Perfluorooctane sulfonate （PFOS） is a class of stable organic compounds with wide industrial,commercial, and consumer applications, such as in textiles, paper, pesticides, and shampoos;. It is readily absorbed, but ...Perfluorooctane sulfonate （PFOS） is a class of stable organic compounds with wide industrial,commercial, and consumer applications, such as in textiles, paper, pesticides, and shampoos;. It is readily absorbed, but poorly eliminated, with the elimination half-life of approximately 5 years;.Hence, there have been concerns regarding its potential damage to human health. Some studies展开更多
The pathological mechanisms associated with the trans-activating response DNA/RNA binding protein（TDP）-43 remain largely enigmatic.Accumulation,insolubility and post-translational modification of nuclear and cytopla...The pathological mechanisms associated with the trans-activating response DNA/RNA binding protein（TDP）-43 remain largely enigmatic.Accumulation,insolubility and post-translational modification of nuclear and cytoplasmic TDP-43 are evident in many neurodegenerative diseases.TDP-43 constitutes one of the major molecular pathologies associated with RNA metabolism.展开更多
Migration of dendritic cells (DCs) into tissues and secondary lymphoid organs plays a crucial role in the initiation of innate and adaptive immunity. In this article, we show that cyclosporin A (CsA) impairs the migra...Migration of dendritic cells (DCs) into tissues and secondary lymphoid organs plays a crucial role in the initiation of innate and adaptive immunity. In this article, we show that cyclosporin A (CsA) impairs the migration of DCs both in vitro and in vivo. Exposure of DCs to clinical concentrations of CsA neither induces apoptosis nor alters development but does impair cytokine secretion, chemokine receptor expression, and migration. In vitro, CsA impairs the migration of mouse bone marrow-derived DCs toward macrophage inflammatory protein-3beta (MIP-3beta) and induces them to retain responsiveness to MIP-1alpha after lipopolysaccharide (LPS)-stimulated DC maturation, while in vivo administration of CsA inhibits the migration of DCs out of skin and into the secondary lymphoid organs. CsA impairs chemokine receptor and cyclooxygenase-2 (COX-2) expression normally triggered in LPS-stimulated DCs; administration of exogenous prostaglandin E2 (PGE2) reverses the effects of CsA on chemokine receptor expression and DC migration. Inhibition of nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway signaling by CsA may be responsible for the CsA-mediated effects on the regulation of chemokine receptor and cyclooxygenase-2 (COX-2) expression. Impairment of DC migration due to inhibition of PGE2 production and regulation of chemokine receptor expression may contribute, in part, to CsA-mediated immunosuppression.展开更多
Dear Editor： Glucose-dependent insulinotropic polypeptide （GIP） and proglucagon product glucagon-like peptide-1 （GLP- 1） and their corresponding receptors promote secretion of glucose-dependent insulin and may b...Dear Editor： Glucose-dependent insulinotropic polypeptide （GIP） and proglucagon product glucagon-like peptide-1 （GLP- 1） and their corresponding receptors promote secretion of glucose-dependent insulin and may be responsible for up to 70% of postprandial insulin secretions.展开更多
Radiation therapy is a standard treatment for head and neck tumors.However,patients often exhibit cognitive impairments following radiation therapy.Previous studies have revealed that hippocampal dysfunction,specifica...Radiation therapy is a standard treatment for head and neck tumors.However,patients often exhibit cognitive impairments following radiation therapy.Previous studies have revealed that hippocampal dysfunction,specifically abnormal hippocampal neurogenesis or neuroinflammation,plays a key role in radiation-induced cognitive impairment.However,the long-term effects of radiation with respect to the electrophysiological adaptation of hippocampal neurons remain poorly characterized.We found that mice exhibited cognitive impairment 3 months after undergoing 10 minutes of cranial irradiation at a dose rate of 3 Gy/min.Furthermore,we observed a remarkable reduction in spike firing and excitatory synaptic input,as well as greatly enhanced inhibitory inputs,in hippocampal CA1 pyramidal neurons.Corresponding to the electrophysiological adaptation,we found reduced expression of synaptic plasticity marker VGLUT1 and increased expression of VGAT.Furthermore,in irradiated mice,long-term potentiation in the hippocampus was weakened and GluR1 expression was inhibited.These findings suggest that radiation can impair intrinsic excitability and synaptic plasticity in hippocampal CA1 pyramidal neurons.展开更多
Despite the success of combined antiretroviral therapy in recent years, the prevalence of human immunodeficiency virus(HIV)-associated neurocognitive disorders in people living with HIV-1 is increasing, significantly ...Despite the success of combined antiretroviral therapy in recent years, the prevalence of human immunodeficiency virus(HIV)-associated neurocognitive disorders in people living with HIV-1 is increasing, significantly reducing the healthrelated quality of their lives. Although neurons cannot be infected by HIV-1, shed viral proteins such as transactivator of transcription(Tat) can cause dendritic damage. However, the detailed molecular mechanism of Tat-induced neuronal impairment remains unknown. In this study, we first showed that recombinant Tat(1–72 aa) induced neurotoxicity in primary cultured mouse neurons. Second, exposure to Tat_(1–72) was shown to reduce the length and number of dendrites in cultured neurons. Third, Tat_(1–72)(0–6 h) modulates protein phosphatase 1(PP1) expression and enhances its activity by decreasing the phosphorylation level of PP1 at Thr320. Finally, Tat_(1–72)(24 h) downregulates CREB activity and CREBmediated gene(BDNF, c-fos, Egr-1) expression. Together, these findings suggest that Tat_(1–72) might impair cognitive function by regulating the activity of PP1 and the CREB/BDNF pathway.展开更多
Odontoblasts are primarily responsible for synthesizing and secreting extracellular matrix proteins,which are crucial for dentinogenesis.Our previous single-cell profile and RNAscope for odontoblast lineage revealed t...Odontoblasts are primarily responsible for synthesizing and secreting extracellular matrix proteins,which are crucial for dentinogenesis.Our previous single-cell profile and RNAscope for odontoblast lineage revealed that cyclic adenosine monophosphate responsive element-binding protein 3 like 1(Creb3l1)was specifically enriched in the terminal differentiated odontoblasts.In this study,deletion of Creb3l1 in the Wnt1+lineage led to insufficient root elongation and dentin deposition.Assay for transposase-accessible chromatin with high-throughput sequencing(ATAC-seq)and RNA sequencing were performed to revealed that in CREB3L1-deficient mouse dental papilla cells(m DPCs),the genes near the closed chromatin regions were mainly associated with mesenchymal development and the downregulated genes were primarily related to biological processes including cell differentiation,protein biosynthesis and transport,all of which were evidenced by a diminished ability of odontoblastic differentiation,a significant reduction in intracellular proteins,and an even greater decline in extracellular supernatant proteins.Dentin matrix protein 1(Dmp1),dentin sialophosphoprotein(Dspp),and transmembrane protein 30B(Tmem30b)were identified as direct transcriptional regulatory targets.TMEM30B was intensively expressed in the differentiated odontoblasts,and exhibited a significant decline in both CREB3L1-deficient odontoblasts in vivo and in vitro.Deletion of Tmem30b impaired the ability of odontoblastic differentiation,protein synthesis,and protein secretion in mDPCs.Moreover,overexpressing TMEM30B in CREB3L1-deficient mDPCs partially rescued the extracellular proteins secretion.Collectively,our findings suggest that CREB3L1 participates in dentinogenesis and facilitates odontoblastic differentiation by directly enhancing the transcription of Dmp1,Dspp,and other differentiation-related genes and indirectly promoting protein secretion partially via TMEM30B.展开更多
The intersection of visual impairment and mental health has profound effects on quality of life and warrants attention from healthcare providers,educators,and policymakers.With 20 million children under the age of 14 ...The intersection of visual impairment and mental health has profound effects on quality of life and warrants attention from healthcare providers,educators,and policymakers.With 20 million children under the age of 14 affected globally,older adults also experience significant psychological impact including depression,anxiety,and cognitive impairment.The implications of vision-related challenges extend far beyond mere sight.Depression and anxiety,exacerbated by social isolation and reduced physical activity,underscore the need for comprehensive interventions that address both medical and psychosocial dimensions.By recognizing the profound impact of ocular morbidities like strabismus,myopia,glaucoma,and age-related macular degeneration on mental health and investing in effective treatments and inclusive practices,society can pave the way for a healthier,more equitable future for affected individuals.There is evidence that myopic children experience a higher prevalence of depressive symptoms compared to their normal peers,and interventions like the correction of strabismus can enhance psychological outcome-demonstrating the value of an integrated management approach.展开更多
Cognitive impairment is a particularly severe non-motor symptom of Parkinson's disease that significantly diminishes the quality of life of affected individuals.Identifying reliable biomarkers for cognitive impair...Cognitive impairment is a particularly severe non-motor symptom of Parkinson's disease that significantly diminishes the quality of life of affected individuals.Identifying reliable biomarkers for cognitive impairment in Parkinson's disease is essential for early diagnosis,prognostic assessments,and the development of targeted therapies.This review aims to summarize recent advancements in biofluid biomarkers for cognitive impairment in Parkinson's disease,focusing on the detection of specific proteins,metabolites,and other biomarkers in blood,cerebrospinal fluid,and saliva.These biomarkers can shed light on the multifaceted etiology of cognitive impairment in Parkinson's disease,which includes protein misfolding,neurodegeneration,inflammation,and oxidative stress.The integration of biofluid biomarkers with neuroimaging and clinical data can facilitate the development of predictive models to enhance early diagnosis and monitor the progression of cognitive impairment in patients with Parkinson's disease.This comprehensive approach can improve the existing understanding of the mechanisms driving cognitive decline and support the development of targeted therapeutic strategies aimed at modifying the course of cognitive impairment in Parkinson's disease.Despite the promise of these biomarkers in characterizing the mechanisms underlying cognitive decline in Parkinson's disease,further research is necessary to validate their clinical utility and establish a standardized framework for early detection and monitoring of cognitive impairment in Parkinson's disease.展开更多
Brain lesions,such as those caused by stroke or traumatic brain injury(TBI),frequently result in persistent motor and cognitive impairments that significantly affect the individual patient's quality of life.Despit...Brain lesions,such as those caused by stroke or traumatic brain injury(TBI),frequently result in persistent motor and cognitive impairments that significantly affect the individual patient's quality of life.Despite differences in the mechanisms of injury,both conditions share a high prevalence of motor and cognitive impairments.These deficits show only limited natural recovery.展开更多
Chronic cerebral hypoperfusion can lead to neuronal necrosis,trigger inflammatory responses,promote white matter damage,and ultimately result in cognitive impairment.Consequently,chronic cerebral hypoperfusion is an i...Chronic cerebral hypoperfusion can lead to neuronal necrosis,trigger inflammatory responses,promote white matter damage,and ultimately result in cognitive impairment.Consequently,chronic cerebral hypoperfusion is an important factor influencing the onset and progression of vascular dementia.The myelin sheath is a critical component of white matter,and damage and repair of the white matter are closely linked to myelin sheath integrity.This article reviews the role of microglia in vascular dementia,focusing on their effects on myelin sheaths and the potential therapeutic implications.The findings suggest that ischemia and hypoxia cause disruption of the blood-brain barrier and activate microglia,which may worsen blood-brain barrier damage through the release of matrix-degrading enzymes.Microglia-mediated metabolic reprogramming is recognized as an important driver of inflammation.Damage to the blood-brain barrier and subsequent inflammation can lead to myelin injury and accelerate the progression of vascular dementia.Early activation of microglia is a protective response that contributes to the maintenance of blood-brain barrier integrity through sensing,debris-clearing,and defensive mechanisms.However,prolonged activation can trigger a shift in microglia toward the pro-inflammatory M1 phenotype,resulting in myelin damage and cognitive impairment.Triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells 1 have been identified as potential biomarkers for vascular dementia,as both are closely linked to cognitive decline.Although effective clinical treatments for myelin damage in the central nervous system are currently lacking,researchers are actively working to develop targeted therapies.Several drugs,including nimodipine,dopaminergic agents,simvastatin,biotin,and quetiapine,have been evaluated for clinical use in treating microglial and myelin damage.Future research will face challenges in developing targeted therapeutic strategies for vascular dementia,requiring further investigation into the timing,duration,and specific mechanisms of microglial activation,as well as the exploration of new drug combinations and additional therapeutic targets.展开更多
With the intensification of population aging in China,the problem of cognitive impairment in the elderly has become increasingly prominent,attracting widespread attention from all sectors of society.Geriatric cognitiv...With the intensification of population aging in China,the problem of cognitive impairment in the elderly has become increasingly prominent,attracting widespread attention from all sectors of society.Geriatric cognitive impairment is characterized by chronicity,which not only seriously threatens the health of the elderly and reduces their quality of life,but also imposes a heavy burden on families and society due to its long course.Attaching importance to and strengthening the chronic disease management of elderly cognitive impairment has profound significance for delaying disease progression,improving patients’quality of life,and reducing the burden of family care.Therefore,this paper first comprehensively understands elderly cognitive impairment by briefly elaborating on its definition and characteristics;on this basis,it focuses on exploring effective strategies for the chronic disease management of elderly cognitive impairment,hoping to provide new ideas and methods for the management of this condition and offer useful references for relevant clinical research and practice.展开更多
Adult hippocampal neurogenesis is linked to memory formation in the adult brain,with new neurons in the hippocampus exhibiting greater plasticity during their immature stages compared to mature neurons.Abnormal adult ...Adult hippocampal neurogenesis is linked to memory formation in the adult brain,with new neurons in the hippocampus exhibiting greater plasticity during their immature stages compared to mature neurons.Abnormal adult hippocampal neurogenesis is closely associated with cognitive impairment in central nervous system diseases.Targeting and regulating adult hippocampal neurogenesis have been shown to improve cognitive deficits.This review aims to expand the current understanding and prospects of targeting neurogenesis in the treatment of cognitive impairment.Recent research indicates the presence of abnormalities in AHN in several diseases associated with cognitive impairment,including cerebrovascular diseases,Alzheimer's disease,aging-related conditions,and issues related to anesthesia and surgery.The role of these abnormalities in the cognitive deficits caused by these diseases has been widely recognized,and targeting AHN is considered a promising approach for treating cognitive impairment.However,the underlying mechanisms of this role are not yet fully understood,and the effectiveness of targeting abnormal adult hippocampal neurogenesis for treatment remains limited,with a need for further development of treatment methods and detection techniques.By reviewing recent studies,we classify the potential mechanisms of adult hippocampal neurogenesis abnormalities into four categories:immunity,energy metabolism,aging,and pathological states.In immunity-related mechanisms,abnormalities in meningeal,brain,and peripheral immunity can disrupt normal adult hippocampal neurogenesis.Lipid metabolism and mitochondrial function disorders are significant energy metabolism factors that lead to abnormal adult hippocampal neurogenesis.During aging,the inflammatory state of the neurogenic niche and the expression of aging-related microRNAs contribute to reduced adult hippocampal neurogenesis and cognitive impairment in older adult patients.Pathological states of the body and emotional disorders may also result in abnormal adult hippocampal neurogenesis.Among the current strategies used to enhance this form of neurogenesis,physical therapies such as exercise,transcutaneous electrical nerve stimulation,and enriched environments have proven effective.Dietary interventions,including energy intake restriction and nutrient optimization,have shown efficacy in both basic research and clinical trials.However,drug treatments,such as antidepressants and stem cell therapy,are primarily reported in basic research,with limited clinical application.The relationship between abnormal adult hippocampal neurogenesis and cognitive impairment has garnered widespread attention,and targeting the former may be an important strategy for treating the latter.However,the mechanisms underlying abnormal adult hippocampal neurogenesis remain unclear,and treatments are lacking.This highlights the need for greater focus on translating research findings into clinical practice.展开更多
The increasing global prevalence of mild cognitive impairment(MCI)necessitates a paradigm shift in early detection strategies.Conventional neuropsychological assessment methods,predominantly paper-and-pencil tests suc...The increasing global prevalence of mild cognitive impairment(MCI)necessitates a paradigm shift in early detection strategies.Conventional neuropsychological assessment methods,predominantly paper-and-pencil tests such as the Mini-Mental State Examination and the Montreal Cognitive Assessment,exhibit inherent limitations with respect to accessibility,administration burden,and sensitivity to subtle cognitive decline,particularly among diverse populations.This commentary critically examines a recent study that champions a novel approach:The integration of gait and handwriting kinematic parameters analyzed via machine learning for MCI screening.The present study positions itself within the broader landscape of MCI detection,with a view to comparing its advantages against established neuropsychological batteries,advanced neuroimaging(e.g.,positron emission tomography,magnetic resonance imaging),and emerging fluid biomarkers(e.g.,cerebrospinal fluid,blood-based assays).While the study demonstrates promising accuracy(74.44%area under the curve 0.74 with gait and graphic handwriting)and addresses key unmet needs in accessibility and objectivity,we highlight its cross-sectional nature,limited sample diversity,and lack of dual-task assessment as areas for future refinement.This commentary posits that kinematic biomarkers offer a distinctive,scalable,and ecologically valid approach to widespread MCI screening,thereby complementing existing methods by providing real-world functional insights.Future research should prioritize longitudinal validation,expansion to diverse cohorts,integration with multimodal data including dual-tasking,and the development of highly portable,artificial intelligence-driven solutions to achieve the democratization of early MCI detection and enable timely interventions.展开更多
Ischemic stroke,which is characterized by hypoxia and ischemia,triggers a cascade of injury responses,including neurotoxicity,inflammation,oxidative stress,disruption of the blood-brain barrier,and neuronal death.In t...Ischemic stroke,which is characterized by hypoxia and ischemia,triggers a cascade of injury responses,including neurotoxicity,inflammation,oxidative stress,disruption of the blood-brain barrier,and neuronal death.In this context,tryptophan metabolites and enzymes,which are synthesized through the kynurenine and 5-hydroxytryptamine pathways,play dual roles.The delicate balance between neurotoxic and neuroprotective substances is a crucial factor influencing the progression of ischemic stroke.Neuroprotective metabolites,such as kynurenic acid,exert their effects through various mechanisms,including competitive blockade of N-methyl-D-aspartate receptors,modulation ofα7 nicotinic acetylcholine receptors,and scavenging of reactive oxygen species.In contrast,neurotoxic substances such as quinolinic acid can hinder the development of vascular glucose transporter proteins,induce neurotoxicity mediated by reactive oxygen species,and disrupt mitochondrial function.Additionally,the enzymes involved in tryptophan metabolism play major roles in these processes.Indoleamine 2,3-dioxygenase in the kynurenine pathway and tryptophan hydroxylase in the 5-hydroxytryptamine pathway influence neuroinflammation and brain homeostasis.Consequently,the metabolites generated through tryptophan metabolism have substantial effects on the development and progression of ischemic stroke.Stroke treatment aims to restore the balance of various metabolite levels;however,precise regulation of tryptophan metabolism within the central nervous system remains a major challenge for the treatment of ischemic stroke.Therefore,this review aimed to elucidate the complex interactions between tryptophan metabolites and enzymes in ischemic stroke and develop targeted therapies that can restore the delicate balance between neurotoxicity and neuroprotection.展开更多
[Objectives]To investigate the clinical efficacy of core stability training combined with conventional rehabilitation in the functional recovery of patients suffering from chronic low back pain.[Methods]A randomized c...[Objectives]To investigate the clinical efficacy of core stability training combined with conventional rehabilitation in the functional recovery of patients suffering from chronic low back pain.[Methods]A randomized controlled trial design was employed in this study.Ninety patients with chronic low back pain were recruited and randomly assigned to either a control group(n=45),which received conventional rehabilitation,or an experimental group(n=45),which received conventional rehabilitation combined with core stability training.Both groups underwent treatment for 6 weeks.Assessments were conducted using the visual analogue scale(VAS),Oswestry disability index(ODI),and finger-to-floor test prior to treatment,6 weeks following treatment,and during the follow-up period,respectively.[Results]Prior to treatment,no statistically significant differences were observed between the two patient groups in terms of general information and various baseline measurements(P>0.05).Following 6 weeks of treatment and throughout the follow-up period,both groups demonstrated significant improvements in VAS scores,ODI scores,and lumbar anteflexion range of motion compared to baseline measurements(P<0.05).Notably,the magnitude of improvement in the experimental group exceeded that of the control group,with this inter-group difference reaching statistical significance(P<0.05).No serious adverse reactions were reported during the treatment process.[Conclusions]Core stability training combined with conventional rehabilitation can significantly enhance the alleviation of pain and functional impairments in patients suffering from chronic low back pain.This approach holds valuable implications for the optimization of rehabilitation treatment protocols.展开更多
AIM:To investigate the long-term outcomes in acute primary angle closure(APAC)patients treated with lens extraction(LE)surgery and to identify risk factors for glaucomatous optic neuropathy(GON).METHODS:In this longit...AIM:To investigate the long-term outcomes in acute primary angle closure(APAC)patients treated with lens extraction(LE)surgery and to identify risk factors for glaucomatous optic neuropathy(GON).METHODS:In this longitudinal observational study,detailed medical histories of APAC patients and comprehensive ophthalmic examinations at final followup were collected.Logistic regression analysis was performed to identify predictors of blindness.Univariate and multivariate linear regression analyses were conducted to determine risk factors associated with visual outcomes.RESULTS:This study included 39 affected eyes of 31 subjects(26 females)with an average age of 74.1±8.0y.At 6.7±4.2y after APAC attack,2(5.7%)eyes had bestcorrected visual acuity(VA)worse than 3/60.Advanced glaucomatous visual field loss was observed in 15(39.5%)affected eyes and 5(25.0%)fellow eyes.Nine affected eyes(23.7%)had GON,and 11(28.9%)were blind.Six(15.4%)affected eyes and 2(9.1%)fellow eyes had suspicious progression.A significantly higher blindness rate in factory workers compared to office workers.Logistic regression identified that worse VA at attack(OR 10.568,95%CI 1.288-86.695;P=0.028)and worse early postoperative VA(OR 13.214,95%CI 1.157-150.881;P=0.038)were risk factors for blindness.Multivariate regression showed that longer duration of elevated intraocular pressure(P=0.004)and worse early postoperative VA(P=0.009)were associated with worse visual outcomes.CONCLUSION:Despite LE surgery,some APAC patients experience continued visual function deterioration.Lifelong monitoring is necessary.Target pressure and progression rates should be re-evaluated during follow-up.展开更多
Drug development for Alzheimer’s disease is extremely challenging,as demonstrated by the repeated failures of amyloid-β-targeted therapeutics and the controversies surrounding the amyloid-βcascade hypothesis.More r...Drug development for Alzheimer’s disease is extremely challenging,as demonstrated by the repeated failures of amyloid-β-targeted therapeutics and the controversies surrounding the amyloid-βcascade hypothesis.More recently,advances in the development of Lecanemab,an anti-amyloid-βmonoclonal antibody,have shown positive results in reducing brain A burden and slowing cognitive decline in patients with early-stage Alzheimer’s disease in the Phase Ⅲ clinical trial(Clarity Alzheimer’s disease).Despite these promising results,side effects such as amyloid-related imaging abnormalities(ARIA)may limit its usage.ARIA can manifest as ARIA-E(cerebral edema or effusions)and ARIA-H(microhemorrhages or superficial siderosis)and is thought to be caused by increased vascular permeability due to inflammatory responses,leading to leakages of blood products and protein-rich fluid into brain parenchyma.Endothelial dysfunction is an early pathological feature of Alzheimer’s disease,and the blood-brain barrier becomes increasingly leaky as the disease progresses.In addition,APOE4,the strongest genetic risk factor for Alzheimer’s disease,is associated with higher vascular amyloid burden,increased ARIA incidence,and accelerated blood-brain barrier disruptions.These interconnected vascular abnormalities highlight the importance of vascular contributions to the pathophysiology of Alzheimer’s disease.Here,we will closely examine recent research evaluating the heterogeneity of brain endothelial cells in the microvasculature of different brain regions and their relationships with Alzheimer’s disease progression.展开更多
Traumatic axonal lesions of peripheral nerves disrupt neuronal connections with their targets,resulting in the loss of motor and sensory functions.Despite the peripheral nervous system’s capacity for axonal regrowth,...Traumatic axonal lesions of peripheral nerves disrupt neuronal connections with their targets,resulting in the loss of motor and sensory functions.Despite the peripheral nervous system’s capacity for axonal regrowth,this may lead to permanent impairements resulting in a loss of quality of life and a high socioeconomic burden.展开更多
Complex genetic relationships between neurodegenerative disorders and neuropsychiatric symptoms have been shown, suggesting shared pathogenic mechanisms and emphasizing the potential for developing common therapeutic ...Complex genetic relationships between neurodegenerative disorders and neuropsychiatric symptoms have been shown, suggesting shared pathogenic mechanisms and emphasizing the potential for developing common therapeutic targets. Apolipoprotein E(APOE) genotypes and their corresponding protein(Apo E) isoforms may influence the biophysical properties of the cell membrane lipid bilayer. However, the role of APOE in central nervous system pathophysiology extended beyond its lipid transport function. In the present review article, we analyzed the links existing between APOE genotypes and the neurobiology of neuropsychiatric symptoms in neurodegenerative and vascular diseases. APOE genotypes(APOE ε2, APOE ε3, and APOE ε4) were implicated in common mechanisms underlying a wide spectrum of neurodegenerative diseases, including sporadic Alzheimer's disease, synucleinopathies such as Parkinson's disease and Lewy body disease, stroke, and traumatic brain injury. These shared pathways often involved neuroinflammation, abnormal protein accumulation, or responses to acute detrimental events. Across these conditions, APOE variants are believed to contribute to the modulation of inflammatory responses, the regulation of amyloid and tau pathology, as well as the clearance of proteins such as α-synuclein. The bidirectional interactions among Apo E, amyloid and mitochondrial metabolism, immunomodulatory effects, neuronal repair, and remodeling underscored the complexity of Apo E's role in neuropsychiatric symptoms associated with these conditions since from early phases of cognitive impairment such as mild cognitive impairment and mild behavioral impairment. Besides Apo E-specific isoforms' link to increased neuropsychiatric symptoms in Alzheimer's disease(depression, psychosis, aberrant motor behaviors, and anxiety, not apathy), the APOE ε4 genotype was also considered a significant genetic risk factor for Lewy body disease and its worse cognitive outcomes. Conversely, the APOE ε2 variant has been observed not to exert a protective effect equally in all neurodegenerative diseases. Specifically, in Lewy body disease, this variant may delay disease onset, paralleling its protective role in Alzheimer's disease, although its role in frontotemporal dementia is uncertain. The APOE ε4 genotype has been associated with adverse cognitive outcomes across other various neurodegenerative conditions. In Parkinson's disease, the APOE ε4 allele significantly impacted cognitive performance, increasing the risk of developing dementia, even in cases of pure synucleinopathies with minimal co-pathology from Alzheimer's disease. Similarly, in traumatic brain injury, recovery rates varied, with APOE ε4 carriers demonstrating a greater risk of poor long-term cognitive outcomes and elevated levels of neuropsychiatric symptoms. Furthermore, APOE ε4 influenced the age of onset and severity of stroke, as well as the likelihood of developing stroke-associated dementia, potentially due to its role in compromising endothelial integrity and promoting blood–brain barrier dysfunction.展开更多
基金supported by awards from National Natural Science Foundation of China [No.81703260]the Education Department of Jiangsu Province [No.16KJB330010]+2 种基金the Science and Technology Department of Jiangsu Province [No.BK20160227]the China Postdoctoral Science Foundation funded project [No.2016M601892]the Priority Academic Program for the Development of Jiangsu Higher Education Institutions(PAPD)
文摘Perfluorooctane sulfonate （PFOS） is a class of stable organic compounds with wide industrial,commercial, and consumer applications, such as in textiles, paper, pesticides, and shampoos;. It is readily absorbed, but poorly eliminated, with the elimination half-life of approximately 5 years;.Hence, there have been concerns regarding its potential damage to human health. Some studies
基金supported by Georgetown University funding to Moussa CE.Moussa CE,M.D.,Ph.D.,is listed as an inventoron a pending U.S.patent application to use tyrosine kinase inhibitors as a treatment for neurodegenerative diseases
文摘The pathological mechanisms associated with the trans-activating response DNA/RNA binding protein（TDP）-43 remain largely enigmatic.Accumulation,insolubility and post-translational modification of nuclear and cytoplasmic TDP-43 are evident in many neurodegenerative diseases.TDP-43 constitutes one of the major molecular pathologies associated with RNA metabolism.
文摘Migration of dendritic cells (DCs) into tissues and secondary lymphoid organs plays a crucial role in the initiation of innate and adaptive immunity. In this article, we show that cyclosporin A (CsA) impairs the migration of DCs both in vitro and in vivo. Exposure of DCs to clinical concentrations of CsA neither induces apoptosis nor alters development but does impair cytokine secretion, chemokine receptor expression, and migration. In vitro, CsA impairs the migration of mouse bone marrow-derived DCs toward macrophage inflammatory protein-3beta (MIP-3beta) and induces them to retain responsiveness to MIP-1alpha after lipopolysaccharide (LPS)-stimulated DC maturation, while in vivo administration of CsA inhibits the migration of DCs out of skin and into the secondary lymphoid organs. CsA impairs chemokine receptor and cyclooxygenase-2 (COX-2) expression normally triggered in LPS-stimulated DCs; administration of exogenous prostaglandin E2 (PGE2) reverses the effects of CsA on chemokine receptor expression and DC migration. Inhibition of nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway signaling by CsA may be responsible for the CsA-mediated effects on the regulation of chemokine receptor and cyclooxygenase-2 (COX-2) expression. Impairment of DC migration due to inhibition of PGE2 production and regulation of chemokine receptor expression may contribute, in part, to CsA-mediated immunosuppression.
文摘Dear Editor： Glucose-dependent insulinotropic polypeptide （GIP） and proglucagon product glucagon-like peptide-1 （GLP- 1） and their corresponding receptors promote secretion of glucose-dependent insulin and may be responsible for up to 70% of postprandial insulin secretions.
基金supported by the National Natural Science Foundation of China,Nos.81925031(to YT),81820108026(to YT),81972967(to WJL),81872549(to YL)the Youth Program of National Natural Science Foundation of China,No.81801229(to YTX)+3 种基金a grant from Guangdong Science and Technology Department of China,Nos.2020B1212060018(to WJL),2020B1212030004(to WJL)the Natural Science Foundation of Guangdong Province,No.2019A1515011754(to WJL)the Science and Technology Program of Guangzhou of China,No.202007030001(to YT)the Science and Technology Planning Project of Guangzhou of China,No.201704030033(to YL).
文摘Radiation therapy is a standard treatment for head and neck tumors.However,patients often exhibit cognitive impairments following radiation therapy.Previous studies have revealed that hippocampal dysfunction,specifically abnormal hippocampal neurogenesis or neuroinflammation,plays a key role in radiation-induced cognitive impairment.However,the long-term effects of radiation with respect to the electrophysiological adaptation of hippocampal neurons remain poorly characterized.We found that mice exhibited cognitive impairment 3 months after undergoing 10 minutes of cranial irradiation at a dose rate of 3 Gy/min.Furthermore,we observed a remarkable reduction in spike firing and excitatory synaptic input,as well as greatly enhanced inhibitory inputs,in hippocampal CA1 pyramidal neurons.Corresponding to the electrophysiological adaptation,we found reduced expression of synaptic plasticity marker VGLUT1 and increased expression of VGAT.Furthermore,in irradiated mice,long-term potentiation in the hippocampus was weakened and GluR1 expression was inhibited.These findings suggest that radiation can impair intrinsic excitability and synaptic plasticity in hippocampal CA1 pyramidal neurons.
基金supported by Grants from the National Natural Science Foundation of China (81571987)
文摘Despite the success of combined antiretroviral therapy in recent years, the prevalence of human immunodeficiency virus(HIV)-associated neurocognitive disorders in people living with HIV-1 is increasing, significantly reducing the healthrelated quality of their lives. Although neurons cannot be infected by HIV-1, shed viral proteins such as transactivator of transcription(Tat) can cause dendritic damage. However, the detailed molecular mechanism of Tat-induced neuronal impairment remains unknown. In this study, we first showed that recombinant Tat(1–72 aa) induced neurotoxicity in primary cultured mouse neurons. Second, exposure to Tat_(1–72) was shown to reduce the length and number of dendrites in cultured neurons. Third, Tat_(1–72)(0–6 h) modulates protein phosphatase 1(PP1) expression and enhances its activity by decreasing the phosphorylation level of PP1 at Thr320. Finally, Tat_(1–72)(24 h) downregulates CREB activity and CREBmediated gene(BDNF, c-fos, Egr-1) expression. Together, these findings suggest that Tat_(1–72) might impair cognitive function by regulating the activity of PP1 and the CREB/BDNF pathway.
基金supported by the National Natural Science Foundation of China(NSFC)(Key Program No.82230029 and No.82071110)to Z.C.the NSFC(No.82322014 and No.82270948)+3 种基金The Interdisciplinary Research Project of School of Stomatology Wuhan University(No.XNJC202306)the Fundamental Research Funds for the Central Universities(No.2042024kf1023 and No.2042022dx0003)to H.L.the Fundamental Research Funds for the Central Universities(No.2042023kf0144)the Hubei Provincial Natural Science Foundation of China(No.2023AFB098)to Y.L。
文摘Odontoblasts are primarily responsible for synthesizing and secreting extracellular matrix proteins,which are crucial for dentinogenesis.Our previous single-cell profile and RNAscope for odontoblast lineage revealed that cyclic adenosine monophosphate responsive element-binding protein 3 like 1(Creb3l1)was specifically enriched in the terminal differentiated odontoblasts.In this study,deletion of Creb3l1 in the Wnt1+lineage led to insufficient root elongation and dentin deposition.Assay for transposase-accessible chromatin with high-throughput sequencing(ATAC-seq)and RNA sequencing were performed to revealed that in CREB3L1-deficient mouse dental papilla cells(m DPCs),the genes near the closed chromatin regions were mainly associated with mesenchymal development and the downregulated genes were primarily related to biological processes including cell differentiation,protein biosynthesis and transport,all of which were evidenced by a diminished ability of odontoblastic differentiation,a significant reduction in intracellular proteins,and an even greater decline in extracellular supernatant proteins.Dentin matrix protein 1(Dmp1),dentin sialophosphoprotein(Dspp),and transmembrane protein 30B(Tmem30b)were identified as direct transcriptional regulatory targets.TMEM30B was intensively expressed in the differentiated odontoblasts,and exhibited a significant decline in both CREB3L1-deficient odontoblasts in vivo and in vitro.Deletion of Tmem30b impaired the ability of odontoblastic differentiation,protein synthesis,and protein secretion in mDPCs.Moreover,overexpressing TMEM30B in CREB3L1-deficient mDPCs partially rescued the extracellular proteins secretion.Collectively,our findings suggest that CREB3L1 participates in dentinogenesis and facilitates odontoblastic differentiation by directly enhancing the transcription of Dmp1,Dspp,and other differentiation-related genes and indirectly promoting protein secretion partially via TMEM30B.
文摘The intersection of visual impairment and mental health has profound effects on quality of life and warrants attention from healthcare providers,educators,and policymakers.With 20 million children under the age of 14 affected globally,older adults also experience significant psychological impact including depression,anxiety,and cognitive impairment.The implications of vision-related challenges extend far beyond mere sight.Depression and anxiety,exacerbated by social isolation and reduced physical activity,underscore the need for comprehensive interventions that address both medical and psychosocial dimensions.By recognizing the profound impact of ocular morbidities like strabismus,myopia,glaucoma,and age-related macular degeneration on mental health and investing in effective treatments and inclusive practices,society can pave the way for a healthier,more equitable future for affected individuals.There is evidence that myopic children experience a higher prevalence of depressive symptoms compared to their normal peers,and interventions like the correction of strabismus can enhance psychological outcome-demonstrating the value of an integrated management approach.
基金supported by Applied Basic Research Foundation of Yunnan Province,Nos.202301AS070045,202101AY070001-115(to XY and BL)National Natural Science Foundation of China,No.81960242(to XY)。
文摘Cognitive impairment is a particularly severe non-motor symptom of Parkinson's disease that significantly diminishes the quality of life of affected individuals.Identifying reliable biomarkers for cognitive impairment in Parkinson's disease is essential for early diagnosis,prognostic assessments,and the development of targeted therapies.This review aims to summarize recent advancements in biofluid biomarkers for cognitive impairment in Parkinson's disease,focusing on the detection of specific proteins,metabolites,and other biomarkers in blood,cerebrospinal fluid,and saliva.These biomarkers can shed light on the multifaceted etiology of cognitive impairment in Parkinson's disease,which includes protein misfolding,neurodegeneration,inflammation,and oxidative stress.The integration of biofluid biomarkers with neuroimaging and clinical data can facilitate the development of predictive models to enhance early diagnosis and monitor the progression of cognitive impairment in patients with Parkinson's disease.This comprehensive approach can improve the existing understanding of the mechanisms driving cognitive decline and support the development of targeted therapeutic strategies aimed at modifying the course of cognitive impairment in Parkinson's disease.Despite the promise of these biomarkers in characterizing the mechanisms underlying cognitive decline in Parkinson's disease,further research is necessary to validate their clinical utility and establish a standardized framework for early detection and monitoring of cognitive impairment in Parkinson's disease.
基金supported by the Defitech Foundation(Morges,CH)to FCHthe Bertarelli Foundation-Catalyst program(Gstaad,CH)to FCH+2 种基金the Wyss Center for Bio and Neuroengineering the Lighthouse Partnership for AI-guided Neuromodulation to FCHthe Fonds de recherche du Quebec-Sante(FRQS#342969)to CEPthe Neuro X Postdoctoral Fellowship Program to CEP。
文摘Brain lesions,such as those caused by stroke or traumatic brain injury(TBI),frequently result in persistent motor and cognitive impairments that significantly affect the individual patient's quality of life.Despite differences in the mechanisms of injury,both conditions share a high prevalence of motor and cognitive impairments.These deficits show only limited natural recovery.
基金supported by the Natural Science Foundation of Beijing,No.7232279(to XW)the National Natural Science Foundation of China,No.U21A20400(to QW)Key Project of Beijing University of Chinese Medicine,Nos.2022-JYB-JBZR-004(to XW),2024-JYB-JBZD-043(to CL).
文摘Chronic cerebral hypoperfusion can lead to neuronal necrosis,trigger inflammatory responses,promote white matter damage,and ultimately result in cognitive impairment.Consequently,chronic cerebral hypoperfusion is an important factor influencing the onset and progression of vascular dementia.The myelin sheath is a critical component of white matter,and damage and repair of the white matter are closely linked to myelin sheath integrity.This article reviews the role of microglia in vascular dementia,focusing on their effects on myelin sheaths and the potential therapeutic implications.The findings suggest that ischemia and hypoxia cause disruption of the blood-brain barrier and activate microglia,which may worsen blood-brain barrier damage through the release of matrix-degrading enzymes.Microglia-mediated metabolic reprogramming is recognized as an important driver of inflammation.Damage to the blood-brain barrier and subsequent inflammation can lead to myelin injury and accelerate the progression of vascular dementia.Early activation of microglia is a protective response that contributes to the maintenance of blood-brain barrier integrity through sensing,debris-clearing,and defensive mechanisms.However,prolonged activation can trigger a shift in microglia toward the pro-inflammatory M1 phenotype,resulting in myelin damage and cognitive impairment.Triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells 1 have been identified as potential biomarkers for vascular dementia,as both are closely linked to cognitive decline.Although effective clinical treatments for myelin damage in the central nervous system are currently lacking,researchers are actively working to develop targeted therapies.Several drugs,including nimodipine,dopaminergic agents,simvastatin,biotin,and quetiapine,have been evaluated for clinical use in treating microglial and myelin damage.Future research will face challenges in developing targeted therapeutic strategies for vascular dementia,requiring further investigation into the timing,duration,and specific mechanisms of microglial activation,as well as the exploration of new drug combinations and additional therapeutic targets.
文摘With the intensification of population aging in China,the problem of cognitive impairment in the elderly has become increasingly prominent,attracting widespread attention from all sectors of society.Geriatric cognitive impairment is characterized by chronicity,which not only seriously threatens the health of the elderly and reduces their quality of life,but also imposes a heavy burden on families and society due to its long course.Attaching importance to and strengthening the chronic disease management of elderly cognitive impairment has profound significance for delaying disease progression,improving patients’quality of life,and reducing the burden of family care.Therefore,this paper first comprehensively understands elderly cognitive impairment by briefly elaborating on its definition and characteristics;on this basis,it focuses on exploring effective strategies for the chronic disease management of elderly cognitive impairment,hoping to provide new ideas and methods for the management of this condition and offer useful references for relevant clinical research and practice.
基金supported by Technological Innovation 2030-Major Projects of“Brain Science and Brain-like Research,”No.2022ZD0206200(to XG)the National Natural Science Foundation of China,No.82371245(to SJ),82102246(to XD),81701092(to XG)+2 种基金the Natural Science Foundation of Shandong Province,No.ZR2020MH129(to SJ)Shanghai Municipal Key Clinical Specialty,No.shslczdzk03601Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation,No.20DZ2254200。
文摘Adult hippocampal neurogenesis is linked to memory formation in the adult brain,with new neurons in the hippocampus exhibiting greater plasticity during their immature stages compared to mature neurons.Abnormal adult hippocampal neurogenesis is closely associated with cognitive impairment in central nervous system diseases.Targeting and regulating adult hippocampal neurogenesis have been shown to improve cognitive deficits.This review aims to expand the current understanding and prospects of targeting neurogenesis in the treatment of cognitive impairment.Recent research indicates the presence of abnormalities in AHN in several diseases associated with cognitive impairment,including cerebrovascular diseases,Alzheimer's disease,aging-related conditions,and issues related to anesthesia and surgery.The role of these abnormalities in the cognitive deficits caused by these diseases has been widely recognized,and targeting AHN is considered a promising approach for treating cognitive impairment.However,the underlying mechanisms of this role are not yet fully understood,and the effectiveness of targeting abnormal adult hippocampal neurogenesis for treatment remains limited,with a need for further development of treatment methods and detection techniques.By reviewing recent studies,we classify the potential mechanisms of adult hippocampal neurogenesis abnormalities into four categories:immunity,energy metabolism,aging,and pathological states.In immunity-related mechanisms,abnormalities in meningeal,brain,and peripheral immunity can disrupt normal adult hippocampal neurogenesis.Lipid metabolism and mitochondrial function disorders are significant energy metabolism factors that lead to abnormal adult hippocampal neurogenesis.During aging,the inflammatory state of the neurogenic niche and the expression of aging-related microRNAs contribute to reduced adult hippocampal neurogenesis and cognitive impairment in older adult patients.Pathological states of the body and emotional disorders may also result in abnormal adult hippocampal neurogenesis.Among the current strategies used to enhance this form of neurogenesis,physical therapies such as exercise,transcutaneous electrical nerve stimulation,and enriched environments have proven effective.Dietary interventions,including energy intake restriction and nutrient optimization,have shown efficacy in both basic research and clinical trials.However,drug treatments,such as antidepressants and stem cell therapy,are primarily reported in basic research,with limited clinical application.The relationship between abnormal adult hippocampal neurogenesis and cognitive impairment has garnered widespread attention,and targeting the former may be an important strategy for treating the latter.However,the mechanisms underlying abnormal adult hippocampal neurogenesis remain unclear,and treatments are lacking.This highlights the need for greater focus on translating research findings into clinical practice.
文摘The increasing global prevalence of mild cognitive impairment(MCI)necessitates a paradigm shift in early detection strategies.Conventional neuropsychological assessment methods,predominantly paper-and-pencil tests such as the Mini-Mental State Examination and the Montreal Cognitive Assessment,exhibit inherent limitations with respect to accessibility,administration burden,and sensitivity to subtle cognitive decline,particularly among diverse populations.This commentary critically examines a recent study that champions a novel approach:The integration of gait and handwriting kinematic parameters analyzed via machine learning for MCI screening.The present study positions itself within the broader landscape of MCI detection,with a view to comparing its advantages against established neuropsychological batteries,advanced neuroimaging(e.g.,positron emission tomography,magnetic resonance imaging),and emerging fluid biomarkers(e.g.,cerebrospinal fluid,blood-based assays).While the study demonstrates promising accuracy(74.44%area under the curve 0.74 with gait and graphic handwriting)and addresses key unmet needs in accessibility and objectivity,we highlight its cross-sectional nature,limited sample diversity,and lack of dual-task assessment as areas for future refinement.This commentary posits that kinematic biomarkers offer a distinctive,scalable,and ecologically valid approach to widespread MCI screening,thereby complementing existing methods by providing real-world functional insights.Future research should prioritize longitudinal validation,expansion to diverse cohorts,integration with multimodal data including dual-tasking,and the development of highly portable,artificial intelligence-driven solutions to achieve the democratization of early MCI detection and enable timely interventions.
基金supported by Shanghai Shenkang Center Demonstration Research Ward Construction,No.SHDC2022CRW010(to MF)Shanghai Shenkang Center Medical Enterprise Integration and Innovation Collaborative Special Project,No.SHDC2022CRT018(to MF)+4 种基金Shanghai Health System Key Supported Discipline-Rehabilitation Medicine,No.2023ZDFC0301(to JT)Science and Technology Development Project of Shanghai University of Traditional Chinese Medicine,No.23KFL009(to JT)Shanghai Postdoctoral Excellence Program,No.2022515(to CY)Yangfan Special Project of Shanghai Science and Technology Innovation Action Plan,No.23YF1447600(to CY)China Postdoctoral Science Foundation,No.2023M732338(to CY).
文摘Ischemic stroke,which is characterized by hypoxia and ischemia,triggers a cascade of injury responses,including neurotoxicity,inflammation,oxidative stress,disruption of the blood-brain barrier,and neuronal death.In this context,tryptophan metabolites and enzymes,which are synthesized through the kynurenine and 5-hydroxytryptamine pathways,play dual roles.The delicate balance between neurotoxic and neuroprotective substances is a crucial factor influencing the progression of ischemic stroke.Neuroprotective metabolites,such as kynurenic acid,exert their effects through various mechanisms,including competitive blockade of N-methyl-D-aspartate receptors,modulation ofα7 nicotinic acetylcholine receptors,and scavenging of reactive oxygen species.In contrast,neurotoxic substances such as quinolinic acid can hinder the development of vascular glucose transporter proteins,induce neurotoxicity mediated by reactive oxygen species,and disrupt mitochondrial function.Additionally,the enzymes involved in tryptophan metabolism play major roles in these processes.Indoleamine 2,3-dioxygenase in the kynurenine pathway and tryptophan hydroxylase in the 5-hydroxytryptamine pathway influence neuroinflammation and brain homeostasis.Consequently,the metabolites generated through tryptophan metabolism have substantial effects on the development and progression of ischemic stroke.Stroke treatment aims to restore the balance of various metabolite levels;however,precise regulation of tryptophan metabolism within the central nervous system remains a major challenge for the treatment of ischemic stroke.Therefore,this review aimed to elucidate the complex interactions between tryptophan metabolites and enzymes in ischemic stroke and develop targeted therapies that can restore the delicate balance between neurotoxicity and neuroprotection.
文摘[Objectives]To investigate the clinical efficacy of core stability training combined with conventional rehabilitation in the functional recovery of patients suffering from chronic low back pain.[Methods]A randomized controlled trial design was employed in this study.Ninety patients with chronic low back pain were recruited and randomly assigned to either a control group(n=45),which received conventional rehabilitation,or an experimental group(n=45),which received conventional rehabilitation combined with core stability training.Both groups underwent treatment for 6 weeks.Assessments were conducted using the visual analogue scale(VAS),Oswestry disability index(ODI),and finger-to-floor test prior to treatment,6 weeks following treatment,and during the follow-up period,respectively.[Results]Prior to treatment,no statistically significant differences were observed between the two patient groups in terms of general information and various baseline measurements(P>0.05).Following 6 weeks of treatment and throughout the follow-up period,both groups demonstrated significant improvements in VAS scores,ODI scores,and lumbar anteflexion range of motion compared to baseline measurements(P<0.05).Notably,the magnitude of improvement in the experimental group exceeded that of the control group,with this inter-group difference reaching statistical significance(P<0.05).No serious adverse reactions were reported during the treatment process.[Conclusions]Core stability training combined with conventional rehabilitation can significantly enhance the alleviation of pain and functional impairments in patients suffering from chronic low back pain.This approach holds valuable implications for the optimization of rehabilitation treatment protocols.
文摘AIM:To investigate the long-term outcomes in acute primary angle closure(APAC)patients treated with lens extraction(LE)surgery and to identify risk factors for glaucomatous optic neuropathy(GON).METHODS:In this longitudinal observational study,detailed medical histories of APAC patients and comprehensive ophthalmic examinations at final followup were collected.Logistic regression analysis was performed to identify predictors of blindness.Univariate and multivariate linear regression analyses were conducted to determine risk factors associated with visual outcomes.RESULTS:This study included 39 affected eyes of 31 subjects(26 females)with an average age of 74.1±8.0y.At 6.7±4.2y after APAC attack,2(5.7%)eyes had bestcorrected visual acuity(VA)worse than 3/60.Advanced glaucomatous visual field loss was observed in 15(39.5%)affected eyes and 5(25.0%)fellow eyes.Nine affected eyes(23.7%)had GON,and 11(28.9%)were blind.Six(15.4%)affected eyes and 2(9.1%)fellow eyes had suspicious progression.A significantly higher blindness rate in factory workers compared to office workers.Logistic regression identified that worse VA at attack(OR 10.568,95%CI 1.288-86.695;P=0.028)and worse early postoperative VA(OR 13.214,95%CI 1.157-150.881;P=0.038)were risk factors for blindness.Multivariate regression showed that longer duration of elevated intraocular pressure(P=0.004)and worse early postoperative VA(P=0.009)were associated with worse visual outcomes.CONCLUSION:Despite LE surgery,some APAC patients experience continued visual function deterioration.Lifelong monitoring is necessary.Target pressure and progression rates should be re-evaluated during follow-up.
基金supported by the National Natural Science Foundation of China,Nos.82404892(to QY),82061160374(to ZZ)the Science and Technology Development Fund,Macao Special Administrative Region,China,Nos.0023/2020/AFJ,0035/2020/AGJ+2 种基金the University of Macao Research Grant,Nos.MYRG2022-00248-ICMS,MYRG-CRG2022-00010-ICMS(to MPMH)the Natural Science Foundation of Guangdong Province,No.2024A1515012818(to ZZ)the Fundamental Research Funds for the Central Universities,No.21623114(to ZZ).
文摘Drug development for Alzheimer’s disease is extremely challenging,as demonstrated by the repeated failures of amyloid-β-targeted therapeutics and the controversies surrounding the amyloid-βcascade hypothesis.More recently,advances in the development of Lecanemab,an anti-amyloid-βmonoclonal antibody,have shown positive results in reducing brain A burden and slowing cognitive decline in patients with early-stage Alzheimer’s disease in the Phase Ⅲ clinical trial(Clarity Alzheimer’s disease).Despite these promising results,side effects such as amyloid-related imaging abnormalities(ARIA)may limit its usage.ARIA can manifest as ARIA-E(cerebral edema or effusions)and ARIA-H(microhemorrhages or superficial siderosis)and is thought to be caused by increased vascular permeability due to inflammatory responses,leading to leakages of blood products and protein-rich fluid into brain parenchyma.Endothelial dysfunction is an early pathological feature of Alzheimer’s disease,and the blood-brain barrier becomes increasingly leaky as the disease progresses.In addition,APOE4,the strongest genetic risk factor for Alzheimer’s disease,is associated with higher vascular amyloid burden,increased ARIA incidence,and accelerated blood-brain barrier disruptions.These interconnected vascular abnormalities highlight the importance of vascular contributions to the pathophysiology of Alzheimer’s disease.Here,we will closely examine recent research evaluating the heterogeneity of brain endothelial cells in the microvasculature of different brain regions and their relationships with Alzheimer’s disease progression.
文摘Traumatic axonal lesions of peripheral nerves disrupt neuronal connections with their targets,resulting in the loss of motor and sensory functions.Despite the peripheral nervous system’s capacity for axonal regrowth,this may lead to permanent impairements resulting in a loss of quality of life and a high socioeconomic burden.
文摘Complex genetic relationships between neurodegenerative disorders and neuropsychiatric symptoms have been shown, suggesting shared pathogenic mechanisms and emphasizing the potential for developing common therapeutic targets. Apolipoprotein E(APOE) genotypes and their corresponding protein(Apo E) isoforms may influence the biophysical properties of the cell membrane lipid bilayer. However, the role of APOE in central nervous system pathophysiology extended beyond its lipid transport function. In the present review article, we analyzed the links existing between APOE genotypes and the neurobiology of neuropsychiatric symptoms in neurodegenerative and vascular diseases. APOE genotypes(APOE ε2, APOE ε3, and APOE ε4) were implicated in common mechanisms underlying a wide spectrum of neurodegenerative diseases, including sporadic Alzheimer's disease, synucleinopathies such as Parkinson's disease and Lewy body disease, stroke, and traumatic brain injury. These shared pathways often involved neuroinflammation, abnormal protein accumulation, or responses to acute detrimental events. Across these conditions, APOE variants are believed to contribute to the modulation of inflammatory responses, the regulation of amyloid and tau pathology, as well as the clearance of proteins such as α-synuclein. The bidirectional interactions among Apo E, amyloid and mitochondrial metabolism, immunomodulatory effects, neuronal repair, and remodeling underscored the complexity of Apo E's role in neuropsychiatric symptoms associated with these conditions since from early phases of cognitive impairment such as mild cognitive impairment and mild behavioral impairment. Besides Apo E-specific isoforms' link to increased neuropsychiatric symptoms in Alzheimer's disease(depression, psychosis, aberrant motor behaviors, and anxiety, not apathy), the APOE ε4 genotype was also considered a significant genetic risk factor for Lewy body disease and its worse cognitive outcomes. Conversely, the APOE ε2 variant has been observed not to exert a protective effect equally in all neurodegenerative diseases. Specifically, in Lewy body disease, this variant may delay disease onset, paralleling its protective role in Alzheimer's disease, although its role in frontotemporal dementia is uncertain. The APOE ε4 genotype has been associated with adverse cognitive outcomes across other various neurodegenerative conditions. In Parkinson's disease, the APOE ε4 allele significantly impacted cognitive performance, increasing the risk of developing dementia, even in cases of pure synucleinopathies with minimal co-pathology from Alzheimer's disease. Similarly, in traumatic brain injury, recovery rates varied, with APOE ε4 carriers demonstrating a greater risk of poor long-term cognitive outcomes and elevated levels of neuropsychiatric symptoms. Furthermore, APOE ε4 influenced the age of onset and severity of stroke, as well as the likelihood of developing stroke-associated dementia, potentially due to its role in compromising endothelial integrity and promoting blood–brain barrier dysfunction.
