Abstract:Alzheimer disease （AD） is one of the most common neurodegenerative disease with a heavy disease burden. At present， the pathogenesis of AD is unknown. Therefore， there is a lack of disease modifying medicines that can reverse or delay the progress of AD. This paper describes the research on disease modifying pharmacological therapy based on the theory of main pathogenesis of AD. It includes the research using Aβ， tau or other biomarkers as targets and new clinical trials of old medicines. Among them， most trials terminated at a certain stage of the drug research and development process or clinical trial process， and some are still ongoing. The relationship between AD pathogenesis research and disease modifying therapy is mutual promotion and verification. The breakthrough of basic research may bring new hope to drug research and development. At the same time， the success or failure of clinical trial in a certain direction is a test of its theoretical basis. There is still a long way to go from the research on the pathogenesis of AD to the development of disease modifying medicines， and then to their widely clinical use.

Abstract:Objective To investigate the effect of voice handicap on quality of life in patients with Parkinson disease （PD）. Methods A total of 86 early and middle stage PD patients hospitalized in the Parkinson's Medical Center of Beijing Rehabilitation Hospital affiliated to Capital Medical University from April 2020 to August 2021 were selected as PD group， and 47 healthy controls recruited from society from December 2021 to February 2022 were selected. General data of the subjects were collected. The clinical classification of PD patients was determined by Hoehn & Yahr （H&Y） staging. The motor symptoms of PD patients were evaluated by the International Association of Motion Disorders Unified Parkinson's Disease Rating Scale Part Ⅲ （MDS-UPDRS- Ⅲ）. The quality of life， depression， anxiety， cognitive function， swallowing function and voice status of the subjects were evaluated with 39 items of Parkinson's Disease Questionnaire （PDQ-39）， Geriatric Depression Scale （GDS）， Hamilton Anxiety Scale （HAMA）， Montreal Cognitive Assessment Scale （MoCA）， Swallowing Disorder Questionnaire （SDQ） and Voice Handicap Index （VHI-10）. The scores of VHI-10 and PDQ- 39 in the two groups were compared by covariance analysis. Spearman correlation was used to analyze the related factors of voice handicap and quality of life in early and middle stage PD patients. Results The results of covariance analysis showed that the scores of VHI-10 and PDQ-39 in PD group were higher than those in control group ［8.0（4.0，11.3） vs 0（0，0）； 23.4（15.4，29.0） vs 0（0，3.0）］. The difference was statistically significant （P＜ 0.01）. The PDQ-39 score of male PD patients was lower than that of female patients ［21.2（14.7，26.2） vs 26.3 （18.6，31.4）］， and the difference was statistically significant（Z=-2.41，P＜ 0.05）. Spearman correlation analysis showed that the VHI-10 score of PD patients was positively correlated with age， HAMA score， GDS score and SDQ score （r=0.25，0.31，0.42，0.64；P ＜ 0.05）； PDQ-39 score was positively correlated with H&Y stage， UPDRS-Ⅲ score， GDS score， HAMA score， SDQ score and VHI-10 score （r=0.22，0.24，0.54，0.37，0.33， 0.47； P＜ 0.05）. Multiple linear regression analysis showed that GDS score， VHI-10 score and gender were the influencing factors of quality of life in patients with early and middle stage PD （P＜ 0.01）. Conclusions Early and middle stage PD patients have voice handicap， and voice handicap will reduce their quality of life.

Abstract:Objective To explore the effects of urine sediment indicators on the detection level of Alzheimer-associated neuronal thread protein （AD7c-NTP）. Methods A total of 314 healthy physical examination subjects in Affiliated Hospital of Guilin Medical University from July 2021 to October 2021 were included. Urine samples were collected for AD7c-NTP enzyme linked immunosorbent assay （ELISA） detection. Age， gender， and urine sediment detection indicators were collected and the effects of urinary sediment indexes on AD7c-NTP levels were analyzed. Results The levels of AD7c-NTP in the urine of male subjects with different levels of red blood cells， white blood cells， epithelial cells， small round epithelial cells， casts， yeast like bacteria and crystals showed no statistically significant difference （P ＞ 0.05）； In males， the AD7c-NTP levels in low conductivity group ［0.68 （0.48，1.40） ng/ml］， medium conductivity group ［0.50（0.32，1.06） ng/ml］ and high conductivity group ［0.34（0.31，0.51） ng/ml］ showed a significant decreasing trend. The difference is statistically significant （Z=-3.823，P ＜ 0.05）. There is no statistically significant difference in AD7c-NTP levels in urine of female subjects with different levels of red blood cells， white blood cells， epithelial cells， small round epithelial cells， tube types， yeast like bacteria and electrical conductivity （P＞ 0.05）； The AD7cNTP levels in urine of female subjects with high crystal level ［0.51（0.33，0.62） ng/ml］ was lower than that of female subjects with low crystal level ［0.65（0.42，1.18） ng/ml］. The difference is statistically significant （Z= -2.331， P＜ 0.05）. Conclusions Among all the urine sediment indicators， the conductivity in male and the crystal in female may affect the detection level of AD7c-NTP.

Abstract:Objective To analyze the changes of neurotransmitter metabolites in the hippocampus and cortex of six-month-old APP/PS1 transgenic mice and wild-type mice of the same age. Methods A total of 8 healthy female 6-month-old wild-type mice and 8 APP/PS1 transgenic mice were selected. Congo red test was conducted in 3 mice， and ultrahigh performance liquid chromatography tandem mass spectrometry was used to analyze the content of neurotransmitter metabolites in hippocampus and cortex in 5 mice. The difference metabolites between groups were screened by independent sample t test P＜ 0.05 or the fold change （FC） ≥ 1.2 or FC ≤ 0.8， on the basis of variable influence on projection （VIP） ≥ 1 of the principal component of orthogonal partial least squares discriminant analysis （OPLS-DA） model. Results Amyloid-β protein deposition appears in hippocampus and cortex of 6-month-old APP/PS1 transgenic mice. The metabolic profiles of hippocampus and cortex of the two groups of mice showed a trend of separation. A total of 17 different metabolites were identified in the hippocampus of mice， including epinephrine， norepinephrine， levodopa， dopamine， 3， 4-dihydroxyphenylacetate （DOPAC）， 3，4-dihydroxyphenyldiol， 3，4-dihydroxymandelic acid， methoxy norepinephrine （NMN）， 4-hydroxy-3-methoxyphenylene glycol （MHPG）， 4-hydroxy-3-methoxy-mandelic acid/homovanillic acid （HVA）， glutamine， glutamate γ-aminobutyric acid， 5-hydroxytryptamine （5-HT）， hydroxyindoleacetic acid （5-HIAA）， ornithine and tyramine. A total of 12 different metabolites were identified in the cortex of mice， including dopamine， DOPAC， NMN， 3-methoxy tyramine， MHPG， HVA， 5-HT， 5-HIAA， ethanolamine， L-tyrosine， L-phenylalanine and threonine. Conclusions The trend of neurotransmitter metabolism in hippocampus and cortex of APP/PS1 transgenic mice is different， which can be used as the target of early pathological changes in cognitive dysfunction of APP/PS1 transgenic mice.

Abstract:Alzheimer disease （AD） is a chronic neurodegenerative disorder with insidious onset and gradual aggravation， with complex pathogenesis. At present， there is no drug to reverse the course of the disease. CRISPR/Cas9 technology has the advantages of short cycle， low cytotoxicity， low price and simple transmission. Because it can be genetically modified for different cells， tissues or animal models， it shows great potential in the study of neurodegenerative diseases. This paper introduces the development， principle and delivery system of CRISPR/Cas9 technology， as well as the application and potential of CRISPR/Cas9 technology in AD model construction， pathogenesis research and targeted therapy， hoping to play a reference role for researchers in related fields.

Abstract:As the population aging， the prevalence of dementia remains high. Dementia will deteriorate patients' quality of life， but also bring a heavy burden to the family and society. Therefore， the treatment and prevention of dementia have always been the focus of scientists' attention. In recent years， motoric cognitive risk syndrome （MCR）， as an important research model， can be used to evaluate the decline of individual cognitive ability with reduced walking speed， to understand the pathophysiological mechanism of developing from predementia stage to dementia stage. The purpose of this review was to summary the blood biomarkers and imaging characteristics of MCR， to enhance the understanding of the biological mechanism of MCR.

Abstract:Alzheimer disease （AD） is one of the most common chronic diseases in the elderly. The prevalence of AD is closely related to age. Synaptic structure， as a key part of information transmission between neurons， is closely related to AD. The loss of synaptic structure and function is considered to be a sign of early AD. Postsynaptic density protein-95， shank and Homer proteins are the main postsynaptic scaffold proteins， which play an important role in maintaining synaptic structure and function. We systematically describe the research progress of postsynaptic scaffold proteins and AD.

Abstract:Objective To investigate the impact of electroacupuncture on behavior and the gut microbiome in chronic unpredictable mild stress （CUMS） mouse model. Methods A total of 40 male C57BL/6 mice were randomly distributed into control group， electroacupuncture group， CUMS group and treatment group （CUMS + electroacupuncture）， with 10 mice in each group. CUMS group and CUMS + electroacupuncture group accepted CUMS modeling. After the completion of modeling， mice in the control group and CUMS group were given sham stimulation for 7 days， and mice in the electroacupuncture group and CUMS + electroacupuncture group were given 2/15 Hz， 1.0 mA electroacupuncture stimulation for 7 days. 24 hours after the last intervention， feces were collected and stored at -80℃. Sugar preference test， open field test and forced swimming test were conducted on mice. 16S rDNA sequencing was performed on the feces of four groups of mice. α diversity，β diversity analysis and Linear Discriminant analysis Effect Size （LEfSe） were carried out by Operational Taxonomic Units （OTU） information. Spearman correlation analysis of the correlation between the behavioral indicators of mice and the enrichment levels of different bacterial populations. Results The time of exploring the open field center area of CUMS group mice was shorter than that of the control group ［（22.058±4.148） s vs （37.864±4.407） s］， the sugar preference rate was lower than that of the control group ［（53.427±14.550）% vs （76.514±15.701）%］， and the forced swimming immobility time was longer than that of the control group ［（82.599±32.369） s vs （47.606±15.344） s］， the difference was statistically significant （P＜ 0.01）. The time of exploring the open field center area of CUMS + electroacupuncture group mice was longer than that of the CUMS group ［（30.604±6.060） s vs （22.058±4.148） s］， the sugar preference rate was higher than that of the CUMS group ［（72.731±13.933）% vs （53.427±14.550）%］， and the forced swimming immobility time was shorter than that of the CUMS group ［（53.633±17.933） s vs （82.599±32.369） s］， the difference was statistically significant （P ＜ 0.05）. The number of OTU， ACE index and Chao index of intestinal flora in CUMS group were lower than those in the control group， and the difference was statistically significant （P ＜ 0.05）， but there was no statistical significance in the difference between CUMS + electroacupuncture group and CUMS group （P＞0.05）. Ruminococcaceae_UCG-002， Lachnoclostridium and Rikenella ceae_RC9_gut_group were abundant in the CUMS group， which were positively correlated with depressive-like behavior （P＜ 0.05）. Phylum Actinobacteria and genus Rikenella， Dubosiella， Ileibacterium， Bifidobacterium and Allobaculum were enriched in the electroacupuncture group and CUMS + electroacupuncture groups， all of which were negatively correlated with depressive-like behaviors. Conclusions Electroacupuncture treatment can ameliorate depressive-like behavior and regulate the composition of gut microbiota in CUMS-treated mice.

Abstract:Objective To investigate the clinical efficacy of low-frequency repetitive transcranial magnetic stimulation （rTMS） combined with fluvoxamine in the treatment of children and adolescents with firstepisode obsessive-compulsive disorder （OCD）. Methods A total of 58 children with first-episode OCD who met the diagnostic criteria of the American Diagnostic Statistical Manual of Mental Disorders Fifth Edition （DSM-5） from June 2021 to March 2022 in outpatient and inpatient department of Qingdao Mental Health Center were selected. All children were randomly and double-blindly divided into experimental group and control group， with 29 cases in each group. The experimental group was treated with low-frequency rTMS combined with fluvoxamine， and the control group was treated with pseudo-stimulation combined with fluvoxamine. Both groups were observed and treated for 8 weeks. The Yale-Brown Obsessive-Compulsive Disorder Scale （Y-BOCS）， Hamilton Anxiety Scale （HAMA）， and Treatment Emergent Symptoms Scale （TESS） were used to evaluate he efficacy. The severity of OCD and anxiety of the two groups were analyzed and compared by repeated measures analysis of variance （ANOVA） before treatment， and at the end of 2nd， 4th， 6th and 8th week of the treatment. The total effective rate and the incidence of adverse reactions between the two groups were compared. Results The differences in scores of Y-BOCS and HAMA before treatment between the two groups were not statistically significant （P ＞ 0.05）. The differences in the score of Y-BOCS between the experiment group and the control group at the end of 2nd， 4th， 6th and 8th week ［（26.10±5.11） vs （30.24±3.79）， （22.48±5.09） vs （25.76±4.60）， （17.34±5.15） vs （20.31±5.65）， （12.59±5.82） vs （16.31±6.71）］ were statistically significant （P＜0.05）. The differences in the score of HAMA between the experiment group and the control group at the end of 2nd， 4th， 6th and 8th week ［（19.41±4.02） vs （22.55±3.88）， （15.62±4.53） vs （18.90±3.39）， （11.66±3.11） vs （15.62±3.23）， （8.31±2.19） vs （12.55±2.68）］ were statistically significant （P＜ 0.01）. The results of repeated measurement ANOVA showed that the Y-BOCS and HAMA scores of the two groups had inter group， time and interaction effects， and the differences were statistically significant （P＜ 0.05）. Further analysis found that the experimental group had an effect at the 2nd week of treatment （P＜ 0.001）， while the control group had an effect at the 4th week of treatment. The total effective rate ［93.11%（27/29）］ of the experimental group was higher than that of the control group ［72.41%（21/29）］， and the difference was statistically significant （Z=1.980， P＜ 0.05）. There was no significant difference in the incidence of adverse reactions between the two groups ［37.93% （11/29） vs 27.59% （8/29）］ （χ2 =0.704，P ＞ 0.05）. Conclusions Low-frequency rTMS combined with fluvoxamine in the treatment of children and adolescents with first-episode OCD can significantly improve the obsessivecompulsive symptoms and anxiety symptoms of children， with a high treatment efficiency， and obvious curative effects can be achieved within 2 weeks.

Abstract:Objective To analyze the depression， anxiety symptoms and personality traits of patients with psychogenic non-epileptic seizures （PNES）. Methods The general demographic and related clinical data of 22 patients with psychogenic non epileptic seizures （PNES group） and 40 patients with epilepsy （epilepsy group） from the Department of Neurology， Xuanwu Hospital， Capital Medical University from January 2020 to March 2021 were collected. The depression， anxiety and personality traits of the patients were evaluated by Hamilton Depression Scale （HAMD）， Hamilton Anxiety Scale （HAMA） and Minnesota Multiphasic Personality Inventory （MMPI）. The differences between the two groups in general demographic characteristics， clinical data， depression， anxiety and personality traits were compared and analyzed. Results The proportion of seizure with inducing factors and seizure frequency in the PNES group were significantly higher than those in the epilepsy group （P ＜ 0.05）. In the PNES group， the total score of HAMA ［11.80（7.00，15.50） vs 8.50 （5.00，14.00）］， somatic anxiety factor ［5.30（2.00，9.50） vs 3.10（1.00，4.75）］， total score of HAMD ［10.60 （5.50，14.50） vs 7.30（5.00，8.50）］， anxiety somatization factor ［4.00（2.50，5.00） vs 2.80（2.00，4.00）］， sleep disorder factor ［1.80（0，3.00） vs 1.00（0，2.00）］， and the despair factor ［1.10（0，2.00） vs 0.40（0，1.50）］ were significantly higher than those of epilepsy group （Z=2.13，1.98，1.97，2.64，2.15，2.76； P＜ 0.05）. The standard scores of hypochondriasis ［（67.36±2.02） vs （56.79±1.21）］， depression ［（64.09±2.10） vs （52.07±1.97）］， hysteria ［（67.00±1.79） vs （54.62±1.17）］， neurasthenia ［（65.55±2.15） vs （58.40±1.82）］ in MMPI of PNES group were higher than those of epilepsy group； The score of neuroticism ［（71.32±2.05） vs （56.88±1.12）］ and masked factor ［（45.09±2.38） vs （38.57±0.98）］ in PNES group were significantly higher than those in epilepsy group （t=4.77，4.15， 6.00，2.42，6.72，2.53； P＜ 0.05）. The non-social factor in PNES group was lower than that in epilepsy group ［（44.91±2.03） vs （53.24±1.63）］， and the difference was statistically significant （t=-3.10， P＜ 0.01）. Conclusions Patients with PNES have significant depression and anxiety symptoms compared with epileptic patients， and have neurotic and masked personality traits， while epileptic patients have a more obvious tendency of non-socialization.

Abstract:Ischemic stroke is the common type of stroke and one of the major diseases threatening human health. Neuroinflammatory response is considered to be an important pathological mechanism of ischemic stroke. Microglia are resident immune cells in the central nervous system and play an important role in initiating innate and adaptive immune responses. Microglia-mediated neuroinflammatory response is closely related to the development and prognosis of ischemic stroke. This article reviews the correlation between microglia and ischemic stroke.

Abstract:Executive dysfunction is an important feature of obsessive-compulsive disorder （OCD）. Neuroimaging and genetic studies have shown that the functional abnormalities in cortico-striatal-thalamocortical circuits， parietal lobes， cerebellum and other brain regions， as well as genetic variants in serotonin and glutamate systemsin patients with OCD， may lead to their executive dysfunction. However， due to the heterogeneity of OCD and the complexity of executive function， no consistent conclusions have been drawn about the neural mechanism of executive dysfunction in OCD. Integrating the neural mechanisms and genetic patterns of executive dysfunction in OCD will help deepen the understanding of the pathogenesis of OCD； combining neuroimaging and genetic findings to identify markers will help provide new directions in the identification and intervention of executive dysfunction in OCD. This article reviews the brain structure， neural mechanism of brain function and genetic research of executive dysfunction in OCD.

Abstract:The Klotho gene is an anti-aging gene， and the Klotho encoded protein has the effect of antiaging and prolonging lifespan， which is closely related to cognitive function. Klotho protein plays an important role in cognitive impairment of neurodegenerative diseases such as Alzheimer disease， Parkinson disease， and frontotemporal dementia， and vascular cognitive impairment. It can protect cognitive function by such means as mitigation β-amyloid protein burden， reduce inflammatory reaction， resist oxidative stress and other ways. This paper summarizes the current research progress on Klotho gene， Klotho protein and various types of cognitive impairment at home and abroad， in order to provide a theoretical basis for the research in this field.