Olfactory stimulation has emerged as a non-invasive strategy to modulate brain function; however, the molecular mechanisms linking odorant-receptor interactions to central neurobiological outcomes remain poorly defined. In this study, we investigated the antidepressant-like effects of linalyl acetate (LA) and elucidated its olfactory-driven signaling mechanisms using integrated computational, transcriptomic, and in vivo approaches. In silico analyses identified OR2B3 as a candidate olfactory receptor for LA, supported by structural similarity assessment and docking simulations. In human nasal epithelial cells, LA treatment induced coordinated transcriptional programs enriched for olfactory receptors, chemosensory cilia, GPCR signaling, and synapse-related pathways, indicating activation of receptor-guided sensory signaling networks. These findings were further supported by RT-PCR validation, which confirmed significant upregulation of OR2B3 and OR6A2, as well as modulation of cilium-associated signaling components, including ADCY3. In vivo, repeated LA inhalation significantly reduced immobility time in the tail suspension test, demonstrating antidepressant-like behavioral effects. These behavioral outcomes were accompanied by decreased serum corticosterone and pro-inflammatory cytokines, together with increased brain-derived neurotrophic factor levels in serum, cerebral cortex, and hippocampus. Neurochemical analyses further revealed enhanced monoaminergic (dopamine, noradrenaline, serotonin) and cholinergic signaling. Transcriptomic profiling of the olfactory bulb and hippocampus revealed dose-dependent enrichment of metabolic, synaptic, neurotrophin, and intracellular signaling pathways, highlighting coordinated metabolic-synaptic coupling and neuroplasticity-associated programs. Collectively, these findings demonstrate that LA engages olfactory receptors to activate cilia-centered chemosensory signaling that propagates into central metabolic, synaptic, and neurotrophic networks, ultimately modulating stress-related neurobiology. This study establishes a molecular framework for odorant-mediated neuromodulation and supports the therapeutic potential of olfactory-based interventions for mood regulation.
Across the globe, rates of mood and anxiety disorders have been increasing steadily, a trend accelerated by the COVID-19 pandemic. Stress triggers these disorders, precipitating initial episodes and provoking relapses. In this perspective, we argue that the stress system is not merely a threat mechanism but also an ongoing and active monitor of the environment and that resilience is not simply the lack of sensitivity to stress but an active function with an intrinsic neurobiology. Through the interplay of genetic, developmental, and experiential mechanisms, individuals evolve their own "stress-resilience algorithm" that determines their stress reactivity and the resulting adaptive or maladaptive consequences. This algorithm represents a dynamic, lifelong process that is often self-reinforcing. We underscore the importance of focusing on prevention by assessing and enhancing an individual's "stress fitness." This perspective offers a new conceptualization of the neurobiology of stress and resilience as a framework for basic and translational neuroscience research aimed at confronting the challenges of stress disorders.
Growing evidence challenges the long-standing assumption that the paternal germline is insulated from environmental perturbation and identifies preconception paternal exposure as an underrecognized pathway of developmental neurotoxicity. Across mammalian models, paternal exposure to substances of abuse, including cocaine, nicotine, ethanol, morphine, and cannabinoids, induces reproducible, often sex-specific alterations in offspring brain function and behavior, including changes in cognition, stress responsivity, reward processing, and affective behaviors, accompanied by transcriptional and epigenetic modifications. A critical but underappreciated determinant of these outcomes is exposure design, particularly exposure duration relative to the spermatogenic cycle, which emerges as a primary toxicodynamic relevant variable. Exposures spanning a full spermatogenic cycle frequently produce persistent neurobehavioral and molecular alterations, whereas shorter exposures targeting late spermatids or mature sperm can also generate robust offspring phenotypes, highlighting stage-specific germ cell vulnerability. Importantly, delaying mating beyond a complete spermatogenic cycle often attenuates offspring effects, suggesting that temporal separation between exposure and conception may mitigate neurodevelopmental risk. Mechanistically, paternal exposures disrupt sperm epigenetic regulation, including altered DNA methylation, histone modifications, and small RNA profiles, often linked to germline oxidative stress as a potential upstream mediator. Exposure dose and route further modulate transmission through pharmacokinetic effects on systemic and germline exposure. We propose a stage-specific framework in which paternal transmission magnitude and persistence are primarily determined by exposure duration relative to spermatogenesis, with dose and route acting as key modifiers. This framework integrates behavioral and molecular findings and provides a biologically grounded basis for developmental neurotoxicity risk assessment and male preconception health.
Cognitive impairment (CI) is a frequent and disabling manifestation of multiple sclerosis (MS), yet its molecular underpinnings remain poorly understood. This study aimed to identify microRNA (miRNA) signatures and related gene expression changes associated with CI in MS. Forty-six people with MS underwent clinical, radiological, and cognitive assessment. Peripheral blood mononuclear cells were collected for miRNA profiling using the miRCURY LNA miRNA Focus PCR Panel and validated through RT-qPCR. Experimentally validated miRNA target genes were retrieved using miRWalk with miRTarBase filtering. Target networks were constructed in Cytoscape, followed by protein-protein interaction analysis using STRING and functional enrichment analysis with database for annotation, visualization, and integrated discovery (DAVID) ( https://davidbioinformatics.nih.gov/ ). Selected target genes were further evaluated by gene expression analysis. The results showed that three miRNAs (i.e., miR-146a-5p, miR-let-7a-5p, and miR-21-5p) were significantly dysregulated in patients with MS with CI compared to those with preserved cognition. Gene expression analysis identified differential regulations of IL-1B, IL-6, SLC16A10, and NEFL, supporting the involvement of inflammatory and neurodegenerative pathways. Correlation analyses indicated specific miRNA-mRNA relationships underlying these alterations. These findings suggest that the combined dysregulation of miR-146a-5p and miR-21-5p, together with their target genes, constitutes a molecular signature associated with CI in MS. This profile could contribute to the development of miRNA-based biomarkers for early detection and monitoring of cognitive dysfunction in MS.
Social behavior depends on neural circuits that encode social identity, memory, and motivational value. These processes engage coordinated activity across hippocampal subregions, medial prefrontal cortex, thalamic and hypothalamic nuclei, as well as the mesocorticolimbic dopaminergic systems that regulate internal state, hierarchy, and social reward. In Rett syndrome and MeCP2-deficient rodent models, basic sociability is often preserved, alongside impairments in social memory, dominance behavior, aggression control, and flexible social responding, frequently accompanied by anxiety-like and sensorimotor disturbances. These behavioral phenotypes are associated with MeCP2-dependent molecular dysfunctions, including altered activity-dependent transcription, reduced BDNF-TrkB signaling, disrupted synaptic maturation, and altered network activity within prefrontal and hippocampal circuits. Together, these findings indicate that Rett-related social deficits reflect impaired integration and valuation of social information rather than a primary loss of social interest. Understanding how MeCP2 regulates the development and function of distributed social circuits may inform strategies to restore adaptive social behavior in Rett syndrome and related neurodevelopmental disorders.
Sex differences in autism spectrum disorder (ASD) are increasingly recognized, not only in symptom presentation but also in underlying neurobiology and response to environmental factors. However, current diagnostic practices and animal models are male-centric, overlooking female-specific phenotypes and mechanisms. We conducted a multimodal, cross-species study to assess sex-dependent ASD phenotypes. In high-functioning adults with ASD and typically developing (TD) controls, we evaluated self-reported autistic traits, self-reported sensory sensitivity, and clinician-observed behaviors using standardized tools: Autism-Spectrum Quotient, Adolescent/Adult Sensory Profile, and Autism Diagnostic Observation Schedule, Second Edition (ADOS-2). In parallel, we assessed behavioral phenotypes in a paternal 15q11-q13 duplication mouse model (15q dup/+) using open-field, light-dark transition, and augmented reality-based behavioral assays. Among humans, individuals with ASD showed greater self-reported sensory sensitivity and autistic traits than TD individuals. Within the ASD group, female participants reported greater self-reported sensory sensitivity and exhibited lower clinician-rated impairments (ADOS-2) than male participants, despite comparable self-reported autistic traits. No sex differences were found among TD individuals. In contrast, female 15q dup/+ mice exhibited heightened light-related sensory reactivity and reduced exploratory behavior under bright light. These findings suggest that sex differences in light-related sensory reactivity may be more readily detected through behavioral measures in animal models. Our findings underscore the importance of considering sex as a biological and behavioral variable in ASD research. Cross-species, phenotype-oriented approaches that integrate human and animal data may uncover subtle phenotypic variations and enhance sex-informed diagnostics and interventions.
Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons, with mitochondrial dysfunction playing a critical role in its pathogenesis. As a critical organelle in eukaryotic cells, mitochondria not only serve as the central hub for energy metabolism but also play a pivotal role in regulating inflammation and cell apoptosis. However, mitochondrial damage leads to the accumulation of reactive oxygen species (ROS), oxidative stress, and abnormal aggregation of α-synuclein (α-Syn), which collectively contribute to neuronal injury and cell death. Therefore, targeting mitochondrial dysfunction has emerged as a promising therapeutic approach for PD. Exosomes, as extracellular vesicles (EVs) secreted by cells, encapsulate various substances, including proteins, nucleic acids, and lipids. Exosomes exhibit inherent targeting ability, high stability, and low immunogenicity. Additionally, the molecular contents within exosomes can regulate the biological responses of recipient cells by modulating cellular functions and signaling pathways. These characteristics of exosomes have contributed to significant achievements in the treatment of neurodegenerative diseases over the years. This review explores the latest advancements regarding the impact of stem cell-derived exosomes on mitochondrial function in PD, focuses on the regulation of mitochondrial dysfunction in recipient cells by the exosomal cargo, and presents recent evidence that suggests mitochondrial components within exosomes may facilitate cellular recovery. The aim is to provide new insights into potential therapeutic strategies for PD and to highlight directions for future research.
The Disrupted-in-Schizophrenia 1 (DISC1) gene and negative symptoms in schizophrenia are both implicated in neurodevelopmental abnormalities. However, their relationship remains unclear. Thus, this study aimed to compare plasma DISC1 levels and negative symptoms severity between first-episode schizophrenia (FDS) patients and healthy controls (HCs), and examine their association. Sixty-six FDS patients meeting the DSM-IV diagnostic criteria, and 66 age- and sex-matched HCs were enrolled in this case-control study. Plasma DISC1 protein levels were measured by enzyme-linked immunosorbent assay (ELISA). Negative symptoms were assessed using the Clinical Assessment Interview for Negative Symptoms (CAINS). Compared to HCs, patients showed significantly higher CAINS scores for Motivation and Pleasure (MAP, F (1,130) = 5.24, p = 0.02), Expression (EXP, F (1, 130) = 33.89, p < 0.001), and total symptoms (F (1, 130) = 15.14, p < 0.001), alongside lower plasma DISC1 levels (F (1, 130) = 4.622, p = 0.034) after adjusting for convariates. Plasma DISC1 levels were negatively correlated with EXP score in patients (r = -0.30, p = 0.02), but not shown in HCs (r = -0.14, p = 0.26). Multiple linear regression identified lower plasma DISC1 levels as an independent predictor of higher EXP score in patients (β = -3.46, t = 2.23, p = 0.03), but not in HCs (β = 0.15, t = 0.29, p = 0.77). These findings suggest that reduced plasma DISC1 levels in FDS patients are significantly associated with greater expressive deficits, further supporting a potential role for DISC1 in the neurobiology of negative symptoms of schizophrenia.
Spinocerebellar ataxias (SCAs) are a group of neurodegenerative diseases characterized by progressive cerebellar dysfunction, which leads to impaired coordination, dysarthria, oculomotor disorders, and subsequently to a marked reduction in quality of life and high disability. In addition to the main motor symptoms, patients often suffer from cerebellar cognitive-affective syndrome, depression, and sleep disturbances. Despite advances in understanding the molecular and genetic underpinnings of SCAs, there are currently no disease-modifying therapies approved by the FDA (U.S. Food and Drug Administration) or EMA (European Medicines Agency), and management remains largely symptomatic, focusing on improving quality of life and functional independence. Recent systematic reviews and clinical guidelines emphasize a combination of pharmacological, non-pharmacological, and novel gene and cell therapies that are currently under investigation, with varying levels of evidence for their efficacy. The transition to precision medicine and early intervention at the pre-ataxic stage are essential for effectively combating neurodegeneration. This review summarizes the latest data on the treatment of SCA, including existing and new treatments, their effectiveness, limitations, and future prospects.
The medial olivocochlear (MOC) efferent system modulates outer hair cell (OHC) excitability and protects cochlea from overstimulation. Cholinergic activation of α9α10 nicotinic acetylcholine receptors (nAChRs) triggers Ca⁺2 influx, activating BK and SK2 Ca⁺2-dependent K⁺ channels, and K⁺ extrusion through KCNQ4 to restore membrane potential. KCNQ4-loss causes chronic depolarization, OHC dysfunction, and hearing loss. Here, we investigated how KCNQ4 deficiency affects cochlear efferent synapse development and organization. Using confocal immunofluorescence, we analyzed efferent innervation in the organ of Corti of Kcnq4-/- (KO) and Kcnq4+/+ (WT) mice at 2, 3, 4, and 10 postnatal weeks (W). At 2 W, efferent terminals were similarly distributed between basal and lateral OHC membrane domains in both genotypes. During maturation, WT mice exhibited complete relocation of MOC terminals to the basal domain, whereas KO mice showed delayed maturation, with some terminals laterally displaced up to 10 W. KCNQ4 absence was associated with reduced number and volume of synaptic vesicles per efferent boutons on OHCs. Milder morphometric alterations were observed in efferent boutons within the inner hair cell region. At the molecular level, qPCR revealed downregulation of α10 nAChR subunit, BK, and SK2 transcripts in KO at 4 W, with recovery to 10 W. Despite this recovery, BK protein showed reduced expression, mislocalization, and disorganized synaptic plaques in OHCs. KO also displayed age-dependent upregulation of the calcium-binding proteins calbindin and calretinin, suggesting compensatory responses to altered Ca+2 homeostasis. Together, these findings demonstrate that KCNQ4 is essential for OHC repolarization, maturation and maintenance of cochlear efferent synapses.
Disease-modifying therapies have significantly influenced the clinical course of spinal muscular atrophy (SMA), yet objective biomarkers for monitoring disease progression and treatment remain limited. We profiled four muscle-specific miRNAs (myomiRs), ten bioinformatically predicted mRNA targets, two functionally associated lncRNAs, and SMN transcripts in whole blood from 50 adults with SMA types II-IV. Using RT-qPCR, we assessed associations between baseline RNA expression and demographic and clinical parameters, including SMA type, ambulatory status, motor and respiratory function, and explored longitudinal changes during nusinersen (24 months) and risdiplam (6/12 months) treatment. At baseline, miR-206 was higher in type III than in type II and in ambulatory compared to non-ambulatory patients, while it correlated positively with motor and respiratory function and with SMN mRNA variants (total, FL, and ∆7). SMN transcript levels were higher in patients with more SMN2 copies and in ambulatory patients and showed positive correlations with motor and respiratory function. miR-133a-3p and miR-133b correlated negatively with upper limb and respiratory function, and sex-related differences were observed for miR-133a-3p, FGFR1, ANXA2, and LINCMD1. During nusinersen treatment, we observed a decrease in miR-206, LINCMD1, and lnc-GJA1-2, alongside modest reductions in SMN-∆7 and total SMN. In contrast, risdiplam induced a peripheral splicing shift: SMN-FL and the FL/∆7 ratio increased, while SMN-∆7 decreased; miR-133a-3p also decreased at 6 months. By integrating muscle-derived RNAs, particularly miR-206, with blood SMN2 splicing changes, we propose a composite, blood-based biomarker approach for assessing SMA status and treatment-associated molecular changes and highlight myomiR-lncRNA-mRNA networks that suggest disease-relevant mechanisms.
The ribosome has emerged as a signalling hub that can sense metabolic perturbations and coordinate responses that either restore homeostasis or initiate cell death. The range of insults that signal via the ribosome and the mechanisms governing such cell fate decisions remain uncharacterized. Here we identify the atypical E3 ligase HOIL-1 as an unexpected node in the ribosome signalling network that resolves cellular stress. We find that truncating HOIL-1 mutations associated with dilated cardiomyopathy exacerbate cardiac dysfunction in mice and broadly sensitize cells to nutrient and translational stress. These diverse signals converge on the MAP3K ZAKα, a sentinel of ribotoxic stress. Mechanistically, HOIL-1 promotes ribosome ubiquitination and facilitates cytoprotective ribosome-associated quality control. HOIL-1 loss of function causes glucose starvation to become ribotoxic, leading to ZAKα-dependent ATF4 activation and disulfidptosis driven by the cystine-glutamate antiporter xCT. These data reveal a molecular circuit controlling cell fate during nutrient stress and establish the ribosome as a signalosome that responds to cellular glucose levels.
Compulsive behaviors across psychiatric diagnoses often recur despite diagnostic clarity, pharmacologic stabilization, and structured psychotherapy. Substance use disorders and behavioral addictions demonstrate high relapse rates, particularly under stress, while many patients describe not a pursuit of pleasure but an inability to tolerate stillness, boredom, or emotional deadness. Although the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) provides descriptive reliability and the Research Domain Criteria (RDoC) framework advances dimensional neurobiological insight, neither alone offers a clinically operational explanation for stress-triggered recurrence. This discussion paper proposes the Imprinted Arousal Pattern (IAP) framework, a transdiagnostic clinical reasoning model conceptualizing compulsive behaviors as conditioned arousal-affect-meaning-behavior loops consolidated through reinforcement and stress sensitization. The framework draws from addiction science, conditioning theory, attachment research, and trauma-informed neurobiology and is mapped onto RDoC domains. IAP reframes compulsive behaviors as learned regulatory architectures-once adaptive solutions for managing threat, shame, or dysregulation, now rigid and self-perpetuating across contexts. The framework provides a structured explanation for intolerance of low-arousal states and predictable stress-reactive relapse and translates into practical assessment and treatment considerations for psychiatric-mental health nurse practitioners. By shifting focus from symptom suppression to restructuring maladaptive regulatory systems, IAP offers a coherent, dignity-preserving formulation for compulsive behaviors. As a portable explanatory framework, it provides structured language for patterns long recognized in psychiatric nursing practice but insufficiently named.
Neuromyelitis optica (NMO) is a severe autoimmune disorder of the central nervous system (CNS) characterized by aquaporin-4 antibody (AQP4-IgG)-mediated astrocyte injury. IL-1β-mediated inflammatory signaling plays a critical role in amplifying astrocyte damage and propagating CNS inflammation in NMO. However, the astrocyte-intrinsic mechanisms linking IL-1β signaling to downstream pathways, such as STING activation, remain poorly understood. To address this knowledge gap, in this study, we aim to elucidate the astrocyte-intrinsic mechanisms, specifically the IL-1β-IL-1R STING signaling axis, that contribute to NMO pathogenesis, and to evaluate the therapeutic potential of IL-1β-targeting antisense oligonucleotides (ASOs). Using a multi-level experimental system comprising in vitro primary astrocytes, ex vivo organotypic cerebellar slices, and in vivo NMO mouse models, we systematically investigated the critical role of the astrocytic IL-1β-IL-1R STING signaling axis in NMO pathogenesis. Utilizing diverse interventions-including an IL-1β-neutralizing antibody, astrocyte-specific IL-1β knockout, the IL-1R inhibitor Anakinra, STING genetic ablation, and IL-1β ASOs-in conjunction with behavioral, histopathological, and molecular analyses, we comprehensively delineated the impact of this signaling pathway on NMO pathology. These data support the translation of targeted therapeutic strategies. IL-1β signals through the IL-1 receptor (IL-1R) to induce STING-dependent proinflammatory cytokine production in astrocytes. This inflammatory cascade can be suppressed by the IL-1R antagonist anakinra or genetic ablation of STING. Therapeutic administration of lead IL-1β targeting ASO reduces IL-1β expression, preserves AQP4 levels and myelin integrity, and improves functional outcomes. The IL-1β-IL-1R STING signaling axis is a central contributor to NMO pathogenesis and supports IL-1β ASO therapy as a promising potential disease-modifying approach. ANN NEUROL 2026.
Synaptic function and plasticity depend on the precise control of protein abundance and turnover, governed by the balance of synthesis and degradation. This review examines the regulatory mechanisms that maintain synaptic protein stability, focusing on the Ubiquitin-Proteasome System (UPS), autophagy-lysosomal pathways, and related proteolytic systems. We detail how key enzymes, including E3 ligases such as Nedd4-1, Mdm2, and Parkin, and deubiquitinating enzymes like USP46 and USP8, dynamically regulate the degradation of critical synaptic components from AMPA and NMDA receptors to scaffolds like PSD-95 and SHANK3. We further explore how autophagy, including chaperone-mediated and activity-dependent forms, contributes to synaptic remodeling and quality control. Crucially, dysfunction of synaptic degradation pathways is a common thread in neurodevelopmental and neurodegenerative disorders. We summarize evidence linking proteostatic malfunction to the pathogenesis of Alzheimer's disease (through impaired clearance of Aβ and tau), Parkinson's disease (via α-synuclein turnover), epilepsy, autism spectrum disorder, and ischemic injury. The review highlights how genetic mutations in degradation machinery or their synaptic targets converge to disrupt synaptic integrity and neural circuit function. By integrating findings from basic neurobiology and disease models, this review underscores the central importance of synaptic proteostasis and aims to identify critical regulatory molecules that retain potentials for diagnostic biomarkers and therapeutic targets for neurological disease.
An estimated 30%-50% of male individuals with fragile X syndrome (FXS) meet criteria for autism spectrum disorder (ASD), indicating phenotypic overlap but potentially distinct neurobiology. Here, we aimed to characterize shared and divergent cortical features between FXS and ASD. High-resolution, motion-corrected quantitative MRI was used to compare cortical morphometry and relaxometry in 61 male participants (9-18 years) with FXS or ASD. To increase power, ASD participants were pooled from multiple MPnRAGE studies and harmonized across protocols using ComBat. Cortical thickness and R1 (longitudinal relaxation rate; proxy for myelination) were computed across the cerebral cortex. Relative to ASD, FXS exhibited greater cortical thickness predominantly in early sensory cortices implicated in low-level visual and auditory processing spanning occipital, parietal, and temporal regions. No significant group differences in R1 were found. Thicker cortex in FXS within primary and early associative sensory areas suggests divergent early sensory processing mechanisms between FXS and ASD. Characterizing different neuroanatomical features between the two disorders provides a grounding to develop more disorder-specific interventions despite similar behavioral difficulties. Future work should test developmental trajectories, include females and comorbidities, and link imaging markers to individual sensory/clinical profiles to inform and improve personalized therapies and interventions.
SARS-CoV-2 infection is linked to persistent neurological symptoms Post-Acute Sequelae SARS-CoV-2 (neuro-PASC) and elevated risk of neurodegenerative disease, but molecular events connecting acute viral injury to long-term CNS dysfunction remain unclear. Here, we advance a perspective that Extracellular Vesicles (EVs) act as active mediators bridging SARS-CoV-2 infection and neurodegenerative processes. As nanoscale messengers capable of crossing the blood-brain barrier, EVs can transmit post-viral signals and orchestrate multi-target gene regulation in recipient cells through their microRNA (EV-miRNA) cargo. Our integrative analysis suggests that EV-miRNAs dysregulated in acute COVID-19, Alzheimer's Disease (AD), and Parkinson's Disease (PD) converge on pathways governing neurovascular integrity, redox and metabolic homeostasis, and neuronal proteostasis. We propose that sustained dysregulation of these interconnected modules-driven by EV-mediated signalling-may underlie the perpetuation of neuro-PASC and accelerate neurodegeneration in susceptible individuals. Viewing EVs as mechanistic agents that both transmit and amplify pathogenic cues reframes them as actionable targets for intervention and risk stratification. This perspective calls for translational frameworks that leverage EVs to illuminate, predict, and modify the trajectory of post-viral neurodegeneration.
Critical limits represent quantitative decision thresholds for drugs that require immediate clinician notification and potential life-saving intervention. United States hospitals lack a national standard for drug critical limits. We collected critical limits from 417 US hospitals across all 50 states and Washington, D.C.; of these, 411 maintained drug critical limit lists. We classified hospitals by US Census division and network-affiliated vs. independent status. We applied non-parametric statistical analyses, examined critical limits for 111 drugs, and observed significant inter-institutional variability. Listing frequencies were highest for digoxin 99.8% (410/411), theophylline 72.3% (297/411), lithium 94.9% (390/411), and acetaminophen 86.9% (357/411). Non-therapeutic measurands also appeared, led by ethanol 47.2% (194/411). Kruskal-Wallis analysis revealed highly significant differences (P < 0.01) across census divisions. Mann-Whitney U analysis comparing network vs. independent hospitals yielded significant differences (P < 0.05) in 16 analytes. Qualitative critical values were listed for volatile alcohols and methotrexate. All digoxin critical limits exceeded levels associated with increased hazard ratios. Only 33.9% of hospitals aligned with consensus guidelines for acetaminophen poisoning. Vancomycin and aminoglycoside critical limits showed wide ranges, overlapping peaks and troughs, and random values inconsistently aligned with peak and troughs. Immunosuppressant critical limits often exceeded thresholds associated with toxicity. Psychotropic drugs, including antiepileptics, tricyclic antidepressants, and lithium, demonstrated variability and misalignment relative to consensus guidelines. Drugs of abuse did not appear in critical notification lists. Results provide hospitals with references that will enhance hospital notification practices and patient safety. We encourage sharing of critical notification lists to foster future research efforts and enhance standards of care.
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Cognitive impairment (CI) is a prevalent and debilitating non-motor symptom in Parkinson's disease (PD), yet reliable early diagnostic biomarkers are lacking. This study aimed to identify serum biomarkers associated with PD-CI and investigate the synergistic contributions of lipid metabolism and inflammatory signaling. In this retrospective, cross-sectional study, six candidate proteins (INPP5D, FLNA, ICAM-1, PCSK9, JAK1, and LCAT) were selected based on our previously published discovery-phase serum proteomics analysis and were quantified via ELISA in an independent cohort of 75 PD patients and 35 age-matched healthy controls (HCs). All participants underwent comprehensive cognitive assessments (MoCA, MMSE, CDR). Multivariate regression, receiver operating characteristic (ROC) analysis, and bioinformatics tools were employed to evaluate diagnostic potential and pathway associations. PD patients showed significantly lower MoCA and MMSE scores than HC, accompanied by elevated serum ICAM-1, PCSK9, and JAK1, and decreased INPP5D and FLNA. Notably, as MoCA scores declined, serum ICAM-1, PCSK9, JAK1, and LCAT levels gradually increased, while INPP5D and FLNA decreased. ROC analysis indicated that these biomarkers, particularly PCSK9 and LCAT, effectively distinguished PD-NC from PD-CI. Bioinformatics analyses highlighted focal adhesion and JAK-STAT signaling as key pathways, with ICAM1 and ITGB2 as central nodes in the protein-protein interaction network. All six serum biomarkers showed potential in distinguishing PD-NC from PD-CI, with PCSK9 and LCAT being the most effective. The findings propose a pathogenic cascade integrating neuroinflammation, lipid metabolism, and cell adhesion dysfunction, offering new mechanistic insights and potential avenues for early diagnosis and therapeutic intervention in PD-CI.