Selective vulnerability of hippocampal sub-regions in patients with subcortical vascular mild cognitive impairment.

Early diagnosis of subcortical vascular mild cognitive impairment (svMCI) is clinically essential because it is the most reversible subtype of all cognitive impairments. Since structural alterations of hippocampal sub-regions have been well studied in neurodegenerative diseases with pathophysiological cognitive impairments, we were eager to determine whether there is a selective vulnerability of hippocampal sub-fields in patients with svMCI. Our study included 34 svMCI patients and 34 normal controls (NCs), with analysis of T1 images and Montreal Cognitive Assessment (MoCA) scores. Gray matter volume (GMV) of hippocampal sub-regions was quantified and compared between the groups, adjusting for age, sex, and education. Additionally, we explored correlations between altered GMV in hippocampal sub-fields and MoCA scores in svMCI patients. Patients with svMCI exhibited selectively reduced GMV in several left hippocampal sub-regions, such as the hippocampal tail, hippocampal fissure, CA1 head, ML-HP head, CA4 head, and CA3 head, as well as decreased GMV in the right hippocampal tail. Specifically, GMV in the left CA3 head was inversely correlated with MoCA scores in svMCI patients. Our findings indicate that the atrophy pattern of patients with svMCI was predominantly located in the left hippocampal sub-regions. The left CA3 might be a crucial area underlying the distinct pathophysiological mechanisms of cognitive impairments with subcortical vascular origins.

Growth-suppressor microRNAs mediate synaptic overgrowth and behavioral deficits in Fragile X mental retardation protein deficiency.

Abnormal neuronal and synapse growth is a core pathology resulting from deficiency of the Fragile X mental retardation protein (FMRP), but molecular links underlying the excessive synthesis of key synaptic proteins remain incompletely defined. We find that basal brain levels of the growth suppressor let-7 microRNA (miRNA) family are selectively lowered in FMRP-deficient mice and activity-dependent let-7 downregulation is abrogated. Primary let-7 miRNA transcripts are not altered in FMRP-deficiency and posttranscriptional misregulation occurs downstream of MAPK pathway induction and elevation of Lin28a, a let-7 biogenesis inhibitor. Neonatal restoration of brain let-7 miRNAs corrects hallmarks of FMRP-deficiency, including dendritic spine overgrowth and social and cognitive behavioral deficits, in adult mice. Blockade of MAPK hyperactivation normalizes let-7 miRNA levels in both brain and peripheral blood plasma from Fmr1 KO mice. These results implicate dysregulated let-7 miRNA biogenesis in the pathogenesis of FMRP-deficiency, and highlight let-7 miRNA-based strategies for future biomarker and therapeutic development.

Computational Analysis Tutorial for Chimeric Small Noncoding RNA: Target RNA Sequencing Libraries.

An understanding of the in vivo gene regulatory interactions of small noncoding RNAs (sncRNAs), such as microRNAs (miRNAs), with their target RNAs has been advanced in recent years by biochemical approaches which use cross-linking followed by ligation to capture sncRNA:target RNA interactions through the formation of chimeric RNAs and subsequent sequencing libraries. While datasets from chimeric RNA sequencing provide genome-wide and substantially less ambiguous input than miRNA prediction software, distilling this data into meaningful and actionable information requires additional analyses and may dissuade investigators lacking a computational background. This report provides a tutorial to support entry-level computational biologists in installing and applying a recent open-source software tool: Small Chimeric RNA Analysis Pipeline (SCRAP). Platform requirements, updates, and an explanation of pipeline steps and manipulation of key user-input variables is provided. Reducing a barrier for biologists to gain insights from chimeric RNA sequencing approaches has the potential to springboard discovery-based investigations of regulatory sncRNA:target RNA interactions in multiple biological contexts.

Consistent functional abnormalities in patients with postpartum depression.

Postpartum depression (PPD) is a common public health concern. A wide range of functional abnormalities in various brain regions have been reported in fMRI studies on PPD, however, a consistent functional changing pattern is still lacking. Herein, we obtained functional Magnetic Resonance Imaging (fMRI) data from 52 patients with PPD and 24 healthy postpartum women (HPW). Functional indexes (low-frequency fluctuation, degree centrality, and regional homogeneity) were calculated and compared among these groups to explore the functional changing patterns of PPD. Then, correlation analyses were performed to investigate the relationship between changed functional indexes and clinical measurements in the PPD. Finally, support vector machine (SVM) was performed to test whether these abnormal features can be used to distinguish PPD from HPW. As a result, we identified significantly and consistently functional changing pattern characterizing by increased functional activity in the left inferior occipital gyrus and decreased functional activity right anterior cingulate cortex in the PPD as compared to HPW. These functional values in the right anterior cingulate cortex were significantly correlated with depression symptoms in the PPD, and can be used as features to distinguish PPD from HPW. In conclusion, our results suggested that the right anterior cingulate cortex could be served as a functional neuro-imaging biomarker for PPD, which might be used as a potential target for neuro-modulation.

Regulation by noncoding RNAs of local translation, injury responses, and pain in the peripheral nervous system.

Neuropathic pain is a chronic condition arising from damage to somatosensory pathways that results in pathological hypersensitivity. Persistent pain can be viewed as a consequence of maladaptive plasticity which, like most enduring forms of cellular plasticity, requires altered expression of specific gene programs. Control of gene expression at the level of protein synthesis is broadly utilized to directly modulate changes in activity and responsiveness in nociceptive pathways and provides an effective mechanism for compartmentalized regulation of the proteome in peripheral nerves through local translation. Levels of noncoding RNAs (ncRNAs) are commonly impacted by peripheral nerve injury leading to persistent pain. NcRNAs exert spatiotemporal regulation of local proteomes and affect signaling cascades supporting altered sensory responses that contribute to hyperalgesia. This review discusses ncRNAs found in the peripheral nervous system (PNS) that are dysregulated following nerve injury and the current understanding of their roles in pathophysiological pain-related responses including neuroimmune interactions, neuronal survival and axon regeneration, Schwann cell dedifferentiation and proliferation, intercellular communication, and the generation of ectopic action potentials in primary afferents. We review progress in the field beyond cataloging, with a focus on the relevant target transcripts and mechanisms underlying pain modulation by ncRNAs.

Acupuncture Treatment Modulate Regional Homogeneity of Dorsal Lateral Prefrontal Cortex in Patients with Amnesic Mild Cognitive Impairment.

BACKGROUND: Although acupuncture is widely used to improve cognitive and memory in the amnesic mild cognitive impairment (aMCI) patients with impressive effectiveness, its neural mechanism remains largely unclear. OBJECTIVE: We aimed to explore functional magnetic resonance imaging (fMRI) mechanism of acupuncture for aMCI. METHODS: A randomized, controlled, single-blind research was performed. A total of 46 aMCI patients were randomly assigned into verum and sham acupuncture group, who received a total of 24 times treatments (3 times/week, 8 weeks). Clinical evaluation and fMRI scanning were performed at baseline and after treatment for all aMCI patients. The interaction effects and inter-group effects of regional homogeneity (ReHo) were performed using mixed effect models, and the correlations between clinical improvement and neuroimaging changes before and after verum acupuncture treatment were analyzed using Pearson correlations. RESULTS: As a result, interaction effects showed increased ReHo value in left dorsal lateral prefrontal cortex (DLPFC), increased functional connectivity between left DLPFC and left precuneus, and decreased functional connectivity between left DLPFC and left inferior temporal gyrus after verum acupuncture but inversely after sham acupuncture in the aMCI. Condition effects showed increased ReHo in right lingual gyrus, and bilateral post-central gyrus after verum and sham acupuncture in the aMCI. In addition, the changed Montreal Cognitive Assessment scores in verum acupuncture group were significantly correlated with changed ReHo values in left DLPFC. CONCLUSION: Together, our findings further confirmed that acupuncture could be used as a promising complementary therapy for aMCI by modulating function of left DLPFC to improve cognitive symptoms.

Fast Independent Component Analysis Algorithm-Based Diagnosis of L5 Nerve Root Compression and Changes of Brain Functional Areas Using 3D Functional Magnetic Resonance Imaging.

In this paper, the application of 3-dimensional (3D) functional magnetic resonance imaging (FMRI) in the diagnosis of the 5th lumbar (L5) nerve root compression and brain functional areas in patients with lumbar disc herniation (LDH) was analyzed. The traditional fast independent component analysis (Fast ICA) algorithm was optimized based on the modified whitening matrix to establish a new type of Modified-Fast ICA (M-Fast ICA) algorithm that was compared with the introduced traditional Fast ICA and ICA. M-Fast ICA was applied to the 3D FMRI diffusion tensor imaging (DTI) evaluation of 65 patients with L5 nerve root pain due to LDH (group A) and 50 healthy volunteers (group B). The values of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in the lumbar nerve roots (L3, L4, L5, and the 1st sacral vertebra (S1)) were recorded among subjects from the two groups. Besides, the score of edema degree in the lumbar nerve roots (L5 and S1) and activity of brain functional areas were also recorded among all subjects of the two groups. The results showed that the mean square error of M-Fast ICA was smaller than that of traditional Fast ICA and ICA, while its signal-to-noise ratio (SNR) was greater than that of Fast ICA and ICA (P < 0.05). The FA of L5 and S1 nerve roots in patients of group A was sharply lower than the values of group B, while the ADC of patients in group A was greater than that of the control group (P < 0.05). Besides, the score of edema in L5 and S1 nerve roots of patients in group A increased in contrast to group B (P < 0.05). The brain areas were activated after surgery including bilateral temporal lobe, left thalamus, splenium of corpus callosum, and right internal capsule. In conclusion, the 3D image denoising performance of M-Fast ICA optimized and constructed in this study was superior to that of the traditional Fast ICA and ICA. The FA of patients with L5 nerve root pain due to LDH decreased steeply, while the ADC increased dramatically. L5 nerve root pain caused by LDH resulted in changes in brain functional areas of the patients to inhibit the resting state default network activity, and the corresponding brain functional areas could be activated through treatment.

Combined single-molecule fluorescence in situ hybridization and immunohistochemistry analysis in intact murine dorsal root ganglia and sciatic nerve.

Single-molecule fluorescence in situ hybridization (smFISH) allows spatial mapping of gene expression. This protocol presents advances in smFISH fidelity and flexibility in intact murine sensory nervous system tissue. An approach using RNAscope probes allows multiplexing, enhanced target specificity, and immunohistochemistry compatibility. Computational strategies increase quantification accuracy of mRNA puncta with a point spread function for clustered transcripts in the dorsal root ganglion and 3D masking for intermingled sciatic nerve cell types. Approaches are validated for mRNAs of modest (Lin28a) and medium (Ppib) steady-state abundance in neurons.

Countermeasures against economic crisis from COVID-19 pandemic in China: An analysis of effectiveness and trade-offs.

The effectiveness of different countermeasures to economic crisis from the public health emergency is still inadequately understood. We establish an illustrative scenario, specifying the shocks of COVID-19 pandemic and countermeasures applying a general equilibrium model to analyze the effectiveness of countermeasures with a particular focus on trade-offs in the impacts of monetary and fiscal policies. We find that both monetary and fiscal countermeasures could effectively mitigate the economic damages to GDP and employment. However, they would also produce adverse side-effects such as an increase in consumer price by 1.05% and 0.57%, respectively, and a decline in exports by 2.61% and 1.05%, respectively. Monetary policies would exacerbate the damages to external demand by supply-side shocks of the pandemic, but they are more suitable for mitigating demand-side shocks. While fiscal policies would benefit nearly all producing sectors, monetary policies would mainly affect export-oriented manufacturing sectors negatively.

Multi-Level Regulatory Interactions between NF-κB and the Pluripotency Factor Lin28.

An appreciation for the complex interactions between the NF-κB transcription factor and the Lin28 RNA binding protein/let-7 microRNA pathways has grown substantially over the past decade. Both the NF-κB and Lin28/let-7 pathways are master regulators impacting cell survival, growth and proliferation, and an understanding of how interfaces between these pathways participate in governing pluripotency, progenitor differentiation, and neuroplastic responses remains an emerging area of research. In this review, we provide a concise summary of the respective pathways and focus on the function of signaling interactions at both the transcriptional and post-transcriptional levels. Regulatory loops capable of providing both reinforcing and extinguishing feedback have been described. We highlight convergent findings in disparate biological systems and indicate future directions for investigation.

The m6A reader YTHDF1 regulates axon guidance through translational control of Robo3.1 expression.

N 6-Methyladenosine (m6A) is a dynamic mRNA modification which regulates protein expression in various posttranscriptional levels. Functional studies of m6A in nervous system have focused on its writers and erasers so far, whether and how m6A readers mediate m6A functions through recognizing and binding their target mRNA remains poorly understood. Here, we find that the expression of axon guidance receptor Robo3.1 which plays important roles in midline crossing of spinal commissural axons is regulated precisely at translational level. The m6A reader YTHDF1 binds to and positively regulates translation of m6A-modified Robo3.1 mRNA. Either mutation of m6A sites in Robo3.1 mRNA or YTHDF1 knockdown or knockout leads to dramatic reduction of Robo3.1 protein without affecting Robo3.1 mRNA level. Specific ablation of Ythdf1 in spinal commissural neurons results in pre-crossing axon guidance defects. Our findings identify a mechanism that YTHDF1-mediated translation of m6A-modified Robo3.1 mRNA controls pre-crossing axon guidance in spinal cord.

Comparative analysis of the diffusion kurtosis imaging and diffusion tensor imaging in grading gliomas, predicting tumour cell proliferation and IDH-1 gene mutation status.

INTRODUCTION: Few studies have applied diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) for the comprehensive assessment of gliomas [tumour grade, isocitrate dehydrogenase-1 (IDH-1) mutation status and tumour proliferation rate (Ki-67)]. This study describes the efficacy of DKI and DTI to comprehensively evaluate gliomas, compares their results. METHODS: Fifty-two patients (18 females; median age, 47.5 years) with pathologically proved gliomas were prospectively included. All cases underwent DKI examination. DKI (mean kurtosis: MK, axial kurtosis: Ka, radial kurtosis: Kr) and DTI (mean diffusivity: MD, fractional anisotropy: FA) maps of each metric was derived. Three ROIs were manually drawn. RESULTS: MK, Ka, Kr and FA were significantly higher in HGGs than in LGGs, whereas MD was significantly lower in HGGs than in LGGs (P < 0.01). ROC analysis demonstrated that MK (specificity: 100% sensitivity: 79%) and Ka (specificity: 96% sensitivity: 82%) had the same and highest (AUC: 0.93) diagnostic value. Moreover, MK, Ka, and Kr were significantly higher in grade III than II gliomas (P ≦ 0.01). Further, DKI and DTI can significantly identify IDH-1 mutation status (P ≦ 0.03). Ka (sensitivity: 74%, specificity: 75%, AUC: 0.72) showed the highest diagnostic value. In addition, DKI metrics and MD showed significant correlations with Ki-67 (P ≦ 0.01) and Ka had the highest correlation coefficient (rs = 0.72). CONCLUSIONS: Compared with DTI, DKI has great advantages for the comprehensive assessment of gliomas. Ka might serve as a promising imaging index in predicting glioma grading, tumour cell proliferation rate and IDH-1 gene mutation status.

The diagnostic efficacy of amide proton transfer imaging in grading gliomas and predicting tumor proliferation.

Glioma is the most common primary intracranial tumor. Molecular neuropathology was introduced into the new 2016 WHO classification of brain tumor. Among the molecular biomarkers, Ki-67 antigen is the most important one, which reflects the proliferation rate and invasive ability of tumor cells. The amide proton transfer imaging, as a novel functional MR technique, can detect the free protein and polypeptide noninvasively, which might be a novel imaging method for predicting the WHO grading of glioma. In our study, the asymmetric magnetization transfer ratio (MTRasym) of high-grade gliomas (4.5%±2.3%) was significantly higher than of low-grade gliomas (2.9±1.1%), and the high-grade gliomas also showed higher expression of Ki-67 (38.9±21.0%) than did low-grade gliomas (4.3±2.8%). The MTRasym was positively correlated with Ki-67 values (r=0.25, P<0.001). The area under the receiver operating characteristic curve of MTRasym was 0.719. Furthermore, the diagnosis efficiency of MTRasym is better than that of the apparent diffusion coefficient (area under the receiver operating characteristic curve=0.682). This prospective study demonstrates that amide proton transfer may help in grading gliomas and has great potency in predicting tumor cell proliferation.

Quantitative analysis of neurite orientation dispersion and density imaging in grading gliomas and detecting IDH-1 gene mutation status.

Background and purpose: Neurite orientation dispersion and density imaging (NODDI) is a new diffusion MRI technique that has rarely been applied for glioma grading. The purpose of this study was to quantitatively evaluate the diagnostic efficiency of NODDI in tumour parenchyma (TP) and peritumoural area (PT) for grading gliomas and detecting isocitrate dehydrogenase-1 (IDH-1) mutation status. Methods: Forty-two patients (male: 23, female: 19, mean age: 44.5 y) were recruited and underwent whole brain NODDI examination. Intracellular volume fraction (icvf) and orientation dispersion index (ODI) maps were derived. Three ROIs were manually placed on TP and PT regions for each case. The corresponding average values of icvf and ODI were calculated, and their diagnostic efficiency was assessed. Results: Tumours with high icvfTP (≥0.306) and low icvfPT (≤0.331) were more likely to be high-grade gliomas (HGGs), while lesions with low icvfTP (<0.306) and high icvfPT (>0.331) were prone to be low-grade gliomas (LGGs) (P < 0.001). A multivariate logistic regression model including patient age and icvf values in TP and PT regions most accurately predicted glioma grade (AUC = 0.92, P < 0.001), with a sensitivity and specificity of 92% and 89%, respectively. However, no significant differences were found in NODDI metrics for differentiating IDH-1 mutation status. Conclusions: The quantitative NODDI metrics in the TP and PT regions are highly valuable for glioma grading. A multivariate logistic regression model using the patient age and the icvf values in TP and PT regions showed very high predictive power. However, the utility of NODDI metrics for detecting IDH-1 mutation status has not been fully explored, as a larger sample size may be necessary to uncover benefits.

The asymmetry of neural symptoms in Wilson's disease patients detecting by diffusion tensor imaging, resting-state functional MRI, and susceptibility-weighted imaging.

Objective: To investigate the cause of the motor asymmetry in Wilson's disease (WD) patients using functional MRI. Methods: Fifty patients with WD and 20 age-matched healthy controls were enrolled. Neurological symptoms were scored using the modified Young Scale. All study subjects underwent diffusion tensor imaging (DTI), susceptibility-weighted imaging (SWI), and resting-state functional MRI (rs-fMRI) of the brain. Six regions of interest (ROI) were chosen. Fiber volumes between ROIs on DTI, corrected phase (CP) values on SWI, amplitude of low-frequency fluctuation (ALFF), and regional homogeneity (REHO) values on rs-fMRI were determined. Asymmetry index (right or left value/left or right value) was evaluated. Results: Asymmetry of rigidity, tremor, choreic movement, and gait abnormality (asymmetry index = 1.33, 1.39, 1.36, 1.40), fiber tracts between the GP and substantia nigra (SN), GP and PU, SN and thalamus (TH), SN and cerebellum, head of the caudate nucleus (CA) and SN, PU and CA, CA and TH, TH and cerebellum (asymmetry index = 1.233, 1.260, 1.269, 1.437, 1.503, 1.138, 1.145, 1.279), CP values in the TH, SN (asymmetry index = 1.327, 1.166), ALFF values, and REHO values of the TH (asymmetry index = 1.192, 1.233) were found. Positive correlation between asymmetry index of rigidity and fiber volumes between the GP and SN, SN and TH (r = .221, .133, p = .043, .036), and tremor and fiber volumes between the CA and TH (r = .045, p = .040) was found. Conclusions: The neurological symptoms of patients with WD were asymmetry. The asymmetry of fiber projections may be the main cause of motor asymmetry in patients with WD.

A study of neurite orientation dispersion and density imaging in wilson's disease.

BACKGROUND: Previous studies have indicated that neurite orientation dispersion and density imaging (NODDI) could be used as a biomarker for detecting microstructural changes of brain. PURPOSE: To quantitatively evaluate the changes in basal ganglia (BG) and thalamus in Wilson's disease (WD) by NODDI and assess the correlation between parameters and disease severity. STUDY TYPE: Prospective case-control study. POPULATION: In total, 24 WD patients and 25 age- and sex-matched normal controls were involved in this study. FIELD STRENGTH/SEQUENCE: EPI diffusion-weighted MR images (b-values = 0, 1000, and 2000 with 30 diffusion gradient directions) were acquired on a 3T scanner. ASSESSMENT: Diffusion data were analyzed using voxel-based analysis. NODDI indices including intracellular volume fraction (Vic), orientation dispersion index (ODI), and isotropic volume fraction (Viso) were estimated from the BG and thalamus. The disease severity was assessed by two experienced neurologists based on the Global Assessment Scale (GAS). The relative importance of NODDI indices in diagnosing WD and predictive accuracy were also analyzed. STATISTICAL TESTING: The Shapiro-Wilk test, Student's t-test, χ2 test, Mann-Whitney-Wilcoxon test, Spearman rank correlation coefficient analysis and random-forest analysis were used for statistical analyses. RESULTS: The Vic and ODI in the BG and thalamus were significantly lower in WD patients than normal controls, while the Viso in the BG and thalamus were significantly higher (P < 0.01). The Vic in the putamen and ODI in the globus pallidus were negatively correlated with clinical severity (rvic = -0.727, P < 0.001; rodi = -0.705, P < 0.001). The Vic in the putamen was the most valuable predictor for diagnosing WD and the prediction accuracy of NODDI was 95.92%. DATA CONCLUSION: NODDI can effectively evaluate the changes of microstructure and metabolism during copper deposition in WD, and thus, it is likely to be useful in detecting the changes in the brain of this disease and assessing its progression. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage 2 J. MAGN. RESON. IMAGING 2018;48:423-430.

Radiosynthesis and Preliminary Biological Evaluation of 18F-Fluoropropionyl-Chlorotoxin as a Potential PET Tracer for Glioma Imaging.

Purposes: Chlorotoxin can specifically bind to matrix metalloproteinase 2 (MMP-2), which are overexpressed in the glioma. In this work, radiosynthesis of [18F]-fluoropropionyl-chlorotoxin ([18F]-FP-chlorotoxin) as a novel PET tracer was investigated, and biodistribution in vivo and PET imaging were performed in the C6 glioma model. Procedures: [18F]-FP-chlorotoxin was prepared from the reaction of chlorotoxin with [18F]-NFB (4-nitrophenyl 2-[18F]-fluoropropionate), which was synthesized from multistep reactions. Biodistribution was determined in 20 normal Kunming mice. Small-animal PET imaging with [18F]-FP-chlorotoxin was performed on the same rats bearing orthotopic C6 glioma at different time points (60 min, 90 min, and 120 min) after injection and compared with 2-deoxy-2-[18F] fluoro-D-glucose ([18F]-FDG). Results: [18F]-FP-Chlorotoxin was successfully synthesized in the radiochemical yield of 41% and the radiochemical purity of more than 98%. Among all the organs, the brain had the lowest and stable uptake of [18F]-FP-chlorotoxin, while the kidney showed the highest uptake. Compared with [18F]-FDG, a low uptake of [18F]-FP-chlorotoxin was detected in normal brain parenchyma and a high accumulation of [18F]-FP-chlorotoxin was found in the gliomas tissue. The glioma to normal brain uptake ratio of [18F]-FP-chlorotoxin was higher than that of [18F]-FDG. Furthermore, the uptake of [18F]-FP-chlorotoxin at 90 min after injection was better than that at 60 min after injection. Conclusions: Compared with [18F]-FDG, [18F]-FP-chlorotoxin has a low and stable uptake in normal brain parenchyma. [18F]-FP-Chlorotoxin seems to be a potential PET tracer with a good performance in diagnosis of the glioma.