The G protein-coupled receptor associated sorting protein 2 (GPRASP2) gene mutation is one of only three deafness genes identified to be implicated in X-linked recessive syndromic hearing loss (SHL) to date. However, the function of GPRASP2 in the auditory system has not yet been fully understood. In this study, we generated Gprasp2-deficient mice and found that they exhibited a hearing loss phenotype and depression-like behaviors. In addition, we observed a disordered arrangement of cochlear hair cells in Gprasp2-deficient mice. GPRASP2 binds to NCAM1. Gprasp2 deficiency decreased NCAM1 level and further enhanced ferritinophagy in cochlear hair cells. This study could improve our understanding of the role of GPRASP2 deficiency in auditory cells, which contributes to the pathophysiology of X-linked SHL.

Background: To analyse the risk factors of Diabetes Mellitus (DM) through a five-year retrospective study of pre-diabetes mellitus (Pre DM) cadres.Methods: The cadres who underwent physical examination and were diagnosed with pre-diabetes in the First People's Hospital of Huzhou City from April 2019 to November 2024 were selected as the research objects, and their basic information (age, gender, body mass index, etc.), lifestyle (diet, exercise, smoking and drinking, etc.), family medical history, biochemical indicators (blood sugar, blood lipid, blood pressure, etc.) and other data were collected. People were divided into two groups based on whether they developed diabetes, and the risk factors for diabetes were determined using univariate analysis and multivariate Logistic regression analysis.Results: A total of 174 Pre DM cadres were included, and 30 of them developed diabetes. Univariate analysis revealed significant differences in age, body mass index, fasting blood glucose, triglycerides, uric acid, blood pressure, blood lipids, liver function, and renal function between the two groups (P< 0.05). The results of the multivariate Logistic regression analysis showed that age, BMI, SBP TG, TC, BUN, TBIL, and ALT were independent risk factors for the development of diabetes in the pre-diabetic healthcare population within 5 years (P< 0.05).Conclusions: This study demonstrates that age, BMI, blood pressure, blood lipid levels, liver and kidney function indexes, and gender are significant risk factors for patients with Pre DM to develop into DM. Monitoring and managing these factors can reduce the risk of pre-diabetes patients progressing to diabetes. This provides personalised health management suggestions for pre-diabetes (Pre DM) cadres and healthcare professionals and also offers theoretical support for the formulation of relevant health policies.

BACKGROUND:Neonatal inflammation increases the risk of adult depression, but the mechanisms remain unclear. Under the two-hit hypothesis, early-life inflammation may enhance vulnerability to later-life stress. Whether neonatal inflammation induces depression susceptibility via microglial priming, and the molecular basis of this process, remain unknown. METHODS:Neonatal mice (postnatal day 4) received intraperitoneal injections of lipopolysaccharide (LPS; 10, 50, or 100 μg/kg) or saline. In adulthood, mice were exposed to a subthreshold 2-week chronic unpredictable mild stress (CUMS) paradigm. Depression-like behaviors, microglial priming, molecular alterations, and DNA methylation were assessed. Genetic (Bag3 knockout) and pharmacological (minocycline; S-adenosylmethionine, SAM) interventions were applied. RESULTS:Neonatal exposure to a moderate dose of LPS (50 μg/kg), but not lower or higher doses, selectively increased susceptibility to adult depression-like behaviors and induced microglial priming in the ventral hippocampus (vHPC). Subthreshold CUMS alone failed to induce microglial activation or depressive phenotypes, but robustly activated primed vHPC microglia, triggered neuroinflammation, and precipitated depressive-like behaviors in neonatally LPS-exposed mice; these effects were fully reversed by minocycline. Neonatal moderate LPS induced sustained BAG3 upregulation in the vHPC. Genetic deletion of Bag3 abolished microglial priming and depression susceptibility. At the epigenetic level, neonatal moderate LPS caused persistent hypomethylation of the Bag3 promoter, which was reversed by SAM supplementation. CONCLUSION:Moderate neonatal inflammation establishes a BAG3-dependent microglial primed state in the vHPC via persistent epigenetic remodeling, thereby enhancing vulnerability to adult stress-induced depression. These findings identify BAG3-centered epigenetic-microglial crosstalk as a critical mechanistic hub linking early-life inflammation to later depression susceptibility.

Oxysterol-binding protein-like 2 (OSBPL2) is a lipid transfer protein that modulates intracellular lipid homeostasis; however, its regulatory role in coordinating iron and fatty acid homeostasis remains largely elusive. A recent study has reported a strong positive correlation between iron overload and the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Herein, we found that OSBPL2 binds to HSP90β, and OSBPL2 deficiency inhibits ACSL4 expression while altering hepatic fatty acid distribution by impairing lipolysis. Depletion of OSBPL2 conferred resistance to ferroptosis via the ACSL4-mediated ferroptosis pathway and further attenuated diet-induced liver fibrosis in mice. Our findings provide important insights into the function of OSBPL2 in ferroptosis and suggest that OSBPL2 may serve as a potential therapeutic target for MASLD.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and nonmotor symptoms, with cognitive impairment significantly affecting patients' quality of life. This study aimed to investigate the relationships among glymphatic dysfunction, white matter (WM) injury and cognitive decline in PD patients. Seventy PD patients and 82 healthy controls (HCs) underwent clinical evaluations and magnetic resonance imaging (MRI) scans. Key metrics included the diffusion tensor imaging-along the perivascular space (DTI-ALPS) index, choroid plexus volume (CPV), white matter free water (WM-FW), and peak width of skeletonized mean diffusivity (PSMD). Statistical analyses included correlation analyses, mediation analysis and receiver operating characteristic (ROC) analyses. PD patients exhibited lower DTI-ALPS index (p < 0.001) and higher CPV (p < 0.001), WM-FW (p = 0.010), and PSMD (p < 0.001) compared to the HCs. The DTI-ALPS index was negatively correlated with WM-FW (r = -0.612, p < 0.001) and PSMD (r = -0.484, p < 0.001), whereas CPV was positively correlated with both (r = 0.613, p < 0.001; r = 0.540, p < 0.001). The DTI-ALPS index correlated positively with Montreal Cognitive Assessment (MoCA) score (ρ = 0.471, p < 0.001). CPV (ρ = -0.421, p = 0.002), WM-FW (ρ = -0.296, p = 0.029), and PSMD (ρ = -0.273, p = 0.044) correlated negatively with the MoCA score. Mediation analysis suggested that DTI-ALPS and CPV may be involved in the association between white matter injury and cognition, but the independent role of each individual indicator was not confirmed. Diagnostic performance evaluations indicated that the PSMD best predicted PD individually (AUC = 0.836), with the integrated four-biomarker model performing best (AUC = 0.855). These findings highlight the correlation between glymphatic function, WM integrity, and cognition in PD patients, supporting the use of these neuroimaging biomarkers for early diagnosis and monitoring of cognitive decline.

OSBPL2 was identified as a causal gene responsible for autosomal dominant non-syndromic hearing loss. Previous study revealed that OSBPL2-mediated AMPK signalling was crucial for cholesterol-homeostasis in inner ear. AMPK is the downstream component of a kinase cascade as the key regulator of autophagy, metabolism, cell growth and apoptosis, etc. In addition, OSBPL2 deficiency could lead to autophagy impairment in auditory cells, indicating the potential role of OSBPL2-mediated AMPK signalling in autophagy. In the present study, autophagy function was characterized in hair cells (HCs) of Osbpl2-knockout mice and in Osbpl2-knockdown HEI-OC1 cells. The results showed that OSBPL2 deficiency impaired autophagy by inhibiting AMPK-TFEB signalling, resulting in aberrant accumulation of lipid droplets and apoptosis in auditory cells, which could be partially reversed by trehalose treatment. This study revealed the implications of OSBPL2 for autophagy in auditory cell and contributed to elucidating the pathogenesis of OSBPL2 mutations in hearing loss.

BACKGROUND:Gestational diabetes mellitus (GDM) affects the transfer of fatty acid (FA) from mother to fetus. However, the specific transport alterations remain unclear. This study investigated FA transport from mother to fetus in GDM. METHODS:Maternal serum, umbilical cord serum, and placental tissues were collected from 20 healthy (normal group) and 20 GDM pregnancies receiving glycemic management (GDM group). Fifty-one FA were quantified by gas chromatography-mass spectrometry. Placenta/mother and fetus/placenta ratios of FA compositions were compared between groups using Student's t-test or Mann-Whitney U test, as appropriate. RESULTS:The concentrations and compositions of FA profiles were both changed in GDM. The placenta/mother ratios of cis-11,14,17-eicosatrienoic acid (GDM vs normal: 0.648 vs 0.484, p = 0.001), cis-5,8,11,14,17-eicosapentaenoic acid (0.449 vs 0.338, p = 0.048), cis-13,16-docosadienoic acid (DDA, 1.436 vs 1.187, p = 0.047), palmitelaidic acid (2.882 vs 2.272, p = 0.023), petroselaidic acid (2.177 vs 1.746, p = 0.004) and linoelaidic acid (1.770 vs 1.423, p = 0.014) were significantly higher in GDM, while the ratio of trans-10-nonadecenoic acid (0.537 vs 0.799, p < 0.001) was lower. The fetus/placenta ratio of total omega-6 long chain polyunsaturated FA (LC PUFA, 0.545 vs 0.590, p = 0.002) with DDA (4.031 vs 4.951, p = 0.031) and cis-7,10,13,16-docosatetraenoic acid (0.494 vs 0.778, p < 0.001) was lower in GDM. CONCLUSIONS:FA profiles in mother, placenta, and fetus were affected by GDM despite glycemic management, especially in omega-3 and omega-6 LC PUFAs. This finding indicates that addressing fetal FA deficiency may depend on correcting placental dysfunction rather than solely increasing maternal FA supplementation, offering insights for developing nutritional and therapeutic strategies for GDM.

OSBPL2 was one of the causal genes responsible for autosomal dominant non-syndromic hearing loss (DFNA) and the pathogenic mechanism of OSBPL2 mutations remain elusive. OSBPL2 was detected to be highly expressed in stria vascularis (SV) of mouse cochleae, in which the blood-labyrinth barrier (BLB) was located as an essential component of cochlear spiral duct. The present study explored a potential pathologic mechanism of OSBPL2 deficiency underlying the structural and functional impact on BLB. Osbpl2-knockout (KO) mice were used to characterize SV permeability, which was measured using FITC-dextran injection. OSBPL2-deficient human umbilical vein endothelial cells (HUVECs) were used to evaluate the endothelial permeability in vitro. Tight junctions (TJs) in SV and HUVECs were characterized using immunofluorescent staining. The results showed that significant SV leakage was detected in cochleae of 10-month-old Osbpl2-KO mice, which was consistent with the increased endothelial permeability in OSBPL2-deficient HUVECs. It was also noted that OSBPL2 deficiency led to TJs disruption and induced inflammation-mediated apoptosis via the activation of NF-κB signaling. This study revealed the potential pathogenic mechanism of OSBPL2 deficiency in SV lesion, which helped to elucidate the underlying pathogenesis of OSBPL2 mutations in DFNA.

INTRODUCTION:To explore microstructure changes across brain white matter and gray matter in tinnitus patients and its effect on neuropsychological performance. METHODS:The cross-sectional study used Multi-shell Diffusion Weighted Imaging data and neuropsychological assessment from 48 tinnitus patients and 48 healthy controls. Microstructural features across over white matter and gray matter based on Diffusion Tensor Imaging (DTI) and Neurite Orientation Dispersion and Density Imaging (NODDI) model using Tract-Based Spatial Statistics (TBSS) and Gray Matter-Based Spatial Statistics (GBSS), as well as topological properties were derived from an advanced tractography model in subjects. Brain-neuropsychological performance correlations were analyzed. RESULTS:Tinnitus patients showed decreased axial diffusivity in forceps minor and right corticospinal tract, increased orientation dispersion in forceps minor, decreased connection strength between the right caudate and pericalcarine, right caudate and superior temporal lobe, and left putamen and cuneus. Global network efficiency and local network efficiency were significantly less in tinnitus patients while feeder connection strength was significantly less in tinnitus patients. The orientation dispersion value mediated the relationship between tinnitus status and Trail Making Test-Part B scores. However, no obvious microstructural changes in gray matter were observed. CONCLUSION:Leveraging multi-shell DWI data, the current study indicated that fiber disruption and internal connectivity organizational changes in brain white matter, rather than gray matter, were more susceptible in tinnitus patients. These microstructural changes in white matter could be associated with changes in cognitive function in tinnitus patients.

Background The basal ganglia area is a frequent site of stroke, which commonly causes intricate functional impairments. This study aims to uncover disparities in static and dynamic functional connectivity (FC) of the brain in patients afflicted with left-sided basal ganglia stroke (L-BGS) and right-sided basal ganglia region stroke (R-BGS), furthermore scrutinising the mechanism behind the lateralisation of the stroke. Methods A total of 23 patients with L-BGS and 20 patients with R-BGS were recruited, alongside 20 healthy control subjects. Resting-state functional magnetic resonance imaging and sliding window techniques were employed to conduct static and dynamic FC analyses on both patient groups and controls, which can enable a more refined evaluation of the variations in neural signals. Results The inter-network connectivity analysis showed significant changes only in the L-BGS patient group (p < 0.05). The R-BGS group showed increased connectivity in the auditory and posterior visual networks, while the L-BGS group showed reduced connectivity. In dynamic connectivity analyses, the L-BGS group exhibited greater positive network connectivity reorganization. Conclusion Within one month of stroke onset, the L-BGS group showed a more pronounced impairment of inter-network connectivity, alongside enhanced FC compensatory changes of a positive nature. Differential changes in the two patient groups may provide useful information for individualized rehabilitation strategies.

Background:Chemotherapy-related cognitive impairments (CRCIs) are frequently reported by patients with non-small cell lung cancer (NSCLC) following chemotherapy treatment. Studies have revealed that cognitive impairment may be linked to abnormal spontaneous neuronal activity and changes in cerebral blood flow (CBF). However, the specific impact of neurovascular coupling (NVC) alterations on patients who have undergone chemotherapy has not been clarified. The aim of this study was to examine the variations in NVC in patients with lung cancer postchemotherapy and to determine potential correlations between these NVC alterations and neurocognitive dysfunction. Methods:A sample of 43 patients with NSCLC was recruited, including 20 patients treated with chemotherapy [CT(+)] and 23 chemotherapy-naïve [CT(-)] individuals who underwent pseudocontinuous arterial spin labeling (pCASL) scans and resting-state functional magnetic resonance imaging (rs-fMRI), along with neurocognitive evaluations. Global and regional NVC indices were assessed according to correlation coefficients and the ratios between CBF and neuronal activity-derived metrics, including the amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo). Statistical analyses were conducted to calculate the difference between groups and characterize relationships between alterations in global and regional NVC and cognitive performance. Results:In comparison to the CT(-) group, the CT(+) group exhibited significantly lower coupling strength for global CBF-ALFF and CBF-ReHo correlations (P<0.05). Regionally, the CT(+) group demonstrated a decreased CBF:ALFF ratio in the right middle temporal gyrus (MTG) and left middle frontal gyrus (MFG), as well as an increased CBF:ALFF ratio in the left thalamus and left parahippocampal region. Furthermore, the CT(+) group had higher CBF:ReHo ratios in the left precuneus, right central operculum, right inferior parietal lobule, and right superior occipital gyrus but lower CBF:ReHo ratios in the left inferior frontal gyrus and right MFG (false-discovery rate-corrected P value <0.05). Notably, there was a negative correlation observed between Montreal Cognitive Assessment scores and memory scores and the CBF:ALFF ratios in the right MFG and left parahippocampal region. Conclusions:This research offers comprehensive insights into the neurological foundations of CRCI. The application of multimodal neuroimaging analyses combining rs-fMRI and pCASL may uncover the induction of neurovascular decoupling in lung cancer patients undergoing chemotherapy.

The ApoE-ε4 gene is a well-established genetic risk factor for neurodegenerative diseases, such as Alzheimer’s disease and multiple sclerosis, which are characterized by axonal demyelination in the central nervous system. Recent studies have implicated ApoE-ε4 in age-related hearing loss (ARHL), suggesting a potential role of APOE4 isoform in peripheral nervous system degeneration. However, the role of APOE4 in ARHL are still unclear. In this study, we explored the potential role of APOE4 in axonal demyelination of spiral ganglion neurons (SGNs). ApoE-ε4/ε4 (APOE4) and ApoE-ε3/ε3 (APOE3) mice were used to characterize SGNs. The effect of APOE4 on phagocytosis and autophagy as well as intracellular cholesterol level was evaluated in resident cochlear macrophages (RCMs) and mouse bone marrow-derived macrophages (BMDMs). The results showed that significant axonal demyelination was observed in SGNs of 10-month-old APOE4 mice, accompanied by the presence of myelin debris engulfed by RCMs. Meanwhile, inhibited phagocytosis of myelin debris and impaired lipophagy were detected in APOE4 RCMs and APOE4 BMDMs with an aberrant accumulation of lipid droplets (LDs), which could be reversed by trehalose treatment. This study provided a deep insight into the pathogenesis of APOE4-induced axonal demyelination of SGNs associated with the impaired lipophagy in RCMs, which helped to elucidate the underlying mechanism of ApoE-ε4 in ARHL.

PURPOSE:Metabolic disturbances are hallmark pathological features of Parkinson's disease (PD) and can be noninvasively captured by arterial spin labeling (ASL). However, the metabolic pattern of disconnections beyond regional alterations remains scarcely documented. We aimed to comprehensively investigate metabolic impairments in PD at the individual network scale by utilizing abundant hemodynamic metrics. METHODS:The multi-delay (m-ASL) was employed to obtain corrected cerebral blood flow (CBF), arterial cerebral blood volume and arterial transit time from groups of PD patients and healthy controls (HCs). For the comparison or cross-modality analysis, the uncorrected CBF and grey matter volume were also acquired via the ASL approach with single post-labeling delay (s-ASL) and T1 sequences, respectively. Metabolic similarity network (MSN) based on perfusion data and structural similarity network (SSN) were constructed for each individual, followed by analyses of connectivity, topology, classification and coupling. RESULTS:Metabolic similarity networks in patients with PD belong to small-world connectomes but exhibit decreased global integration and local segregation at the global level. The impairments in nodal centralities, modular architectures and connectivity strengths were diverse among MSNs. m-ASL improved the diagnostic efficiency of CBF-MSN by the CBF correction and further optimized the classification performance via the integration of all MSNs. Decoupling of SSN-MSN presented pathologically increased coefficients within subnetworks, deriving from altered metabolic and structural connectivity. CONCLUSION:Our study revealed the complex metabolic disconnections and SSN-MSN decoupling that underlie the complicated neurodegenerative process in PD, highlighting the clinical implications of m-ASL for comprehensive investigations of the metabolic pattern of disconnection syndromes.

Age-Related Hearing Loss (ARHL), a prevalent sensory deficit linked to cognitive decline, lacks well-defined neuropathological mechanisms. This study investigated glymphatic dysfunction and brain network reorganization in ARHL using multimodal MRI. We enrolled 178 participants (69 healthy controls, 79 mild ARHL, 30 moderate ARHL), assessing glymphatic activity via diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, perivascular space (PVS) volume, choroid plexus volume (CPV), and functional network topology. Results revealed progressive glymphatic impairment (DTI-ALPS decline, PVS volume enlargement, and increased CPV) alongside cognitive decline, reflected by reduced Montreal Cognitive Assessment (MoCA) and Complex Figure Test-delayed recall (CFTd) scores. Brain networks exhibited abnormal global and nodal metrics. Mediation analysis demonstrated that glymphatic dysfunction partially explains the association between disrupted global network efficiency and cognitive deficits. A combined biomarker model (DTI-ALPS + PVS + CPV) demonstrated superior diagnostic accuracy compared to individual markers. These findings indicate that glymphatic dysfunction and brain network reorganization are associated with ARHL severity, with the integrated biomarker panel showing potential for clinical stratification.

Background:The neural mechanisms associated with age-related hearing loss (ARHL) and their broader implications for brain function remain incompletely understood. This study explored the dynamic network reconfiguration in ARHL using dynamic graph theory and multilayer network analysis. Methods:Resting-state functional magnetic resonance imaging (MRI) assessments were conducted on 62 patients with ARHL and 58 healthy controls (HCs) matched for age (≥60 years), sex (ARHL: 32 males, 30 females; HCs: 30 males and 28 females), and education level (all at least 8 years). Cognitive performance was comprehensively assessed in both groups with a battery of standardized neuropsychological tests. Dynamic brain functional networks were analyzed via graph theory to investigate local and global network metrics. Multilayer network analysis was employed to identify changes in global brain network exchanges in ARHL. Spearman correlation analysis was used to calculate the relationship between functional MRI data and cognitive scores. Results:No demographic differences were observed between patients with ARHL and HCs (P>0.05). However, patients with ARHL exhibited significantly poorer pure-tone audiometry results (P<0.001) and inferior performance on both Trail Making Test-B and Complex Figure Test delayed tests (P<0.05). The ARHL group exhibited reduced local efficiency (P=0.01) and increased node efficiency (P=0.00054). Significant differences in network-switching rates were observed in the left orbital middle frontal gyrus (P=0.006), right frontal orbital inferior (P=0.032), right olfactory cortex (P=0.010), left medial superior frontal gyrus (P=0.045), right middle occipital gyrus (P=0.021), right superior parietal gyrus (P=0.008), left inferior parietal lobule (P=0.034), right caudate nucleus (P=0.020), left globus pallidus (P=0.007), and left superior temporal pole (TPOsup.L) (P=0.022). The network-switching rate of the left TPOsup in the ARHL group was positively correlated with cognitive scores (r=0.270; P=0.034). Conclusions:Based on dynamic graph theory and multilayer network analysis, abnormal dynamic network reconfiguration in patients with ARHL were revealed, with reduced network-switching rates in several brain regions. These findings highlight the functional significance of network-switching rates and provide new insights into the neural mechanisms associated with ARHL.

Mutation in oxysterol-binding protein-like 2 ( OSBPL2) has been identified as the genetic cause of autosomal dominant nonsyndromic hearing loss (DFNA67, OMIM No. 616340). However, the pathogenesis of the OSBPL2 mutation in DFNA remains unclear. Our previous work showed that OSBPL2 deficiency impaired cell adhesion in auditory HEI-OC1 cells. In addition, loss of hair cells (HCs) and morphological abnormalities of HC stereocilia were detected in OSBPL2-disrupted pigs, suggesting that OSBPL2 plays an important role in the regulation of the actin cytoskeleton in auditory cells. In the present study, we found that OSBPL2 deficiency inhibited the Rho/ROCK2 signaling pathway and downregulated phosphorylated Ezrin-Radixin-Moesin (p-ERM), resulting in abnormal F-actin morphology in HEI-OC1 cells and stereociliary defects in mouse HCs. The present study demonstrates the underlying mechanism of OSBPL2 in the regulation of the actin cytoskeleton in HCs, which contributes to a deeper understanding of the pathogenesis of OSBPL2 mutations in DFNA.

The mechanisms linking hearing ability, inflammation, glymphatic system function, and cognitive impairment in older adults are largely unknown. To investigate this issues, magnetic resonance imaging (MRI) was used to test for dysfunctions in the glymphatic system of older adults with hearing loss and to determine the relationship of glymphatic dysfunction, inflammation and cognitive deficits. This cross-sectional observational study included participants with ARHL and healthy controls (HCs) between January 2021 and December 2023. Participants underwent MRI scans of the glymphatic indices and clinical assessment of auditory, neuropsychological, and inflammatory measures. Multimodal MRI indices were used as proxies of glymphatic function and compared with measures of inflammation and cognition dysfunction in the older adults with hearing loss and control groups. Mann–Whitney U test, Spearman rank correlation and Mediation analysis were conducted. A total of 130 hearing loss patients (mean age years, 64.10 ± 3.43 [SD], 67 males) and 121 healthy controls (mean age years, 63.55 ± 3.49 [SD], 68 males) were included. The hearing loss group differed significantly from normal hearing control on MRI glymphatic measures of choroid plexus volume (CPV) (1.48 vs 1.37, p = 0.0004), enlarged perivascular spaces (EPVS) (1.74 vs 1.55, p < 0.0001) and diffusion tensor image analysis along the perivascular space (DTI-ALPS) (1.47 vs 1.63, p < 0.0001). Hearing loss severity was associated with higher values of CPV and EPVS and lower values of ALPS and strongly correlated with higher levels of inflammation (all FDR q < 0.05). Mediation analysis showed that ALPS and CPV mediate the relationship between hearing loss and scores on the Montreal Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST), respectively. Our findings support a potential associative pathway that inflammation and glymphatic dysfunction act as plausible intermediate factors facilitating the pathological relationship linking the increase in hearing loss in older adults to decline in cognition.

PurposeSensorineural hearing loss (SNHL) is the most common form of sensory deprivation and is often unrecognized by patients, inducing not only auditory but also nonauditory symptoms. Data-driven classifier modeling with the combination of neural static and dynamic imaging features could be effectively used to classify SNHL individuals and healthy controls (HCs).MethodsWe conducted hearing evaluation, neurological scale tests and resting-state MRI on 110 SNHL patients and 106 HCs. A total of 1,267 static and dynamic imaging characteristics were extracted from MRI data, and three methods of feature selection were computed, including the Spearman rank correlation test, least absolute shrinkage and selection operator (LASSO) and t test as well as LASSO. Linear, polynomial, radial basis functional kernel (RBF) and sigmoid support vector machine (SVM) models were chosen as the classifiers with fivefold cross-validation. The receiver operating characteristic curve, area under the curve (AUC), sensitivity, specificity and accuracy were calculated for each model.ResultsSNHL subjects had higher hearing thresholds in each frequency, as well as worse performance in cognitive and emotional evaluations, than HCs. After comparison, the selected brain regions using LASSO based on static and dynamic features were consistent with the between-group analysis, including auditory and nonauditory areas. The subsequent AUCs of the four SVM models (linear, polynomial, RBF and sigmoid) were as follows: 0.8075, 0.7340, 0.8462 and 0.8562. The RBF and sigmoid SVM had relatively higher accuracy, sensitivity and specificity.ConclusionOur research raised attention to static and dynamic alterations underlying hearing deprivation. Machine learning-based models may provide several useful biomarkers for the classification and diagnosis of SNHL.

G protein-coupled receptor-associated sorting protein 2 (GPRASP2) has been identified as the causative gene for X-linked recessive syndromic hearing loss (SHL) in our previous study. However, the role of GPRASP2 in auditory function remains unclear. The present study demonstrated that Gprasp2 overexpression in mouse organoids promoted the proliferation of supporting cells (SCs), which was mainly mediated by the Hedgehog signalling pathway. Meanwhile, GPRASP2 promoted hair cell (HC) formation from SCs via β-catenin signalling. In addition, GPRASP2 deficiency resulted in increased lysosomal degradation of SMO protein, leading to decreased expression of β-catenin and the Hedgehog pathway transcription factor GLI1. In neomycin-treated mouse cochlear explant, the smoothened agonist (SAG) recured the HC loss and further facilitated AAV-ie-Gprasp2 to promote the proliferation of SCs and formation of HCs. Our results suggested that GPRASP2 could be a potential candidate for gene therapy in the regeneration of HCs.

Objective The hippocampus and amygdala, as important components of the limbic system, play crucial roles in central remodeling in congenital hearing loss. This study aimed to investigate the morphological integrity and network properties of the subfields of hippocampus and amygdala in children with congenital hearing loss. Methods A total of 24 children with congenital hearing loss and 17 age- and sex- matched healthy controls (HC) are included in the study. T1-weighted images are analyzed by segmenting the brain into cortical and subcortical regions. Intergroup difference of volumes were explored. Structural covariance networks for the whole brain and hippocampus-amygdala subregions were constructed. Between-group differences of network property are investigated by comparing area under a range of network sparsity. Results Patients with congenital hearing loss exhibited significantly larger volumes in the right dentate gyrus and CA3 of the hippocampus. However, there were no significant differences in total hippocampal or showed decreased global efficiency and increased characteristic path length, indicating reduced network integration. Lower betweenness centrality was observed in the left hippocampal fissure in the hearing loss group. The changes in volume and network topological properties are not affected by age and sex. Conclusion Children with congenital hearing loss display specific volumetric increases in hippocampal subregions, suggesting compensatory adaptations to auditory deprivation. The hippocampus-amygdala network shows significant reorganization, potentially underpinning cognitive and behavioral development issues associated with congenital hearing loss. These findings highlight the importance of targeted neural substrates in understanding and addressing the developmental challenges faced by children with congenital hearing loss.