Inflammatory diseases, such as periodontitis, are characterized by dysregulated immune responses and progressive tissue damage, posing significant therapeutic challenges and necessitating the development of novel, application-oriented strategies. However, achieving precise targeting of specific immune cells for immunomodulation remains challenging. In this study, we constructed an apoptotic vesicle-hybridized nanosponge system that enables dual-phase immunomodulation of macrophages in a chronic periodontitis model. This system was engineered by fusing “nanosponge” neutrophil membranes with membranes of immunomodulatory apoptotic vesicles (ApoVs) onto a mesoporous polydopamine (MPDA) core loaded with carbon monoxide (CO). Comprehensive characterization confirmed its successful fabrication and stability. Functionally, these nanosponges demonstrated a synergistic capacity to neutralize inflammatory cytokines in the extracellular milieu and, upon apoptotic signal-mediated internalization by macrophages, triggered CO release to promote macrophage polarization toward the regenerative M2 phenotype. Transcriptomic analysis further delineated the underlying mechanistic dichotomy: apoptosis-mediated anti-inflammatory reprogramming, primarily through upregulation of transforming growth factor-beta (TGF-β) signaling and downregulation of nuclear factor-kappa B (NF-κB) signaling pathways, while CO-induced metabolic regulation, involving the modulation of peroxisome proliferator-activated receptor (PPAR) signaling. Importantly, this immunomodulation functionally enhanced the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) through paracrine effect. Consequently, in the rat model of periodontitis, this targeted approach effectively resolved inflammation and robustly promoted periodontal bone regeneration, without inducing observable systemic toxicity in major organs. In summary, these findings provide a proof-of-concept strategy for targeted immunomodulatory therapy in inflammatory periodontal diseases.

Abnormal cognitive aging is characterized by memory decline beyond normal age-related physiological changes. Nevertheless, the intrinsic mechanisms driving individual memory heterogeneity during aging remain poorly elucidated. Given the critical roles of brain interstitial fluid (ISF) dynamics and extracellular space (ECS) transport in maintaining neural homeostasis, the present study aimed to explore whether ECS compartmentalization and ISF drainage disturbance contribute to interindividual variations in memory performance during aging. Aged rats were stratified according to their memory performance. A multi-modal strategy combining behavioral assessment, microdialysis, metabolomics, and electrophysiological recording was applied to detect structural and functional deficits in ECS barrier integrity and ISF drainage, with the assistance of MRI-based tracer imaging, fluorescence imaging, and ultrastructural observation. The results demonstrated that memory-impaired aged rats exhibited region-specific neurotransmitter imbalance in the caudate nucleus and thalamus, which was closely associated with age-related ECS barrier dysfunction. Such barrier dysfunction induced ISF drainage disturbance, thereby reducing local neurotransmitter concentrations in the caudate nucleus and impairing thalamocortical oscillations during non-rapid eye movement sleep, and ultimately disturbing memory consolidation. Further tracer imaging and electron microscopy examinations confirmed that compromised myelin integrity in the internal capsule served as the structural basis for age-related ISF drainage disturbance. Collectively, these findings reveal that ISF drainage disturbance induced by age-related ECS barrier alterations acts as a non-degenerative mechanism underlying memory heterogeneity in cognitive aging. This work highlights ECS compartment integrity as a promising biomarker and therapeutic target for intervening age-related cognitive decline.

Mechanical force-induced hard tissue defects are clinically prevalent, particularly in dentistry. Excessive mechanical stimulation could induce pathological tooth root resorption (RR), which leads to tooth mobility and even tooth loss. This process is closely associated with dysregulated biological alterations in adjacent periodontal ligament stem cells (PDLSCs) and disrupted crosstalk between PDLSCs and osteoclast precursors, yet the specific molecular and cellular mechanisms remain insufficiently understood, severely limiting the development of targeted therapeutic strategies for such hard tissue defects. To address this gap, a mouse model of heavy force-induced RR was established. The results revealed that PDLSC pyroptosis peaked at 14 days after excessive force stimuli and positively correlated with RR severity. Moreover, pyroptosis modulators and Caspase-1 knockout mice were further utilized to confirm the role of Caspase-1-dependent pyroptosis in RR progression. Then, Caspase-1-targeting small interfering RNA (siRNA) nanoparticles (PMSN@siCasp1) was fabricated by modifying mesoporous silica nanoparticles (MSNs) with low-molecular-weight polyethylenimine (PEI), and their RNA loading capacity, lysosomal escape capability and the function of inhibiting excessive-force induced RR were further characterized. PMSN@siCasp1 exhibited excellent biocompatibility and efficient cellular delivery. Additionally, PMSN@siCasp1 was able to penetrate the periodontal ligament and reach the root surface to suppress RR in vivo, with persistent retention on the root surface for an extended period. Mechanically, PMSN@siCasp1 suppressed RR by inhibiting pyroptosis, blocking damaged mitochondrial transfer from PDLSCs to osteoclast precursors, reducing reactive oxygen species (ROS) levels in precursors, and decreasing osteoclast numbers. This study confirms pyroptosis as a key mediator of excessive force-induced RR and presents PMSN@siCasp1 as a promising targeted therapeutic strategy for inhibiting excessive force-induced RR.

Neurochemical imbalance is a contributing factor to neurological symptoms in multiple sclerosis (MS). The matured myelin sheath is crucial for substance transportation within the extracellular space (ECS) and for maintaining local homeostasis. Therefore, we hypothesize that disturbed ECS transportation following demyelinating lesions might lead to neurochemical imbalance in MS. In the current study, a lysophosphatidylcholine-induced unilateral MS model was used to investigate spatial neurochemical alterations. The results demonstrated that 168 substances were altered around the demyelination site in the ipsilateral hemisphere, compared to the contralateral hemisphere, with significant enrichment in the purine and arginine-proline metabolic pathways. Notably, dopamine was unexpectedly detected in the demyelinated region and the adjacent thalamus. Tracer-based MRI further revealed that the tracer injected into the striatum abnormally refluxed to the thalamus, with the area of reflux consistent with the altered dopamine distribution. The interstitial fluid drained extensively but was confined to the unilateral hemisphere, which may explain the observed widespread changes in other neuroactive substances. Importantly, after the restoration of ECS integrity, both interstitial fluid drainage and neurochemical imbalance, including dopamine, were normalized, supporting the potential link between ECS dysfunction and neurochemical imbalance. These observations highlight the crucial role of ECS transport in maintaining neurochemical homeostasis in the brain, providing new insights into the mechanisms that may underline the neuropsychiatric symptoms of MS.

OBJECTIVES:Chronic internal carotid artery occlusion (CICAO) poses a considerable risk for stroke. While endovascular revascularization holds promise as a potential therapy, its real-world efficacy, safety, and long-term outcomes remain underexplored. This study aims to assess the effectiveness, safety, and long-term outcomes of endovascular revascularization in symptomatic CICAO patients refractory to medical therapy. MATERIALS AND METHODS:A retrospective cohort study was conducted to collect clinical and surgical data from CICAO patients meeting the inclusion criteria for endovascular revascularization therapy. Patients were categorized into groups based on the success or failure of revascularization procedures. Follow-up assessments were undertaken to ascertain patients' prognoses and survival outcomes. Logistic multivariate analysis was employed to identify risk factors associated with primary and secondary outcome events. COX proportional hazard regression was used to compare the risk ratios of these events between the two groups. RESULTS:The study included 59 patients undergoing 62 procedures with a 75.81 % success rate for revascularization. Perioperative complications were 6.45 %, and the average follow-up duration was 36.53 ± 3.92 months. In the successful revascularization group, the primary endpoint event rate was 6.52 %, contrasting with 23.08 % in the non-revascularization group. Carotid artery occlusion and diabetes emerged as independent risk factors for primary endpoint events. A significant difference was observed between the two groups in both primary endpoint (RR 0.16, [95 %CI, 0.03-0.84]) and total endpoint event rates (RR 0.27, [95 %CI, 0.08-0.96]) CONCLUSIONS: Failure of revascularization may be associated with an increased risk of recurrent cerebrovascular events in patients with CICAO, while successful endovascular revascularization appears to be linked to a lower incidence of such events. However, these results should be interpreted with caution due the relatively small sample size.

Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective therapy for Parkinson's disease (PD). However, the therapeutic mechanisms remain incompletely understood, particularly regarding the extracellular space (ECS), a critical microenvironment where molecular diffusion and interstitial fluid (ISF) dynamics are essential for neural function. This study aims to explore the regulatory mechanisms of the ECS in the substantia nigra (SN) of PD rats following STN-DBS. To evaluate whether STN-DBS can modulate ECS diffusion and drainage, we conducted quantitative measurements using a tracer-based magnetic resonance imaging. Our findings indicated that, compared to the PD group, STN-DBS treatment resulted in a decreased diffusion coefficient (D*), shorted half-life (T 1/2), and increased clearance coefficient (k') in the SN. To investigate the mechanisms underlying these changes in molecular diffusion, we employed enzyme-linked immunosorbent assay (ELISA), Western blotting (WB), and microdialysis techniques. The results revealed that STN-DBS led to an increase in hyaluronic acid content, elevated expression of excitatory amino acid transporter 2 (EAAT2), and a reduction in extracellular glutamate concentration. Additionally, to further elucidate the mechanisms influencing ISF drainage, we employed immunofluorescence and immunohistochemical techniques for staining aquaporin-4 (AQP-4) and α-synuclein. The results demonstrated that STN-DBS restored the expression of AQP-4 while decreasing the expression of α-synuclein. In conclusion, our findings suggest that STN-DBS improves PD symptoms by modifying the ECS and enhancing ISF drainage in the SN regions. These results offer new insights into the mechanisms and long-term outcomes of DBS in ECS, paving the way for precision therapies.

3D bioprinting has been advanced from creating simple, static structures with single materials to sophisticated multimaterial and multidimensional designs. This evolution has improved printing precision, the range of application and dynamic functionality. Multimaterial and multidimensional bioprinting represent significant advancements in regenerative medicine. By integrating a range of materials and employing diverse printing techniques, these approaches address the limitations of single-material and fixed-dimension methods, thereby overcoming the constraints of traditional, uniform complexity. Multimaterial bioprinting fabricates additive manufacturing structures simultaneously with materials vary in composition and mechanical strength, which increases the complexity in biomedical applications. Meanwhile, multidimensional bioprinting involves incorporating additional dimensions (such as time or space) into printing process, which allows for dynamic configuration transformations and functional responses. Here, the basic concepts and components are summarized of multimaterial and multidimensional bioprinting, the medical adaptation is discussed and the advantages, challenges as well as future perspectives of current approaches are analyzed. Moreover, this review provides perspective on multimaterial and multidimensional bioprinting, and highlights new opportunities in regenerative medicine tissue engineering, particularly in bone tissue engineering bioprinting.

Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective therapy for Parkinson's disease (PD). However, the therapeutic mechanisms remain incompletely understood, particularly regarding the extracellular space (ECS), a critical microenvironment where molecular diffusion and interstitial fluid (ISF) dynamics are essential for neural function. This study aims to explore the regulatory mechanisms of the ECS in the substantia nigra (SN) of PD rats following STN-DBS. To evaluate whether STN-DBS can modulate ECS diffusion and drainage, we conducted quantitative measurements using a tracer-based magnetic resonance imaging. Our findings indicated that, compared to the PD group, STN-DBS treatment resulted in a decreased diffusion coefficient (D*), shorted half-life (T 1/2), and increased clearance coefficient (k') in the SN. To investigate the mechanisms underlying these changes in molecular diffusion, we employed enzyme-linked immunosorbent assay (ELISA), Western blotting (WB), and microdialysis techniques. The results revealed that STN-DBS led to an increase in hyaluronic acid content, elevated expression of excitatory amino acid transporter 2 (EAAT2), and a reduction in extracellular glutamate concentration. Additionally, to further elucidate the mechanisms influencing ISF drainage, we employed immunofluorescence and immunohistochemical techniques for staining aquaporin-4 (AQP-4) and α-synuclein. The results demonstrated that STN-DBS restored the expression of AQP-4 while decreasing the expression of α-synuclein. In conclusion, our findings suggest that STN-DBS improves PD symptoms by modifying the ECS and enhancing ISF drainage in the SN regions. These results offer new insights into the mechanisms and long-term outcomes of DBS in ECS, paving the way for precision therapies.

Temporomandibular joint (TMJ) disc displacement is one of the most significant subtypes of temporomandibular joint disorders, but its etiology and mechanism are poorly understood. In this study, we elucidated the mechanisms by which destruction of inflamed collagen fibrils induces alterations in the mechanical properties and positioning of the TMJ disc. By constructing a rat model of TMJ arthritis, we observed anteriorly dislocated TMJ discs with aggravated deformity in vivo from five weeks to six months after a local injection of Freund’s complete adjuvant. By mimicking inflammatory conditions with interleukin-1 beta in vitro, we observed enhanced expression of collagen-synthesis markers in primary TMJ disc cells cultured in a conventional two-dimensional environment. In contrast, three-dimensional (3D)-cultivated disc cell sheets demonstrated the disordered assembly of inflamed collagen fibrils, inappropriate arrangement, and decreased Young’s modulus. Mechanistically, inflammation-related activation of the nuclear factor kappa-B (NF-κB) pathway occurs during the progression of TMJ arthritis. NF-κB inhibition reduced the collagen fibril destruction in the inflamed disc cell sheets in vitro, and early NF-κB blockade alleviated collagen degeneration and dislocation of the TMJ discs in vivo. Therefore, the NF-κB pathway participates in the collagen remodeling in inflamed TMJ discs, offering a potential therapeutic target for disc displacement.

To design and develop an electrical properties measurement strategy with Tracer-based MRI system to comprehensively and simultaneously detect the structure parameters, diffusion coefficients and electrical characteristics of brain extracellular space (ECS). A Tracer-based MRI system, integrated with Electrical Impedance Tomography (EIT), was developed to simultaneously measurement brain ECS structural parameters, diffusion coefficients, and electrical characteristics. Twelve adult Sprague–Dawley rats were randomly divided into two groups: the first group was assessed using traditional Tracer-based MRI alone (n = 6), and the second group with the integration of EIT compatible with impedance measurements (n = 6). The diffusion coefficient, volume fraction, and electrical performance parameters were analysed. The study demonstrated the feasibility of obtaining electrical properties of the ECS, including conductivity (2.006 S/m), dielectric constant (84.77), diffusion rate (3.54*10–4 mm2/s), and volume fraction(17.43

Ischemic stroke is a leading cause of death and disability worldwide. Inflammatory response after stroke determines the outcome of ischemic injury. A recent study has reported an efficient method, epidural arterial implantation (EAI), for accelerating interstitial fluid (ISF) drainage, which provides a promising strategy to clear pro-inflammatory cytokines in the brain extracellular space (ECS). In this study, the method of EAI was modified (m-EAI) to control its function of accelerating the ISF drainage at different time points following ischemic attack. The neuroprotective effect of m-EAI on ischemic stroke was evaluated with the transient middle cerebral artery occlusion (tMCAO) rat model. The results demonstrated the accumulation of IL-1β, IL-6, and TNF-α was significantly decreased by activating m-EAI at 7 d before and immediately after ischemic attack in tMCAO rats, accompanied with decreased infarct volume and improved neurological function. This study consolidates the hypothesis of exacerbated ischemic damage by inflammatory response and provides a new perspective to treat encephalopathy via brain ECS. Further research is essential to investigate whether m-EAI combined with neuroprotective drugs could enhance the therapeutic effect on ischemic stroke.

Abstract Background In this study, we sought to quantify the influence of vertical control assisted by a temporary anchorage device (TAD) on orthodontic treatment efficacy for skeletal class II patients with a hyperdivergent facial type and probe into the critical factors of profile improvement. Methods A total of 36 adult patients with skeletal class II and a hyperdivergent facial type were included in this retrospective case–control study. To exclude the effect of sagittal anchorage reinforcement, the patients were divided into two groups: a maxillary maximum anchorage (MMA) group (N = 17), in which TADs were only used to help with anterior tooth retraction, and the MMA with vertical control (MMA + VC) group (N = 19), for which TADs were also used to intrude the maxillary molars and incisors. The treatment outcome was evaluated using dental, skeletal, and soft-tissue-related parameters via a cephalometric analysis and cast superimposition. Results A significant decrease in ANB (P < 0.05 for both groups), the retraction and uprighting of the maxillary and mandibular incisors, and the retraction of protruded upper and lower lips were observed in both groups. Moreover, a significant intrusion of the maxillary molars was observed via the cephalometric analysis (− 1.56 ± 1.52 mm, P < 0.05) and cast superimposition (− 2.25 ± 1.03 mm, P < 0.05) of the MMA + VC group but not the MMA group, which resulted in a remarkable decrease in the mandibular plane angle (− 1.82 ± 1.38°, P < 0.05). The Z angle (15.25 ± 5.30°, P < 0.05) and Chin thickness (− 0.97 ± 0.45°, P < 0.05) also improved dramatically in the MMA + VC group, indicating a better profile and a relaxed mentalis. Multivariate regression showed that the improvement in the soft tissue was closely related to the counterclockwise rotation of the mandible plane (P < 0.05). Conclusions TAD-assisted vertical control can achieve intrusion of approximately 2 mm for the upper first molars and induce mandibular counterclockwise rotation of approximately 1.8°. Moreover, it is especially important for patients without sufficient retraction of the upper incisors or a satisfactory chin shape.

Objective: Citicoline can be used to reduce acute ischemic stroke injury via venous infusion, however, its protective effects in the brain extracellular space remain largely unknown. Herein, we investigated the brain protective effects of citicoline administered via the brain extracellular space and sought precise effective dosage range that can protect against ischemic injury after experimental ischemic stroke in rats. Methods: Fifty-six Sprague-Dawley rats were randomly divided into control, intraperitoneal (IP), caudate-putamen (CPu)-25, CPu-40, CPu-50, CPu-60 and CPu-75 groups based on the infusion site and concentration of citicoline. Two hours after the administration of citicoline, the rats were subjected to a permanent middle cerebral artery occlusion to mimic acute ischemic stroke. Then, the brain infarct volume in rats after stroke was measured and their neurological deficiency was evaluated to explain the protective effects and effective dosage range of citicoline. Results: Compared to the control and IP groups, brain infarct volume of rats in CPu-40, CPu-50, and CPu-60 groups is significant smaller. Furthermore, the brain infarct volume of rats in CPu-50 is the least. Conclusions: Here, we showed that citicoline can decrease the brain infarct volume, thus protecting the brain from acute ischemic stroke injury. We also found that the appropriate effective citicoline dose delivered via the brain extracellular space is 50 mM. Our study provides novel insights into the precise treatment of acute ischemic stroke by citicoline via the brain extracellular space, further guiding the treatment of brain disease.

The Boltzmann Tyranny, set by thermionic statistics, dictates the lower limit of switching slope (SS) of a MOSFET to be 60 mV/dec, the fundamental barrier for low-dissipative electronics. The large SS leads to nonscalable voltage, significant leakage, and power consumption, particularly at short channels, making transistor scaling an intimidating challenge. In recent decades, an array of steep-slope transistors has been proposed; none is close to an ideal switch with ultimately abrupt switching (SS ∼ 0 mV/dec) between the binary logic states. We demonstrated an all-2D-materials van-der-Waals-heterostructure (vdW)-based FET that exhibits ultrasteep switching (0.33 mV/dec), a large on/off current ratio (∼107), and an ultralow off current (∼0.1 pA). The "Subthreshold-Free" operation achieved by the collective behavior of functional materials enables FET switching directly from the OFF-state to the ON-state with entirely eliminated subthreshold region, behaving as the ideal logic switch. Two-inch wafer-scale device fabrication is demonstrated. Boosted by device innovation and emerging materials, the research presents an advancement in achieving the "beyond-Boltzmann" transistors, overcoming one of the CMOS electronics' most infamous technology barriers that have plagued the research community for decades.

Multi-modal data can provide complementary information of Alzheimer’s disease (AD) and its development from different perspectives. Such information is closely related to the diagnosis, prevention, and treatment of AD, and hence it is necessary and critical to study AD through multi-modal data. Existing learning methods, however, usually ignore the influence of feature heterogeneity and directly fuse features in the last stages. Furthermore, most of these methods only focus on local fusion features or global fusion features, neglecting the complementariness of features at different levels and thus not sufficiently leveraging information embedded in multi-modal data. To overcome these shortcomings, we propose a novel framework for AD diagnosis that fuses gene, imaging, protein, and clinical data. Our framework learns feature representations under the same feature space for different modalities through a feature induction learning (FIL) module, thereby alleviating the impact of feature heterogeneity. Furthermore, in our framework, local and global salient multi-modal feature interaction information at different levels is extracted through a novel dual multilevel graph neural network (DMGNN). We extensively validate the proposed method on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset and experimental results demonstrate our method consistently outperforms other state-of-the-art multi-modal fusion methods. The code is publicly available on the GitHub website. (https://github.com/xiankantingqianxue/MIA-code.git)

Background and purpose Clinical studies have demonstrated that edaravone dexborneol can improve the functional outcomes in patients with acute ischaemic stroke (AIS). The present clinical trial aimed at testing the efficacy and safety of Y-2 sublingual tablet on 90-day functional outcome in patients with AIS. Methods and design This is a randomised, double-blind, placebo-controlled, multicentre, parallel-group trial of Y-2 sublingual tablet on patients with AIS. An estimated 914 patients at age of 18–80 years with AIS within 48 hours after symptom onset from 40 hospitals will be randomly assigned to receive Y-2 sublingual tablet or placebo for 14 days. Patients are at score 6–20 points on National Institutes of Health Stroke Scale (NIHSS) and had a modified Rankin Scale (mRS) ≤1 before this stroke, except mechanical thrombectomy and neuroprotective agents treatment. Study outcomes The primary outcome is the proportion of patients with mRS ≤1 on day 90 after randomisation. Secondary efficacy outcomes include mRS score on day 90, the proportion of patients with mRS ≤2 on day 90; the change of NIHSS score from baseline to day 14 and the proportion of patients with NIHSS score ≤1 at the days 14, 30 and 90. Discussion This trial will provide valuable evidence for the efficacy and safety of Y-2 sublingual table for improving 90 days the functional outcomes in patients with AIS. Trial registration number NCT04950920 .

IMPORTANCE Sublingual edaravone dexborneol, which can rapidly diffuse and be absorbed through the oral mucosa after sublingual exposure, is a multitarget brain cytoprotection composed of antioxidant and anti-inflammatory ingredients edaravone and dexborneol. OBJECTIVE To investigate the efficacy and safety of sublingual edaravone dexborneol on 90-day functional outcome in patients with acute ischemic stroke (AIS). DESIGN, SETTING, AND PARTICIPANTS Thiswas a double-blind, placebo-controlled, multicenter, parallel-group, phase 3 randomized clinical trial conducted from June 28, 2021, to August 10, 2022, with 90-day follow-up. Participants were recruited from 33 centers in China. Patients randomly assigned to treatment groups were aged 18 to 80 years and had a National Institutes of Health Stroke Scale score between 6 and 20, a total motor deficit score of the upper and lower limbs of 2 or greater, a clinically diagnosed AIS symptom within 48 hours, and a modified Rankin Scale (mRS) score of 1 or less before stroke. Patients who did not meet the eligibility criteria or declined to participate were excluded. INTERVENTION Patients were assigned, in a 1:1 ratio, to receive sublingual edaravone dexborneol (edaravone, 30mg; dexborneol, 6mg) or placebo (edaravone, 0mg; dexborneol, 60 mu g) twice daily for 14 days and were followed up until 90 days. MAIN OUTCOMES AND MEASURES The primary efficacy outcomewas the proportion of patients with mRS score of 1 or less on day 90 after randomization. RESULTS Of 956 patients, 42 were excluded. A total of 914 patients (median [IQR] age, 64.0 [56.0-70.0] years; 608 male [66.5%]) were randomly allocated to the edaravone dexborneol group (450 [49.2%]) or placebo group (464 [50.8%]). The edaravone dexborneol group showed a significantly higher proportion of patients experiencing good functional outcomes on day 90 after randomization compared with the placebo group (290 [64.4%] vs 254 [54.7%]; risk difference, 9.70%; 95% CI, 3.37%-16.03%; odds ratio, 1.50; 95% CI, 1.15-1.95, P =.003). The rate of adverse events was similar between the 2 groups (89.8%[405 of 450] vs 90.1%[418 of 464]). CONCLUSION AND RELEVANCE Among patients with AIS within 48 hours, sublingual edaravone dexborneol could improve the proportion of those achieving a favorable functional outcome at 90 days compared with placebo.

ObjectivesThe aims of this study were to investigate whether CSF sTREM2 may be a potential marker of disease monitoring for amyotrophic lateral sclerosis (ALS).MethodsWe investigated whether CSF sTREM2 levels are altered in ALS patients and are correlated with upper motor neuron (UMN) burden and disease progression.ResultsCSF sTREM2 was greater in the ALS patients than in the controls (p = 0.002). Elevated CSF sTREM2 was associated with the UMN score (r = 0.38, p = 0.009), ΔFS (r = 0.30, p = 0.04) and serum NFL (lg) (r = 0.35, p = 0.015). As the motor band sign (MBS) score increased, the CSF sTREM2 level increased (p-trend = 0.014). Furthermore, the correlations became stronger (UMN score (r = 0.50, p = 0.01) ΔFRS (r = 0.52, p = 0.008) and serum NFL (lg) (r = 0.55, p = 0.004) when estimated only among patients with a disease duration >12 months.ConclusionWe found that CSF sTREM2 is elevated in ALS patients and may be a novel marker, probably reflecting upper motor unit severity and prognosis.

Background: Previous studies have suggested that antidiabetic drug use may be associated with amyotrophic lateral sclerosis. However, these studies are limited by many confounding and reverse causality biases. We aimed to determine whether antidiabetic drug use has causal effects on ALS. Methods: Drug-target Mendelian randomization analysis was conducted to evaluate the association between genetic variation in the targets of antidiabetic drugs and ALS risk. The antidiabetic drugs included sulfonylureas, GLP-1 analogues, thiazolidinediones, insulin/insulin analogues, metformin, and SGLT2 inhibitors. Summary statistics for ALS were retrieved from previous genome-wide association studies comprising 27,205 ALS patients and 55,058 controls. The instrumental variables for these drugs are from previous published articles. Results: Genetic variation in SGLT2 inhibition targets was associated with lower risk of ALS (odds ratio [OR] = 0.32, 95% CI = 0.14-0.74; p = 0.008). We did not find that genetic variation in metformin targets was associated with ALS (OR = 1.61, 95% CI = 0.94-2.73; p = 0.081). Nevertheless, mitochondrial complex I, a target of metformin, was associated with a higher risk of ALS (OR = 1.83, 95% CI = 1.01-3.32; p = 0.047). The analysis showed that genetic variation in sulfonylureas, GLP-1 analogues, thiazolidinediones, insulin or insulin analogues targets was not associated with ALS (all p > 0.05). Conclusions: The complex interaction between hypoglycemic, antioxidation, and anti-inflammatory effects may account for the different results across antidiabetic drug types. These findings provide key evidence to guide the use of antidiabetic drugs and will help to identify novel therapeutic targets in ALS.