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Purpose of ReviewThis review aims to comprehensively examine the immune response following traumatic brain injury (TBI) and how its disruption can impact healing and recovery.Recent FindingsThe immune response is now considered a key element in the pathophysiology of TBI, with consequences far beyond the acute phase after injury. A delicate equilibrium is crucial for a healthy recovery. When this equilibrium is disrupted, chronic inflammation and immune imbalance can lead to detrimental effects on survival and disability.SummaryGlobally, traumatic brain injury (TBI) imposes a substantial burden in terms of both years of life lost and years lived with disability. Although its epidemiology exhibits dynamic trends over time and across regions, TBI disproportionally affects the younger populations, posing psychosocial and financial challenge for communities and families. Following the initial trauma, the primary injury is succeeded by an inflammatory response, primarily orchestrated by the innate immune system. The inflammasome plays a pivotal role during this stage, catalyzing both programmed cell death pathways and the up-regulation of inflammatory cytokines and transcription factors. These events trigger the activation and differentiation of microglia, thereby intensifying the inflammatory response to a systemic level and facilitating the migration of immune cells and edema. This inflammatory response, initially originated in the brain, is monitored by our autonomic nervous system. Through the vagus nerve and adrenergic and cholinergic receptors in various peripheral lymphoid organs and immune cells, bidirectional communication and regulation between the immune and nervous systems is established.

Purpose We investigated the volumetric changes in the components of the cholinergic pathway for patients with early mild cognitive impairment (EMCI) and those with late mild cognitive impairment (LMCI). The effect of patients’ apolipoprotein 4 (APOE-ε4) allele status on the structural changes were analyzed. Methods Structural magnetic resonance imaging data were collected. Patients’ demographic information, plasma data, and validated global cognitive composite scores were included. Relevant features were extracted for constructing machine learning models to differentiate between EMCI (n = 312) and LMCI (n = 541) and predict patients’ neurocognitive function. The data were analyzed primarily through one-way analysis of variance and two-way analysis of covariance. Results Considerable differences were observed in cholinergic structural changes between patients with EMCI and LMCI. Cholinergic atrophy was more prominent in the LMCI cohort than in the EMCI cohort (P < 0.05 family-wise error corrected). APOE-ε4 differentially affected cholinergic atrophy in the LMCI and EMCI cohorts. For LMCI cohort, APOE-ε4 carriers exhibited increased brain atrophy (left amygdala: P = 0.001; right amygdala: P = 0.006, and right Ch123, P = 0.032). EMCI and LCMI patients showed distinctive associations of gray matter volumes in cholinergic regions with executive (R 2  = 0.063 and 0.030 for EMCI and LMCI, respectively) and language (R 2  = 0.095 and 0.042 for EMCI and LMCI, respectively) function. Conclusions Our data confirmed significant cholinergic atrophy differences between early and late stages of mild cognitive impairment. The impact of the APOE-ε4 allele on cholinergic atrophy varied between the LMCI and EMCI groups.

Cholinergic treatments with an emphasis on M1 muscarinic acetylcholine receptor (mAChR) agonists as potential modulating agents are a new approach in Alzheimer’s disease (AD) therapy. In previous research, we designed and characterized novel thiazolidine-2,4-dione (TZD)-derived compounds that possess anti-AD properties and enhance the expression of mAChRM1 in rats. This study evaluated a novel orthosteric agonist of mAChRM1 from related pathways that has shown promising anti-Alzheimer’s disease activity. PC12 cells were exposed to various concentrations of TZ4M before they were exposed to scopolamine (3 µM). Immunocytochemistry and western blot analyses revealed that TZ4M increased the expression of mAChRM1 in differentiated cells induced by scopolamine-treated PC12 cells. The results showed that TZ4M (3 and 5 µM) markedly upregulated PKC and ChAT protein expression, and the cells were significantly protected against increased ROS levels followed by neuronal cell loss, as evidenced by the MTT assay. TUNEL staining indicated that TZ4M impeded the shaping of apoptotic bodies. Analysis of the amino acid sequences of the ligand–protein binding site indicated that TZ4M is bound to the orthosteric site (acetylcholine site). This study revealed that TZ4M, a derivative of TZD, effectively protects against scopolamine-induced damage. TZ4M, a novel mACRM1 orthosteric agonist, is promising for treating AD.

Our previous studies have reported that agonist of α7 nicotinic acetylcholine receptors prevented electrophysiological dysfunction of rats with ischaemic cardiomyopathy (ICM) by eliciting the cholinergic anti‐inflammatory pathway (CAP). Adenosine monophosphate‐activated protein kinase (AMPK) signalling is widely recognized exerting cardioprotective effect in various cardiomyopathy. Here, we aimed to investigate whether the protective effects of the CAP are associated with AMPK signalling in ICM. In vivo, coronary artery of rats was ligated for 4 weeks to induce the ICM and then treated with PNU‐282987 (CAP agonist) and BML‐275 dihydrochloride (AMPK antagonist) for 4 weeks. In vitro, primary macrophages harvested from rats were induced inflammation by Lipopolysaccharide (LPS) treatment and then treated with PNU‐282987 and BML‐275 dihydrochloride. In vivo, exciting CAP by PUN‐282987 elicited an activation of AMPK signalling, alleviated ventricular remodeling, modified the cardiac electrophysiological function, reduced the cardiac expression of collagens and inflammatory cytokines and maintained the integrity of ultrastructure in the ischemic heart. However, the benefits of CAP excitation were blunted by AMPK signaling antagonization. In vitro, excitation of the CAP was observed inhibiting the nuclear transfer of NF‐κB p65 of macrophages and promoting the transformation of Ly‐6Chigh macrophages into Ly‐6Clow macrophages. However, inhibiting AMPK signalling by BML‐275 dihydrochloride reversed the CAP effect on LPS‐treated macrophages. Finally, our findings suggest that eliciting the CAP modulates the inflammatory response in ICM through regulating AMPK signalling.

Introduction: Gynura procumbens (GP), otherwise known as longevity spinach or \"Sambung Nyawa\" in Malay, is an evergreen herb found in Africa and Southeast Asian countries (including Brunei) used traditionally to treat various diseases such as fever, diabetes and hypertension. We examined GP's vasodilatory action to determine its possible role via the cholinergic-mediated pathway. Methods: GP leaves were prepared by filtration and evaporation to obtain the aqueous (AEGP) and methanol (MEGP) extracts followed by screening for phytochemical constituents. The total phenol, total flavonoid and flavonol contents were determined using the corresponding Folin-Ciocalteau, and aluminium colorimetric methods and the presence of kaempferol 3-O-rutinoside in the extracts was detected using HPLC analysis. Organ bath studies were conducted to determine the vasodilatory activity using intact and denuded isolated rat aortic rings by exposure to either increasing concentration of extracts (0.25, 0.5, 1.0, and 2.0 mg/mL) or 10 µg/mL kaempferol 3-O-rutinoside in the presence or absence of acetylcholine (ACh) after pre-contraction by noradrenaline (NA). Results: MEGP contained more phytochemical constituents and higher content of total flavonoid and total flavonol but less phenolic content than AEGP. Furthermore, MEGP yielded a 20% elevated amount of kaempferol 3-O-rutinoside than AEGP. Both extracts significantly amplified ACh-endothelium dependent vasodilation and mediated relaxation at 1 mg/mL in endothelium-intact and endothelium-denuded aortic rings with MEGP as a more effective vasodilator than AEGP. Overall, these results imply the involvement of extracts in potentiating cholinergic pathway, which might be mediated by kaempferol, as shown by its vasorelaxation effects in endothelium-intact and -denuded aorta. Conclusions: The present findings demonstrate that the vasodilatory activities of the two Gynura procumbens extracts, AEGP and MEGP, in thoracic aorta rings isolated from rats are potentially mediated via a cholinergic pathway through the action of a flavonoid particularly kaempferol 3-O-rutinoside.

Continuous sleep deprivation (SD) triggers systemic inflammatory storm and immune dysregulation, yet its specific impact on periodontitis and the corresponding therapeutic interventions remains unclear. Consequently, this study elucidates the neuroimmune mechanisms linking SD to ligature‐induced periodontitis (LIP) in mice and evaluates electroacupuncture (EA) as a novel adjunctive therapy. Screening analyses (ELISA, public databases, flow cytometry, immunofluorescence, etc.) identified pivotal roles of acetylcholine (ACh), α7 nicotinic acetylcholine receptor (α7nAChR), and acetylcholinesterase (AChE) in SD‐aggravated periodontitis with a decrease in ACh levels, down‐regulation of α7nAChR on macrophages, and an increase in trigeminal ganglion‐derived AChE. Clinical validation in periodontitis patients with poor sleep (PSQI ≥ 5) confirmed this tripartite cholinergic imbalance. Ultimately, both in vivo and in vitro data demonstrated that EA inhibits M1 polarization while promoting M2 polarization of macrophages through α7nAChR activation. Therefore, SD exacerbates periodontitis via the AChE‐ACh‐α7nAChR axis‐mediated trigeminal‐periodontal neuroimmune pathway, whereas EA partially reverses this pathology by targeting macrophage α7nAChR. These findings reveal new insights into the “oral‐brain axis” in oral disease pathogenesis and provide novel therapeutic strategies for periodontitis patients with comorbid sleep disorders. Sleep deprivation (SD) exacerbates ligature‐induced periodontitis (LIP) through the trigeminal nerve‐periodontal neuroimmune pathway mediated by the acetylcholinesterase (AChE)‐acetylcholine (ACh)‐α7 nicotinic receptor (α7nAChR) axis. While electroacupuncture (EA) alleviates the condition of LIP combined with SD by activating the α7nAChR.

Background: White matter hyperintensities (WMHs) and regional brain lobe atrophy coexist in the brain of Alzheimer’s disease (AD) patients, but the association between them in AD patients still lacks comprehensive investigation and solid imaging data support. Objective: We explored whether WMHs can promote the pathological process of AD by aggravating atrophy in specific brain regions and tried to explain the regional specificity of these relationships. Methods: A sample of 240 adults including 180 normal controls (NC) and 80 AD cases were drawn from the ADNI database. T1-weighted Magnetic Resonance Imaging (MRI) and T2-weighted fluid-attenuated MRI of the participants were downloaded and were analyzed using AccuBrain® to generate the quantitative the ratio of WMHs (WMHr, WMHs volumes corrected by intracranial volume) and regional brain atrophy. We also divided WMHr into periventricular WMHr (PVWMHr) and deep WMHr (DWMHr) for the purpose of this study. The Cholinergic Pathways Hyperintensities Scale (CHIPS) scores were conducted by two evaluators. Independent-t test, Mann-Whitney U test or χ2 test were used to compare the demographic characteristics and Spearman correlation coefficient values were used to determine the association between WMHs and different regions of brain atrophy. Results: Positive association between WMHr and quantitative medial temporal lobe atrophy(QMTA) (rs=0.281, p=0.011), temporal lobe atrophy (rs=0.285, p=0.011), insular atrophy (rs=0.406, p<0.001) were found in the AD group before Bonferroni correction. PVWMHr contributed to these correlations. Separately analyzed the relationship between PVWMHr and brain atrophy, we found there were still positive correlations after correction in QMTA (rs=0.325, p=0.003), temporal lobe atrophy (rs=0.298, p=0.007) and insular atrophy (rs=0.429, p<0.001) in AD group. Conclusions: WMHs severity are tend to associated with regional brain atrophy in AD patients, especially with medial temporal lobe, temporal lobe and insular lobe atrophy. PVWMHs were devoted to these correlations.

The incidence of cognitive disorders is increasing globally, with a reported prevalence of over 50 million individuals affected, and current interventions offer limited efficacy. This study investigates the effects of sunflower oil fortified with sunflower lecithin, vitamin D, and vitamin A on scopolamine-induced cognitive dysfunction in mice and explores the underlying mechanisms. The incidence of cognitive disorders, such as Alzheimer’s disease, is increasing yearly, and current interventions offer limited efficacy. Therefore, this research aims to evaluate the cognitive improvement effects of the three added functional factors on mice with learning and memory impairments, along with the associated molecular mechanisms. Behavioral tests, biochemical assays, and real-time quantitative polymerase chain reaction (RT-qPCR) were utilized to examine the intervention effects of these functional factors on scopolamine-induced cognitive impairment in mice. The results revealed that the groups treated with sunflower lecithin and vitamin D significantly enhanced the mice’s exploratory behavior, working memory, and spatial memory, with increases of 1.6 times and 4.5 times, respectively, in the open field and novel object recognition tests (VD group). Additionally, these treatments reduced levels of inflammatory markers and IL-6, increased antioxidant GSH levels, and decreased oxidative stress marker MDA levels, with all effects showing significant differences (p < 0.01). The effects were further enhanced when vitamin A was combined with these treatments. Transcriptomic analysis demonstrated that the intervention groups had markedly improved learning and memory abilities through upregulation of key gene expression levels in the PI3K-AKT signaling pathway, cholinergic pathway, and folate biosynthesis pathway. These findings provide a theoretical basis for the development of nutritionally fortified edible oils with added sunflower lecithin, vitamin D, and vitamin A, which may help prevent and ameliorate cognitive disorders.

Background The cholinergic neurotransmitter system is crucial to cognitive function, with the basal forebrain (BF) being particularly susceptible to Alzheimer’s disease (AD) pathology. However, the interaction of white matter hyperintensities (WMH) in cholinergic pathways and BF atrophy without amyloid pathology remains poorly understood. Methods We enrolled patients who underwent neuropsychological tests, magnetic resonance imaging, and 18 F-florbetaben positron emission tomography due to cognitive impairment at the teaching university hospital from 2015 to 2022. Among these, we selected patients with negative amyloid scans and additionally excluded those with Parkinson’s dementia that may be accompanied by BF atrophy. The WMH burden of cholinergic pathways was quantified by the Cholinergic Pathways Hyperintensities Scale (CHIPS) score, and categorized into tertile groups because the CHIPS score did not meet normal distribution. Segmentation of the BF on volumetric T1-weighted MRI was performed using FreeSurfer, then was normalized for total intracranial volume. Multivariable regression analysis was performed to investigate the association between BF volumes and CHIPS scores. Results A total of 187 patients were enrolled. The median CHIPS score was 12 [IQR 5.0; 24.0]. The BF volume of the highest CHIPS tertile group (mean ± SD, 3.51 ± 0.49, CHIPSt3) was significantly decreased than those of the lower CHIPS tertile groups (3.75 ± 0.53, CHIPSt2; 3.83 ± 0.53, CHIPSt1; P  = 0.02). In the univariable regression analysis, factors showing significant associations with the BF volume were the CHIPSt3 group, age, female, education, diabetes mellitus, smoking, previous stroke history, periventricular WMH, and cerebral microbleeds. In multivariable regression analysis, the CHIPSt3 group (standardized beta [ β std ] = -0.25, P  = 0.01), female ( β std = 0.20, P  = 0.04), and diabetes mellitus ( β std = -0.22, P  < 0.01) showed a significant association with the BF volume. Sensitivity analyses showed a negative correlation between CHIPS score and normalized BF volume, regardless of WMH severity. Conclusions We identified a significant correlation between strategic WMH burden in the cholinergic pathway and BF atrophy independently of amyloid positivity and WMH severity. These results suggest a mechanism of cholinergic neuronal loss through the dying-back phenomenon and provide a rationale that strategic WMH assessment may help identify target groups that may benefit from acetylcholinesterase inhibitor treatment.

We aimed to determine whether asymptomatic carotid artery stenosis (ACS) induced cognitive impairments were related to the cholinergic hyperintensity pathway. This cross-sectional study included patients with moderate-to-severe ACS, who were categorized into mild cognitive impairment (MCI) and normal cognition groups on the basis of Montreal Cognitive Assessment (MoCA) scores. The cholinergic pathway hyperintensity scale (CHIPS), Fazekas, and medial temporal atrophy (MTA) scores were assessed. SPSS software was used for statistical analyses. A total of 117 ACS patients (70.89 ± 8.81 years) and 105 controls (67.87 ± 9.49 years) were evaluated (t = 2.46, p = 0.015). The ACS group showed a worse median Mini-Mental Status Examination (MMSE) score (z = −2.41, p = 0.016) and MoCA score (z = −3.51, p < 0.001), and a significantly higher median total CHIPS score (z = 4.88, p < 0.001) and mean Fazekas score (t = 2.39, p = 0.018). In the correlation analysis, the MoCA score showed a significant negative correlation with the CHIPS score (ρ = −0.41, p < 0.001) and Fazekas score (ρ = −0.31, p < 0.001) in ACS group. Logistic regression analyses suggested that CHIPS scores were risk factors for MCI in patients with ACS (odds ratio [OR] = 1.07, 95% Confidence Interval [CI]1.01–1.13 and controls (OR = 1.09, 95%CI 1.01–1.17), while the MTA and Fazekas scores showed no predictive power. The receiver operating characteristic curve showed that the area under the curve of the CHIPS score for predicting MCI was 0.71 in ACS group, but was only 0.57 in controls. Patients with ACS showed poorer cognitive performance and higher CHIPS and Fazekas scores. CHIPS, but not Fazekas, scores were risk factors for cognitive impairment and were a valuable factor to predict MCI in patients with ACS. •Cognitive impairment can result from asymptomatic carotid stenosis.•Asymptomatic carotid stenosis induced cognitive impairments were related to the cholinergic hyperintensity pathway.•More granular analyses of white-matter hyperintensities may provide a deeper understanding of the underlying neuropathology.