Aims: Anticholinergic drugs (ACDs) and the neurodegeneration biomarker neurofilament light chain (NfL) are associated with dementia; however, the interplay between anticholinergic drug exposure and neurodegeneration in dementia risk remains underexplored.
Methods: This prospective cohort study analyzed 1529 dementia-free adults (median follow-up 5.2 years) from the Shanghai Aging Study. Cumulative anticholinergic burden was quantified using the anticholinergic cognitive burden (ACB) scale and total standardized daily dose (TSDD) over 1 year pre-baseline. Neurofilament light chain (NfL) levels were assayed via single-molecule array (Simoa).
Results: Elevated NfL (adjusted HR 1.77, 95% CI, 1.07-2.92) and TSDD exposure (HR 1.55, 1.08-2.24) were independently associated with incident dementia risk. Participants with both TSDD exposure and high NfL levels showed substantially greater cumulative dementia incidence versus those with no TSDD/low NfL (log-rank p < 0.0001; adjusted HR 2.24, 1.20-4.20). Individuals with both high TSDD and high NfL demonstrated a significantly higher dementia risk (HR 6.34, 95% CI, 1.90-21.20) compared to low-burden counterparts.
Conclusions: These findings identify plasma NfL as a critical modifier of anticholinergic-related cognitive vulnerability, providing mechanistic insights for risk stratification and supporting biomarker-guided deprescribing strategies in older adults exposed to ACDs.
To characterize white matter geometric pathology in cerebellar subtype of multiple system atrophy (MSA-C) using director field analysis (DFA) and identify stage-specific biomarkers.
We analyzed single-shell diffusion MRI (b = 1000) in 31 MSA-C patients (15 early-, 16 late-stage) and 33 controls. DFA quantified axonal geometry (splay/bend/twist), complemented by fixel-based analysis (FBA) and brainstem volumetry. Group comparisons used threshold free cluster enhancement (TFCE) (p < 0.05 FWE-corrected). DFA-altered regions were correlated with clinical scores. AutoGluon evaluated classification performance using different feature sets.
MSA-C exhibited distinct geometric degeneration patterns: cerebellar pathways showed reduced splay, bend, and twist (reflecting Wallerian degeneration), whereas brainstem tracts demonstrated dissociated geometry (increased splay/bend but decreased twist). Brainstem twist reduction strongly differentiated early- and late-stage MSA-C (AUC = 0.95). Clinically, middle cerebellar peduncle bend correlated with motor progression (UMSARS-II: r = 0.48), while cerebellar splay reduction predicted ataxia severity (SARA: r = −0.43).
DFA captures circuit-specific white matter pathology in MSA-C, with brainstem twist emerging as a novel biomarker associated with disease stage. The integration of geometric metrics with automated machine learning provides a robust framework for early diagnosis and disease staging, highlighting distinct neurodegenerative mechanisms in cerebellar versus brainstem pathways.
Mitochondrial dysfunction is an initial event of the cascade reactions triggered by ischemic stroke, contributing to the pathogenesis of ischemic brain injury. DL-3-n-butylphthalide (NBP), a compound originally isolated from the seeds of Apium graveolens Linn, exerts neuroprotective effects by improving mitochondrial function in ischemic brain tissues; however, the exact molecular mechanisms underlying its action remain poorly understood.
The OGD-exposed neuronal cells and dMCAO mice were used to investigate the effects of ischemia/hypoxia on mitochondrial function and the protective action of NBP on mitochondrial damage. Co-immunoprecipitation and immunofluorescence staining were performed to identify the interaction between Drp1 and GCN5L1. Western blotting, immunofluorescence and immunohistochemical staining were conducted to detect the expression of GCN5L1, Drp1, ERK1/2, Bax, Bcl2, and caspase-3. The mitochondrial function was analyzed by measuring mitochondrial ROS, ATP production, mitochondrial membrane potential (MMP) and mPTP opening.
We observed that mitochondrial dysfunction occurs in OGD-treated neuronal cells and brain tissues of dMCAO mice, as evidenced by the alteration in the mPTP, MMP, ATP content, and ROS levels, which are accompanied by a significant increase in mitochondrial fission and neuronal apoptosis, as shown by TUNEL staining and the changes in Bcl-2, Bax and caspase-3 expression. Importantly, NBP intervention significantly attenuates ischemia/hypoxia-induced mitochondrial dysfunction and cellular apoptosis in the neuron and mouse brains. Mechanistically, NBP not only reverses the upregulation of Drp1 and GCN5L1 expression by ischemia/hypoxia, but also inhibits the ischemia/hypoxia-induced phosphorylation of Drp1 by blocking the ERK1/2 signaling, which in turn suppresses the interaction between Drp1 and GCN5L1, thereby decreasing Drp1 acetylation by GCN5L1 and excessive mitochondrial fission.
Our findings provide a novel insight into the molecular mechanism whereby NBP protects mitochondria against ischemia/hypoxia damage, offering a promising drug for mitochondria-targeting therapeutics for ischemic stroke.
Naringin, a flavanone glycoside (naringenin 7-O-neohesperidose), exhibits a broad range of pharmacological activities, including neuroprotection. However, its effects on autistic-like behavior have not been extensively studied.
In this investigation, we utilized the autistic BTBR T + tf/J (BTBR) mice to conduct behavioral tests assessing autistic-like phenotypes. We evaluated hippocampal neurogenesis through immunofluorescence and employed molecular biological techniques, along with RNA sequencing, to elucidate the underlying molecular mechanisms.
Our findings revealed that the administration of naringin alleviated autism-associated behaviors in BTBR mice. RNA sequencing analysis indicated that naringin facilitated the recovery of impaired hippocampal neurogenesis in these mice, as evidenced by an increase in doublecortin (DCX)-positive cells and neuronal progenitor cells (NPCs) in the dentate gyrus (DG). Furthermore, we confirmed that the cannabinoid receptor type-1 (CB1) plays a role in the therapeutic effects of naringin.
This research highlights the potential of naringin as a promising treatment option for autism spectrum disorder (ASD) and suggests that targeting hippocampal neurogenesis through the CB1 receptor may be an effective strategy.
Growing evidence implicates dysfunctional myelin in the pathogenesis of temporal lobe epilepsy (TLE). Connexin 47 (Cx47), an oligodendrocytic gap junction protein, maintains myelin integrity. This study investigates the role of Cx47 in myelin impairment and seizure progression in TLE.
Cx47 and phosphorylated Cx47 (p-Cx47) expression was analyzed in human and mouse TLE brain tissues via Western blot and immunofluorescence. Candidate Cx47 phosphorylation kinases revealed by single-cell RNA sequencing were validated through immunofluorescence, protein docking, and co-immunoprecipitation. TLE mice were treated with the CaMKII inhibitor KN93 to evaluate its effects on demyelination and seizure burden.
In a experimental mouse model, phosphorylated Cx47 (p-Cx47) was significantly upregulated, recapitulating a similar trend observed in human TLE tissues. This upregulation was accompanied by marked demyelination in the TLE animals. In mice, increased levels of Cx47 and p-Cx47 were associated with elevated CaMKII and phosphorylated CaMKII (p-CaMKII). The interaction between Cx47 and CaMKII was further confirmed. Moreover, administration of KN93 suppressed the upregulation of Cx47 and p-Cx47, thereby mitigating demyelination and reducing seizure progression.
CaMKII-mediated Cx47 expression and phosphorylation promote demyelination and seizure progression in TLE. Targeting Cx47 phosphorylation may offer a therapeutic strategy for TLE.
Focal cortical dysplasia (FCD) is a leading cause of drug-resistant epilepsy, characterized by cortical malformations and aberrant neuronal-glial interactions. Recently, the role of Liver X Receptor Beta (LXRβ) in neurodevelopment has attracted considerable attention, although its involvement in FCD pathogenesis remains unclear.
We established a freezing lesion-cortical dysplasia (FL-CD) model in neonatal mice to mimic the pathological features of FCD. We evaluated the expression of LXRβ and its downstream target, brain lipid-binding protein (BLBP), using immunohistochemistry and Western blot analysis. LXRβ activation and inhibition were pharmacologically modulated to assess their effects on glial migration, differentiation and cortical electrophysiology. Electroencephalogram (EEG) recordings were analyzed for power spectral density and functional connectivity to further investigate alterations in cortical network activity.
LXRβ and BLBP were significantly downregulated in the lesion cortex during early developmental stages. Activation of LXRβ reduced gliosis, promoted astrocytic differentiation, and modified cortical oscillatory activity, as evidenced by enhanced α power and gamma band functional connectivity, along with adjustments in the theta/beta ratio. In contrast, inhibition of LXRβ exacerbated gliosis and disrupted cortical network synchronization.
Our findings demonstrate that LXRβ plays a critical role in regulating glial migration, differentiation and cortical network remodeling in the FL-CD model. Pharmacological modulation of LXRβ may offer a novel therapeutic strategy for restoring neural circuit stability in FCD, highlighting its potential as a molecular target for intervention in drug-resistant epilepsy.
Compared with healthy individuals, epilepsy patients are more prone to arrhythmias, which may contribute to poor prognosis. To enable early identification of this risk, we developed a clinical prognostic prediction model to assess the risk of arrhythmia comorbidity in epilepsy patients, thereby facilitating timely clinical intervention to improve patient outcomes.
We retrospectively collected clinical data from epilepsy patients treated at the Affiliated Hospital of Qingdao University between January 2022 and February 2025, including gender, age, medical history, antiseizure medications, electrocardiograms and electroencephalograms. A total of 495 eligible patients were enrolled and randomly divided into development and validation datasets at a 7:3 ratio. Variable selection was performed using LASSO regression with a penalty term, and the selected variables were incorporated into the construction of a logistic regression model. The area under the receiver operating characteristic curve (AUC) and its 95% confidence interval were used to preliminarily evaluate the model's discriminative ability, while cross-validation and bootstrapping were employed to assess its generalizability. Calibration curves and the Brier score were utilized to evaluate the model's calibration, and decision curve analysis was plotted to analyze the net clinical benefit.
The C-indices for the development and validation datasets were 0.737 (95% CI 0.675–0.799) and 0.790 (95% CI: 0.707–0.884), respectively, with an overall C-index of 0.752 (95% CI: 0.701–0.804). The corresponding sensitivity and specificity were 74.6% and 68.1%, respectively. Finally, a nomogram was constructed for the visual presentation of the predictive model.
Our predictive model can accurately assess the risk of arrhythmia comorbidity in epilepsy patients, assisting clinicians in early intervention to improve prognosis.
Effective remyelination in multiple sclerosis (MS) requires both the proliferation of endogenous neural stem cells (NSCs) and their lineage-specific differentiation into oligodendrocyte progenitor cells (OPCs). This study aimed to investigate whether electroacupuncture (EA) promoted NSC proliferation and OPC differentiation via β-endorphin (β-EP)–mediated opioid signaling in a murine model of MS.
Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice to model MS. EA stimulation was applied daily at the Zusanli (ST36) acupoint. NSC proliferation and OPC differentiation were assessed via immunofluorescence, flow cytometry (FCM), and RT-qPCR. β-EP expression and opioid receptor involvement were evaluated in the hypothalamus and subventricular zone (SVZ). Naloxone, a nonselective opioid receptor antagonist, was used to determine the role of opioid signaling in EA-induced effects.
EA significantly enhanced NSC proliferation and increased the proportion of NSC-derived OPCs in the SVZ of EAE mice. EA treatment improved clinical score, reduced demyelination, and attenuated leukocyte infiltration of the central nervous system (CNS). Mechanistically, EA upregulated β-EP and its precursor pro-opiomelanocortin (POMC), along with opioid receptors μ-opioid receptor (MOR) and κ-opioid receptor (KOR) (encoded by Oprm1 and Oprk1, respectively). Naloxone administration abolished the beneficial effects of EA on NSC behavior and remyelination, confirming the involvement of opioid receptor-dependent β-EP signaling.
EA promotes remyelination in EAE mice by stimulating β-EP-mediated NSC proliferation and OPC differentiation. These findings reveal a novel neuroregenerative mechanism and support EA as a promising adjunctive strategy for demyelinating diseases such as MS.
Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder. However, its diagnosis and effective treatment present challenges. Understanding neurotransmitter impairments may offer new perspectives into the mechanisms underlying ASD and the potential therapeutic targets for this condition. This study aimed to investigate the spatial associations of ASD-related brain activity patterns and multiple specific neurotransmitter distributions to identify abnormal neurotransmitter alterations in patients with ASD, and to assess how these spatial associations relate to clinical features.
We included 44 patients with ASD and 132 typically developing controls (TDCs) and compared the regional homogeneity (ReHo) differences between the two groups. Associations between the spatial patterns of ReHo alterations and specific neurotransmitter receptor/transporter densities in patients with ASD were evaluated, and the correlations of these associations with the clinical characteristics were analyzed.
In comparison with TDCs, patients with ASD exhibited specific brain activity abnormalities in the visuomotor network, cerebro-cerebellar circuits, angular gyrus, and limbic areas. These atypical brain activity patterns were significantly co-localized with the serotonergic, glutamatergic, GABAergic, dopaminergic, noradrenergic, cholinergic, and cannabinoid neurotransmitter systems in patients with ASD, and the results showed good reproducibility between different neurotransmitter maps. Additionally, the awareness score in the Social Responsiveness Scale (ρ = −0.475, p = 0.009) and the social score in the Autism Diagnostic Observation Schedule (ρ = −0.415, p = 0.049) exhibited negative correlations with the strength of ReHo co-localization of serotonin 5-hydroxytryptamine receptor subtype 2a.
This is the first systematic analysis of multiple neurotransmitter systems to show abnormalities in these systems in patients with ASD. These results will enhance the existing understanding of the mechanisms underlying ASD and may provide the foundation for identifying therapeutic targets.
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