Emerging evidence supports that sleep disorders are the main risk factor for sporadic Alzheimer's disease(AD),and iron dysregulation may be the link between them.Our previous studies have confirmed that ketogenic ...Emerging evidence supports that sleep disorders are the main risk factor for sporadic Alzheimer's disease(AD),and iron dysregulation may be the link between them.Our previous studies have confirmed that ketogenic diet(KD)can prevent chronic sleep deprivation-induced AD.However,it is uncertain whether exogenous ketones supplements(EKS),as an alternative intervention,have the same effects as KD.Thus,we investigated the prophylactic efficiency of EKS on chronic sleep deprivation-induced AD and reveal the underlying mechanism focus on iron metabolism.We observed that the prophylactic efficacy of EKS against chronic sleep deprivation-induced AD was comparable to that of KD.Meanwhile,our results suggest that both EKS and KD inhibited iron metabolism disorder through regulation of iron metabolism-related proteins.Moreover,we found that both EKS and KD reduced hippocampal mitochondrial dysfunction and iron-mediated lipid peroxides.Furthermore,EX527(silent information regulator 1(Sirt1)inhibitor),mostly abrogated these above protections of EKS,suggesting that the prophylactic effect of EKS on AD is partly dependent on Sirt1.Our findings provide novel evidence that EKS can be developed as functional foods to prevent or delay the development of AD,particularly in individuals with sleep disorders.展开更多
Recently,the glymphatic system has been recognised as an important‘waste solutes transport channel’within the brain.1 Studies have shown that blockage of the glymphatic system leads to increased beta-amyloid deposit...Recently,the glymphatic system has been recognised as an important‘waste solutes transport channel’within the brain.1 Studies have shown that blockage of the glymphatic system leads to increased beta-amyloid deposits,accelerating the onset and progression of Alzheimer’s disease(AD).12 Given that cervical lymph nodes receive cerebrospinal fluid from the brain’s glymphatic system,34 we speculated that decompression of the lymphatic trunk and cervical lymphatic-venous anastomosis(LVA)could facilitate the flow of cerebrospinal fluid in the cranial glymphatic system,potentially accelerating the clearance of harmful beta-amyloid and tau proteins.We collaborated with surgeons who specialise in LVA supermicrosurgery for maxillofacial tumours and lymphoedema to develop a procedure to relieve the blockage of the glymphatic system.This surgery employs supermicrosurgery techniques to create LVA connecting the bilateral cervical,deep lymphatic vessels to the veins,resulting in lymphatic trunk decompression,which allows the lymph fluid in the high-pressure lymphatic vessels to flow into the low-pressure venous system.The goal of the minimally invasive surgery is to enhance the removal of proteins,such as beta-amyloid and tau,from the brain’s lymphatic systems to the maxillofacial lymphatic vessels,unclogging protein blockages within the brain.This extracranial procedure is safer than intracranial approaches.展开更多
Alzheimer's disease(AD)is a common cause of dementia,characterised by cerebral amyloid-βdeposition,pathological tau and neurodegeneration.The prodromal stage of AD(pAD)refers to patients with mild cognitive impai...Alzheimer's disease(AD)is a common cause of dementia,characterised by cerebral amyloid-βdeposition,pathological tau and neurodegeneration.The prodromal stage of AD(pAD)refers to patients with mild cognitive impairment(MCl)and evidence of AD's pathology.At this stage,disease-modifying interventions should be used to prevent the progression to dementia.Given the inherent heterogeneity of MCl,more specific biomarkers are needed to elucidate the underlying AD's pathology.Although the uses of cerebrospinal fluid and positron emission tomography are widely accepted methods for detecting AD's pathology,their clinical applications are limited by their high costs and invasiveness,particularly in low-income areas in China.Therefore,to improve the early detection of Alzheimer's disease(AD)pathology through cost-effective screening methods,a panel of 45neurologists,psychiatrists andgerontologistswas invited to establish a formal consensus on the screening of pAD in China.The supportive evidence and grades of recommendations are based on a systematic literature review andfocus group discussion.National meetings were held to allow participants to review,vote and provide their expert opinions to reach a consensus.A majority(two-thirds)decision was used for questions for which consensus could not be reached.Recommended screening methods are presented in this publication,including neuropsychological assessment,peripheral biomarkers and brain imaging.In addition,a general workflow for Screening pAD in China is established,which will help clinicians identify individuals at high risk and determine therapeutic targets.展开更多
Alzheimer's disease is a neurodegenerative disease with complex etiology.Gut microbiota influences the gutbrain axis,which may affect pathways related to the pathogenesis of Alzheimer's disease.Additionally,di...Alzheimer's disease is a neurodegenerative disease with complex etiology.Gut microbiota influences the gutbrain axis,which may affect pathways related to the pathogenesis of Alzheimer's disease.Additionally,diet and physical activity are likely to affect the pathology of Alzheimer's disease as well as the gut microbiota.This demonstrates that it may be possible to prevent or halt the progression of Alzheimer's disease by regulating the gut microbiota using diet and physical activity strategies.Therefore,the present study reviews the association between these two interventions and gut microbiota in the human body.It also summarizes how these two interventions benefit Alzheimer's disease.Furthermore,the primary limitations of these two interventions are discussed and promising strategies are proposed,which may be beneficial to further study and develop the intervening measure for the progression of Alzheimer's disease.展开更多
The gut microbiota-brain axis has emerged as a novel target for Alzheimer's disease(AD),a neurodegenerative disease characterised by behavioural and cognitive impairment.However,most previous microbiome-based inte...The gut microbiota-brain axis has emerged as a novel target for Alzheimer's disease(AD),a neurodegenerative disease characterised by behavioural and cognitive impairment.However,most previous microbiome-based intervention studies have focused on single factors and yielded only modest cognitive improvements.Here,we proposed a multidomain intervention strategy that combined Bifidobacterium breve treatment with environmental enrichment(EE)training.In this study,we found that compared with EE or B.breve treatment alone,B.breve intervention combined with EE amplified its neuroprotective effects on AD mice,as reflected by improved cognition,inhibited neuroinflammation and enhanced synaptic function.Moreover,using microbiome and metabolome profiling,we found that the combination of B.breve and EE treatment restored AD-related gut microbiota dysbiosis and reversed microbial metabolite changes.Finally,by integrating behavioural and neurological data with metabolomic profiles,we revealed that the underlying mechanism may involve the modulation of microbiota-derived glutamine metabolism via gut-brain interactions.Collectively,combined B.breve intervention with EE treatment can alleviate AD-related cognitive impairment and improve brain function by regulating glutamine metabolism of the gut microbiome.Our findings provide a promising multidomain intervention strategy,with a combination of dietary microbiome-based and lifestyle-targeted interventions,to promote brain function and delay the progression of AD.展开更多
Alzheimer’s disease(AD),the major form of neurodegenerative diseases that can severely impede normal cognitive function,makes it one of the most common fatal diseases.There are currently over 50 million AD patients w...Alzheimer’s disease(AD),the major form of neurodegenerative diseases that can severely impede normal cognitive function,makes it one of the most common fatal diseases.There are currently over 50 million AD patients worldwide.The neuropathology of AD is perplexing and there is a scarcity of disease-modifying treatments.Currently,early diagnosis of AD has been made possible with the discovery of biological markers associated with pathology,providing strong support for the improvement of the disease status.The search for inhibitors of AD markers from dietary supplements(DSs)has become a major hot topic.Especially with the widespread use of DSs,DSs containing polyphenols,alkaloids,terpenes,polysaccharides and other bioactive components can prevent AD by reducing Aβdeposition,inhibiting tau protein hyperphosphorylation,reconstructing synaptic dysfunction,weakening cholinesterase activity,regulating mitochondrial oxidative stress,neuronal inflammation and apoptosis.This review summarizes the anti-AD effects of the main DSs and their bioactive constituents,as well as the potential molecular mechanisms covers from 2017 to 2023.Additionally,we discussed the opportunities and challenges faced by DSs in the process of AD prevention and treatment,aiming to further provide new perspectives for functional food development.展开更多
Background Previous studies havedemonstrated that excitatory repetitive transcranial magnetic stimulation(rTMS)can improve the cognitive function of patients with Alzheimer's disease(AD).Intermittent theta burst s...Background Previous studies havedemonstrated that excitatory repetitive transcranial magnetic stimulation(rTMS)can improve the cognitive function of patients with Alzheimer's disease(AD).Intermittent theta burst stimulation(iTBS)is a novel excitatory rTMS protocol for brain activity stimulation with the ability to induce long-term potentiation-like plasticity and represents a promising treatment for AD.However,the long-term effects of iTBS on cognitive decline and brain structure in patients with AD areunknown.Aims We aimed to explore whether repeating accelerated iTBS every three months could slow down the cognitive decline in patients with AD.Methods In this randomised,assessor-blinded,controlled trial,iTBS was administered to the left dorsolateral prefrontal cortex(DLPFC)of 42 patients with AD for 14days every 13weeks.Measurements included the Montreal Cognitive Assessment(MoCA),a comprehensive neuropsychological battery,and the grey matter volume(GMV)of the hippocampus.Patients were evaluated at baseline and after follow-up.The longitudinal pipeline of the Computational Anatomy Toolbox for SPM was used to detect significant treatment-related changes over time.Results The iTBS group maintained MoCA scores relative to the control group(t=3.26,p=0.013)and reduced hippocampal atrophy,which was significantly correlated with global degeneration scale changes.The baseline Mini-Mental State Examination(MMSE)score,apolipoprotein E genotype and Clinical Dementia Rating were indicative of MoCA scores at follow-up.Moreover,the GMV of the left(t=0.08,p=0.996)and right(t=0.19,p=0.977)hippocampus were maintained in the active group but significantly declined in the control group(left:t=4.13,p<0.001;right:t=5.31,p<0.001).GMV change in the left(r=0.35,p=0.023)and right(r=0.36,p=0.021)hippocampus across the intervention positively correlated with MoCA changes;left hippocampal GMV change was negatively correlated with global degeneration scale(r=-0.32,p=0.041)changes.Conclusions DLPFC-iTBS maybe a feasible and easy-to-implement non-pharmacological intervention to slow down the progressive decline of overall cognition and quality of life in patients with AD,providing a new AD treatment option.Trial registration number NCT04754152.展开更多
Background:Episodic memory loss is a prominent clinical manifestation of Alzheimer’s disease(AD),which is closely related to tau pathology and hippocampal impairment.Due to the heterogeneity of brain neurons,the spec...Background:Episodic memory loss is a prominent clinical manifestation of Alzheimer’s disease(AD),which is closely related to tau pathology and hippocampal impairment.Due to the heterogeneity of brain neurons,the specific roles of different brain neurons in terms of their sensitivity to tau accumulation and their contribution to AD-like social memory loss remain unclear.Therefore,further investigation is necessary.Methods:We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic analysis,social behavioural tests,hippocampal electrophysiology,immunofluorescence staining and in vivo optical fibre recording of GCaMP6f and iGABASnFR.Additionally,we utilized optogenetics and administered ursolic acid(UA)via oral gavage to examine the effects of these agents on social memory in mice.Results:The results of proteomic and phosphoproteomic analyses revealed the characteristics of ventral hippocampal CA1(vCA1)under both physiological conditions and AD-like tau pathology.As tau progressively accumulated,vCA1,especially its excitatory and parvalbumin(PV)neurons,were fully filled with mislocated and phosphorylated tau(p-Tau).This finding was not observed for dorsal hippocampal CA1(dCA1).The overexpression of human tau(hTau)in excitatory and PV neurons mimicked AD-like tau accumulation,significantly inhibited neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1.Photoactivating excitatory and PV neurons in vCA1 at specific rhythms and time windows efficiently ameliorated tau-impaired social memory.Notably,1 month of UA administration efficiently decreased tau accumulation via autophagy in a transcription factor EB(TFEB)-dependent manner and restored the vCA1 microcircuit to ameliorate tau-impaired social memory.Conclusion:This study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1 and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation.Notably,our novel findings regarding the efficacy of UA in reducing tau load and targeting the vCA1 microcircuit may provide a promising strategy for treating AD in the future.展开更多
Grape crops are a great source of income for farmers.The yield and quality of grapes can be improved by preventing and treating diseases.The farmer’s yield will be dramatically impacted if diseases are found on grape...Grape crops are a great source of income for farmers.The yield and quality of grapes can be improved by preventing and treating diseases.The farmer’s yield will be dramatically impacted if diseases are found on grape leaves.Automatic detection can reduce the chances of leaf diseases affecting other healthy plants.Several studies have been conducted to detect grape leaf diseases,but most fail to engage with end users and integrate the model with real-time mobile applications.This study developed a mobile-based grape leaf disease detection(GLDD)application to identify infected leaves,Grape Guard,based on a TensorFlow Lite(TFLite)model generated from the You Only Look Once(YOLO)v8 model.A public grape leaf disease dataset containing four classes was used to train the model.The results of this study were relied on the YOLO architecture,specifically YOLOv5 and YOLOv8.After extensive experiments with different image sizes,YOLOv8 performed better than YOLOv5.YOLOv8 achieved 99.9%precision,100%recall,99.5%mean average precision(mAP),and 88%mAP50-95 for all classes to detect grape leaf diseases.The Grape Guard android mobile application can accurately detect the grape leaf disease by capturing images from grape vines.展开更多
Uric acid(UA)is a naturally antioxidant that is strongly associated with the development and progression of Parkinson's disease(PD).The purine diet is an important exogenous pathway that modulates blood UA levels....Uric acid(UA)is a naturally antioxidant that is strongly associated with the development and progression of Parkinson's disease(PD).The purine diet is an important exogenous pathway that modulates blood UA levels.Deep brain stimulation(DBS)is an important tool for PD treatment.This study aimed to explore the effects of preoperative purine diet on the prognosis of patients with PD after DBS.Sixty-four patients with PD who underwent DBS were included in this study,and their clinical data,blood UA levels,and daily purine intake.Patients were followed up for improvement 1 year after surgery.We found that patient higher purine intake was strongly associated with the rate of improvement after DBS and was a protective factor for patient prognosis.Daily purine intake from meat and seafood was significantly higher in the responsive patients than in the lessresponsive patients.Mediation analysis showed that UA mediated 78%of the effect of purine intake on motor symptom improvement after DBS.In summary,we observed that purine intake is strongly associated with the rate of improvement in motor symptoms after subthalamic nucleus-DBS in patients with PD.This study provides a reference for preoperative diet planning in patients with PD undergoing DBS.展开更多
Parkinson's disease(PD)is one of the most common neurodegenerative diseases.The loss of dopaminergic(DAergic)neurons in the substantia nigra and the decrease of dopamine(DA)levels accelerate the process of PD.L-Er...Parkinson's disease(PD)is one of the most common neurodegenerative diseases.The loss of dopaminergic(DAergic)neurons in the substantia nigra and the decrease of dopamine(DA)levels accelerate the process of PD.L-Ergothioneine(EGT)is a natural antioxidant derived from microorganisms,especially in edible mushrooms.EGT can penetrate blood-brain barrier and its levels are significantly decreased in the plasma of PD patients.Therefore,we speculated that EGT could ameliorate PD,and determined its effect on PD development by using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced PD mouse models and neurotoxin 1-methyl-4-phenylpyridinium(MPP^(+))-induced cell models.Our results show that EGT alleviated MPTP-induced behavioral dysfunction in mice.Mechanistically,we innovatively revealed that EGT was a key regulator of DJ-1.EGT restored DA levels by activating the DJ-1-nuclear receptor-related factor 1(Nurr1)axis.Furthermore,it reduced reactive oxygen species(ROS)levels by regulating the DJ-1-nuclear factor erythroid 2-related factor 2(Nrf2)pathway,which inhibited oxidative stress-induced DAergic neuronal apoptosis.Combined treatment with DJ-1-si RNA transfection revealed that blocking DJ-1 reversed EGT upregulated Nurr1 and Nrf2 expression in the nucleus,which significantly decreased the benefits of EGT.Taken together,our study suggests that EGT can ameliorate PD and be considered as a strategy for PD treatment.展开更多
Non-alcoholic fatty liver disease(NAFLD)is one of the most common chronic liver diseases worldwide.Gut microbiota and its metabolites alteration are closely related to NAFLD.Nootkatone is an edible flavorant derived f...Non-alcoholic fatty liver disease(NAFLD)is one of the most common chronic liver diseases worldwide.Gut microbiota and its metabolites alteration are closely related to NAFLD.Nootkatone is an edible flavorant derived from grapefruit which has a variety of biological activities.However,the precise mechanisms of nootkatone on NAFLD remains to be defined.Our results showed that nootkatone prevented body weight gain and decreased serum lipid level,hepatic lipogenesis,hepatic proinflammatory cytokines secretion in NAFLD mice.Also,nootkatone attenuated inflammatory response via inhibiting TLR4/NF-κB/NLRP3 pathway.Moreover,nootkatone restored intestinal barrier damage through increasing tight junction proteins and short chain fatty acids contents.Further 16S rRNA sequencing of colonic content suggested that nootkatone recovered the disturbed gut microbiota to improve NAFLD.Spearman correlation analysis between gut microbiota and NAFLD related parameters indicated that nootkatone regulated lipid metabolism and immunity via altering the gut microbiota.In conclusion,these findings revealed that nootkatone alleviated hepatic lipid homeostasis and inflammatory response in NAFLD mice,which associated with intestinal barrier integrity and the regulation of gut microbiota.This study provides new perspectives that nootkatone has efficacy on NAFLD via“gut-liver axis”,and nootkatone is expected to be developed as a functional food additive.展开更多
Accurate identification of Alzheimer＇s disease （AD） and mild cognitive impairment （MCI） is crucial so as to improve diagnosis techniques and to better understand the neurodegenerative process. In this work, we ai...Accurate identification of Alzheimer＇s disease （AD） and mild cognitive impairment （MCI） is crucial so as to improve diagnosis techniques and to better understand the neurodegenerative process. In this work, we aim to apply the machine learning method to individual identification and identify the discriminate features associated with AD and MCI. Diffusion tensor imaging scans of 48 patients with AD, 39 patients with late MCI, 75 patients with early MCI, and 51 age-matched healthy controls （HCs） are acquired from the Alzheimer＇s Disease Neuroimaging Initiative database. In addition to the common fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity metrics, there are two novel metrics, named local diffusion homogeneity that used Spearman＇s rank correlation coefficient and Kendall＇s coefficient concordance, which are taken as classification metrics. The recursive feature elimination method for support vector machine （SVM） and logistic regression （LR） combined with leave-one-out cross validation are applied to determine the optimal feature dimensions. Then the SVM and LR methods perform the classification process and compare the classification performance. The results show that not only can the multi-type combined metrics obtain higher accuracy than the single metric, but also the SVM classifier with multi-type combined metrics has better classification performance than the LR classifier. Statistically, the average accuracy of the combined metric is more than 92% for all between-group comparisons of SVM classifier. In addition to the high recognition rate, significant differences are found in the statistical analysis of cognitive scores between groups. We further execute the permutation test, receiver operating characteristic curves, and area under the curve to validate the robustness of the classifiers, and indicate that the SVM classifier is more stable and efficient than the LR classifier. Finally, the uncinated fasciculus, cingulum, corpus callosum, corona radiate, external capsule, and internal capsule have been regarded as the most important white matter tracts to identify AD, MCI, and HC. Our findings reveal a guidance role for machine-learning based image analysis on clinical diagnosis.展开更多
Alzheimer’s disease(AD)is the most common neurodegenerative disease characterized by cognitive decline and memory impairment.Many lines of evidence indicate that excessiveβ-amyloid peptide(Aβ)generation and aggrega...Alzheimer’s disease(AD)is the most common neurodegenerative disease characterized by cognitive decline and memory impairment.Many lines of evidence indicate that excessiveβ-amyloid peptide(Aβ)generation and aggregation play pivotal roles in the initiation of AD,leading to various biochemical alteration including oxidative damage,mitochondrial dysfunction,neuroinflammation,signaling pathway and finally resulting in neuronal death.AD has a complex pathogenic mechanism,and a single-target approach for anti-AD strategy is thus full of challenges.To overcome these limitations,the present study focused to review on one of multiple target-compounds,(-)-epigallocatechin-3-gallate(EGCG)for the prevention and treatment of AD.EGCG is a main bioactive polyphenol in green tea and has been reported to exert potent neuroprotective properties in a wide array of both cellular and animal models in AD.This review demonstrated multiple neuroprotective efficacies of EGCG by focusing on the involvement of Aβ-evoked damage and its Aβregulation.Furthermore,to understand its mechanism of action on the brain,the permeability of the blood-brain barrier was also discussed.展开更多
Applications of multifractal analysis to white matter structure changes on magnetic resonance imaging（MRI） have recently received increasing attentions. Although some progresses have been made, there is no evident s...Applications of multifractal analysis to white matter structure changes on magnetic resonance imaging（MRI） have recently received increasing attentions. Although some progresses have been made, there is no evident study on applying multifractal analysis to evaluate the white matter structural changes on MRI for Alzheimer＇s disease（AD） research. In this paper, to explore multifractal analysis of white matter structural changes on 3D MRI volumes between normal aging and early AD, we not only extend the traditional box-counting multifractal analysis（BCMA） into the 3D case, but also propose a modified integer ratio based BCMA（IRBCMA） algorithm to compensate for the rigid division rule in BCMA. We verify multifractal characteristics in 3D white matter MRI volumes. In addition to the previously well studied multifractal feature,△α, we also demonstrated △ f as an alternative and effective multifractal feature to distinguish NC from AD subjects.Both △α and △ f are found to have strong positive correlation with the clinical MMSE scores with statistical significance.Moreover, the proposed IRBCMA can be an alternative and more accurate algorithm for 3D volume analysis. Our findings highlight the potential usefulness of multifractal analysis, which may contribute to clarify some aspects of the etiology of AD through detection of structural changes in white matter.展开更多
Background There have been no effective treatments for slowing or reversing Alzheimer’s disease(AD)until now.Growing preclinical evidence,including this study,suggests that mesenchymal stem cells-secreted exosomes(MS...Background There have been no effective treatments for slowing or reversing Alzheimer’s disease(AD)until now.Growing preclinical evidence,including this study,suggests that mesenchymal stem cells-secreted exosomes(MSCs-Exos)have the potential to cure AD.Aims The first three-arm,drug-intervention,phase I/II clinical trial was conducted to explore the safety and efficacy of allogenic human adipose MSCs-Exos(ahaMSCs-Exos)in patients with mild to moderate AD.Methods The eligible subjects were assigned to one of three dosage groups,intranasally administrated with ahaMSCs-Exos two times per week for 12 weeks,and underwent follow-up visits at weeks 16,24,36 and 48.Results No adverse events were reported.In the medium-dose arm,Alzheimer’s Disease Assessment Scale–Cognitive section(ADAS-cog)scores decreased by 2.33(1.19)and the basic version of Montreal Cognitive Assessment scores increased by 2.38(0.58)at week 12 compared with baseline levels,indicating improved cognitive function.Moreover,the ADAS-cog scores in the medium-dose arm decreased continuously by 3.98 points until week 36.There were no significant differences in altered amyloid or tau deposition among the three arms,but hippocampal volume shrank less in the medium-dose arm to some extent.Conclusions Intranasal administration of ahaMSCs-Exos was safe and well tolerated,and a dose of at least 4×10^(8)particles could be selected for further clinical trials.展开更多
Objective To investigate the relationship of plasma homocysteine (Hcy) levels and the gene polymorphisms of N5, N10-methylenetetrahydrofolate reductase (MTHFR), cystathionine β-synthase (CBS) with Alzheimer’s diseas...Objective To investigate the relationship of plasma homocysteine (Hcy) levels and the gene polymorphisms of N5, N10-methylenetetrahydrofolate reductase (MTHFR), cystathionine β-synthase (CBS) with Alzheimer’s disease (AD). Methods Plasma Hcy levels were measured by means of high voltage capillary electrophoresis with ultra-violet detection, the polymorphisms of C677T in exon 4 of MTHFR gene and 844ins68 in exon 8 of CBS gene were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 105 AD patients and 102 non-AD controls. All controls were excluded from cardiocerebrovascular disorders and other diseases. Results The plasma Hcy level in AD patients (16.04 ± 3.84 μmol/L) was significantly higher than that in the controls(11.94 ± 3.87 μmol/L, P < 0.001). There were no significant differences of the genotype and allele frequencies of MTHFR C677T mutation and CBS 844ins68 mutation between the patients and controls. However, the T allele of MTHFR gene was found to relate with the plasma Hcy level increase in all subjects. Conclusion The elevated plasma Hcy level in AD patients is probably involved in the pathogenesis of AD, which may be due to the environmental factor rather than genetic factors of the mutations of MTHFR and CBS.展开更多
Background Dementia is a chronic brain disorder classified by four distinct diseases that impact cognition and mental degeneration. Each subgroup exhibits similar brain deficiencies and mutations. This review will foc...Background Dementia is a chronic brain disorder classified by four distinct diseases that impact cognition and mental degeneration. Each subgroup exhibits similar brain deficiencies and mutations. This review will focus on four dementia subgroups: Alzheimer's disease, vascular dementia, frontotemporal dementia and dementia Lewy body. Aim The aim of this systematic review is to create a concise overview of unique similarities within dementia used to locate and identify new biomarker methods in diagnosing dementia. Methods 123 300 articles published after 2010 were identified from PubMed, JSTOR, WorldCat Online Computer Library and PALNI (Private Academic Library Network of Indiana) using the following search items (in title or abstract):'Neurodegenerative Diseases' OR 'Biomarkers' OR 'Alzheimer's Disease' OR 'Frontal Temporal Lobe Dementia' OR 'Vascular Dementia, OR 'Dementia Lewy Body' OR 'Cerebral Spinal Fluid' OR 'Mental Cognitive Impairment'. 47 studies were included in the qualitative synthesis. Results Evidence suggested neuroimaging with amyloid positron emission tomography (PET) scanning and newly found PET tracers to be more effective in diagnosing Alzheimer's and amnesiac mental cognitive impairment than carbon-11 Pittsburgh compound-B radioisotope tracer. Newly created methods to make PET scans more accurate and practical in clinical settings signify a major shift in diagnosing dementia and neurodegenerative diseases. Conclusion Vast improvements in neuroimaging techniques have led to newly discovered biomarkers and diagnostics. Neuroimaging with amyloid PET scanning surpasses what had been considered the dominant method of neuroimaging and MRI. Newly created methods to make PET scans more accurate and practical in clinical settings signify a major shift in diagnosing dementia pathology. Continued research and studies must be conducted to improve current findings and streamline methods to further subcategorise neurodegenerative disorders and diagnosis.展开更多
基金supported by Natural Science Foundation of Shandong province(ZR2021QH022,ZR2021QB198)National Natural Science Foundation of China(82001286)the Open Project of Liaocheng University Animal Husbandry Discipline(319462207-24)。
文摘Emerging evidence supports that sleep disorders are the main risk factor for sporadic Alzheimer's disease(AD),and iron dysregulation may be the link between them.Our previous studies have confirmed that ketogenic diet(KD)can prevent chronic sleep deprivation-induced AD.However,it is uncertain whether exogenous ketones supplements(EKS),as an alternative intervention,have the same effects as KD.Thus,we investigated the prophylactic efficiency of EKS on chronic sleep deprivation-induced AD and reveal the underlying mechanism focus on iron metabolism.We observed that the prophylactic efficacy of EKS against chronic sleep deprivation-induced AD was comparable to that of KD.Meanwhile,our results suggest that both EKS and KD inhibited iron metabolism disorder through regulation of iron metabolism-related proteins.Moreover,we found that both EKS and KD reduced hippocampal mitochondrial dysfunction and iron-mediated lipid peroxides.Furthermore,EX527(silent information regulator 1(Sirt1)inhibitor),mostly abrogated these above protections of EKS,suggesting that the prophylactic effect of EKS on AD is partly dependent on Sirt1.Our findings provide novel evidence that EKS can be developed as functional foods to prevent or delay the development of AD,particularly in individuals with sleep disorders.
基金supported by the National Key R&D Program of China(2023YFC36003200)Shanghai Mental Health Center investigator-initiated trial programme(2024-TX-001)+1 种基金Shanghai's Top Priority Research Center(2022ZZ01017)CAMS Innovation Fund for Medical Sciences(2019-12M-5-037).
文摘Recently,the glymphatic system has been recognised as an important‘waste solutes transport channel’within the brain.1 Studies have shown that blockage of the glymphatic system leads to increased beta-amyloid deposits,accelerating the onset and progression of Alzheimer’s disease(AD).12 Given that cervical lymph nodes receive cerebrospinal fluid from the brain’s glymphatic system,34 we speculated that decompression of the lymphatic trunk and cervical lymphatic-venous anastomosis(LVA)could facilitate the flow of cerebrospinal fluid in the cranial glymphatic system,potentially accelerating the clearance of harmful beta-amyloid and tau proteins.We collaborated with surgeons who specialise in LVA supermicrosurgery for maxillofacial tumours and lymphoedema to develop a procedure to relieve the blockage of the glymphatic system.This surgery employs supermicrosurgery techniques to create LVA connecting the bilateral cervical,deep lymphatic vessels to the veins,resulting in lymphatic trunk decompression,which allows the lymph fluid in the high-pressure lymphatic vessels to flow into the low-pressure venous system.The goal of the minimally invasive surgery is to enhance the removal of proteins,such as beta-amyloid and tau,from the brain’s lymphatic systems to the maxillofacial lymphatic vessels,unclogging protein blockages within the brain.This extracranial procedure is safer than intracranial approaches.
基金the National Natural Science Foundation of China(82171198,U20A20354)the Sci-Tech Innovation 2030 Agenda of China(2022ZD0211603).
文摘Alzheimer's disease(AD)is a common cause of dementia,characterised by cerebral amyloid-βdeposition,pathological tau and neurodegeneration.The prodromal stage of AD(pAD)refers to patients with mild cognitive impairment(MCl)and evidence of AD's pathology.At this stage,disease-modifying interventions should be used to prevent the progression to dementia.Given the inherent heterogeneity of MCl,more specific biomarkers are needed to elucidate the underlying AD's pathology.Although the uses of cerebrospinal fluid and positron emission tomography are widely accepted methods for detecting AD's pathology,their clinical applications are limited by their high costs and invasiveness,particularly in low-income areas in China.Therefore,to improve the early detection of Alzheimer's disease(AD)pathology through cost-effective screening methods,a panel of 45neurologists,psychiatrists andgerontologistswas invited to establish a formal consensus on the screening of pAD in China.The supportive evidence and grades of recommendations are based on a systematic literature review andfocus group discussion.National meetings were held to allow participants to review,vote and provide their expert opinions to reach a consensus.A majority(two-thirds)decision was used for questions for which consensus could not be reached.Recommended screening methods are presented in this publication,including neuropsychological assessment,peripheral biomarkers and brain imaging.In addition,a general workflow for Screening pAD in China is established,which will help clinicians identify individuals at high risk and determine therapeutic targets.
基金financially supported by National Natural Science Foundation of China(32171035)the major fund project of Ningbo Science and Technology Bureau(2019B10034)+4 种基金Opened-end Fund of Key Laboratory(KFJJ-202101,ZPKLP202202)Public Project of Ningbo(202002N3167)Project of Yinzhou(2022AS025)Ningbo Rehabilitation Hospital(2022KY02)sponsored by a K.C.Wong Magna Fund in Ningbo University。
文摘Alzheimer's disease is a neurodegenerative disease with complex etiology.Gut microbiota influences the gutbrain axis,which may affect pathways related to the pathogenesis of Alzheimer's disease.Additionally,diet and physical activity are likely to affect the pathology of Alzheimer's disease as well as the gut microbiota.This demonstrates that it may be possible to prevent or halt the progression of Alzheimer's disease by regulating the gut microbiota using diet and physical activity strategies.Therefore,the present study reviews the association between these two interventions and gut microbiota in the human body.It also summarizes how these two interventions benefit Alzheimer's disease.Furthermore,the primary limitations of these two interventions are discussed and promising strategies are proposed,which may be beneficial to further study and develop the intervening measure for the progression of Alzheimer's disease.
基金supported by the National Natural Science Foundation of China(31972052,32021005,31820103010)the Fundamental Research Funds for the Central Universities(JUSRP22006,JUSRP51501)the Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province。
文摘The gut microbiota-brain axis has emerged as a novel target for Alzheimer's disease(AD),a neurodegenerative disease characterised by behavioural and cognitive impairment.However,most previous microbiome-based intervention studies have focused on single factors and yielded only modest cognitive improvements.Here,we proposed a multidomain intervention strategy that combined Bifidobacterium breve treatment with environmental enrichment(EE)training.In this study,we found that compared with EE or B.breve treatment alone,B.breve intervention combined with EE amplified its neuroprotective effects on AD mice,as reflected by improved cognition,inhibited neuroinflammation and enhanced synaptic function.Moreover,using microbiome and metabolome profiling,we found that the combination of B.breve and EE treatment restored AD-related gut microbiota dysbiosis and reversed microbial metabolite changes.Finally,by integrating behavioural and neurological data with metabolomic profiles,we revealed that the underlying mechanism may involve the modulation of microbiota-derived glutamine metabolism via gut-brain interactions.Collectively,combined B.breve intervention with EE treatment can alleviate AD-related cognitive impairment and improve brain function by regulating glutamine metabolism of the gut microbiome.Our findings provide a promising multidomain intervention strategy,with a combination of dietary microbiome-based and lifestyle-targeted interventions,to promote brain function and delay the progression of AD.
基金financially supported by the National Key R&D Program of China(2022YFF1100301)Yunnan Revitalization Talents Support Plan-Young Talent Project(YNWRQNBJ-2018-357)。
文摘Alzheimer’s disease(AD),the major form of neurodegenerative diseases that can severely impede normal cognitive function,makes it one of the most common fatal diseases.There are currently over 50 million AD patients worldwide.The neuropathology of AD is perplexing and there is a scarcity of disease-modifying treatments.Currently,early diagnosis of AD has been made possible with the discovery of biological markers associated with pathology,providing strong support for the improvement of the disease status.The search for inhibitors of AD markers from dietary supplements(DSs)has become a major hot topic.Especially with the widespread use of DSs,DSs containing polyphenols,alkaloids,terpenes,polysaccharides and other bioactive components can prevent AD by reducing Aβdeposition,inhibiting tau protein hyperphosphorylation,reconstructing synaptic dysfunction,weakening cholinesterase activity,regulating mitochondrial oxidative stress,neuronal inflammation and apoptosis.This review summarizes the anti-AD effects of the main DSs and their bioactive constituents,as well as the potential molecular mechanisms covers from 2017 to 2023.Additionally,we discussed the opportunities and challenges faced by DSs in the process of AD prevention and treatment,aiming to further provide new perspectives for functional food development.
基金the National Natural Science Foundation of China(No.82101498 to XW)STI2030-Major Prjects of China(No.20212D0201801 to PH)+1 种基金National Natural Science Foundation of China(No.82171917 to PH,No.82090034 and 31970979 to KW and 32071054 to YT)the 2021 Youth Foundation Training Program of the First Affiliated Hospital of Anhui Medical University(No.2021kj19 to XW).
文摘Background Previous studies havedemonstrated that excitatory repetitive transcranial magnetic stimulation(rTMS)can improve the cognitive function of patients with Alzheimer's disease(AD).Intermittent theta burst stimulation(iTBS)is a novel excitatory rTMS protocol for brain activity stimulation with the ability to induce long-term potentiation-like plasticity and represents a promising treatment for AD.However,the long-term effects of iTBS on cognitive decline and brain structure in patients with AD areunknown.Aims We aimed to explore whether repeating accelerated iTBS every three months could slow down the cognitive decline in patients with AD.Methods In this randomised,assessor-blinded,controlled trial,iTBS was administered to the left dorsolateral prefrontal cortex(DLPFC)of 42 patients with AD for 14days every 13weeks.Measurements included the Montreal Cognitive Assessment(MoCA),a comprehensive neuropsychological battery,and the grey matter volume(GMV)of the hippocampus.Patients were evaluated at baseline and after follow-up.The longitudinal pipeline of the Computational Anatomy Toolbox for SPM was used to detect significant treatment-related changes over time.Results The iTBS group maintained MoCA scores relative to the control group(t=3.26,p=0.013)and reduced hippocampal atrophy,which was significantly correlated with global degeneration scale changes.The baseline Mini-Mental State Examination(MMSE)score,apolipoprotein E genotype and Clinical Dementia Rating were indicative of MoCA scores at follow-up.Moreover,the GMV of the left(t=0.08,p=0.996)and right(t=0.19,p=0.977)hippocampus were maintained in the active group but significantly declined in the control group(left:t=4.13,p<0.001;right:t=5.31,p<0.001).GMV change in the left(r=0.35,p=0.023)and right(r=0.36,p=0.021)hippocampus across the intervention positively correlated with MoCA changes;left hippocampal GMV change was negatively correlated with global degeneration scale(r=-0.32,p=0.041)changes.Conclusions DLPFC-iTBS maybe a feasible and easy-to-implement non-pharmacological intervention to slow down the progressive decline of overall cognition and quality of life in patients with AD,providing a new AD treatment option.Trial registration number NCT04754152.
基金supported in part by the National Natural Science Foundation of China(91949205,82071219,82001134,31730035,81721005,and 82201584)the Hubei Provincial Key S&T Program(2018ACA142)the Guangdong Provincial Key S&T Program(2018B030336001).
文摘Background:Episodic memory loss is a prominent clinical manifestation of Alzheimer’s disease(AD),which is closely related to tau pathology and hippocampal impairment.Due to the heterogeneity of brain neurons,the specific roles of different brain neurons in terms of their sensitivity to tau accumulation and their contribution to AD-like social memory loss remain unclear.Therefore,further investigation is necessary.Methods:We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic analysis,social behavioural tests,hippocampal electrophysiology,immunofluorescence staining and in vivo optical fibre recording of GCaMP6f and iGABASnFR.Additionally,we utilized optogenetics and administered ursolic acid(UA)via oral gavage to examine the effects of these agents on social memory in mice.Results:The results of proteomic and phosphoproteomic analyses revealed the characteristics of ventral hippocampal CA1(vCA1)under both physiological conditions and AD-like tau pathology.As tau progressively accumulated,vCA1,especially its excitatory and parvalbumin(PV)neurons,were fully filled with mislocated and phosphorylated tau(p-Tau).This finding was not observed for dorsal hippocampal CA1(dCA1).The overexpression of human tau(hTau)in excitatory and PV neurons mimicked AD-like tau accumulation,significantly inhibited neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1.Photoactivating excitatory and PV neurons in vCA1 at specific rhythms and time windows efficiently ameliorated tau-impaired social memory.Notably,1 month of UA administration efficiently decreased tau accumulation via autophagy in a transcription factor EB(TFEB)-dependent manner and restored the vCA1 microcircuit to ameliorate tau-impaired social memory.Conclusion:This study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1 and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation.Notably,our novel findings regarding the efficacy of UA in reducing tau load and targeting the vCA1 microcircuit may provide a promising strategy for treating AD in the future.
文摘Grape crops are a great source of income for farmers.The yield and quality of grapes can be improved by preventing and treating diseases.The farmer’s yield will be dramatically impacted if diseases are found on grape leaves.Automatic detection can reduce the chances of leaf diseases affecting other healthy plants.Several studies have been conducted to detect grape leaf diseases,but most fail to engage with end users and integrate the model with real-time mobile applications.This study developed a mobile-based grape leaf disease detection(GLDD)application to identify infected leaves,Grape Guard,based on a TensorFlow Lite(TFLite)model generated from the You Only Look Once(YOLO)v8 model.A public grape leaf disease dataset containing four classes was used to train the model.The results of this study were relied on the YOLO architecture,specifically YOLOv5 and YOLOv8.After extensive experiments with different image sizes,YOLOv8 performed better than YOLOv5.YOLOv8 achieved 99.9%precision,100%recall,99.5%mean average precision(mAP),and 88%mAP50-95 for all classes to detect grape leaf diseases.The Grape Guard android mobile application can accurately detect the grape leaf disease by capturing images from grape vines.
文摘Uric acid(UA)is a naturally antioxidant that is strongly associated with the development and progression of Parkinson's disease(PD).The purine diet is an important exogenous pathway that modulates blood UA levels.Deep brain stimulation(DBS)is an important tool for PD treatment.This study aimed to explore the effects of preoperative purine diet on the prognosis of patients with PD after DBS.Sixty-four patients with PD who underwent DBS were included in this study,and their clinical data,blood UA levels,and daily purine intake.Patients were followed up for improvement 1 year after surgery.We found that patient higher purine intake was strongly associated with the rate of improvement after DBS and was a protective factor for patient prognosis.Daily purine intake from meat and seafood was significantly higher in the responsive patients than in the lessresponsive patients.Mediation analysis showed that UA mediated 78%of the effect of purine intake on motor symptom improvement after DBS.In summary,we observed that purine intake is strongly associated with the rate of improvement in motor symptoms after subthalamic nucleus-DBS in patients with PD.This study provides a reference for preoperative diet planning in patients with PD undergoing DBS.
基金supported by the National Natural Science Foundation of China(U22A20272,82173807,82170497)。
文摘Parkinson's disease(PD)is one of the most common neurodegenerative diseases.The loss of dopaminergic(DAergic)neurons in the substantia nigra and the decrease of dopamine(DA)levels accelerate the process of PD.L-Ergothioneine(EGT)is a natural antioxidant derived from microorganisms,especially in edible mushrooms.EGT can penetrate blood-brain barrier and its levels are significantly decreased in the plasma of PD patients.Therefore,we speculated that EGT could ameliorate PD,and determined its effect on PD development by using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced PD mouse models and neurotoxin 1-methyl-4-phenylpyridinium(MPP^(+))-induced cell models.Our results show that EGT alleviated MPTP-induced behavioral dysfunction in mice.Mechanistically,we innovatively revealed that EGT was a key regulator of DJ-1.EGT restored DA levels by activating the DJ-1-nuclear receptor-related factor 1(Nurr1)axis.Furthermore,it reduced reactive oxygen species(ROS)levels by regulating the DJ-1-nuclear factor erythroid 2-related factor 2(Nrf2)pathway,which inhibited oxidative stress-induced DAergic neuronal apoptosis.Combined treatment with DJ-1-si RNA transfection revealed that blocking DJ-1 reversed EGT upregulated Nurr1 and Nrf2 expression in the nucleus,which significantly decreased the benefits of EGT.Taken together,our study suggests that EGT can ameliorate PD and be considered as a strategy for PD treatment.
基金supported by grants from National Natural Science Foundation of China(82072709,81902441)Natural Science Foundation of Tianjin Municipal(23JCYBJC00850)+1 种基金China Postdoctoral Science Foundation(2022M712374)Tianjin“131”Innovative Talent Team Project(201926)。
文摘Non-alcoholic fatty liver disease(NAFLD)is one of the most common chronic liver diseases worldwide.Gut microbiota and its metabolites alteration are closely related to NAFLD.Nootkatone is an edible flavorant derived from grapefruit which has a variety of biological activities.However,the precise mechanisms of nootkatone on NAFLD remains to be defined.Our results showed that nootkatone prevented body weight gain and decreased serum lipid level,hepatic lipogenesis,hepatic proinflammatory cytokines secretion in NAFLD mice.Also,nootkatone attenuated inflammatory response via inhibiting TLR4/NF-κB/NLRP3 pathway.Moreover,nootkatone restored intestinal barrier damage through increasing tight junction proteins and short chain fatty acids contents.Further 16S rRNA sequencing of colonic content suggested that nootkatone recovered the disturbed gut microbiota to improve NAFLD.Spearman correlation analysis between gut microbiota and NAFLD related parameters indicated that nootkatone regulated lipid metabolism and immunity via altering the gut microbiota.In conclusion,these findings revealed that nootkatone alleviated hepatic lipid homeostasis and inflammatory response in NAFLD mice,which associated with intestinal barrier integrity and the regulation of gut microbiota.This study provides new perspectives that nootkatone has efficacy on NAFLD via“gut-liver axis”,and nootkatone is expected to be developed as a functional food additive.
基金Project supported by the National Natural Science Foundation of China(Grant No.11572127)
文摘Accurate identification of Alzheimer＇s disease （AD） and mild cognitive impairment （MCI） is crucial so as to improve diagnosis techniques and to better understand the neurodegenerative process. In this work, we aim to apply the machine learning method to individual identification and identify the discriminate features associated with AD and MCI. Diffusion tensor imaging scans of 48 patients with AD, 39 patients with late MCI, 75 patients with early MCI, and 51 age-matched healthy controls （HCs） are acquired from the Alzheimer＇s Disease Neuroimaging Initiative database. In addition to the common fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity metrics, there are two novel metrics, named local diffusion homogeneity that used Spearman＇s rank correlation coefficient and Kendall＇s coefficient concordance, which are taken as classification metrics. The recursive feature elimination method for support vector machine （SVM） and logistic regression （LR） combined with leave-one-out cross validation are applied to determine the optimal feature dimensions. Then the SVM and LR methods perform the classification process and compare the classification performance. The results show that not only can the multi-type combined metrics obtain higher accuracy than the single metric, but also the SVM classifier with multi-type combined metrics has better classification performance than the LR classifier. Statistically, the average accuracy of the combined metric is more than 92% for all between-group comparisons of SVM classifier. In addition to the high recognition rate, significant differences are found in the statistical analysis of cognitive scores between groups. We further execute the permutation test, receiver operating characteristic curves, and area under the curve to validate the robustness of the classifiers, and indicate that the SVM classifier is more stable and efficient than the LR classifier. Finally, the uncinated fasciculus, cingulum, corpus callosum, corona radiate, external capsule, and internal capsule have been regarded as the most important white matter tracts to identify AD, MCI, and HC. Our findings reveal a guidance role for machine-learning based image analysis on clinical diagnosis.
文摘Alzheimer’s disease(AD)is the most common neurodegenerative disease characterized by cognitive decline and memory impairment.Many lines of evidence indicate that excessiveβ-amyloid peptide(Aβ)generation and aggregation play pivotal roles in the initiation of AD,leading to various biochemical alteration including oxidative damage,mitochondrial dysfunction,neuroinflammation,signaling pathway and finally resulting in neuronal death.AD has a complex pathogenic mechanism,and a single-target approach for anti-AD strategy is thus full of challenges.To overcome these limitations,the present study focused to review on one of multiple target-compounds,(-)-epigallocatechin-3-gallate(EGCG)for the prevention and treatment of AD.EGCG is a main bioactive polyphenol in green tea and has been reported to exert potent neuroprotective properties in a wide array of both cellular and animal models in AD.This review demonstrated multiple neuroprotective efficacies of EGCG by focusing on the involvement of Aβ-evoked damage and its Aβregulation.Furthermore,to understand its mechanism of action on the brain,the permeability of the blood-brain barrier was also discussed.
基金Project supported by the National Natural Science Foundation of China(Grant No.61271079)the Vice Chancellor Research Grant in University of Wollongongthe Priority Academic Program Development of Jiangsu Higher Education Institutions,China
文摘Applications of multifractal analysis to white matter structure changes on magnetic resonance imaging（MRI） have recently received increasing attentions. Although some progresses have been made, there is no evident study on applying multifractal analysis to evaluate the white matter structural changes on MRI for Alzheimer＇s disease（AD） research. In this paper, to explore multifractal analysis of white matter structural changes on 3D MRI volumes between normal aging and early AD, we not only extend the traditional box-counting multifractal analysis（BCMA） into the 3D case, but also propose a modified integer ratio based BCMA（IRBCMA） algorithm to compensate for the rigid division rule in BCMA. We verify multifractal characteristics in 3D white matter MRI volumes. In addition to the previously well studied multifractal feature,△α, we also demonstrated △ f as an alternative and effective multifractal feature to distinguish NC from AD subjects.Both △α and △ f are found to have strong positive correlation with the clinical MMSE scores with statistical significance.Moreover, the proposed IRBCMA can be an alternative and more accurate algorithm for 3D volume analysis. Our findings highlight the potential usefulness of multifractal analysis, which may contribute to clarify some aspects of the etiology of AD through detection of structural changes in white matter.
基金supported by the Ministry of Science and Technology of the People's Republic of China(2021ZD0201804,GW)National Natural Science Foundation of China(92068111,81973272,XG,81903582,QS)+1 种基金Natural Science Foundation of Shanghai(219ZR1431500,GW)Shanghai Science and Technology Committee(121XD1422200,XG)and Cellular Biomedicine Group(CBMG,Shanghai,China).
文摘Background There have been no effective treatments for slowing or reversing Alzheimer’s disease(AD)until now.Growing preclinical evidence,including this study,suggests that mesenchymal stem cells-secreted exosomes(MSCs-Exos)have the potential to cure AD.Aims The first three-arm,drug-intervention,phase I/II clinical trial was conducted to explore the safety and efficacy of allogenic human adipose MSCs-Exos(ahaMSCs-Exos)in patients with mild to moderate AD.Methods The eligible subjects were assigned to one of three dosage groups,intranasally administrated with ahaMSCs-Exos two times per week for 12 weeks,and underwent follow-up visits at weeks 16,24,36 and 48.Results No adverse events were reported.In the medium-dose arm,Alzheimer’s Disease Assessment Scale–Cognitive section(ADAS-cog)scores decreased by 2.33(1.19)and the basic version of Montreal Cognitive Assessment scores increased by 2.38(0.58)at week 12 compared with baseline levels,indicating improved cognitive function.Moreover,the ADAS-cog scores in the medium-dose arm decreased continuously by 3.98 points until week 36.There were no significant differences in altered amyloid or tau deposition among the three arms,but hippocampal volume shrank less in the medium-dose arm to some extent.Conclusions Intranasal administration of ahaMSCs-Exos was safe and well tolerated,and a dose of at least 4×10^(8)particles could be selected for further clinical trials.
文摘Objective To investigate the relationship of plasma homocysteine (Hcy) levels and the gene polymorphisms of N5, N10-methylenetetrahydrofolate reductase (MTHFR), cystathionine β-synthase (CBS) with Alzheimer’s disease (AD). Methods Plasma Hcy levels were measured by means of high voltage capillary electrophoresis with ultra-violet detection, the polymorphisms of C677T in exon 4 of MTHFR gene and 844ins68 in exon 8 of CBS gene were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 105 AD patients and 102 non-AD controls. All controls were excluded from cardiocerebrovascular disorders and other diseases. Results The plasma Hcy level in AD patients (16.04 ± 3.84 μmol/L) was significantly higher than that in the controls(11.94 ± 3.87 μmol/L, P < 0.001). There were no significant differences of the genotype and allele frequencies of MTHFR C677T mutation and CBS 844ins68 mutation between the patients and controls. However, the T allele of MTHFR gene was found to relate with the plasma Hcy level increase in all subjects. Conclusion The elevated plasma Hcy level in AD patients is probably involved in the pathogenesis of AD, which may be due to the environmental factor rather than genetic factors of the mutations of MTHFR and CBS.
基金the Municipal Human Resources Development Program for Outstanding Leaders in Medical Discipline in Shanghai (2017BR054)Shanghai Jiao Tong University School of Medicine Collaborative Innovation Project (TM201728)+1 种基金Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20172029)the National Natural Science Foundation of China (81571298).
文摘Background Dementia is a chronic brain disorder classified by four distinct diseases that impact cognition and mental degeneration. Each subgroup exhibits similar brain deficiencies and mutations. This review will focus on four dementia subgroups: Alzheimer's disease, vascular dementia, frontotemporal dementia and dementia Lewy body. Aim The aim of this systematic review is to create a concise overview of unique similarities within dementia used to locate and identify new biomarker methods in diagnosing dementia. Methods 123 300 articles published after 2010 were identified from PubMed, JSTOR, WorldCat Online Computer Library and PALNI (Private Academic Library Network of Indiana) using the following search items (in title or abstract):'Neurodegenerative Diseases' OR 'Biomarkers' OR 'Alzheimer's Disease' OR 'Frontal Temporal Lobe Dementia' OR 'Vascular Dementia, OR 'Dementia Lewy Body' OR 'Cerebral Spinal Fluid' OR 'Mental Cognitive Impairment'. 47 studies were included in the qualitative synthesis. Results Evidence suggested neuroimaging with amyloid positron emission tomography (PET) scanning and newly found PET tracers to be more effective in diagnosing Alzheimer's and amnesiac mental cognitive impairment than carbon-11 Pittsburgh compound-B radioisotope tracer. Newly created methods to make PET scans more accurate and practical in clinical settings signify a major shift in diagnosing dementia and neurodegenerative diseases. Conclusion Vast improvements in neuroimaging techniques have led to newly discovered biomarkers and diagnostics. Neuroimaging with amyloid PET scanning surpasses what had been considered the dominant method of neuroimaging and MRI. Newly created methods to make PET scans more accurate and practical in clinical settings signify a major shift in diagnosing dementia pathology. Continued research and studies must be conducted to improve current findings and streamline methods to further subcategorise neurodegenerative disorders and diagnosis.
