The vascular contribution of apolipoprotein E to Alzheimer's disease.

Alzheimer's disease, the most prevalent form of dementia, imposes a substantial societal burden. The persistent inadequacy of disease-modifying drugs targeting amyloid plaques and neurofibrillary tangles suggests the contribution of alternative pathogenic mechanisms. A frequently overlooked aspect is cerebrovascular dysfunction, which may manifest early in the progression of Alzheimer's disease pathology. Mounting evidence underscores the pivotal role of the apolipoprotein E gene, particularly the apolipoprotein ε4 allele as the strongest genetic risk factor for late-onset AD, in the cerebrovascular pathology associated with Alzheimer's disease. In this review, we examine the evidence elucidating the cerebrovascular impact of both central and peripheral apolipoprotein E on the pathogenesis of Alzheimer's disease. We present a novel three-hit hypothesis, outlining potential mechanisms that shed light on the intricate relationship among different pathogenic events. Finally, we discuss prospective therapeutics targeting the cerebrovascular pathology associated with apolipoprotein E and explore their implications for future research endeavors.

Cell-in-cell-mediated intercellular communication exacerbates the pro-inflammatory progression in asthma.

Cell-in-cell (CIC) structures have been suggested to mediate intracellular substance transport between cells and have been found widely in inflammatory lung tissue of asthma. The aim of this study was to investigate the significance of CIC structures in inflammatory progress of asthma. CIC structures and related inflammatory pathways were analyzed in asthmatic lung tissue and normal lung tissue of mouse model. In vitro, the activation of inflammatory pathways by CIC-mediated intercellular communication was analyzed by RNA-Seq and verified by Western blotting and immunofluorescence. Results showed that CIC structures of lymphocytes and alveolar epithelial cells in asthmatic lung tissue mediated intercellular substance (such as mitochondria) transfer and promoted pro-inflammation in two phases. At early phase, internal lymphocytes triggered inflammasome-dependent pro-inflammation and cell death of itself. Then, degraded lymphocytes released cellular contents such as mitochondria inside alveolar epithelial cells, further activated multi-pattern-recognition receptors and NF-kappa B signaling pathways of alveolar epithelial cells, and thereby amplified pro-inflammatory response in asthma. Our work supplements the mechanism of asthma pro-inflammation progression from the perspective of CIC structure of lymphocytes and alveolar epithelial cells, and provides a new idea for anti-inflammatory therapy of asthma.

NODDI Identifies Cognitive Associations with In Vivo Microstructural Changes in Remote Cortical Regions and Thalamocortical Pathways in Thalamic Stroke.

The roles of cerebral structures distal to isolated thalamic infarcts in cognitive deficits remain unclear. We aimed to identify the in vivo microstructural characteristics of remote gray matter (GM) and thalamic pathways and elucidate their roles across cognitive domains. Patients with isolated ischemic thalamic stroke and healthy controls underwent neuropsychological assessment and magnetic resonance imaging. Neurite orientation dispersion and density imaging (NODDI) was modeled to derive the intracellular volume fraction (VFic) and orientation dispersion index. Fiber density (FD) was determined by constrained spherical deconvolution, and tensor-derived fractional anisotropy (FA) was calculated. Voxel-wise GM analysis and thalamic pathway tractography were performed. Twenty-six patients and 26 healthy controls were included. Patients exhibited reduced VFic in remote GM regions, including ipsilesional insular and temporal subregions. The microstructural metrics VFic, FD, and FA within ipsilesional thalamic pathways decreased (false discovery rate [FDR]-p < 0.05). Noteworthy associations emerged as VFic within insular cortices (ρ = -0.791 to -0.630; FDR-p < 0.05) and FD in tracts connecting the thalamus and insula (ρ = 0.830 to 0.971; FDR-p < 0.001) were closely associated with executive function. The VFic in Brodmann area 52 (ρ = -0.839; FDR-p = 0.005) and FA within its thalamic pathway (ρ = -0.799; FDR-p = 0.003) correlated with total auditory memory scores. In conclusion, NODDI revealed neurite loss in remote normal-appearing GM regions and ipsilesional thalamic pathways in thalamic stroke. Reduced cortical dendritic density and axonal density of thalamocortical tracts in specific subregions were associated with improved cognitive functions. Subacute microstructural alterations beyond focal thalamic infarcts might reflect beneficial remodeling indicating post-stroke plasticity.

Identification of Candidate Biomarkers of Alzheimer's Disease via Multiplex Cerebrospinal Fluid and Serum Proteomics.

Alzheimer's disease (AD) is the most prevalent form of dementia among elderly people worldwide. Cerebrospinal fluid (CSF) is the optimal fluid source for AD biomarkers, while serum biomarkers are much more achievable. To search for novel diagnostic AD biomarkers, we performed a quantitative proteomic analysis of CSF and serum samples from AD and normal cognitive controls (NC). CSF and serum proteomes were analyzed via data-independent acquisition quantitative mass spectrometry. Our bioinformatic analysis was based on Gene Ontology (GO) functional annotation analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. In comparison to the controls, 8 proteins were more abundant in AD CSF, and 60 were less abundant in AD CSF, whereas 55 proteins were more and 10 were less abundant in the serum samples. ATPase-associated activity for CSF and mitochondrial functions for CSF and serum were the most enriched GO terms of the DEPs. KEGG enrichment analysis showed that the most significant pathways for the differentially expressed proteins were the N-glycan biosynthesis pathways. The area under the curve (AUC) values for CSF sodium-/potassium-transporting ATPase subunit beta-1 (AT1B1), serglycin (SRGN), and thioredoxin-dependent peroxide reductase, mitochondrial (PRDX3) were 0.867 (p = 0.004), 0.833 (p = 0.008), and 0.783 (p = 0.025), respectively. A panel of the above three CSF proteins accurately differentiated AD (AUC = 0.933, p = 0.001) from NC. The AUC values for serum probable phospholipid-transporting ATPase IM (AT8B4) and SRGN were moderate. The AUC of the CSF SRGN + serum SRGN was 0.842 (p = 0.007). These novel AD biomarker candidates are mainly associated with inflammation, ATPase activity, oxidative stress, and mitochondrial dysfunction. Further studies are needed to investigate the molecular mechanisms by which these potential biomarkers are involved in AD.

Identification of heat shock protein family A member 5 (HSPA5) targets involved in nonalcoholic fatty liver disease.

Heat shock protein family A (Hsp70) member 5 (HSPA5) is an endoplasmic reticulum chaperone, which regulates cell metabolism, particularly lipid metabolism. While HSPA5's role in regulating cell function is well described, HSPA5 binding to RNA and its biological function in nonalcoholic fatty liver disease (NAFLD) is still lacking. In the present study, the ability of HSPA5 to modulate alternative splicing (AS) of cellular genes was assessed using Real-Time PCR on 89 NAFLD-associated genes. RNA immunoprecipitation coupled to RNA sequencing (RIP-Seq) assays were also performed to identify cellular mRNAs bound by HSPA5. We obtained the HSPA5-bound RNA profile in HeLa cells and peak calling analysis revealed that HSPA5 binds to coding genes and lncRNAs. Moreover, RIP-Seq assays demonstrated that HSPA5 immunoprecipitates specific cellular mRNAs such as EGFR, NEAT1, LRP1 and TGFß1, which are important in the pathology of NAFLD. Finally, HSPA5 binding sites may be associated with splicing sites. We used the HOMER algorithm to search for motifs enriched in coding sequence (CDs) peaks, which identified over-representation of the AGAG motif in both sets of immunoprecipitated peaks. HSPA5 regulated genes at the 5'UTR alternative splicing and introns and in an AG-rich sequence-dependent manner. We propose that the HSPA5-AGAG interaction might play an important role in regulating alternative splicing of NAFLD-related genes. This report is the first to demonstrate that HSPA5 regulated pre-RNA alternative splicing, stability, or translation and affected target protein(s) via binding to lncRNA and mRNA linked to NAFLD.

Case report: A longitudinal study of an unusual rapidly progressive dementia case.

It is daunting to determine the etiology of rapidly progressive dementia (RPD), which includes metabolic, neoplastic, infectious, autoimmune, neurodegenerative and other conditions. Herein, we illustrate an unusual case of a patient primarily exhibiting RPD, overlapping sleep dysfunction, psychosis and abnormal movement, which was finally defined as anti-IgLON5 disease, a novel and rare autoimmune encephalopathy. Furthermore, we longitudinally described his cognitive and psychological performance in detail, and determined that early initiation of immunotherapy in this patient did not result in a good outcome. These data highlight anti-IgLON5 disease as a possible differential diagnosis in patients with RPD.

Key genes associated with non-alcoholic fatty liver disease and hepatocellular carcinoma with metabolic risk factors.

Background: Hepatocellular carcinoma (HCC) has become the world's primary cause of cancer death. Obesity, hyperglycemia, and dyslipidemia are all illnesses that are part of the metabolic syndrome. In recent years, this risk factor has become increasingly recognized as a contributing factor to HCC. Around the world, non-alcoholic fatty liver disease (NAFLD) is on the rise, especially in western countries. In the past, the exact pathogenesis of NAFLD that progressed to metabolic risk factors (MFRs)-associated HCC has not been fully understood. Methods: Two groups of the GEO dataset (including normal/NAFLD and HCC with MFRs) were used to analyze differential expression. Differentially expressed genes of HCC were verified by overlapping in TCGA. In addition, functional enrichment analysis, modular analysis, Receiver Operating Characteristic (ROC) analysis, LASSO analysis, and Genes with key survival characteristics were analyzed. Results: We identified six hub genes (FABP5, SCD, CCL20, AGPAT9(GPAT3), PLIN1, and IL1RN) that may be closely related to NAFLD and HCC with MFRs. We constructed survival and prognosis gene markers based on FABP5, CCL20, AGPAT9(GPAT3), PLIN1, and IL1RN.This gene signature has shown good diagnostic accuracy in both NAFLD and HCC and in predicting HCC overall survival rates. Conclusion: As a result of the findings of this study, there is some guiding significance for the diagnosis and treatment of liver disease associated with NAFLD progression.

Statistical learning in patients in the minimally conscious state.

When listening to speech, cortical activity can track mentally constructed linguistic units such as words, phrases, and sentences. Recent studies have also shown that the neural responses to mentally constructed linguistic units can predict the outcome of patients with disorders of consciousness (DoC). In healthy individuals, cortical tracking of linguistic units can be driven by both long-term linguistic knowledge and online learning of the transitional probability between syllables. Here, we investigated whether statistical learning could occur in patients in the minimally conscious state (MCS) and patients emerged from the MCS (EMCS) using electroencephalography (EEG). In Experiment 1, we presented to participants an isochronous sequence of syllables, which were composed of either 4 real disyllabic words or 4 reversed disyllabic words. An inter-trial phase coherence analysis revealed that the patient groups showed similar word tracking responses to real and reversed words. In Experiment 2, we presented trisyllabic artificial words that were defined by the transitional probability between words, and a significant word-rate EEG response was observed for MCS patients. These results suggested that statistical learning can occur with a minimal conscious level. The residual statistical learning ability in MCS patients could potentially be harnessed to induce neural plasticity.

Serum Uric Acid Levels Are Associated With Macula Microvasculature Changes In Hypertensive White Matter Hyperintensity Patients.

PURPOSE: To characterize the macula microvasculature using fractal dimension (FD) in hypertensive white matter hyperintensity (WMH) participants and explore the association between the microvascular changes and serum uric acid levels. METHODS: Thirty-eight WMH participants were dementia and stroke-free, and 37 healthy controls were enrolled. Optical coherence tomographic angiography (OCTA) was used to image the superficial vascular complex (SVC), deep vascular complex (DVC), and inner vascular complex (IVC) in a 2.5-mm diameter concentric circle (excluding the foveal avascular zone FAZ). A commercial algorithm was used to quantify the complexity and density of the three capillary layers by fractal analysis. RESULTS: WMH participants showed significantly lower FD value in the SVC (P = 0.002), DVC (P < 0.001) and IVC (P = 0.012) macula microvasculature compared with control group. After adjusting for risk factors (hypertension, diabetes, age and gender) SVC (P = 0.035) and IVC (P = 0.030) significantly correlated with serum uric acid. CONCLUSION: Serum uric acid levels are associated with microvascular changes in WMH. Fractal dimension based on OCTA imaging could help quantitatively characterize the macula microvasculature changes in WMH and may be a potential screening tool to detect serum uric acid level changes.

Sleep patterns correlates with the efficacy of tDCS on post-stroke patients with prolonged disorders of consciousness.

BACKGROUND: The subclassification of prolonged disorders of consciousness (DoC) based on sleep patterns is important for the evaluation and treatment of the disease. This study evaluates the correlation between polysomnographic patterns and the efficacy of transcranial direct current stimulation (tDCS) in patients with prolonged DoC due to stroke. METHODS: In total, 33 patients in the vegetative state (VS) with sleep cycles or without sleep cycles were randomly assigned to either active or sham tDCS groups. Polysomnography was used to monitor sleep changes before and after intervention. Additionally, clinical scale scores and electroencephalogram (EEG) analysis were performed before and after intervention to evaluate the efficacy of tDCS on the patients subclassified according to their sleep patterns. RESULTS: The results suggest that tDCS improved the sleep structure, significantly prolonged total sleep time (TST) (95%CI: 14.387-283.527, P = 0.013) and NREM sleep stage 2 (95%CI: 3.157-246.165, P = 0.040) of the VS patients with sleep cycles. It also significantly enhanced brain function of patients with sleep cycles, which were reflected by the increased clinical scores (95%CI: 0.340-3.440, P < 0.001), the EEG powers and functional connectivity in the brain and the 6-month prognosis. Moreover, the changes in NREM sleep stage 2 had a significant positive correlation with each index of the ß band. CONCLUSION: This study reveals the importance of sleep patterns in the prognosis and treatment of prolonged DoC and provides new evidence for the efficacy of tDCS in post-stroke patients with VS patients subclassified by sleep pattern. Trial registration URL: https://www. CLINICALTRIALS: gov . Unique identifier: NCT03809936. Registered 18 January 2019.

Clinical comparison and functional study of the L703P: a recurrent mutation in human SCN4A that causes sodium channel myotonia.

The non-dystrophic myotonias are inherited skeletal muscle disorders characterized by skeletal muscle stiffness after voluntary contraction, without muscle atrophy. Based on their clinical features, non-dystrophic myotonias are classified into myotonia congenita, paramyotonia congenita, and sodium channel myotonia. Using whole-exome next-generation sequencing, we identified a L703P mutation (c.2108T>C, p.L703P) in SCN4A in a Chinese family diagnosed with non-dystrophic myotonias. The clinical findings of patients in this family included muscle stiffness and hypertrophy. The biophysical properties of wildtype and mutant channels were investigated using whole-cell patch clamp. L703P causes both gain-of-function and loss-of-function changes in Nav1.4 properties, including decreased current density, impaired recovery, enhanced activation and slow inactivation. Our study demonstrates that L703P is a pathogenic variant for myotonia, and provides additional electrophysiological information for understanding the pathogenic mechanism of SCN4A-associated channelopathies.

Human umbilical cord-derived mesenchymal stem cells ameliorate experimental colitis by normalizing the gut microbiota.

BACKGROUND: Crohn's disease (CD) is a chronic non-specific inflammatory bowel disease. Current CD therapeutics cannot fundamentally change the natural course of CD. Therefore, it is of great significance to find new treatment strategies for CD. Preclinical and clinical studies have shown that mesenchymal stromal cells (MSCs) are a promising therapeutic approach. However, the mechanism by which MSCs alleviate CD and how MSCs affect gut microbes are still unclear and need further elucidation. METHODS: We used 2,4,6-trinitrobenzenesulfonic acid (TNBS) to induce experimental colitis in mice and analysed the microbiota in faecal samples from the control group, the TNBS group and the TNBS + MSC group with faecal 16S rDNA sequencing. Subsequent analyses of alpha and beta diversity were all performed based on the rarified data. PICRUStII analysis was performed on the 16S rRNA gene sequences to infer the gut microbiome functions. RESULTS: MSC Treatment improved TNBS-induced colitis by increasing survival rates and relieving symptoms. A distinct bacterial signature was found in the TNBS group that differed from the TNBS + MSC group and controls. MSCs prevented gut microbiota dysbiosis, including increasing α-diversity and the amount of Bacteroidetes Firmicutes and Tenericutes at the phylum level and decreasing the amount of Proteobacteria at the phylum level. MSCs alleviated the increased activities of sulphur and riboflavin metabolism. Meanwhile some metabolic pathways such as biosynthesis of amino acids lysine biosynthesis sphingolipid metabolism and secondary bile acid biosynthesis were decreased in the TNBS group compared with the control group and the TNBS + MSC group CONCLUSIONS: Overall, our findings preliminarily confirmed that colitis in mice is closely related to microbial and metabolic dysbiosis. MSC treatment could modulate the dysregulated metabolism pathways in mice with colitis, restoring the abnormal microbiota function to that of the normal control group. This study provides insight into specific intestinal microbiota and metabolism pathways linked with MSC treatment, suggesting a new approach to the treatment of CD.

Altered Intestinal Microbiomes and Lipid Metabolism in Patients With Prolonged Disorders of Consciousness.

The intestinal microbiota regulate the brain function of the host through the production of a myriad of metabolites and are associated with various neurological diseases. Understanding the intestinal microbiome of patients with prolonged disorders of consciousness (DoC) is important for the evaluation and treatment of the disease. To investigate the differences in the intestinal microbiome and short-chain fatty acids (SCFAs) among patients in a vegetative state (VS), a minimally conscious state (MCS), and emerged from MCS (EMCS), as well as the influence of antibiotics on these patients, 16S ribosomal RNA (16S rRNA) sequencing and targeted lipidomics were performed on fecal samples from patients; in addition, analysis of the electroencephalogram (EEG) signals was performed to evaluate the brain function of these patients. The results showed that the intestinal microbiome of the three groups differed greatly, and some microbial communities showed a reduced production of SCFAs in VS patients compared to the other two groups. Moreover, reduced microbial communities and five major SCFAs, along with attenuated brain functional connectivity, were observed in MCS patients who were treated with antibiotics compared to those who did not receive antibiotic treatment, but not in the other pairwise comparisons. Finally, three genus-level microbiota-Faecailbacterium, Enterococcus, and Methanobrevibacter-were considered as potential biomarkers to distinguish MCS from VS patients, with high accuracy both in the discovery and validation cohorts. Together, our findings improved the understanding of patients with prolonged DoC from the intestinal microbiome perspective and provided a new reference for the exploration of therapeutic targets.

Classification and Interpretability of Mild Cognitive Impairment Based on Resting-State Functional Magnetic Resonance and Ensemble Learning.

The combination and integration of multimodal imaging and clinical markers have introduced numerous classifiers to improve diagnostic accuracy in detecting and predicting AD; however, many studies cannot ensure the homogeneity of data sets and consistency of results. In our study, the XGBoost algorithm was used to classify mild cognitive impairment (MCI) and normal control (NC) populations through five rs-fMRI analysis datasets. Shapley Additive exPlanations (SHAP) is used to analyze the interpretability of the model. The highest accuracy for diagnosing MCI was 65.14% (using the mPerAF dataset). The characteristics of the left insula, right middle frontal gyrus, and right cuneus correlated positively with the output value using DC datasets. The characteristics of left cerebellum 6, right inferior frontal gyrus, opercular part, and vermis 6 correlated positively with the output value using fALFF datasets. The characteristics of the right middle temporal gyrus, left middle temporal gyrus, left temporal pole, and middle temporal gyrus correlated positively with the output value using mPerAF datasets. The characteristics of the right middle temporal gyrus, left middle temporal gyrus, and left hippocampus correlated positively with the output value using PerAF datasets. The characteristics of left cerebellum 9, vermis 9, and right precentral gyrus, right amygdala, and left middle occipital gyrus correlated positively with the output value using Wavelet-ALFF datasets. We found that the XGBoost algorithm constructed from rs-fMRI data is effective for the diagnosis and classification of MCI. The accuracy rates obtained by different rs-fMRI data analysis methods are similar, but the important features are different and involve multiple brain regions, which suggests that MCI may have a negative impact on brain function.

Altered Coupling Between Cerebral Blood Flow and Voxel-Mirrored Homotopic Connectivity Affects Stroke-Induced Speech Comprehension Deficits.

The neurophysiological basis of the association between interhemispheric connectivity and speech comprehension processing remains unclear. This prospective study examined regional cerebral blood flow (CBF), homotopic functional connectivity, and neurovascular coupling, and their effects on comprehension performance in post-stroke aphasia. Multimodal imaging data (including data from functional magnetic resonance imaging and arterial spin labeling imaging) of 19 patients with post-stroke aphasia and 22 healthy volunteers were collected. CBF, voxel-mirrored homotopic connectivity (VMHC), CBF-VMHC correlation, and CBF/VMHC ratio maps were calculated. Between-group comparisons were performed to identify neurovascular changes, and correlation analyses were conducted to examine their relationship with the comprehension domain. The correlation between CBF and VMHC of the global gray matter decreased in patients with post-stroke aphasia. The total speech comprehension score was significantly associated with VMHC in the peri-Wernicke area [posterior superior temporal sulcus (pSTS): r = 0.748, p = 0.001; rostroventral area 39: r = 0.641, p = 0.008]. The decreased CBF/VMHC ratio was also mainly associated with the peri-Wernicke temporoparietal areas. Additionally, a negative relationship between the mean CBF/VMHC ratio of the cingulate gyrus subregion and sentence-level comprehension was observed (r = -0.658, p = 0.006). These findings indicate the contribution of peri-Wernicke homotopic functional connectivity to speech comprehension and reveal that abnormal neurovascular coupling of the cingulate gyrus subregion may underly comprehension deficits in patients with post-stroke aphasia.

Irregular degree centrality in neuromyelitis optica spectrum disorder patients with optic neuritis: A resting-state functional magnetic resonance imaging study.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disorder that causes significant changes in brain connectivity and visual impairment. Degree centrality (DC), a graph-based assessment of network organization was performed to explore the connectivity changes in NMOSD patients and their correlation with clinical consequences. METHODS: Twenty-two NMOSD patients and 22 healthy controls (HC) were included. Participants underwent visual acuity examination and resting-state functional magnetic resonance imaging (fMRI) of the brain. We first performed DC analysis to identify voxels that showed changes in whole-brain functional connectivity (FC) with other voxels. DC was calculated by the fMRI graph method and comparison between the two groups was done by two-sample t-test. GraphPad Prism was used to assess the association between DC changes and clinical consequences. RESULTS: Out of the 22 NMOSD patients, 7 (31.82%) had ON once while 15 (68.18%) had ON twice or more. Decreased DC value (P < 0.001) in the left frontal superior orbital gyrus (ORBsup), left angular gyrus (ANG) and right parietal superior gyrus (SPG) was found in NMOSD patients when compared with healthy controls respectively. Reduced visual acuity significantly correlated (R2 = 0.212, P = 0.040) with DC values in SPG while the frequency of ON significantly correlated (R2 = 0.04, P = 0.040) with DC values in the ANG in NMOSD patients. CONCLUSIONS: NMOSD patients experience neural network dysfunction which may be associated with their clinical implications.

Cerebral perfusion mediated by thalamo-cortical functional connectivity in non-dominant thalamus affects naming ability in aphasia.

Naming is a commonly impaired language domain in various types of aphasia. Emerging evidence supports the cortico-subcortical circuitry subserving naming processing, although neurovascular regulation of the non-dominant thalamic and basal ganglia subregions underlying post-stroke naming difficulty remains unclear. Data from 25 subacute stroke patients and 26 age-, sex-, and education-matched healthy volunteers were analyzed. Region-of-interest-wise functional connectivity (FC) was calculated to measure the strength of cortico-subcortical connections. Cerebral blood flow (CBF) was determined to reflect perfusion levels. Correlation and mediation analyses were performed to identify the relationship between cortico-subcortical connectivity, regional cerebral perfusion, and naming performance. We observed increased right-hemispheric subcortical connectivity in patients. FC between the right posterior superior temporal sulcus (pSTS) and lateral/medial prefrontal thalamus (lPFtha/mPFtha) exhibited significantly negative correlations with total naming score. Trend-level increased CBF in subcortical nuclei, including that in the right lPFtha, and significant negative correlations between naming and regional perfusion of the right lPFtha were observed. The relationship between CBF in the right lPFtha and naming was fully mediated by the lPFtha-pSTS connectivity in the non-dominant hemisphere. Our findings suggest that perfusion changes in the right thalamic subregions affect naming performance through thalamo-cortical circuits in post-stroke aphasia. This study highlights the neurovascular pathophysiology of the non-dominant hemisphere and demonstrates thalamic involvement in naming after stroke.

Metabolic Disorders Combined with Noninvasive Tests to Screen Advanced Fibrosis in Nonalcoholic Fatty Liver Disease.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic disorders. This study aimed to explore the role of metabolic disorders in screening advanced fibrosis in NAFLD patients. METHODS: A total of 246 histologically-proven NAFLD patients were enrolled across 14 centers. We compared the severity of fibrosis in patients with different components of metabolic disorders. Based on standard noninvasive tests and metabolic disorders, we developed new algorithms to identify advanced fibrosis. RESULTS: Metabolic syndrome (MetS) was frequent in NAFLD patients (133/246, 54%). Patients with MetS had a higher proportion of significant fibrosis (p=0.014) and higher LSM values (9.2 kPa, vs. 7.4 kPa, p=0.002) than those without MetS. Patients with more metabolic disorders had higher fibrosis stages (p=0.017). Reduced high-density lipoprotein cholesterol (odds ratio [OR]: 2.241, 95% confidence interval [CI]: 1.004-5.002, p=0.049) and raised fasting glucose (OR: 4.500, 95% CI: 2.083-9.725, p<0.001) were significantly associated with advanced fibrosis. Using these two metabolic disorders as a screening tool, a sensitivity, specificity and accuracy of 92%, 81% and 83% was achieved, respectively. With the new algorithms combining metabolic disorders with noninvasive measurements, the number of patients requiring liver biopsy was reduced, especially in combination with the Fibrosis-4 score and metabolic disorders (36% to 17%, p<0.001). In addition, this stepwise algorithm could achieve a high accuracy (85%) and high negative predictive value (93%). CONCLUSIONS: Metabolic disorders should be taken into consideration in the diagnosis of advanced fibrosis. With further validation and investigation, new algorithms could be recommended in primary care units to spare patients from unnecessary referral and liver biopsies.

Superficial Macula Capillary Complexity Changes Are Associated With Disability in Neuromyelitis Optica Spectrum Disorders.

Purpose: We examined the macular microvascular changes of the macula in neuromyelitis optica spectrum disorder (NMOSD) patients and its association with their disability and other clinical variables. Methods: Thirty-four NMOSD (13 patients without optic neuritis, NMOSD-NON, and 21 patients with a history of optic neuritis, NMOSD-ON) and 44 healthy controls (HCs) were included in the study. Optical coherence tomographic angiography (OCTA) was used to image the superficial (SCP), deep (DCP), and whole capillary plexus (WCP) in a 2.5-mm-diameter concentric circle [excluding the foveal avascular zone (FAZ)]. An algorithm (Dbox) was used to quantify the complexity of the three capillary layers by fractal analysis. We also evaluated the expanded disability scale status (EDSS). Results: Dbox values were significantly reduced in SCP (p < 0.001), DCP (p < 0.001), and WCP (p = 0.003) of NMOSD when compared with HCs. Dbox values were significantly reduced in NMOSD eyes with optic neuritis when compared with healthy controls (p < 0.001) and eyes without optic neuritis (p = 0.004) in the SCP. In the DCP, eyes with optic neuritis showed significantly reduced Dbox values when compared with eyes without optic neuritis (p = 0.016) and healthy controls (p < 0.001); eyes without optic neuritis showed significantly reduced Dbox values (p = 0.007) in the DCP when compared with healthy controls. A significant negative correlation (Rho = -0.475, p = 0.005) was shown between the superficial macula Dbox values and the EDSS in NMOSD patients. Additionally, a negative correlation (Rho = -0.715, p = 0.006) was seen in the superficial Dbox values in [e]eyes without optic neuritis and EDSS. Conclusions: Macular microvascular damage in the superficial plexus is associated with disability in NMOSD. Macular microvascular alterations arise independently of the occurrence of ON in NMOSD.