Application of wearable devices in the diagnosis and treatment of Parkinson disease / 中华老年医学杂志

Parkinson disease(PD)is the second most common neurodegenerative disease,and its motor and non-motor symptoms seriously affect the patients' quality of life.The existing methods of evaluation of PD contain a lot of shortages,such as inter-rater variability and recall bias,which promote patients,clinicians and researchers to have a strong demand for more objective and long-term assessment and monitoring methods.The wearable device-based quantitative technology,which is easy to operate and have the features of objective quantification,daily permanence and meticulous accuracy,makes it have an extensive series of perspective and advantage for application in the management of PD.This article describes,and illustrates with several examples,the applications of wearable devices in the diagnosis and treatment of various motor symptoms such as bradykinesia,resting tremor,gait disorder,motor fluctuation,dyskinesia and non-motor symptoms.We also discuss its current limitations and future directions.

Functional Connectivity-Based Modelling Simulates Subject-Specific Network Spreading Effects of Focal Brain Stimulation / 神经科学通报·英文版

Neurostimulation remarkably alleviates the symptoms in a variety of brain disorders by modulating the brain-wide network. However, how brain-wide effects on the direct and indirect pathways evoked by focal neurostimulation elicit therapeutic effects in an individual patient is unknown. Understanding this remains crucial for advancing neural circuit-based guidance to optimize candidate patient screening, pre-surgical target selection, and post-surgical parameter tuning. To address this issue, we propose a functional brain connectome-based modeling approach that simulates the spreading effects of stimulating different brain regions and quantifies the rectification of abnormal network topology in silico. We validated these analyses by pinpointing nuclei in the basal ganglia circuits as top-ranked targets for 43 local patients with Parkinson's disease and 90 patients from a public database. Individual connectome-based analysis demonstrated that the globus pallidus was the best choice for 21.1% and the subthalamic nucleus for 19.5% of patients. Down-regulation of functional connectivity (up to 12%) at these prioritized targets optimally maximized the therapeutic effects. Notably, the priority rank of the subthalamic nucleus significantly correlated with motor symptom severity (Unified Parkinson's Disease Rating Scale III) in the local cohort. These findings underscore the potential of neural network modeling for advancing personalized brain stimulation therapy, and warrant future experimental investigation to validate its clinical utility.

Study on detection biomarkers of Alzheimer's disease based on plasma immune and inflammatory proteins / 上海交通大学学报（医学版）

Objective·To explore plasma immune and inflammatory proteins that could serve as potential screening markers for Alzheimer's disease (AD).Methods·Healthy controls (n=19) and AD patients (n=19) were enrolled.Plasma samples were collected and 70 kinds of immune and inflammatory proteins were detected.The immune and inflammatory proteins associated with AD were screened by Mann-Whitney U test and partial correlation analysis.Discriminant analysis was used to develop multi-protein combined algorithm to distinguish plasma samples of AD patients from those of healthy controls.Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic efficacy for the multi-protein combined algorithm.Results·Among the 70 proteins analyzed,23 were significantly higher in AD patients (P＜0.05),among which 19 were strongly correlated with AD (P＜0.05).These 19 proteins were analyzed with Wilks' lambda stepwise analysis to develop discriminant algorithm for detecting plasma samples of AD.Finally,the discriminant algorithm established by 11 plasma immune and inflammatory proteins (EGF,GRO,MDC,MCP-1,MCP-2,MCP-4,TARC,SCF,TRAIL,CTACK,GCP-2) was found to have an optimal diagnostic efficacy (AUC=0.994).The optimal cutoff value of the algorithm was-0.609.When the optimal cutoff value was obtained,the sensitivity of the equation could reach 100％ and the specificity could reach 94.7％.Conclusion·The discriminant equation composed of the above 11 plasma immune and inflammatory proteins has the potential to assist AD screening.

Correlation between plasma macrophage inflammatory protein and early Parkinson's disease / 中华神经科杂志

Objective To detect the plasma macrophage inflammatory protein (MIP) levels in patients with early Parkinson' s disease (PD) and to investigate whether plasma MIP was associated with motor and non-motor symptoms in early PD.Methods Fifty-nine patients with early idiopathic PD (Hoehn-Yahr Staging Scale from 1.0 to 2.5) treated in our hospital from January 28,2013 to September 30,2013 and 54 healthy controls were recruited.Plasma MIP-1α and MIP-1β levels were measured by enzyme-linked immunosorbent assay.Motor function was assessed by Unified Parkinson' s Disease Rating Scale Part Ⅲ and Hoehn-Yahr Staging Scale during “on” period.Total non-motor symptoms were assessed by Non-motor Symptoms Questionnaire.Cognitive dysfunction was assessed by Mini Mental State Examination.Autonotic dysfunction was assessed by Scales for Outcomes in Parkinson' s disease-Autonomic.Depression was assessed by Hamilton Depressive Scale (HAMD).Rapid eye movement (REM) sleep behavior disorder was assessed by REM sleep behavior disorder screening questionnaire (RBDSQ).Correlation between plasma MIP levels and scale scores was analyzed by Spearman rank correlation.Results Plasma MIP-1o and MIP-1β levels were not significantly different between early PD patients and healthy controls.However,plasma MIP-1 α level negatively correlated with depression (HAMD score,r =-0.520,P =0.027) and rapid eye movement sleep behavior disorder (RBDSQ score,r =-0.537,P =0.039).Conclusion MIP-1 α may be correlated with depression and RBD in early PD.

Comparison of neurological resident training system between Australia and China / 中华医学教育探索杂志

From the four aspects of residency training plan,the actual clinical teaching arrangement,clinical operation skill training and examination system,we compared the pros and cons of neurological resident training systems in two famous hospitals in Australia and China,aiming to provide useful suggestions to improve the current neurological resident training system.

Application of 360-degree evaluation in evaluating professional ethics and communication skills of intern doctors / 中华医学教育探索杂志

Objective To evaluate the effectiveness of intern doctor training by 360 degree evaluation scale and to provide references for formulating targeted training plan. Methods A 360-degree evaluation scale with 6 subscales(Attendings, Peers, Nurse, Patients, Directors and Students) was employed to measure the status quo of medical education , represented by professional ethics and communication skills, among 129 intern doctors in medical clinical college. Cronbach's alpha was used to evaluate the reliability of the scale,one-way ANOVA was used to compare the difference of score among different scorers,and t test and Mann-Whitney test were employed to compare scores be-tween male group and female group, 5-year class and 8-year class (The significance level was set at P0.05). Conclusions 360 degree evaluation scale has reasonable reliability and it can provide valuable references for future similar survey in China. Meanwhile, intern doctors exhibit rela-tively good performances in professional ethics and communication ability & interpersonal relationship in the present study.

Construction and utilization of quintessential courses of colleges / 中华医学教育探索杂志

Quintessential course is a kind of demonstration course,therefore,various colleges paid great attention to the construction and utilization of quintessential courses.In order to promote educational reform,improve teaching quality of medicine and reflect the value of quintessential courses,we should adopt a variety of measures to ensure the smooth undergoing of the whole process in teaching and research section of neurology including information resource sharing,video recording of class teaching,network platform constructing,teaching team constructing as well as individuation and diversification.

The application of translational medicine in cultivating postgraduates of neurology / 中华医学教育探索杂志

Translational medicine is a new term recently which aims to eliminate the barrier between preclinical and clinical medicine,to efficiendy and effectively translate basic scientific findings into drugs and medical devices that benefits patients.This article discussed the meaning of translational medicine in cultivating postgraduates of neurology.According to the preliminary attempt,it is beneficial for postgraduates to form translational medicine philosophy and be high-quality medical talents.

Toxic effect of carboxyl-terminal peptide of β-amyloid precursor protein (APPC31) on Neuro2a cells / 中华神经科杂志

Objective To investigate the toxic effect of the carboxyl-terminal peptide of β-amyloid precursor protein (APPC31) on Neuro2a cells as well as its role in the toxic process in Neuro2a cells induced by Aβ42 in vitro.Methods The plasmid vector and the APPC31 construct were transiently transfected into Neuro2a cells respectively by lipofectamine 2000.The viability of the cells was measured by the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay at 48 h after transfection,and their morphocytology was observed by 4', 6-diamidino-2-phenylindole (DAPI) nucleus staining.Afterword different constructs including vector, WTAPP695, APP( D664A), the amino-terminal peptide of β-amyloid precursor protein (APP△C31) and APPC31 were transiently transfected into Neuro2a cells respectively via the same method.At 24 h after transfection Aβ42 was added into the culture medium of Neuro2a cells with the desired concentration for another 24 h for cell studies.The viabihty and morphocytology of the cells were measured by using the MTT assay and DAPI nucleus staining, respectively.Results When incubated in the absence of Aβ42, the viability of cells transfected with vector and APPC31construct were 0.81 ±0.10 and 0.88 ±0.12 respectively, and accordingly there was no significant difference between the these two groups (t = - 0.78, P = 0.48 ); meanwhile no obvious cell nuclear morphological changes of apoptosis or death occurred.However when incubated in the presence of Aβ42, the viability of cells transfected with vector, WTAPP695, APP( D664A), APP△C31 and APPC31 constructs were 0.82 ±0.01, 0.78 ±0.03, 0.55 ±0.04, 0.81 ±0.04, 0.78 ±0.02 and 0.54 ±0.02 respectively.The viability of cells transfected with WTAPP construct and APPC31 construct decreased significantly ( F = 47.53, P ＜0.05) compared with the control group, meanwhile cells displayed condensed nuclear and even nuclear fragmentation.Conclusions In vitro, over-expression of a certain level of APPC31 in Neuro2a cells fails in causing cell death, but this short peptide enhances cytotoxicity induced by Aβ42 in Neuro2a cells.Thus,these results provide the experimental basis for the further explication of the pathogenesis of Alzheimer's disease.

Multicenter randomized, double-blind, placebo-controlled trial of zonisamide as add-on therapy in patients with refractor partial seizures / 中华神经科杂志

Objective To evaluate the efficacy and tolerability of zonisamide (ZNS) as add-on therapy in patients with refractory partial seizures.Methods In this Chinese muiticenter, double-blind, randomized, placebo-contrclled trial, ZNS was compared with placebo add-on therapy in 217 patients (intent-to treat (ITT) population) with uncontrolled partial-onset seizures.All patients entered a 3-month baseline period followed by a 4-week titration interval and a 12-week maintenance period.The starting dose of ZNS group was 100 mg/d, increased by 100 mg/d every week and reached the goal of 400 mg/d.The main outcome was measured by the median of the percentage of decreased seizure frequency.The secondary ouwomes points included the percentage of patients who had seizure attacks decreased by more than 50%,and adverse events.Results The median of the percentage of decreased seizure frequency in ZNS group was 33.33%, and the placebo group was 0.Thirty-eight patients (34.23%) experienced more than 50% reduction in the seizure frequency in ZNS group, compared with 19.81% of patients (21 cases) in the placebo group (χ2 =5.7159,P =0.0168) ; Moreover, 13 (11.71%) patients in ZNS group and 5 patients in placebo group were seizure free, 25 patients in ZNS group and 16 patients in placebo group who had seizure attacks decreased by more than 50%.The availability rate in ZNS group was higher than placebo group (34.23% vs 19.81%, U=2.4701, P=0.0135).The most common adverse events in ZNS group were drowsiness, fatigue, decreased appetite, gastrointestinal complaints, insomnia and constipation.Conclusion Zonisamide treatment was generally well tolerated and was associated with significant reductions in seizure frequency as adjunctive treatment for partial-onset seizures.

Investigation of chronic kidney diseases from inpatients with cerebrovascular diseases in Shanghai / 中华肾脏病杂志

ObjectiveTo investigate the prevalence of chronic kidney diseases (CKD) from inpatients with cerebrovascular diseases in Shanghai district. MethodsInpatients with cerebrovascular diseases from neurology department of five hospitals in Shanghai from Jun. 2007 to Feb. 2008 were recruited . All the patients were respectively diagnosed by brain CT, CTA, MRI, MRA and TCD. Laboratory data included urinary microalbumin-to-creatinine ratio (ACR), routine urinalysis, fasting plasma glucose, 2-hour-postprandial plasma glucose, Scr, uric acid, etc. All the serum creatinine samples were uniformly tested in central laboratory of Shanghai Ruijin Hospital.Glomendar filtration rate (GFR) was estimated by complicated MDRD equation and CKD stage was classified according to K/DOQI guidelines. ResultsA total of 1014 hospitalized patients with cerebrovascular diseases were enrolled during the observation period, with M/F ratio of 559/455 and mean age of (68.56±12.17) years. Cerebrovascular diseases included ischemic stroke (708 cases), hemorrhagic stroke (197 cases) and transient cerebral ischemie attack (TIA) (109 cases). Microalbuminuria (MAU) was detected in 11.2%, while 24.8% patients had proteinuria. The prevalence of CKD was 47.7%. The percentage of these inpatients in CKD stage 1 to 5 was approximately 6.90%, 14.69%, 21.60%, 2.56% and 1.97% respectively. The Logistic regression model showed that the risk factors of short-term (<30 days) prognosis were albuminuria, hyperglycemia (fast glucose) and anemia. ConclusionsThe prevalence of CKD in inpatients with cerebrovascular diseases was 47.7% in Shanghai. It is significant to evaluate CKD among patients with cerebrovascular diseases, especially to use the screening of ACR in the early stage.

Microarray analysis of DHPG-induced rat hippocampal slice epileptic seizure model / 上海交通大学学报（医学版）

Objective To investigate the gene expression pattern of metabotropic glutamate receptor- Ⅰ ( mGluR-Ⅰ ), D-p-hydroxyphenylglycine (DHPG) -induced rat hippocampal slice epileptic seizure model. Methods In vitro rat hippocampal sclice was continously perfused with artificial cerebrospinal fluid containing 50 μmol DHPG, and epileptic seizure model was established (DHPG group, n = 3). cDNA microarray chip was applied to explore the gene expression pattern in DHPG group, the differentially expressed genes were screened in comparison with control group ( n = 3), and functional classification analysis was conducted. Results There were 206 up-regulated genes and 489 down-regulated genes, among which 67 up-regulated genes and 86 down-regulated genes differentially expressed by 1.5 fold, 6 up-regulated genes differentially expressed by more than 2.0 folds, and 25 down-regulated genes differentially expressed by less than 0.5 fold. Functional classification analysis revealed that differentially expressed gene function involved in protein binding (19 genes), molecular function, calcium ion binding and nucleotide binding. Conclusion Epileptic seizure and roles of mGluR-Ⅰ agonist may be related to various genes, which is a complicated process. This experiment provides evidences for further researches.

Advance of the study on LRRK2 gene in Parkinson's disease / 中华医学遗传学杂志

The leucine-rich repeat kinase2 (LRRK2) has been identified to be the gene causing autosomal dominant inherited Parkinson's disease(PD)8. The clinical features of this type of PD are similar to those of idiopathic PD, but the pathological changes are diverse. The mutation types and frequencies of the LRRK2 distribute unevenly in different populations. LRRK2 is a large complex protein with multiple functions and expresses widely in human body. Sequence alignment shows that LRRK2 might be a multiple function kinase for substrate phosphorylation and might also act as a scaffolding protein. Further study on the physiological function and pathogenic mechanism of LRRK2 will help to find out the possible pathogenesis and new treatment for PD.

Clinical features and mutation analysis of LRRK2 gene in patients with autosomal dominant familial Parkinson's disease / 中华神经科杂志

Objective To investigate the clinical features and LRRK2 gene mutation in patients with autosomal dominant familial Parkinson's disease (PD). Methods The clinical features of 16 autosomal dominant familial PD probands were analyzed in terms of age at onset, onset symptoms, UPDRS scores, response to the levodopa treatment and drug-induced dyskinesia. The LRRK2 gene exons 5,13,31,32,35,37,41 and 48 of 16 probands were sequenced after polymerase chain reaction. The novel mutation was further screened in 24D sporadic PD patients and 214 controls using PCR-RFLP for the genotypo frequency analysis. Results Clinically, most of 16 probands had late-onset age. Resting tremor (9patients, 56. 25%,t=0.558,P=0.679)and bradykinesia (9 patients,56.25%,t=0.369,P=0.454)were common onset symptoms followed by rigidity(6 patients,37.50%,t=1.324,P=0.735)and postural instability(5 patients,31.25%,t=2.369,P=0.956).Majority of them had good response to levedopa treatment and rare occurrence of drug-induced dyskinesia. Among the 16 autosomal dominant familial PD probands,6 variants were identified:c.457 T＞C(Leu153Leu),c.1432 G＞T(Asp478Tyr),c.5457 T＞C(Gly1819Gly),c.7153 G＞A(Gly2385Arg),IVS31+28 T＞G and IVS37+162 T＞C. The c.1432G＞T(Asp478Tyr)variant was a novel mutation and it was not detected in 240 sporadic PD patients and 214 controls. The reported mutations associated with the PD, such as Arg1441 Cys/Gly/His, Arg1514Gln, Tyr1699Cys, Ile2012Thr, Gly2019Ser and Ile2020Thr,were not found in our study. Conclusions The autosomal dominant familial PD patients present with classical symptoms of PD and bear the LRRK2 variantsAsp478Tyr and Gly2385Arg.

Therapeutic Potential of ?-Secretase in Alzheimer's Disease / 生物化学与生物物理进展

Alzheimer!s disease (AD) is one of the commonest neurodegenerative diseases affected mainly theelderly. AD is characterized by the formation of neuritic plaque in brain, which is composed mainly of extracellular?amyloid deposion, the A?. A?is deprived from serial hydrolysis of amyloid precursor protein (APP) by twosecretases, the ?and ?-secretase respectively. Alternatively, APP can also be sequential processed by ?-secretaseand ?-secretase, which not only preclude the formation of A?, but also generate a large ectodomain (sAPP?) whohas several neuroprotective properties. Thus the secondary processing pathway has become the focus of ADresearch. Many results have indicated that members of the adamalysin family of proteins, mainly the ADAM 10,ADAM 17 and ADAM 9, fulfill some of the criteria required of ?-secretase. Here the biological characteristics of?-secretase, its activity regulation and its potential function as targets for the treatment of AD were summerized.

COGNITIVE AND MOTOR OUTCOME AFTER LONG-TERM GLOBUS PALLIDUS EXTERNA DEEP BRAIN STIMULATION TO TRANSGENIC HUNTINGTON'S DISEASE RAT / 神经解剖学杂志

In this study, we treated transgenic Huntington's disease (tgHD) model rat with deep brain stimulation (DBS) and evaluated the cognitive and motor outcome. The results showed that the surgery of implanting electrode improved cognition, increased correct rate and decreased response bias in choice reaction time (CRT) task, with similar extent on various genotypes. After long-term DBS to globus pallidus externa( GPe), correct rate was enhanced. The enhancement was genotype related. Additionally, the motor time and reaction time in CRT task reflecting the movement initiation kept the same value, but the chorea-form movement of homozygous rats was rectified prominently after the treatment of DBS. The present results demonstrated that the operation of long-term DBS to globus pallidus externa can improve the cognition and motor outcome of tgHD rats, which implied DBS operation might shed light on HD patients in the future.

Relationship between motor complications of Parkinson's disease and phosphorylated GluR1Ser845 / 中华神经科杂志

Objective To explore the relationship between motor complications of Parkinson's disease(PD)with chronic L-dopa treatment and striatal phosphorylated GluR1Ser845.Methods The hemi-parkinsonian rat model was produced by injecting stereotaxically 6-OHDA to right medial forebrain bundle(MFB).Then the hemi-parkinsonian rat was treated intraperitoneally with L-dopa methylester(25 mg?kg-1?d-1,twice one day)for 22 days and rotational duration and frequency of off period were respectively estimated.After they were sacrificed,their subcellualr distribution of GluR1 and GluR1Ser845 phosphorylation was observed with immunofluorescence and Western blot.Results After the chronic treatment with L-dopa methylester,PD rats displayed shortened rotational duration and increased frequency of off period,which was similar to fluctuations of the symptoms and on-off phenomenon in PD patients.In the lesioned striatum of PD rats,the amount of GluR1 and phosphorylated GluR1Ser845 in striatal membrane was reduced to 73.0%?4.8% and 42.0%?5.6%,respectively,compared with those non-lesioned.After chronic treatment of PD rats with L-dopa,the amount of GluR1 and phosphorylated GluR1Ser845 in striatal membranes were increased to 104.0%?5.5% and 112.0%?3.4%.These unique changes occurred only in parvalbumin-positive interneurons.Conclusions These findings suggest that subcellular distribution and phosphorylation state of GluR1Ser845 in parvalbumin-positive interneurons may play a significant role in the pathogenesis of motor complications of chronic L-dopa treatment for PD.

Open-label and non-randomized study of therapeutic effect of amantadine monotherapy and concomitant amantadine with salvia miltiorrhiza compound or selegiline on early Parkinson's disease / 中国康复理论与实践

@# Objective To assess the clinical efficacy and safety of amantadine monotherapy and concomitant amantadine with salvia miltiorrhiza compound or selegiline of the treatment of Parkinson's disease.Methods The clinical trial was performed in the multicenter, open label study. Amantadine group: 35 cases, amantadine plus salvia miltiorrhiza compound group: 34 cases and amantadine plus selegiline group: 29 cases. The clinical efficacy had been assessed with modified Webster scale (WR) and motor dysfunction rating scale for Parkinson's disease (MDRSPD) with interval of two months for one year. The safety data included blood glucose, hepatic and renal function tests, blood and urine routine tests.Results The clinical improved rates were 42.9% (WR) and 37.1% (MDRSPD) in amantadine group, respectively. The clinical score was improved in 34.2% (WR) and 26.5% (MDRSPD) in amantadine plus salvia miltiorrhiza compound group, respectively. The clinical improvement was 51.1% (WR)and 48.3% (MDRSPD) in amantadine plus selegiline group, respectively. There were no significant differences among these three groups (t-test,P>0.05). The clinical marked efficacy rates in assessment of MDRSPD were 2.8% in amantadine group, 11.8% in amantadine plus salvia miltiorrhiza compound group and 27.6% in amantadine plus selegiline group, respectively. There was significant difference between amantadine group and amantadine plus selegiline group, but no significant difference between amantadine group and amantadine plus salvia miltiorrhiza compound group. The adverse event rates were 27.8% in amantadine group, 8.8% in amantadine plus salvia miltiorrhiza compound group and 31.0% in amantadine plus selegiline group, respectively. All these events were mild, of short duration and resolved without treatment. Conclusion There was some efficacy rate in all three groups. Comparing with amantadine group, there was higher marked efficacy rate in amantadine plus selegiline group.

C-Jun N-terminal kinase pathway and neurodegenerative disease / 中国药理学通报

c-Jun N-terminal kinases(JNKs)play an integral role in neuronal death in multiple cell lines following a wide variety of stimuli and in a number of physiological functions which have been recognized as important enzymes in cellular function.JNK has been implicated in several neurodegenerative diseases.Data are emerging to extend the understanding of the JNK signaling and confirm the possibility that targeting JNK signaling may offer an effective therapy for pathological conditions in the near future.Because of the involvement of JNK in neuronal diseases,the inhibition of this enzyme is an attractive therapeutic target.