Causal association of micronutrients and supplements with pressure ulcer: A Mendelian randomization study.

BACKGROUND: Pressure ulcer (PU) is known to be associated with abnormalities of micronutrient status. However, to date, it is not clear whether a causal relationship exists between circulating levels of micronutrients and their supplementations and PU. METHODS: A two-sample Mendelian randomization (MR) study was conducted using summary statistics from Genome-Wide Association Studies (GWAS). Genetic instrumental variables (IVs) for 13 micronutrients were identified from a GWAS of 67 582 participants, IVs for supplement zinc were acquired from 18 826 cases and 44 255 880 controls, and IVs for PU were obtained from 663 PUs and 207 482 controls. The MR analysis was conducted using the MR base platform. The main analysis method was inverse variance weighted (IVW) analysis, supplemented by MR Egger, Weighted median, Weighted mode, and Simple mode analyses. Heterogeneity was assessed using Cochran's Q statistic for MR-IVW and Rucker's Q statistic for MR-Egger. Pleiotropy was determined by the MR-Egger regression. Sensitivity analysis was conducted using the leave-one-out method, and publication bias was evaluated using funnel plots. RESULTS: Genetically predicted lower circulating zinc levels were found to be causally linked to the development of PU (OR = 0.758, 95%CI 0.583-0.987, P = 0.040). However, there was no significant evidence of a causal relationship between supplemental zinc intake and PU development (P > 0.05). Additionally, no causal association was observed between the other circulating micronutrients and the occurrence of PU. Furthermore, there was no indication of horizontal pleiotropy or heterogeneity among genetic variants (P > 0.05), and the robustness of the findings was confirmed through leave-one-out tests and funnel plots. CONCLUSIONS: Our findings indicate a potential causal association between circulating zinc levels and decreased risk of PU. However, zinc supplementation did not demonstrate a significant reduction in the risk of PU. Further research is warranted to elucidate the underlying mechanisms through which zinc influences the pathogenesis of PU and evaluate the efficacy of zinc supplementation in the prevention and management of PU.

Optimization of structural connectomes and scaled patterns of structural-functional decoupling in Parkinson's disease.

Parkinson's disease (PD) is manifested with disrupted topology of the structural connection network (SCN) and the functional connection network (FCN). However, the SCN and its interactions with the FCN remain to be further investigated. This multimodality study attempted to precisely characterize the SCN using diffusion kurtosis imaging (DKI) and further identify the neuropathological pattern of SCN-FCN decoupling, underscoring the neurodegeneration of PD. Diffusion-weighted imaging and resting-state functional imaging were available for network constructions among sixty-nine patients with PD and seventy demographically matched healthy control (HC) participants. The classification performance and topological prosperities of both the SCN and the FCN were analyzed, followed by quantification of the SCN-FCN couplings across scales. The SCN constructed by kurtosis metrics achieved optimal classification performance (area under the curve 0.89, accuracy 80.55 %, sensitivity 78.40 %, and specificity 80.65 %). Along with diverse alterations of structural and functional network topology, the PD group exhibited decoupling across scales including: reduced global coupling; increased nodal coupling within the sensorimotor network (SMN) and subcortical network (SN); higher intramodular coupling within the SMN and SN and lower intramodular coupling of the default mode network (DMN); decreased coupling between the modules of DMN-fronto-parietal network and DMN-visual network, but increased coupling between the SMN-SN module. Several associations between the coupling coefficient and topological properties of the SCN, as well as between network values and clinical scores, were observed. These findings validated the clinical implementation of DKI for structural network construction with better differentiation ability and characterized the SCN-FCN decoupling as supplementary insight into the pathological process underlying PD.

Motor asymmetry related cerebral perfusion patterns in Parkinson's disease: An arterial spin labeling study.

Persisting asymmetry of motor symptoms are characteristic of Parkinson's disease (PD). We investigated the possible lateralized effects on regional cerebral blood flow (CBF), CBF-connectivity, and laterality index (LI) among PD subtypes using arterial spin labeling (ASL). Forty-four left-sided symptom dominance patients (PDL), forty-eight right-sided symptom dominance patients (PDR), and forty-five matched HCs were included. Group comparisons were performed for the regional normalized CBF, CBF-connectivity and LI of basal ganglia (BA) subregions. The PDL patients had lower CBF in right calcarine sulcus and right supramarginal gyrus compared to the PDR and the HC subjects. Regional perfusion alterations seemed more extensive in the PDL than in the PDR group. In the PDL, correlations were identified between right thalamus and motor severity, between right fusiform gyrus and global cognitive performance. None of correlations survived after multiple comparisons correction. The significantly altered CBF-connectivity among the three groups included: unilateral putamen, unilateral globus pallidus, and right thalamus. LI score in the putamen was significantly different among groups. Motor-symptom laterality in PD may exhibit asymmetric regional and interregional abnormalities of CBF properties, particularly in PDL patients. This preliminary study underlines the necessity of classifying PD subgroups based on asymmetric motor symptoms and the potential application of CBF properties underlying neuropathology in PD.

Can Hybrid Arterial Spin Labeling-Tagged Zero-Echo-Time Magnetic Resonance Angiography Be an Effective Candidate in the Evaluation of Intracranial Artery Diseases? A Clinical Feasibility Study.

BACKGROUND: Flow related artifacts in continuous arterial spin labeling (cASL) zero-echo-time (ZTE) magnetic resonance angiography (MRA) could influence the vasculature visualization. PURPOSE: To investigate the clinical feasibility for the intracranial artery diseases assessment by utilizing hybrid ASL-ZTE-MRA (hASL-ZTE-MRA). STUDY TYPE: Prospective, technical development. POPULATION: Sixty-seven subjects with known/suspected cerebrovascular diseases. FIELD STRENGTH/SEQUENCE: Gradient echo based cASL-/hASL- ZTE-MRA at 3.0 T. ASSESSMENT: Subjective/objective evaluation for sound-levels. Image quality (IQ), signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were analyzed within artery segments. Stenotic grading, aneurysm measurement, and signal intensity of lesions were further analyzed. STATISTICAL TESTS: Kolmogorov-Smirnov test for data normality check. Between two MRAs: Wilcoxon signed-rank test for sound experience/IQ ratings analysis; Paired t test for SNR/CNR comparison. One-way analysis of variance for sound intensity comparison. For stenosis grading/aneurysm measurement: Kendall's W test/intraclass correlation coefficient (ICC) for interobserver agreement test within each modality, weighted kappa statistics/ICC for intermodality agreement test between each MRA and computed tomography angiography. RESULTS: Sound-level perception/intensity was similar (P = 0.86, P = 0.55) between MRAs. The mean IQ score for hASL-ZTE-MRA was on diagnostic scale and slightly higher (P < 0.05) than that of cASL-ZTE-MRA. hASL-ZTE-MRA provided higher (P < 0.05) SNR/CNR than that of cASL-ZTE-MRA. Signal uniformity was improved on hASL-ZTE-MRA, particularly among the anterior circulation (P < 0.05). Comparing to cASL-ZTE-MRA, on hASL-ZTE-MRA, stenotic lesions were accurately assessed; flow in the stent or aneurysm remnant was better depicted (P < 0.05); AVM nidus was preferred with increased SNR (P < 0.05). No significant differences for the aneurysm measurement were found between MRAs (P = 0.95), in addition to the slightly higher SNR (P < 0.05) on hASL-ZTE-MRA. DATA CONCLUSION: Comparing to cASL-ZTE-MRA, hASL-ZTE-MRA is robust and feasible for the evaluation of intracranial artery diseases with diagnostic IQ, improved vessel contrast, and better signal heterogeneity. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: 2.

Alterations of brain network topology and structural connectivity-functional connectivity coupling in capsular versus pontine stroke.

BACKGROUND AND PURPOSE: This study was conducted to investigate whether capsular stroke (CS) and pontine stroke (PS) have different topological alterations of structural connectivity (SC) and functional connectivity (FC), as well as correlations of SC-FC coupling with movement assessment scores. METHODS: Resting-state functional magnetic resonance imaging and diffusion tensor imaging were prospectively acquired in 46 patients with CS, 36 with PS, and 29 healthy controls (HCs). Graph theoretical network analyses of SC and FC were performed. Patients with left and right lesions were analyzed separately. RESULTS: With regard to FC, the PS and CS groups both showed higher local efficiency than the HCs, and the CS group also had a higher clustering coefficient (Cp) than the HCs in the right lesion analysis. With regard to SC, the PS and CS groups both showed different normalized clustering coefficient (γ), small-worldness (σ), and characteristic path length (Lp) compared with the HC group. Additionally, the CS group showed higher normalized characteristic path length (λ) and a lower Cp than the HCs and the PS group showed higher λ and lower global efficiency than the HCs in the right-lesion analysis. However, γ, σ, Cp and Lp were only significantly different in the PS and CS groups compared with the HC group in the right-lesion analysis. Importantly, the CS group was found to have a weaker SC-FC coupling than the PS group and the HC group in the right-lesion analysis. In addition, both patient groups had weaker structural-functional connectome correlation than the HCs. CONCLUSIONS: The CS and PS groups both showed FC and SC disruption and the CS group had a weaker SC-FC coupling than the PS group in the right lesion analysis. This may provide useful information for individualized rehabilitative strategies.

Altered static and dynamic functional network connectivity in post-traumatic headache.

BACKGROUND: Post-traumatic headache (PTH) is a very common symptom following mild traumatic brain injury (mTBI), yet much remains unknown about the underlying pathophysiological mechanisms of PTH. Neuroimaging studies suggest that aberrant functional network connectivity (FNC) may be an important factor in pain disorders. The present study aimed to investigate the functional characteristics of static FNC (sFNC) and dynamic FNC (dFNC) in mTBI patients with PTH. METHODS: With Institutional Review Board (IRB) approval, we prospectively recruited 50 mTBI patients with PTH, who were diagnosed with ICHD-3 beta diagnostic criteria and 39 mTBI without PTH who were well matched for age, gender and education. Resting-state functional magnetic resonance imaging (fMRI) scanning (3.0 T, Philips Medical Systems, Netherlands), Montreal Cognitive Assessment (MoCA) and headache symptom measurement (headache frequency and headache intensity) were performed. The resting-state fMRI sequence took 8 min and 10 s. Independent component analysis and sliding window method were applied to examine the FNC on the basis of nine resting-state networks, namely, default mode network (DMN), sensorimotor network (SMN), executive control network (ECN), auditory network (AuN), attention network (AN), salience network (SN), visual network (VN), and cerebellum network (CN). The differences in sFNC and dFNC were determined and correlated with clinical variables using Pearson rank correlation. RESULTS: For sFNC, compared with mTBI patients without PTH, mTB with PTH group showed four altered interactions, including decreased interactions in SN-SMN and VN-DMN pairs, increased sFNC in SN-ECN and SMN-DMN pairs. For dFNC, significant group differences were found in State 2, including increased connectivity alteration in the DMN with CN, DMN with SMN, and AuN with CN. Significant reduced connectivity changes in the DMN with VN was found in State 4. Furthermore, the number of transitions (r=0.394, p=0.005) between states was positively associated with headache frequency. Additionally, dwell time (r=-0.320, p=0.025) in State 1 was negatively correlated with MoCA score. CONCLUSIONS: MTBI patients with PTH are characterized with altered sFNC and dFNC, which could provide new perspective to understand the neuropathological mechanism underlying the PTH to determine more appropriate management, and may be a useful imaging biomarker for identifying and predicting mTBI with PTH.

Cerebral Blood Flow and Its Connectivity Deficits in Mild Traumatic Brain Injury at the Acute Stage.

Objective: The influence of cognitive impairment after mild traumatic brain injury (mTBI) on cerebral vascular perfusion has been widely concerned, yet the resting-state cerebral blood flow (CBF) connectivity alterations based on arterial spin labeling (ASL) in mild traumatic brain injury (mTBI) remain unclear. This study investigated region CBF and CBF connectivity features in acute mTBI patients, as well as the associations between CBF changes and cognitive impairment. Materials and Methods: Forty-five acute mTBI patients and 42 health controls underwent pseudocontinuous arterial spin labeling (pCASL) perfusion magnetic resonance imaging (MRI). The alterations in regional CBF and relationship between the CBF changes and cognitive impairment were detected. The ASL-CBF connectivity of the brain regions with regional CBF significant differences was also compared between two groups. Neuropsychological tests covered seven cognitive domains. Associations between the CBF changes and cognitive impairment were further investigated. Results: Compared with the healthy controls, the acute mTBI patients exhibited increased CBF in the bilateral inferior temporal gyrus (ITG) and decreased CBF in the right middle frontal gyrus (MFG), the bilateral superior frontal gyrus (SFG), and the right cerebellum posterior lobe (CPL). In the mTBI patients, significant correlations were identified between the CBF changes and cognitive impairment. Importantly, the acute mTBI patients exhibited CBF disconnections between the right CPL and right fusiform gyrus (FG) as well as bilateral ITG, between the left SFG and left middle occipital gyrus (MOG), and between the right SFG and right FG as well as right parahippocampal gyrus. Conclusion: Our results suggest that acute mTBI patients exhibit both regional CBF abnormalities and CBF connectivity deficits, which may underlie the cognitive impairment of the acute mTBI patients.

Follow-up assessment of coiled intracranial aneurysms using zTE MRA as compared with TOF MRA: a preliminary image quality study.

OBJECTIVES: To prospectively assess coiled intracranial aneurysms using a novel non-contrast enhanced zero echo time (zTE) MR angiography (MRA) method, and compare its image quality with time-of-flight (TOF) MRA, using digital subtraction angiography (DSA) as reference. METHODS: Twenty-five patients (10 males and 15 females; age 53.96 ± 12.46 years) were enrolled in this monocentric study. MRA sequences were performed 24 h before DSA. Susceptibility artefact intensity and flow signal within the parent artery were carried out using a 4-point scale. Occlusion status was assessed using the 3-grade Montreal scale. RESULTS: Scores of zTE were higher than TOF for both susceptibility artefact intensity (3.42 ± 0.64, 2.92 ± 0.63, P = 0.01) and flow signal (3.66 ± 0.95, 3.24 ± 1.24, P = 0.01). DSA revealed 17 complete occlusions, five residual neck aneurysms and two residual aneurysms. Inter-observer agreement was excellent (weighted κ: 0.89) for zTE and good (weighted κ: 0.68) for TOF. Intermodality agreement was excellent for zTE (weighted κ: 0.95) and good for TOF (weighted κ: 0.80). Correlations of both MRA sequences with DSA were high (zTE, Spearman's ρ: 0.91; TOF, Spearman's ρ: 0.81). CONCLUSIONS: zTE MRA showed promising results for follow-up assessment of coiled intracranial aneurysms and was superior to TOF MRA for visualizing the parent artery and evaluating occlusion status. KEY POINTS: • Various MRA sequences were applied for follow-up assessment of coiled intracranial aneurysms. • zTE MRA was less sensitive to susceptibility artefacts and haemodynamics. • In this monocentric study, zTE MRA was equivalent to DSA. • zTE MRA maybe an alternative to TOF MRA for follow-up assessment.

Magnetic resonance and near-infrared imaging using a novel dual-modality nano-probe for dendritic cell tracking in vivo.

BACKGROUND AIMS: The effect of cellular-based immunotherapy is highly correlated with the success of dendritic cells (DCs) homing to the draining lymph nodes (LNs) and interacting with antigen-specific CD4(+) T cells. In this study, a novel magneto-fluorescent nano-probe was used to track the in vivo migration of DCs to the draining LNs. METHODS: A dual-modality nano-probe composed of superparamagnetic iron oxide (SPIO) and near-infrared fluorescent (NIRF) dye (NIR797) was developed, and its magnetic and optical contrasting properties were characterized. DCs generated from mouse bone marrow were co-cultured with the probe at a lower concentration of 10 µg/mL. The cell phenotype and function of DCs were also investigated by fluorescence-activated cell sorting analysis and mixed leukocyte reactivity assay. Labeled DCs were injected into the footpad of C57BL/6 mice. Afterward, magnetic resonance imaging, NIRF imaging, Perls staining and CD11c immunofluorescence were used to observe the migration of the labeled DCs into draining LNs. RESULTS: The synthetic SPIO-NIR797 nano-probe had a desirable superparamagnetic and near-infrared behavior. Perls staining showed perfect labeling efficiency. The cell phenotypes, including CD11c, CD80, CD86 and major histocompatibility complex class II, as well as the T-cell activation potential of the mature DCs were insignificantly affected after incubation (P > 0.05). Labeled DCs migrating into LNs could be detected by both magnetic resonance imaging and NIRF imaging simultaneously, which was further confirmed by Perls staining and immunofluorescence. CONCLUSIONS: The novel dual-modality SPIO-NIR797 nano-probe has highly biocompatible characteristics for labeling and tracking DCs, which can be used to evaluate cancer immunotherapy in clinical applications.

Diffusion Kurtosis Imaging in Diagnosing Parkinson's Disease: A Preliminary Comparison Study Between Kurtosis Metric and Radiomic Features.

RATIONALE AND OBJECTIVES: Parkinson's disease (PD) shows small structural changes in nigrostriatal pathways, which can be sensitively captured through diffusion kurtosis imaging (DKI). However, the value of DKI and its radiomic features in the classification performance of PD still need confirmation. This study aimed to compare the diagnostic efficiency of DKI-derived kurtosis metric and its radiomic features with different machine learning models for PD classification. MATERIALS AND METHODS: 75 people with PD and 80 healthy individuals had their brains scanned using DKI. These images were pre-processed and the standard atlas were non-linearly registered to them. With the labels in atlas, different brain regions in nigrostriatal pathways, including the caudate nucleus, putamen, pallidum, thalamus, and substantia nigra, were chosen as the region of interests (ROIs) to warped to the native space to measure the mean kurtosis (MK). Additionally, new radiomic features were developed for comparison. To handle the large amount of data, a statistical method called Z-score normalization and another method called LASSO regression were used to simplify the information. From this, a few most important features were chosen, and a combined score called Radscore was calculated using LASSO regression. For the comprehensive analyses, three different conventional machine learning models were then created: logistic regression (LR), support vector machine (SVM), and random forest (RF). To ensure the models were accurate, a process called 10-fold cross-validation was used, where the data were split into 10 parts for training and testing. RESULTS: Using MK alone, the models achieved good results in correctly identifying PD in the validation set, with LR at 0.90, RF at 0.93, and SVM at 0.90. When the radiomic features were added, the models performed even better, with LR at 0.92, RF at 0.95, and SVM at 0.91. Additionally, a nomogram combining all the information was created to predict the likelihood of someone having PD, which had an AUC of 0.91. CONCLUSION: These findings suggest that the combination of DKI measurements and radiomic features can effectively diagnose PD by providing more detailed information about the brain's condition and the processes involved in the disease.

Effect of maternal cigarette smoke exposure on COPD progression in offspring mice.

OBJECTIVE: To investigate the impact of maternal smoking on chronic obstructive pulmonary disease (COPD) progression in offspring. METHODS: Using female C57BL/6 J mice, a maternal cigarette smoke exposure (CSE) model was established. Mice were exposed to cigarette smoke for 2 hours/day, 7 days/week, with a minimum 4-hour interval between exposures. Experimental groups included control (Con), pregnancy exposure (AS), pre-pregnancy exposure (SA), and pre-pregnancy + pregnancy exposure (SS). Lung function tests (Penh, PAU, TVb, EF50, Tr) were conducted on male offspring at 7 weeks. Histopathology, electron microscopy, and protein level changes were examined. RESULTS: Lung function tests revealed significant impairments in Penh, PAU, TVb, EF50, and Tr in offspring across all exposure scenarios. Specifically, AS experienced significant lung function impairment and mitochondrial dysfunction in offspring, with noticeable pulmonary lesions and increased apoptosis. SA showed similar or even more severe lung function impairment and cellular apoptosis. SS exhibited the most pronounced effects, with the highest levels of lung dysfunction, mitochondrial damage, and apoptosis. Histopathological analysis showed pulmonary lesions in offspring exposed to maternal CSE. Flow cytometry revealed increased apoptosis and reduced mitochondrial membrane potential in offspring lung cells. Electron microscopy confirmed mitochondrial dysfunction. Upregulation of apoptotic proteins and downregulation of anti-apoptotic protein Bcl-2 were found in offspring lung tissue exposed to maternal CSE. CONCLUSION: Maternal smoking induces impaired lung function, pulmonary lesions, and mitochondrial dysfunction in offspring, regardless of exposure timing and duration. Additionally, it alters expression of apoptosis-related proteins in offspring lung tissue, potentially contributing to COPD susceptibility.

Topological disruption of low- and high-order functional networks in presbycusis.

Prior efforts have manifested that functional connectivity (FC) network disruptions are concerned with cognitive disorder in presbycusis. The present research was designed to investigate the topological reorganization and classification performance of low-order functional connectivity (LOFC) and high-order functional connectivity (HOFC) networks in patients with presbycusis. Resting-state functional magnetic resonance imaging (Rs-fMRI) data were obtained in 60 patients with presbycusis and 50 matched healthy control subjects (HCs). LOFC and HOFC networks were then constructed, and the topological metrics obtained from the constructed networks were compared to evaluate topological differences in global, nodal network metrics, modularity and rich-club organization between patients with presbycusis and HCs. The use of HOFC profiles boosted presbycusis classification accuracy, sensitivity and specificity compared to that using LOFC profiles. The brain networks in both patients with presbycusis and HCs exhibited small-world properties within the given threshold range, and striking differences between groups in topological metrics were discovered in the constructed networks (LOFC and HOFC). NBS analysis identified a subnetwork involving 26 nodes and 23 signally altered internodal connections in patients with presbycusis in comparison to HCs in HOFC networks. This study highlighted the topological differences between LOFC and HOFC networks in patients with presbycusis, suggesting that HOFC profiles may help to further identify brain network abnormalities in presbycusis.

Intracerebral hemodynamic abnormalities in patients with Parkinson's disease: Comparison between multi-delay arterial spin labelling and conventional single-delay arterial spin labelling.

PURPOSE: The purpose of this study was to analyze the intracerebral abnormalities of hemodynamics in patients with Parkinson's disease (PD) through arterial spin labelling (ASL) technique with multi-delay ASL (MDASL) and conventional single-delay ASL (SDASL) protocols and to verify the potential clinical application of these features for the diagnosis of PD. MATERIALS AND METHODS: Perfusion data of the brain obtained using MDASL and SDASL in patients with PD were compared to those obtained in healthy control (HC) subjects. Intergroup comparisons of z-scored cerebral blood flow (zCBF), arterial transit time (zATT) and cerebral blood volume (zCBV) were performed via voxel-based analysis. Performance of these perfusion metrics were estimated using area under the receiver operating characteristic curve (AUC) and compared using Delong test. RESULTS: A total of 47 patients with PD (29 men; 18 women; mean age, 69.0 ± 7.6 (standard deviation, [SD]) years; range: 50.0-84.0 years) and 50 HC subjects (28 men; 22 women; mean age, 70.1 ± 6.2 [SD] years; range: 50.0-93.0 years) were included. Relative to the uncorrected-zCBF map, the corrected-zCBF map further refined the distributed brain regions in the PD group versus the HC group, manifested as the extension of motor-related regions (PFWE < 0.001). Compared to the HC subjects, patients with PD had elevated zATT and zCBV in the right putamen, a shortened zATT in the superior frontal gyrus, and specific zCBV variations in the left precuneus and the right supplementary motor area (PFWE < 0.001). The corrected-zCBF (AUC, 0.90; 95% confidence interval [CI]: 0.84-0.96) showed better classification performance than uncorrected-zCBF (AUC, 0.84; 95% CI: 0.75-0.92) (P = 0.035). zCBV achieved an AUC of 0.89 (95% CI: 0.82-0.96) and zATT achieved an AUC of 0.66 (95% CI: 0.55-0.77). The integration model of hemodynamic features from MDASL provided improved performance (AUC, 0.97; 95% CI: 0.95-0.98) for the diagnosis of PD by comparison with each perfusion model (P < 0.001). CONCLUSION: ASL identifies impaired hemodynamics in patients with PD including regional abnormalities of CBF, CBV and ATT, which can better be mapped with MDASL compared to SDASL. These findings provide complementary depictions of perfusion abnormalities in patients with PD and highlight the clinical feasibility of MDASL.

Characterizing microstructural patterns within the cortico-striato-thalamo-cortical circuit in Parkinson's disease.

PURPOSE: Parkinson's disease (PD) involves pathological alterations that include cortical impairments at levels of region and network. However, its microstructural abnormalities remain to be further elucidated via an appropriate diffusion neuroimaging approach. This study aimed to comprehensively demonstrate the microstructural patterns of PD as mapped by diffusion kurtosis imaging (DKI). METHODS: The microstructure of grey matter in both the PD group and the matched healthy control group was quantified by a DKI metric (mean kurtosis). The intergroup difference and classification performance of global microstructural complexity were analyzed in a voxelwise manner and via a machine learning approach, respectively. The patterns of information flows were explored in terms of structural connectivity, network covariance and modular connectivity. RESULTS: Patients with PD exhibited global microstructural impairments that served as an efficient diagnostic indicator. Disrupted structural connections between the striatum and cortices as well as between the thalamus and cortices were widely distributed in the PD group. Aberrant covariance of the striatocortical circuitry and thalamocortical circuitry was observed in patients with PD, who also showed disrupted modular connectivity within the striatum and thalamus as well as across structures of the cortex, striatum and thalamus. CONCLUSION: These findings verified the potential clinical application of DKI for the exploration of microstructural patterns in PD, contributing complementary imaging features that offer a deeper insight into the neurodegenerative process.

Molecular subtype identification and prognosis stratification by a immunogenic cell death-related gene expression signature in colorectal cancer.

OBJECTIVES: This study intended to develop a new immunogenic cell death (ICD)-related prognostic signature for colorectal cancer (CRC) patients. RESEARCH DESIGN AND METHODS: The Non-Negative Matrix Factorization (NMF) algorithm was adopted to cluster tumor samples based on ICD gene expression to obtain ICD-related subtypes. Survival analysis and immune microenvironment analysis were conducted among different subtypes. Regression analysis was used to construct the model. Based on riskscore median, cancer patients were classified into high and low risk groups, and independent prognostic ability of the model was analyzed. The CIBERSORT algorithm was adopted to determine the immune infiltration level of both groups. RESULTS: We analyzed the differential genes between cluster 4 and cluster 1-3 and obtained 12 genes with the best prognostic features finally (NLGN1, SLC30A3, C3orf20, ADAD2, ATOH1, ATP6V1B1, KCNQ2, MUCL3, RGCC, CLEC17A, COL6A5, and INSL4). In addition, patients with lower risk had higher levels of infiltration of most immune cells, lower Tumor Immune Dysfunction and Exclusion (TIDE) level and higher immunophenscore (IPS) level than those with higher risk. CONCLUSIONS: This study constructed and validated the ICD feature signature predicting CRC prognosis and provide a reference criteria for guiding the prognosis and immunotherapy of CRC cancer patients.

Early detection of dopaminergic dysfunction and glymphatic system impairment in Parkinson's disease.

PURPOSE: This study aimed to assess the glymphatic function and its correlation with clinical characteristics and the loss of dopaminergic neurons in Parkinson's disease (PD) using hybrid positron emission tomography (PET)-magnetic resonance imaging (MRI) combined with diffusion tensor image analysis along the perivascular space (DTI-ALPS), choroid plexus volume (CPV), and enlarged perivascular space (EPVS) volume. METHODS: Twenty-five PD patients and thirty matched healthy controls (HC) participated in the study. All participants underwent 18F-fluorodopa (18F-DOPA) PET-MRI scanning. The striatal standardized uptake value ratio (SUVR), DTI-ALPS index, CPV, and EPVS volume were calculated. Furthermore, we also analysed the relationship between the DTI-ALPS index, CPV, EPVS volume and striatal SUVR as well as clinical characteristics of PD patients. RESULTS: PD patients demonstrated significantly lower values in DTI-ALPS (t = 3.053, p = 0.004) and larger CPV (t = 2.743, p = 0.008) and EPVS volume (t = 2.807, p = 0.008) compared to HC. In PD group, the ALPS-index was negatively correlated with the Unified Parkinson's Disease Rating Scale III (UPDRS-III) scores (r = -0.730, p < 0.001), and positively correlated with the mean putaminal SUVR (r = 0.560, p = 0.007) and mean caudal SUVR (r = 0.459, p = 0.032). Moreover, the mean putaminal SUVR was negatively associated with the UPDRS-III scores (r = -0.544, p = 0.009). CONCLUSION: DTI-ALPS has the potential to uncover glymphatic dysfunction in patients with PD, with this dysfunction correlating strongly with the severity of disease, together with the mean putaminal and caudal SUVR. PET- MRI can serve as a potential multimodal imaging biomarker for early-stage PD.

Drooling disrupts the brain functional connectivity network in Parkinson's disease.

AIMS: This study aimed to investigate the causal interaction between significant sensorimotor network (SMN) regions and other brain regions in Parkinson's disease patients with drooling (droolers). METHODS: Twenty-one droolers, 22 PD patients without drooling (non-droolers), and 22 matched healthy controls underwent 3T-MRI resting-state scans. We performed independent component analysis and Granger causality analysis to determine whether significant SMN regions help predict other brain areas. Pearson's correlation was computed between imaging characteristics and clinical characteristics. ROC curves were plotted to assess the diagnostic performance of effective connectivity (EC). RESULTS: Compared with non-droolers and healthy controls, droolers showed abnormal EC of the right caudate nucleus (CAU.R) and right postcentral gyrus to extensive brain regions. In droolers, increased EC from the CAU.R to the right middle temporal gyrus was positively correlated with MDS-UPDRS, MDS-UPDRS II, NMSS, and HAMD scores; increased EC from the right inferior parietal lobe to CAU.R was positively correlated with MDS-UPDRS score. ROC curve analysis showed that these abnormal ECs are of great significance in diagnosing drooling in PD. CONCLUSION: This study identified that PD patients with drooling have abnormal EC in the cortico-limbic-striatal-cerebellar and cortio-cortical networks, which could be potential biomarkers for drooling in PD.

Functional-structural large-scale brain networks are correlated with neurocognitive impairment in acute mild traumatic brain injury.

Background: This study was conducted to investigate topological changes in large-scale functional connectivity (FC) and structural connectivity (SC) networks in acute mild traumatic brain injury (mTBI) and determine their potential relevance to cognitive impairment. Methods: Seventy-one patients with acute mTBI (29 males, 42 females, mean age 43.54 years) from Nanjing First Hospital and 57 matched healthy controls (HC) (33 males, 24 females, mean age 46.16 years) from the local community were recruited in this prospective study. Resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI) were acquired within 14 days (mean 3.29 days) after the onset of mTBI. Then, large-scale FC and SC networks with 116 regions from the automated anatomical labeling (AAL) brain atlas were constructed. Graph theory analysis was used to analyze global and nodal metrics. Finally, correlations were assessed between topological properties and neurocognitive performances evaluated by the Montreal Cognitive Assessment (MoCA). Bonferroni correction was performed out for multiple comparisons in all involved analyses. Results: Compared with HC, acute mTBI patients had a higher normalized clustering coefficient (γ) for FC (Cohen's d=4.076), and higher γ and small worldness (σ) for SC (Cohen's d=0.390 and Cohen's d=0.395). The mTBI group showed aberrant nodal degree (Dc), nodal efficiency (Ne), and nodal local efficiency (Nloc) for FC and aberrant Dc, nodal betweenness (Bc), nodal clustering coefficient (NCp) and Ne for SC mainly in the frontal and temporal, cerebellum, and subcortical areas. Acute mTBI patients also had higher functional-structural coupling strength at both the group and individual levels (Cohen's d=0.415). These aberrant global and nodal topological properties at functional and structural levels were associated with attention, orientation, memory, and naming performances (all P<0.05). Conclusions: Our findings suggested that large-scale FC and SC network changes, higher correlation between FC and SC and cognitive impairment can be detected in the acute stage of mTBI. These network aberrances may be a compensatory mechanism for cognitive impairment in acute mTBI patients.

Topological disruption of high-order functional networks in cognitively preserved Parkinson's disease.

AIMS: This study aimed to characterize the topological alterations and classification performance of high-order functional connectivity (HOFC) networks in cognitively preserved patients with Parkinson's disease (PD), relative to low-order FC (LOFC) networks. METHODS: The topological metrics of the constructed networks (LOFC and HOFC) obtained from fifty-one cognitively normal patients with PD and 60 matched healthy control subjects were analyzed. The discriminative abilities were evaluated using machine learning approach. RESULTS: The HOFC networks in the PD group showed decreased segregation and integration. The normalized clustering coefficient and small-worldness in the HOFC networks were correlated to motor performance. The altered nodal centralities (distributed in the precuneus, putamen, lingual gyrus, supramarginal gyrus, motor area, postcentral gyrus and inferior occipital gyrus) and intermodular FC (frontoparietal and visual networks, sensorimotor and subcortical networks) were specific to HOFC networks. Several highly connected nodes (thalamus, paracentral lobule, calcarine fissure and precuneus) and improved classification performance were found based on HOFC profiles. CONCLUSION: This study identified disrupted topology of functional interactions at a high level with extensive alterations in topological properties and improved differentiation ability in patients with PD prior to clinical symptoms of cognitive impairment, providing complementary insights into complex neurodegeneration in PD.

Exosomal PD­L1 promotes the formation of an immunosuppressive microenvironment in gastric diffuse large B­cell lymphoma.

Gastric diffuse large B­cell lymphoma (GDLBCL) is a common disease with an increasing incidence. However, the regulatory effect of exosomal programmed death­ligand 1 (PD­L1) on the immune microenvironment in GDLBCL is unclear. In the present study, the protein expression levels of exosomal PD­L1 in the supernatants of cultured diffuse large B­cell lymphoma (DLBCL) cells and the plasma of patients with GDLBCL was assessed using immunoblotting. Exosomes derived from DLBCL cells were cocultured with T lymphocytes or injected into tumor xenograft mice by tail vein injection. The relationship between the protein expression level of exosomal PD­L1 in the plasma and the clinical characteristics and immune microenvironmental parameters of GDLBCL was evaluated using immunoblotting and immunohistochemistry. High levels of exosomal PD­L1 were found in the supernatants of cultured DLBCL cells. Exosomes with high levels of PD­L1 promoted growth of tumors formed by DLBCL cells in vivo and inhibited the proliferation of T lymphocytes. Notably, the protein expression level of PD­L1 in plasma exosomes derived from GDLBCL patients was significantly higher than that of healthy individuals. High levels of PD­L1 in plasma exosomes were significantly associated with international prognostic index score, pathological type and advanced Lugano stage, which might lead to the poor prognosis of GDLBCL. Moreover, a high level of PD­L1 in plasma exosomes was significantly associated with an immunosuppressive microenvironment in GDLBCL. Therefore, the results of the present study indicated that exosomal PD­L1 inhibited the proliferation of T lymphocytes and promoted the formation of an immunosuppressive microenvironment in GDLBCL. High expression of exosomal PD­L1 may suggest a poor prognosis of GDLBCL, and exosomal PD­L1 in plasma may be a new diagnostic indicator for GDLBCL.