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In neuroinflammation, distinguishing microglia from macrophages and identifying microglial-specific biomarkers in peripheral blood pose significant challenges. This study comprehensively profiled the extracellular vesicles (EVs) of microglia and macrophages, respectively, revealing co-expressed EVs with UCHL1 and CX3CR1 as EVs derived specifically from microglia in human blood. After extensive validation, using optimized nano flow cytometry, we evaluated plasma CX3CR1 + /UCHL1 + EVs across clinical cohorts [multiple sclerosis (MS), HTLV-1 associated myelopathy (HAM), Alzheimer's disease (AD), and Parkinson's disease (PD)], along with established neurodegenerative markers (NMDAR2A and NFL). The findings discovered a notable rise in CX3CR1 + /UCHL1 + EVs in MS, particularly heightened in HAM, in contrast to controls. Conversely, AD and PD exhibited unaltered or diminished levels of microglial EVs. An integrated model of CX3CR1 + /UCHL1 + , NMDAR2A + , and NFL + EVs demonstrated promising diagnostic potential for distinguishing MS from controls and HAM. As to the disease duration, CX3CR1 + /UCHL1 + EVs increased in the initial five years of MS, stabilizing thereafter, whereas NMDAR2A + and NFL + EVs remained stable initially but increased significantly in the subsequent five years, suggesting their correlation with disease duration. This study uncovers unique blood microglial EVs with potential as biomarkers for MS diagnosis, differentiation from HAM, and correlation with disease duration., (© 2024. The Author(s).)

Alzheimer's disease (AD) is the most prevalent dementia, pathologically featuring abnormal accumulation of amyloid-β (Aβ) and hyperphosphorylated tau, while sleep, divided into rapid eye movement sleep (REM) and nonrapid eye movement sleep (NREM), plays a key role in consolidating social and spatial memory. Emerging evidence has revealed that sleep disorders such as circadian disturbances and disruption of neuronal rhythm activity are considered as both candidate risks and consequence of AD, suggesting a bidirectional relationship between sleep and AD. This review will firstly grasp basic knowledge of AD pathogenesis, then highlight macrostructural and microstructural alteration of sleep along with AD progression, explain the interaction between accumulation of Aβ and hyperphosphorylated tau, which are two critical neuropathological processes of AD, as well as neuroinflammation and sleep, and finally introduce several methods of sleep enhancement as strategies to reduce AD-associated neuropathology. Although theories about the bidirectional relationship and relevant therapeutic methods in mice have been well developed in recent years, the knowledge in human is still limited. More studies on how to effectively ameliorate AD pathology in patients by sleep enhancement and what specific roles of sleep play in AD are needed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Poria cocos is a natural source of fungal food raw materials. Processing method is a key effecting the aroma of Poria cocos. In this study, the aroma compounds of Poria cocos products processed using sweating-low-temperature drying (SW-LD), sweating-high-temperature drying (SW-HD), steaming-low-temperature drying (ST-LD), and steaming-high-temperature drying (ST-HD) were compared by headspace solid-phase microextraction (HS-SPME) combined with gas chromatography-mass spectrometry (GC-MS), and the changes in aroma compounds of Poria cocos products during processing were analyzed. GC-MS analysis showed SW-HD product had highest content of aroma compounds. Aroma activity value (OAV) analysis indicated that 9 aroma compounds contributed to the overall aroma of Poria cocos. Among 9 compounds of Poria cocos, 1-octen-3-ol, hexanal, nonanal, octanal, trans-2-octenal, and heptanal contributed to mushroom, refreshing, sweet and fatty characters. In addition, the aroma compound changes during the processing were analyzed, revealing that steaming and sweating were the key processes affecting the aroma of Poria cocos products. The findings of this study provide valuable theoretical guidance for the development of Poria cocos processing technology., Competing Interests: Declaration of competing interest The authors affirm absence of any known competing financial interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Alzheimer's disease has escalated into a critical public health concern, marked by its neurodegenerative nature that progressively diminishes cognitive abilities. Recognized as a continuously advancing and presently incurable condition, AD underscores the necessity for early-stage diagnosis and interventions aimed at delaying the decline in mental function. Despite the proven efficacy of cerebrospinal fluid and positron emission tomography in diagnosing AD, their broader utility is constrained by significant costs and the invasive nature of these procedures. Consequently, the innovation of blood biomarkers such as Amyloid-beta, phosphorylated-tau, total-tau et al, distinguished by their high sensitivity, minimal invasiveness, accessibility, and cost-efficiency, emerges as a promising avenue for AD diagnosis. The advent of ultra-sensitive detection methodologies, including single-molecule enzyme-linked immunosorbent assay and immunoprecipitation-mass spectrometry, has revolutionized the detection of AD plasma biomarkers, supplanting previous low-sensitivity techniques. This rapid advancement in detection technology facilitates the more accurate quantification of pathological brain proteins and AD-associated biomarkers in the bloodstream. This manuscript meticulously reviews the landscape of current research on immunological markers for AD, anchored in the National Institute on Aging-Alzheimer's Association AT(N) research framework. It highlights a selection of forefront ultra-sensitive detection technologies now integral to assessing AD blood immunological markers. Additionally, this review examines the crucial pre-analytical processing steps for AD blood samples that significantly impact research outcomes and addresses the practical challenges faced during clinical testing. These discussions are crucial for enhancing our comprehension and refining the diagnostic precision of AD using blood-based biomarkers. The review aims to shed light on potential avenues for innovation and improvement in the techniques employed for detecting and investigating AD, thereby contributing to the broader field of neurodegenerative disease research., Competing Interests: The authors declare no conflicts of interest in this work., (© 2024 Zhang et al.)

Eupatorium lindleyanum DC. (EL) is a traditional Chinese herb known for its phlegm-reducing, cough-relieving and asthma-calming properties. It is widely used for treating cough and bronchitis. However, preliminary experiments have revealed wide variations in the composition of its different medicinal parts (flowers, leaves and stems), and the composition and efficacy of its different medicinal parts remain largely underexplored at present. In this study, non-targeted rapid resolution liquid chromatography coupled with a quadruple time-of-flight mass spectrometry (RRLC-Q-TOF-MS)-based metabolomics approach was developed to investigate the differences in the chemical composition of different medicinal parts of EL. We identified or tentatively identified 9 alkaloids, 11 flavonoids, 14 sesquiterpene lactones, 3 diterpenoids and 24 phenolic acids. In addition, heatmap visualization, quantitative analysis by high-performance liquid chromatography (HPLC-PDA) and ultra-high-performance liquid chromatography-triple quadrupole tandem mass spectrometry (UPLC-MS/MS) showed particularly high levels of sesquiterpene lactones, flavonoids and phenolic acids in the flowers, such as eupalinolide A and B and chlorogenic acid, among others. The leaves also contained some flavonoid sesquiterpene lactones and phenolic acids, while the stems were almost absent. The findings of in vitro activity studies indicated that the flowers exhibited a notable inhibitory effect on the release of the inflammatory factors TNF-α and IL-6, surpassing the anti-inflammatory efficacy observed in the leaves. Conversely, the stems demonstrated negligible anti-inflammatory activity. The variations in anti-inflammatory activity among the flowers, leaves and stems of EL can primarily be attributed to the presence of flavonoids, phenolic acids and sesquiterpene lactones in both the flowers and leaves. Additionally, the flowers contain a higher concentration of these active components compared to the leaves. These compounds mediate their anti-inflammatory effects through distinct biochemical pathways. The results of this study are anticipated to provide a scientific basis for the rational and effective utilization of EL resources.

Background: Plasma amyloid-β (Aβ), phosphorylated tau-181 (p-tau181), neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) potentially aid in the diagnosis of neurodegenerative dementias. We aim to conduct a comprehensive comparison between different biomarkers and their combination, which is lacking, in a multicenter Chinese dementia cohort consisting of Alzheimer's disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP)., Methods: We enrolled 92 demented patients [64 AD, 16 FTD, and 12 PSP with dementia] and 20 healthy controls (HC). Their plasma Αβ, p-tau181, NfL, and GFAP were detected by highly sensitive-single molecule immunoassays. Αβ pathology in patients was measured by cerebrospinal fluid or/and amyloid positron emission tomography., Results: All plasma biomarkers tested were significantly altered in dementia patients compared with HC, especially Aβ42/Aβ40 and NfL showed significant performance in distinguishing AD from HC. A combination of plasma Aβ42/Aβ40, p-tau181, NfL, and GFAP could discriminate FTD or PSP well from HC and was able to distinguish AD and non-AD (FTD/PSP)., Conclusions: Our results confirmed the diagnostic performance of individual plasma biomarkers Aβ42/Aβ40, p-tau181, NfL, and GFAP in Chinese dementia patients and noted that a combination of these biomarkers may be more accurate in identifying FTD/PSP patients and distinguishing AD from non-AD dementia., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Cognitive impairment is a primary manifestation of neurological symptoms associated with COVID-19 and may occur after disease resolution. Although cognitive impairment has been extensively reported in the literature, its duration and rate of remission remain controversial. This study discusses the various factors that influence cognitive impairment, including demographic characteristics, genetics, as well as disease course and severity. Furthermore, imaging and laboratory data have suggested various associations with cognitive impairment, most notably changes in EEG patterns, PET imaging, and serum markers. Some findings suggest similarities and potential links between COVID-related cognitive impairment and Alzheimer's disease. Moreover, this study reviews the various mechanisms proposed to explain the development of cognitive impairment in COVID-19, including cytokine storm, damage to the blood-brain barrier, compromise of small vessel integrity, hypoxic conditions, and immune dysregulation., Competing Interests: All authors declare that they have no competing interests., (© 2024 – The authors. Published by IOS Press.)

Background: Posterior cortical atrophy (PCA) is a form of dementia that frequently displays significant visual dysfunction and relatively preserved cognitive and executive functions, thus hindering early diagnosis and treatment. This study aimed to investigate possible fundus markers in PCA patients and compare them with those of typical Alzheimer's disease (AD) patients to seek potential diagnostic patterns., Methods: Age-matched PCA and AD patients and healthy controls (HC) completed optometry, intraocular pressure measurement, neuropsychologic assessments, optical coherence tomography (OCT), and optical coherence tomography angiography (OCTA) examination in one visit. Overall, six outcomes of thicknesses of various retinal layers and seven outcomes of the retinal microvascular network were calculated. After adjusting for age, sex, and years of education, the OCT and OCTA results were analyzed using analysis of covariance and generalized linear models. Correlation analyses were performed using Spearman correlation, and ROC curves were plotted., Results: Twelve PCA patients, nineteen AD patients, and thirty HC, aged 45-80 years were included. Fifty HC, thirty AD, and twenty PCA eyes were available for foveal avascular zone (FAZ) area analysis; forty-nine HC, thirty-four AD, and eighteen PCA eyes were available for OCT and OCTA assessments. PCA patients had thinner retinal nerve fiber layer and ganglion cell layer + inner plexiform layer than HC in the 0-3 mm circle and 1-3 mm ring. Few structural differences were observed between the AD group and the other two groups. The flow area of the superficial capillary plexus and the intermediate capillary plexus was smaller in the PCA group than in the HC group in the 0-1 mm circle, 0-3 mm circle. MMSE performed better than any combination of optical parameters in identifying AD and PCA from HC (AUC = 1), while the combination of MoCA, retinal thickness and vascular density of ICP in the 1-3 mm ring, with flow area of ICP in the 0-1 mm circle showed the strongest ability to distinguish PCA from AD (AUC = 0.944)., Conclusions: PCA patients exhibited similar impairment patterns to AD patients in the fundus structure and microvascular network. OCTA may aid in the non-invasive detection of AD and PCA, but still remains to be substantiated., (© 2024. The Author(s).)

Alzheimer's disease (AD) is the most prevalent form of dementia among elderly people worldwide. Cerebrospinal fluid (CSF) is the optimal fluid source for AD biomarkers, while serum biomarkers are much more achievable. To search for novel diagnostic AD biomarkers, we performed a quantitative proteomic analysis of CSF and serum samples from AD and normal cognitive controls (NC). CSF and serum proteomes were analyzed via data-independent acquisition quantitative mass spectrometry. Our bioinformatic analysis was based on Gene Ontology (GO) functional annotation analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. In comparison to the controls, 8 proteins were more abundant in AD CSF, and 60 were less abundant in AD CSF, whereas 55 proteins were more and 10 were less abundant in the serum samples. ATPase-associated activity for CSF and mitochondrial functions for CSF and serum were the most enriched GO terms of the DEPs. KEGG enrichment analysis showed that the most significant pathways for the differentially expressed proteins were the N-glycan biosynthesis pathways. The area under the curve (AUC) values for CSF sodium-/potassium-transporting ATPase subunit beta-1 (AT1B1), serglycin (SRGN), and thioredoxin-dependent peroxide reductase, mitochondrial (PRDX3) were 0.867 ( p = 0.004), 0.833 ( p = 0.008), and 0.783 ( p = 0.025), respectively. A panel of the above three CSF proteins accurately differentiated AD (AUC = 0.933, p = 0.001) from NC. The AUC values for serum probable phospholipid-transporting ATPase IM (AT8B4) and SRGN were moderate. The AUC of the CSF SRGN + serum SRGN was 0.842 ( p = 0.007). These novel AD biomarker candidates are mainly associated with inflammation, ATPase activity, oxidative stress, and mitochondrial dysfunction. Further studies are needed to investigate the molecular mechanisms by which these potential biomarkers are involved in AD.

Smoking is a modifiable risk factor for Alzheimer's disease (AD). The insula plays a vital role in both smoking and cognition. However, the smoking effects on insula-related networks in cognitively normal controls (CN) and mild cognitive impairment (MCI) patients remain unknown. We identified 129 CN (85 non-smokers and 44 smokers) and 83 MCI (54 non-smokers and 29 smokers). Each underwent neuropsychological assessment and MRI (structural and resting-state functional). Seed-based functional analyses in the anterior and posterior insula were performed to calculate the functional connectivity (FC) with voxels in the whole brain. Mixed-effect analyses were performed to explore the interactive effects on smoking and cognitive status. Associations between FC and neuropsychological scales were assessed. Mixed-effect analyses revealed the FC differences between the right anterior insula (RAI) with the left middle temporal gyrus (LMTG) and that with the right inferior parietal lobule (RIPL) (p < 0.01, cluster level < 0.05, two-tailed, gaussian random field correction). The FC of RAI in both LMTG and RIPL sees a significant decrease in MCI smokers (p < 0.01). Smoking affects insula FC differently between MCI and CN, and could decrease the insula FC in MCI patients. Our study provides evidence of neural mechanisms between smoking and AD., (© 2023. The Author(s).)

Mild cognitive impairment is a nonmotor complication in Parkinson's disease (PD) that have a high risk of developing dementia. White matter is associated with cognitive function in PD and the alterations may occur before the symptoms of the disease. Previous diffusion tensor imaging (DTI) studies lacked specificity to characterize the concrete contributions of distinct white matter tissue properties. This may lead to inconsistent conclusions about the alteration of white matter microstructure. Here, we used neurite orientation dispersion and density imaging (NODDI) and white matter fiber clustering method to uncover local white matter microstructures in PD with mild cognitive impairment (PD-MCI). This study included 23 PD-MCI and 20 PD with normal cognition (PD-NC) and 21 healthy controls (HC). To probe specific and fine-grained differences, metrics of NODDI and DTI in white matter fiber clusters were evaluated using along-tract analysis. Our results showed that PD-MCI patients had significantly lower neurite density index (NDI) and orientation dispersion index (ODI) in white matter fiber clusters in the prefrontal region. Correlation analysis and receiver operating characteristic (ROC) analysis revealed that the diagnostic performance of NODDI-derived metrics in cingulum bundle (2 clusters) and thalamo-frontal (2 clusters) were superior to DTI metrics. Our study provides a more specific insight to uncover local white matter abnormalities in PD-MCI, which benefit understanding the underlying mechanism of cognitive decline in PD and predicting the disease in advance., (© 2023 Wiley Periodicals LLC.)

Neovascular age-related macular degeneration (nAMD) is a common and multifactorial disease in the elderly that may lead to irreversible vision loss; yet the pathogenesis of AMD remains unclear. In this study, nontargeted metabolomics profiling using ultra-performance liquid chromatography coupled with Q-Exactive Orbitrap mass spectrometry was applied to discover the metabolic feature differences in both faeces and serum samples between Chinese nonobese subjects with and without nAMD. In faecal samples, a total of 18 metabolites were significantly altered in nAMD patients, and metabolic dysregulations were prominently involved in glycerolipid metabolism and nicotinate and nicotinamide metabolism. In serum samples, a total of 29 differential metabolites were founded, involved in caffeine metabolism, biosynthesis of unsaturated fatty acids, and purine metabolism. Two faecal metabolites (palmitoyl ethanolamide and uridine) and three serum metabolites (4-hydroxybenzoic acid, adrenic acid, and palmitic acid) were selected as potential biomarkers for nAMD. Additionally, the significant correlations among dysregulated neuroprotective, antineuroinflammatory, or fatty acid metabolites in faecal and serum and IM dysbiosis were found. This comprehensive metabolomics study of faeces and serum samples showed that alterations in IM-mediated neuroprotective metabolites may be involved in the pathophysiology of AMD, offering IM-based nutritional therapeutic targets for nAMD.

Previous studies have shown that Ogt-mediated O-GlcNAcylation is essential for neuronal development and function. However, the function of O-GlcNAc transferase (Ogt) and O-GlcNAcylation in astrocytes remains largely unknown. Here we show that Ogt deficiency induces inflammatory activation of astrocytes in vivo and in vitro, and impairs cognitive function of mice. The restoration of O-GlcNAcylation via GlcNAc supplementation inhibits the activation of astrocytes, inflammation and improves the impaired cognitive function of Ogt deficient mice. Mechanistically, Ogt interacts with NF-κB p65 and catalyzes the O-GlcNAcylation of NF-κB p65 in astrocytes. Ogt deficiency induces the activation of NF-κB signaling pathway by promoting Gsk3β binding. Moreover, Ogt depletion induces the activation of astrocytes derived from human induced pluripotent stem cells. The restoration of O-GlcNAcylation inhibits the activation of astrocytes, inflammation and reduces Aβ plaque of AD mice in vitro and in vivo. Collectively, our study reveals a critical function of Ogt-mediated O-GlcNAcylation in astrocytes through regulating NF-κB signaling pathway., (© 2023. The Author(s).)

Ethnopharmacological Relevance: Celastrus orbiculatus Thunb., also called as oriental bittersweet vine or climbing spindle berry, a traditional Chinese herbal medicine has been used to treat a spectrum of painful and inflammatory diseases for centuries. Explored for their unique medicinal properties, C.orbiculatus offers additional therapeutic effects on cancerous diseases. The effect of single-agent gemcitabine on survival has not long been encouraging, combination therapies provide patients multiple chances of benefit for improved clinical response., Aims of This Study: This study aims at expounding the chemopotentiating effects and underlying mechanisms of betulinic acid, a primary therapeutic triterpene of C. orbiculatus in combination with gemcitabine chemotherapy., Materials and Methods: The preparation of betulinic acid was optimized using ultrasonic-assisted extraction method. Gemcitabine-resistant cell model was established by induction of the cytidine deaminase. MTT, colony formation, EdU incorporation and Annexin V/PI staining assays were used to evaluate cytotoxicity, cell proliferation and apoptosis in BxPC-3 pancreatic cancer cell line and H1299 non-small cell lung carcinoma cell line. Comet assay, metaphase chromosome spread and γH2AX immunostaining were applied for DNA damage assessment. Western blot and co-immunoprecipitation was used to detect the phosphorylation and ubiquitination of Chk1. Mode of action of gemcitabine in combination with betulinic acid was further captured in BxPC-3-derived mouse xenograft model., Results: We noticed that the extraction method had an impact on the thermal stability of C. orbiculatus. Ultrasound-assisted extraction at room temperature in shorter processing time could maximize the overall yields and biological activities of C. orbiculatus. The major constituent was identified as betulinic acid, and the pentacyclic triterpene represented the prominent anticancer activity of C. orbiculatus. Forced expression of cytidine deaminase conferred acquired resistance to gemcitabine, while betulinic acid displayed equivalent cytotoxicity toward gemcitabine-resistant and sensitive cells. A combination therapy of gemcitabine with betulinic acid produced synergistic pharmacologic interaction on cell viability, apoptosis and DNA double-strand breaks. Moreover, betulinic acid abrogated gemcitabine-triggered Chk1 activation by destabilizing Chk1 loading via proteasomal degradation. The combination of gemcitabine and betulinic acid significantly retarded BxPC-3 tumor growth in vivo compared to single-agent gemcitabine treatment alone, accompanied with reduced Chk1 expression., Conclusions: These data provide evidence that betulinic acid is a potential candidate for chemosensitization as a naturally occurring Chk1 inhibitor and warrants further preclinical evaluation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Among enteroviruses, echovirus can cause severe illnesses in neonates or infants, with high morbidity and mortality. Autophagy, a central component of host defense mechanisms, can function against diverse infections. In the present study, we investigated the interplay between echovirus and autophagy. We demonstrated that echovirus infection increases LC3-II expression dose-dependently, accompanied by an increased intracellular LC3 puncta level. In addition, echovirus infection induces the formation of autophagosome. These results suggest that echovirus infection induces autophagy machinery. Furthermore, phosphorylated mTOR and ULK1 were both decreased upon echovirus infection. In contrast, both levels of the vacuolar protein sorting 34 (VPS34) and Beclin-1, the downstream molecules which play essential roles in promoting the formation of autophagic vesicles, increased upon virus infection. These results imply that the signaling pathways involved in autophagosome formation were activated by echovirus infection. Moreover, induction of autophagy promotes echovirus replication and viral protein VP1 expression, while inhibition of autophagy impairs VP1 expression. Our findings suggest that autophagy can be induced by echovirus infection via regulating mTOR/ULK1 signaling pathway and exhibits a proviral function, revealing the potential role of autophagy in echovirus infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer YX declared a shared parent affiliation with the author SL at the time of review., (Copyright © 2023 Wu, Zeng, Yi, Miao, Liu, Wang, Liu, Peng, Zheng and Xia.)

Objective: Alzheimer's disease (AD) is the most prevalent form of dementia among the aging population. Cumulative studies aim to find non-invasive biomarkers in the early stages of AD. Saliva can be obtained easily, and salivary biomarkers have been proven effective in detecting neurodegenerative diseases. To find effective biomarkers in saliva and to help the diagnosis of AD, we performed a meta-analysis focusing on the salivary biomarkers (β-amyloid 1-42 (Aβ 1-42 ), total tau (t-tau), phosphorylated tau (p-tau) and acetylcholinesterase (AChE)) in AD., Methods: We conducted a systematic online search for eligible studies reporting data on salivary biomarkers reflecting Aβ 1-42 , t-tau, p-tau, and AChE in AD cohorts versus controls. Biomarkers' performance was assessed in a random-effects meta-analysis with the ratio of mean (RoM)., Results: A total of thirteen studies were included in the meta-analysis, of them seven involved salivary Aβ 1-42 (271 AD and 489 controls), five involved salivary t-tau (324 AD and 252 controls), four involved salivary p-tau (130 AD and 161 controls), and three involved salivary AChE (81 AD and 54 controls). AD showed significantly higher salivary Aβ 1-42 levels than control (ROM = 1.90 (95% CI 1.28-2.81, P = 0.001), while AD and control did not differ significantly on salivary t-tau, p-tau and AChE (ROM = 0.94, 95% CI 0.67-1.31, P = 0.72; ROM = 0.91, 95% CI 0.56-1.45, P = 0.68; ROM = 0.83, 95% CI 0.24-2.88, P = 0.77; respectively)., Conclusion: The pooled results provide evidence that salivary Aβ 1-42 may serve as a sensitive biomarker for AD; nevertheless, larger AD cohorts are required to further confirm the sensitivity and specificity of salivary Aβ 1-42 for AD diagnosis., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Hyperactivity of pyramidal neurons (PNs) in CA1 is an early event in Alzheimer's disease. However, factors accounting for the hyperactivity of CA1 PNs remain to be completely investigated. In the present study, we report that the serotonergic signaling is abnormal in the hippocampus of hAPP-J20 mice. Interestingly, chemogenetic activation of serotonin (5-hydroxytryptamine; 5-HT) neurons in the median raphe nucleus (MRN) attenuates the activity of CA1 PNs in hAPP-J20 mice by regulating the intrinsic properties or inhibitory synaptic transmission of CA1 PNs through 5-HT3aR and/or 5-HT1aR. Furthermore, activating MRN 5-HT neurons improves memory in hAPP-J20 mice, and this effect is mediated by 5-HT3aR and 5-HT1aR. Direct activation of 5-HT3aR and 5-HT1aR with their selective agonists also improves the memory of hAPP-J20 mice. Together, we identify the impaired 5-HT/5-HT3aR and/or 5-HT/5-HT1aR signaling as pathways contributing to the hyperexcitability of CA1 PNs and the impaired cognition in hAPP-J20 mice., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Frontotemporal lobar degeneration (FTLD) is a group of neurodegenerative diseases with heterogenous clinical, genetic, and pathological characteristics that show similar impairment of areas in the frontal and/or temporal lobes. Prime doctors' lack of awareness of this complex disease makes early identification and accurate intervention difficult. Autoimmune diseases and autoantibodies are manifestations of different levels of autoimmune reactions. This review presents research findings examining the relationship between autoimmunity and FTLD in terms of autoimmune diseases and autoantibodies with a focus on identifying potential diagnosis and treatment approaches. The findings indicate that the same or similar pathophysiological mechanisms may exist from clinical, genetic, and pathological perspectives. However, the existing evidence is not sufficient to extract substantial conclusions. On the basis of the current situation, we propose future research patterns using prospective studies on large populations and combined clinical and experimental research. Autoimmune reactions or, more generally, inflammatory reactions should receive increased attention from doctors and scientists of all disciplines., Competing Interests: The authors declare no competing interests in this work., (© 2023 Sun et al.)

Background: Rapidly progressive dementia (RPD) is a syndrome originating from various diseases. Recent advances have allowed a better understanding of its categories and spectrum; however, it remains challenging to make an accurate differential diagnosis and prognosis prediction., Methods: This study was a retrospective evaluation of all participants admitted to the neurology department of a single center in China from January 2015 to December 2019. The screened patients met the RPD criteria and their characteristics were collected to explore a diagnostic pattern of RPD. In addition, outcomes of RPD were evaluated with the Glasgow Outcome Scale (GOS), activities of daily living scale (ADL), and simplified Mini-Mental State Examination (MMSE), and different prognostic analysis methods were performed to determine the prognostic factors of RPD., Results: A total of 149 RPD patients among 15,731 inpatients were identified with an average MMSE value of 13.0 ± 4.6 at baseline. Etiological epidemiology revealed infectious, neurodegenerative and toxic/metabolic diseases as the three largest groups, accounting for 26.2%, 20.8% and 16.8% of all cases, respectively. In particular, prevalence rates of Creutzfeldt-Jakob disease (13.4%), Alzheimer's disease (11.4%), carbon monoxide poisoning (8.1%), neurosyphilis (5.4%) and dementia with Lewy bodies (5.4%) were highest in this series. A recommended diagnostic framework for RPD etiology was thus established. Follow-up evaluations showed a negative correlation between age and GOS scores (r=-0.421, P < 0.001), as well as age and simplified MMSE scores (r s =- 0.393, P < 0.001), and a positive correlation between age and ADL scores (r s =0.503, P < 0.001), and significantly different GOS, ADL and simplified MMSE scores across various etiologies (P = 0.003; F = 9.463, P < 0.001; F = 6.117, P < 0.001)., Conclusion: Infectious, neurodegenerative and toxic-metabolic entities were the most common RPD categories, and establishing a practical approach to RPD etiology would allow better disease management., (© 2023. The Author(s).)

Light has important effects on plant metabolism. However, the relationship between the chlorogenic acid (CGA) content and light in plants remains unclear. Here, we investigated the effects of shading treatment on gene expression and CGA content in Lonicera macranthoides Hand.-Mazz. (LM), a widely used medicinal plant. A total of 1891 differentially expressed genes (DEGs) were obtained in flower buds and 819 in leaves in response to light in shading treatment compared to the control sample by RNA-Seq. After shading treatment, the content of CGA in LM leaves decreased significantly by 1.78-fold, the carotenoid content increased, and the soluble sugar and starch contents significantly decreased. WGCNA and the expression of related genes verified by qRT‒PCR revealed that CGA synthesis pathway enzyme genes form a co-expression network with genes for carbohydrate synthesis, photosynthesis, light signalling elements, and transcription factor genes (TFs) that affect the accumulation of CGA. Through a virus-induced gene silencing (VIGS) system and CGA assay in Nicotiana benthamiana (NB), we determined that downregulation of NbHY5 expression decreased the CGA content in NB leaves. In this study, we found that light provides energy and material for the accumulation of CGA in LM, and light affects the expression of CGA accumulation-related genes. Our results show that different light intensities have multiple effects on leaves and flower buds in LM and are able to coregulate LmHY5 expression and CGA synthesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

New neurons are abnormal in the adult hippocampus of Alzheimer's disease (AD) mouse models. The effects of modulating adult neurogenesis on AD pathogenesis differ from study to study. We reported recently that ablation of adult neural stem cells (aNSCs) was associated with improved memory in AD models. Here, we found that long-term potentiation (LTP) was improved in the hippocampus of APP/PS1 mice after ablation of aNSCs. This effect was confirmed in hAPP-J20 mice, a second AD mouse model. On the other hand, we found that exposure to enriched environment (EE) dramatically increased the number of DCX + neurons, promoted dendritic growth, and affected the location of newborn neurons in the dentate gyrus of APP/PS1 mice, and EE exposure significantly ameliorated memory deficits in APP/PS1 mice. Together, our data suggest that both inhibiting abnormal adult neurogenesis and enhancing healthy adult neurogenesis could be beneficial for AD, and they are not mutually exclusive., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: New therapies are urgently needed for Alzheimer's disease (AD). Sodium oligomannate (GV-971) is a marine-derived oligosaccharide with a novel proposed mechanism of action. The first phase 3 clinical trial of GV-971 has been completed in China., Methods: We conducted a phase 3, double-blind, placebo-controlled trial in participants with mild-to-moderate AD to assess GV-971 efficacy and safety. Participants were randomized to placebo or GV-971 (900 mg) for 36 weeks. The primary outcome was the drug-placebo difference in change from baseline on the 12-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog12). Secondary endpoints were drug-placebo differences on the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC+), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, and Neuropsychiatric Inventory (NPI). Safety and tolerability were monitored., Results: A total of 818 participants were randomized: 408 to GV-971 and 410 to placebo. A significant drug-placebo difference on the ADAS-Cog12 favoring GV-971 was present at each measurement time point, measurable at the week 4 visit and continuing throughout the trial. The difference between the groups in change from baseline was - 2.15 points (95% confidence interval, - 3.07 to - 1.23; p < 0.0001; effect size 0.531) after 36 weeks of treatment. Treatment-emergent adverse event incidence was comparable between active treatment and placebo (73.9%, 75.4%). Two deaths determined to be unrelated to drug effects occurred in the GV-971 group., Conclusions: GV-971 demonstrated significant efficacy in improving cognition with sustained improvement across all observation periods of a 36-week trial. GV-971 was safe and well-tolerated., Trial Registration: ClinicalTrials.gov, NCT0229391 5. Registered on November 19, 2014.

Adult neurogenesis is impaired in the hippocampus of patients with Alzheimer disease (AD) as well as AD models. However, it is far from clear how modulating adult neurogenesis affects AD neuropathology. We confirm that adult hippocampal neurogenesis is impaired in two AD models. Surprisingly, however, cognitive functions are improved in AD models after ablating adult neural stem cells (aNSCs). Ablation of aNSCs does not affect the levels of amyloid β but restores the normal synaptic transmission in the dentate gyrus (DG) granule cells of AD models. Furthermore, calbindin depletion in the DG of AD mice is ameliorated after aNSC ablation, and knocking down calbindin abolishes the effects of aNSC ablation on synaptic and cognitive functions of AD mice. Together, our data suggest that cognitive functions of AD mice are improved after aNSC ablation, which is associated with the restoration of synaptic transmission in the DG granule cells with calbindin as an important mediator., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Myotonic dystrophy type 1 (DM1) is the most common disease that can cause muscle weakness and atrophy among adults. Normal pressure hydrocephalus (NPH) is characterized by the triad of gait disturbance, cognitive impairment and urinary incontinence. The association between DM1 and NPH is extremely rare. We report a Chinese female patient with DM1 in association with NPH., Case Presentation: The patient presented with a history of 3-year of walking instability and cognitive impairment. Her brain MRI showed ventriculomegaly with normal cerebrospinal fluid (CSF) pressure and the CSF tap-test was positive, which indicated the diagnosis of probable NPH. DM1 was confirmed by genetic testing., Conclusions: Four patients with DM1-NPH association were found before. The association between NPH and DM1 may not be just a coincidence, NPH may occur in DM1 later in life and it is vital to recognize the association as a shunt surgery may improve patients' quality of life.

Objective: (Background): Alzheimer's disease (AD), clinically characterized by the progressive neurodegenerative condition and cognitive impairment, is one of the main causes of disability in elder people worldwide. Recently, several animal studies indicated that the 'gut-brain' axis might contribute to the amyloid deposition of AD. However, data about gut dysbiosis in human AD remains scarce in the literature, especially including the whole process of AD. In this prospective and cross-sectional study, we aimed at identifying differences in microbiome between patients with AD (Pre-onset stage amnestic mild cognitive impairment, aMCI; and AD) and the normal cognition healthy controls (HC). Additionally, the potential association between IM and clinical characteristics of AD was evaluated., Methods: A total of 97 subjects (33 AD, 32 aMCI, and 32 HC) were recruited in the study. The composition of gut bacterial communities was determined by 16S ribosomal RNA Miseq sequencing. In addition, Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was used to predict function shift of intestinal microbiota. The Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) or Clinical Dementia Rating (CDR) scores were used to evaluate the severity of cognitive impairment in patients., Results: The fecal microbial diversity was decreased in AD patients compared with aMCI patients and HC. And the microbial composition was distinct among aMCI, AD and healthy control groups. Among bacterial taxa, the proportion of phylum Firmicutes was significantly reduced (P = 0.008), whereas Proteobacteria (P = 0.024) was highly enriched in the AD compared with HC. In addition, similar alterations were observed at the order, class and family levels of these two phyla. And Gammaproteobacteria, Enterobacteriales and Enterobacteriaceae showed a progressive enriched prevalence from HC to aMCI and AD patients. Further, a significant correlation was observed between the clinical severity scores of AD patients and the abundance of altered microbiomes. Moreover, the KEGG results showed the increased modules related to glycan biosynthesis and metabolism in AD and aMCI patients and decreased pathways related to immune system in AD patients. Importantly, the discriminating models based on predominant microbiota could effectively distinguish aMCI and AD from HC (AUC = 0.890, 0.940, respectively), and also AD from aMCI (AUC = 0.925). Notably, the models based on the abundance of family Enterobacteriaceae could distinguish AD from both aMCI (AUC = 0.688) and HC (AUC = 0.698)., Conclusions: Distinct microbial communities, especially enriched Enterobacteriaceae, were associated with patients with AD when compared with predementia stage aMCI and healthy subjects. These novel findings will give new clues to understand the disease and provide new therapeutic target for intervention or a marker for this disease., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Mild cognitive impairment (MCI) is a transition state between asymptomatic stage and dementia. Amnestic MCI (aMCI) patients who mainly present with memory deficits are highly likely to progress to Alzheimer's disease (AD). At present, no broadly effective drug therapy is available to prevent the progression from memory deficit to dementia. Cognitive control training, which has transfer effects on multiple cognitive capacities including memory function in healthy old adults, has not yet been applied to aMCI., Methods/design: In this single-center, randomized double-blind placebo-controlled study, 70 aMCI patients will be recruited and randomly assigned to the training and control groups. The intervention is an Internet-based cognitive control training program performed for 30 min daily, five days per week, for 12 consecutive weeks. Neuropsychological assessment and structural and functional magnetic resonance imaging (MRI) will be performed at baseline and outcome. Primary outcomes are changes of episodic memory retrieval function. Secondary outcome measures are neuroplasticity changes measured by functional and structural MRI., Discussion: In this study, an Internet-based cognitive control training program is adopted to investigate whether cognitive control training can enhance the retrieval of episodic memory in aMCI patients. The combination of multi-modal MRI and neuropsychological tests could have a good sensitivity in evaluating the effects of cognitive control training and could also uncover the underlying neural underpinning., Trial Registration: ClinicalTrials.gov, NCT03133052 . Registered on 21 April 2017.

Although the functional connectivity of patients with disorders of consciousness (DOC) has been widely examined, less is known about brain white matter connectivity. The aim of this study was to explore structural network alterations for the diagnosis and prognosis of patients with chronic DOC. Eleven DOC patients and 11 sex- and age-matched controls were included in the study. Participants underwent diffusion magnetic resonance imaging (MRI) and T1-weighted structural MRI at 7 tesla (7 T). Graph-theoretical analysis and network-based statistics were used to analyze the group differences. Two patients were scanned twice for a longitudinal study to examine the relationship between connectome metrics and the patients' prognoses. Compared with healthy controls, DOC patients showed significantly elevated transitivity (p < .001), local efficiency (p = .009), and clustering coefficient (p = .039). When comparing the connectome metrics within the three groups (healthy controls, minimally conscious state (MCS), and vegetative state/unresponsive wakefulness syndrome (VS/UWS)), significant group differences were observed in transitivity (p < .001) and local efficiency (p = .031). Significantly increased transitivity was observed in vegetative state/unresponsive wakefulness syndrome compared with minimally conscious state (p = .0217, Bonferroni corrected). Transitivity showed significant negative correlations with the Coma Recovery Scale-Revised score (r = -0.6902, p = .023), consistent with the longitudinal study results. A subnetwork with significantly decreased structural connections was identified using network-based statistical analysis comparing DOC patients with healthy controls, which was mainly located in the frontal cortex, limbic system, and occipital and parietal lobes. This preliminary study suggests that graph theoretical approaches for assessing white matter connectivity may enable various states of DOC to be distinguished. Of the metrics analyzed, transitivity had a critical role in distinguishing the diagnostic groups. Larger cohorts will be necessary to confirm the predictive value of 7 T MRI in the prognosis of DOC patients., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

β-amyloid deposition and neuroinflammation play a crucial part in Alzheimer's disease. Therefore, this study was designed to find the effects of 1-deoxynojirimycin (DNJ) purified from mulberry leaves on pathological deposition of Aβ peptides and neuroinflammation in senescence-accelerated-prone mouse 8 (SAMP8) mice. Compared to senescence-accelerated-resistant mouse 1 (SAMR1) mice, SAMP8 mice exhibited conspicuous declines in spatial memory abilities and brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptors (TrkB) level in hippocampus; increased Aβ deposition, β-secretase (BACE1) level, microglia activation and inflammatory factors, including interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) in the brain. The SAMP8 mice were treated with DNJ (40 or 160 mg/kg/day) by oral administration for two months. Our results indicated that DNJ treatment improved these changes, and the 160-mg/kg/day DNJ group revealed more significant alleviation. Therefore, DNJ potentially has the neuroprotective effect by inhibiting BACE1 expression, attenuating Aβ deposition, remitting neuroinflammation, and up-regulating the BDNF/TrkB signal pathway in the brain., (Copyright © 2018. Published by Elsevier Masson SAS.)

A specific, sensitive, rapid, precise, and reliable UPLC-MS/MS-based method was designed for the first time for the simultaneous determination of 1-deoxynojirimycin (DNJ) and N-methyl-1-deoxynojirimycin (N-CH 3 -DNJ) in rat plasma. Miglitol was served as the internal standard (IS). An MN-NUCLEODUR HILIC column was assessed to separate the two compounds by isocratic elution using acetonitrile: water with 0.05% formic acid and 6.5mM ammonium acetate (72:28, v/v) at a flow rate of 0.4mL/min. A triple quadrupole mass spectrometer was operated in the positive ionization mode using multiple reaction monitoring (MRM), and it was employed to determine transitions of m/z 164.1→110.1, 178.1→100.1, and 208.1→146.1 for DNJ, N-CH 3 -DNJ, and IS, respectively. The method of the two constituents was validated and the results were acceptable. The absolute bioavailability of DNJ and N-CH 3 -DNJ in rats was 50±9% and 62±24%, respectively. The method was then successfully used for the first time to study the pharmacokinetic behavior and absolute bioavailability of DNJ and N-CH 3 -DNJ in rats after intravenous (10mg/kg) and oral administration (80mg/kg). The results of this study might provide more information on preclinical pharmacokinetics and a solid basis for assessing the clinical efficacy of DNJ and N-CH 3 -DNJ., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Eupatorium lindleyanum has traditionally been used as folk medicine in Asian countries for its therapeutic effects on tracheitis and tonsillitis. Investigation of the anti-inflammatory active constituents from E. lindleyanum led to the isolation of two novel sesquiterpene lactones, named eupalinolide L (1: ) and eupalinolide M (2: ), and seven known sesquiterpene lactones (3: -9: ). The structures and configurations of the new compounds were determined on the basis of spectroscopic analysis, especially 2D NMR techniques. In vivo experiments showed that the sesquiterpenes fraction significantly reduced mouse ear edema induced by xylene (18.6%, p < 0.05). In in vitro assays, compounds 1: -9: showed excellent anti-inflammatory activities, as they lowered TNF- α and IL-6 levels in lipopolysaccharide-stimulated murine macrophage RAW 264.7 cells (p < 0.001). The above results suggest that the sesquiterpene lactones from E. lindleyanum can be developed as novel potential natural anti-inflammatory agents., Competing Interests: Conflict of Interest: There are no conflicts of interest to declare., (Georg Thieme Verlag KG Stuttgart · New York.)

Objective: To understand the HIV infection status among MSM in Hubei province and provide scientific evidence for the development of intervention strategy., Methods: A total of 11 438 samples were collected from MSM in sentinel surveillance during 2010-2013 to detect HIV-1 antibody. BED-CEIA was used to identify the recent HIV infection, and the recent HIV infection rate among the MSM was estimated. The age, group and area specific recent infection rate and condom use rate were analyzed., Results: The annual HIV positive rates among MSM were 3.34% , 3.74% , 2.96% and 3.15% respectively and the annual recent infection rates were 2.31% , 1.91% , 1.53% and 1.71% respectively during 2010-2013. The HIV positive rate in age group ≤ 30 years was lower than that in age group >30 years, but the recent HIV incidence rate was higher in age group ≤ 30 years than in age group >30 years. The detection rate of recent HIV infection varied with sample source, the highest detection rate was among the samples form work group/CDC and public bathroom (3.54% and 3.49%, respectively). The recent HIV i nfection rate in Wuhan was highest (5.73%). The proportion of MSM using condoms in each homosexual behavior during past six months was 38.91% . Multiple logistic regression analysis indicated that the factors related to recent HIV infection included sample source (OR = 0.344-0.713), area (OR = 3.581-9.577) and condom usage (OR = 6.686)., Conclusion: The HIV-1 infection rate in MSM was at a high level in Hubei, especially in some areas. The condom use rate was low, it is necessary to strengthen the prevention and control of HIV infection in MSM.

Background: Highly active antiretroviral therapy (HAART) has significantly decreased mortality among Chinese HIV patients. However, emerging HIV drug resistance (HIVDR) poses a growing threat to the long-term success and durability of HAART., Methods: Three cross-sectional surveys were conducted across the country from 2004 to 2006, respectively. Patients completed a questionnaire and provided blood for CD4 cell count, HIV viral load (VL), and HIV resistance genotyping. Factors associated with HIVDR were identified by logistic regression., Results: 3667 unique patients were included across the three surveys. Among 2826 treatment-experienced patients, median duration of treatment was 17.4 (IQR 8.6-28.4) months and HIVDR was identified in 543 (19.2%). Factors significantly associated with HIVDR included ART drug distribution location, CD4 cell count, initial HAART regimen, self-reported medication adherence, and province., Conclusions: Virologic failure increased over time on therapy but a significant proportion of patients in failure had no resistance mutations identified, suggesting that treatment adherence is suboptimal and must be emphasized. Due to the significantly higher risk of HIVDR in certain provinces, additional steps to reduce HIVDR should be taken.