile, LCN2 showed high sensitivity and specificity in discriminating children with ISS from those with growth hormone deficiency, precocious puberty and normal control individuals. The upregulated expression of LCN2 not only suppressed food intake but also impaired chondrocyte proliferation and bone growth in chondrocytes and rats. As a result, the rats presented a short‐stature phenotype. Subsequently, we found that bone growth inhibition recovered after LCN2 overexpression was stopped in immature rats. To our knowledge, this is the first study to report that LCN2 may be a significant target for ISS diagnosis and treatment.

Estimation of Dysbetalipoproteinemia Incidence in Iraqi Patients with Diabetes Mellitus and Cardiovascular Disease

Background: The main obvious manifestations in dysbetalipiproteinemia (DBL) are Apo-B, non-high-density lipoprotein cholesterol (non-HDLc) and Apo-E gene polymorphism, with a remarkable controversy in the results among different workers. The aim of the study was to find a suitable variable or formula for diagnosis of familial or secondary DBL in a sample of Iraqi patients with type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Material and methods: The study involved 50 patients with T2DM (mean age 46.48 ±9.3 years), 26 patients with CVD (mean age: 43.15±7.34 years) and 73 apparently healthy normal control individuals (mean age: 34.51±11.47 years) with almost equal male/female ratio. Serum lipids (TC, TG, HDL-c, LDL-c, VLDL-c, Remnant like particles RLP, Apo-B, and Apo-E) were estimated in patients and controls. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of non-HDL-c and non-HDL-c /Apo-B in the context of discrimination between patients with- and without DBL. Results: All measured serum lipids, were higher in patients than controls, except HDL-c. Using Sniderman algorithm, 13 patients (18.06%) among T2DM and CVD were considered to have DBL, while none of control group had this disorder. Conclusion Based on Sniderman algorithm, ROC revealed a better specificity and sensitivity for non- HDLc to diagnose DBL, Keywords: dysbetalipoproteinemia, Apo-B, Non- HDL cholesterol, Sniderman algorithm, Cardiovascular disease, Diabetes mellitus.

Using Deep Learning Radiomics to Distinguish Cognitively Normal Adults at Risk of Alzheimer's Disease From Normal Control: An Exploratory Study Based on Structural MRI.

ObjectivesWe proposed a novel deep learning radiomics (DLR) method to distinguish cognitively normal adults at risk of Alzheimer’s disease (AD) from normal control based on T1-weighted structural MRI images.MethodsIn this study, we selected MRI data from the Alzheimer’s Disease Neuroimaging Initiative Database (ADNI), which included 417 cognitively normal adults. These subjects were divided into 181 individuals at risk of Alzheimer’s disease (preAD group) and 236 normal control individuals (NC group) according to standard uptake ratio >1.18 calculated by amyloid Positron Emission Tomography (PET). We further divided the preaAD group into APOE+ and APOE− subgroups according to whether APOE ε4 was positive or not. All data sets were divided into one training/validation group and one independent test group. The proposed DLR method included three steps: (1) the pre-training of basic deep learning (DL) models, (2) the extraction, selection and fusion of DLR features, and (3) classification. The support vector machine (SVM) was used as the classifier. In the comparative experiments, we compared our proposed DLR method with three existing models: hippocampal model, clinical model, and traditional radiomics model. Ten-fold cross-validation was performed with 100 time repetitions.ResultsThe DLR method achieved the best classification performance between preAD and NC than other models with an accuracy of 89.85% ± 1.12%. In comparison, the accuracies of the other three models were 72.44% ± 1.37%, 82.00% ± 4.09% and 79.65% ± 2.21%. In addition, the DLR model also showed the best classification performance (85.45% ± 9.04% and 92.80% ± 2.61%) in the subgroup experiment.ConclusionThe results showed that the DLR method provided a potentially clinical value to distinguish preAD from NC.

Expression of Toll-Like Receptors 2, 4 and 5 in Relation to Gut Microbiota in Colon Neoplasm Patients with and without Inflammatory Bowel Disease.

Background:Toll-Like Receptors (TLRs) are the critical mediators of inflammatory routs in the gut, which play an essential role in regulating the immune responses towards various ligands derived from pathogenic bacteria. Also, TLR signaling has been implicated in the development of Inflammatory Bowel Disease (IBD), Adenomatous Polyp (AP), and Colorectal Cancer (CRC). Here, we aimed to examine the expression of some TLRs concerning certain fecal bacteria in AP and CRC patients with and without IBD.Methods:This case-control study collected fecal and colonic tissue samples from 93 patients versus Normal Controls (NC) via colonoscopy. Fecal samples were used for DNA extraction, and the abundance of selected fecal bacteria was determined by absolute real-time PCR. Also, the gene expression of TLR2, 4, and 5 was analyzed using RT-PCR on the colonic tissues of participants.Results:Compared to NC individuals, in AP and CRC patients, the mRNA expressions of TLR4 and TLR2 were significantly increased while TLR5 was decreased. A meaningful association between TLRs mRNA expression levels and the abundance of some selected fecal bacteria was detected. Also, there was a significant relationship between participant’s food regimes, smoking habit and intestinal TLRs expression.Conclusion:Our study proposed the important role of TLRs during adenomatous and CRC formation. Alterations in TLRs expression associated with certain gut bacteria may contribute to disease development.