Activities of daily living and lesion position among multiple sclerosis patients by Bayes network

Magnetic resonance imaging is a highly sensitive approach for diagnosis of multiple sclerosis, and T2-weighted images can reveal lesions in the cerebral white matter, gray matter, and spinal cord. However, the lesions have a poor correlation with measurable clinical disability. In this study, we performed a large-scale epidemiological survey of 238 patients with multiple sclerosis in eleven districts by network member hospitals in Shanghai, China within 1 year. The involved patients were scanned for position and size of lesions by MRI. Results showed that lesions in the cerebrum, spina cord, or supratentorial position had an impact on the activities of daily living in multiple sclerosis patients, as assessed by the Bayes network. On the other hand, brainstem lesions were very unlikely to influence the activities of daily living, and were not associated with the position of lesion, patient＇s gender, and patient＇s living place.

THE EFFECTS OF DEPRENYL AND 1-METHYL-4-PHENYL-1, 2, 3, 6-TETRAHYDROPYRIDINE (MPTP) ON 2-DEOXYGLUCOSE UPTAKE IN THE MOUSE BRAIN

~3H-2-deoxyglucose (2-DG) autoradiographic technique was used to study the ef feets of a monoamine-oxidase-B (MAO-B) inhibitor deprenyl and the neurotoxin Ⅰ-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) on 2-DG uptake in the mouse brain. Following MPTP intoxication, 2-DG uptake was increased in the substantia nigra and lo(?)us ceruleus. At the same time, obvious abnormal behavior of the animals was induced. In the mice pretreated with deprenyl, 2-DG uptake was similar to that of control animal. Ab normal behavior. though present, was significantly milder than in mice given MPTP alone. It is concluded that MPTP interferes with the glucose metabolism in the substantia nigra and locus ceruleus and induces remarkable abnormal behavioral syndrome of mice. These deleterious effects can be blocked by pretreatment with deprenyl.

PROTECTIVE ACTION OF BUDIPINE AGAINST MPTP NEUROTOXICITY

Mice treated with large dose of MPTP showed a reduction in the levels of DA, 5-HT and their metabolites in the striatum. The average levels as compared with the control were reduced by 94% for DA (P【0.001), 61% for DOPAC (P【0.05), 65% for HVA (P【0.01). 5-HT and 5-HIAA were lower than detection limits. In mice pretreated with budipine, although the striatal dopamine level was also reduced, mean DA and 5-HT levels were significantly higher than those in mice given MPTP alone. This result suggested that budipine can partially prevent the MPTP neurotoxicity.

Transcranial focused ultrasound stimulation reduces vasogenic edema after middle cerebral artery occlusion in mice

Blood-brain barrier(BBB)disruption underlies the vasogenic edema and neuronal cell death induced by acute ischemic stroke.Reducing this disruption has therapeutic potential.Transcranial focused ultrasound stimulation has shown neuromodulatory and neuroprotective effects in various brain diseases including ischemic stroke.Ultrasound stimulation can reduce inflammation and promote angiogenesis and neural circuit remodeling.However,its effect on the BBB in the acute phase of ischemic stroke is unknown.In this study of mice subjected to middle cerebral artery occlusion for 90 minutes,low-intensity low-frequency(0.5 MHz)transcranial focused ultrasound stimulation was applied 2,4,and 8 hours after occlusion.Ultrasound stimulation reduced edema volume,improved neurobehavioral outcomes,improved BBB integrity(enhanced tight junction protein ZO-1 expression and reduced IgG leakage),and reduced secretion of the inflammatory factors tumor necrosis factor-αand activation of matrix metalloproteinase-9 in the ischemic brain.Our results show that low-intensity ultrasound stimulation attenuated BBB disruption and edema formation,which suggests it may have therapeutic use in ischemic brain disease as a protector of BBB integrity.

Leukoaraiosis is associated with clinical symptom severity,poor neurological function prognosis and stroke recurrence in mild intracerebral hemorrhage:a prospective multi-center cohort study

Leukoaraiosis(LA)results from ischemic injury in small cerebral vessels,which may be attributable to decreased vascular density,reduced cerebrovascular angiogenesis,decreased cerebral blood flow,or microcirculatory dysfunction in the brain.In this study,we enrolled 357 patients with mild intracerebral hemorrhage(ICH)from five hospitals in China and analyzed the relationships between LA and clinical symptom severity at admission,neurological function prognosis at 3 months,and 1-year stroke recurrence.Patients were divided into groups based on Fazekas scale scores:no LA(n=83),mild LA(n=64),moderate LA(n=98)and severe LA(n=112).More severe LA,larger hematoma volume,and higher blood glucose level at admission were associated with more severe neurological deficit.More severe LA,older age and larger hematoma volume were associated with worse neurological function prognosis at 3 months.In addition,moderate-to-severe LA,admission glucose and symptom-free cerebral infarction were associated with 1-year stroke recurrence.These findings suggest that LA severity may be a potential marker of individual ICH vulnerability,which can be characterized by poor tolerance to intracerebral attack or poor recovery ability after ICH.Evaluating LA severity in patients with mild ICH may help neurologists to optimize treatment protocols.This study was approved by the Ethics Committee of Ruijin Hospital Affiliated to Shanghai Jiao Tong University(approval No.12)on March 10,2011.

MADOPAR-INDUCED DYSKINESIA IN 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE (MPTP) HEMIPARKINSONIAN MONKEY MODEL

Infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the right common carotid artery produced hemiparkinsonian syndrome on contralateral limbs in 5 rhesus monkeys. The hemiparkinsonian syndrome produced responded to madopar medication and the circling motion changed from toward the MPTP-treated side to away from the MPTP-treated side. Long term use of madopar developed a peak-dose dyskinesia of the face and limbs at the contralateral side. The toxic effect of MPTP was confirmed biochemically by reduction of nigrostriatal DA and histologically by degeneration of nigral neurons on the MPTP-treated side. It is concluded that this hemiparkinsonian monkey model will be of value in the elucidation of the neural mechanism underlying L-DOPA or DA agonists induced dyskinesia in Parkinson’s disease and in the search for newer methods of treatment which would produce less dyskinesia.

E674Q(Shanghai APP mutant),a novel amyloid precursor protein mutation,in familial late-onset Alzheimer's disease

Identified as the pathogenic genes of Alzheimer's disease(AD),APP,PSEN1,and PSEN2 mainly lead to early-onset AD,whose course is more aggressive,and atypical symptoms are more common than sporadic AD.Here,a novel missense mutation,APP E674Q(also named“Shanghai APP”),was detected in a Chinese index patient with typical late-onset AD(LOAD)who developed memory decline in his mid-70s.The results from neuroimaging were consistent with AD,where widespread amyloidβdeposition was demonstrated in 18 F-florbetapir Positron Emission Tomography(PET).APP E674Q is close to theβ-secretase cleavage site and the well-studied Swedish APP mutation(KM670/671NL),which was predicted to be pathogenic in silico.Molecular dynamics simulation indicated that the E674Q mutation resulted in a rearrangement of the interaction mode between APP and BACE1 and that the E674Q mutation was more prone to cleavage by BACE1.The in vitro results suggested that the E674Q mutation was pathogenic by facilitating the BACE1-mediated processing of APP and the production of Aβ.Furthermore,we applied an adeno-associated virus(AAV)-mediated transfer of the human E674Q mutant APP gene to the hippocampi of two-month-old C57Bl/6 J mice.AAV-E674Q-injected mice exhibited impaired learning behavior and increased pathological burden in the brain,implying that the E674Q mutation had a pathogenicity that bore a comparison with the classical Swedish mutation.Collectively,we report a strong amyloidogenic effect of the E674Q substitution in AD.To our knowledge,E674Q is the only pathogenic mutation within the amyloid processing sequence causing LOAD.

Histone deacetylase 6 delays motor neuron degeneration by ameliorating the autophagic flux defect in a transgenic mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis （ALS） is a fatal neurodegenerative disorder characterized by the selective loss of motor neurons. Abnormal protein aggregation and impaired protein degradation are believed to contribute to the pathogenesis of this disease. Our previous studies showed that an autophagic flux defect is involved in motor neuron degeneration in the SOD1G93A mouse model of ALS. Histone deacetylase 6 （HDAC6） is a class II deacetylase that promotes autophagy by inducing the fusion of autophagosomes to lysosomes. In the present study, we showed that HDAC6 expression was decreased at the onset of disease and became extremely low at the late stage in ALS mice. Using lentivirus-HDAC6 gene injection, we found that HDAC6 overexpression prolonged the lifespan and delayed the motor neuron degeneration in ALS mice. Moreover, HDAC6 induced the formation of autolysosomes and accelerated the degradation of SOD1 protein aggregates in the motor neurons of ALS mice. Collectively, our results indicate that HDAC6 has neuroprotective effects in an animal model of ALS by improving the autophagic flux in motor neurons, and autophagosome-lysosome fusion might be a therapeutic target for ALS.

Hemiballism-hemichorea induced by ketotic hyperglycemia: case report with PET study and review of the literature

Hemiballism-hemichorea(HB-HC)is commonly used to describe the basal ganglion dysfunction in non-ketotic hyperglycemic elderly patients.Here we report two elderly female patients with acute onset of involuntary movements induced by hyperglycemia with positive urine ketones.We described the computed tomography and magnetic resonance imaging findings in these two patients,which is similar to that of non-ketotic hyperglycemic HB-HC patients.FDG-PET was performed and the glucose metabolism in the corresponding lesion in these two patients was contradictory with each other.We tried to clarify the underlying mechanisms of HB-HC and explain the contradictory neuroradiological findings in FDG-PET as being performed at different clinical stages.

Freezing of gait in Parkinson’s disease: pathophysiology, risk factors and treatments

Background Freezing of gait(FOG)is a common,disabling symptom of Parkinson’s disease(PD),but the mechanisms and treatments of FOG remain great challenges for clinicians and researchers.The main focus of this review is to summarize the possible mechanisms underlying FOG,the risk factors for screening and predicting the onset of FOG,and the clinical trials involving various therapeutic strategies.In addition,the limitations and recommendations for future research design are also discussed.Main body In the mechanism section,we briefly introduced the physiological process of gait control and hypotheses about the mechanism of FOG.In the risk factor section,gait disorders,PIGD phenotype,lower striatal DAT uptake were found to be independent risk factors of FOG with consistent evidence.In the treatment section,we summarized the clinical trials of pharmacological and non-pharmacological treatments.Despite the limited effectiveness of current medications for FOG,especially levodopa resistant FOG,there were some drugs that showed promise such as istradefylline and rasagiline.Non-pharmacological treatments encompass invasive brain and spinal cord stimulation,noninvasive repetitive transcranial magnetic stimulation(rTMS)or transcranial direct current stimulation(tDCS)and vagus nerve stimulation(VNS),and physiotherapeutic approaches including cues and other training strategies.Several novel therapeutic strategies seem to be effective,such as rTMS over supplementary motor area(SMA),dual-site DBS,spinal cord stimulation(SCS)and VNS.Of physiotherapy,wearable cueing devices seem to be generally effective and promising.Conclusion FOG model hypotheses are helpful for better understanding and characterizing FOG and they provide clues for further research exploration.Several risk factors of FOG have been identified,but need combinatorial optimization for predicting FOG more precisely.Although firm conclusions cannot be drawn on therapeutic efficacy,the literature suggested that some therapeutic strategies showed promise.

The development prospection of HDAC inhibitors as a potential therapeutic direction in Alzheimer’s disease

Alzheimer’s disease(AD)is a chronic neurodegenerative disease,which is associated with learning and memory impairment in the elderly.Recent studies have found that treating AD in the way of chromatin remodeling via histone acetylation is a promising therapeutic regimen.In a number of recent studies,inhibitors of histone deacetylase(HDACs)have been found to be a novel promising therapeutic agents for neurological disorders,particularly for AD and other neurodegenerative diseases.Although HDAC inhibitors have the ability to ameliorate cognitive impairment,successful treatments in the classic AD animal model are rarely translated into clinical trials.As for the reduction of unwanted side effects,the development of HDAC inhibitors with increased isoform selectivity or seeking other directions is a key issue that needs to be addressed.The review focused on literatures on epigenetic mechanisms in recent years,especially on histone acetylation in terms of the enhancement of specificity,efficacy and avoiding side effects for treating AD.

Dynamic changes of CX3CL1/CX3CR1 axis during microglial activation and motor neuron loss in the spinal cord of ALS mouse model

Background:Neuron-microglia communication plays a crucial role in the motor neurons(MNs)death in amyotrophic lateral sclerosis(ALS).Neurons can express chemokine(C-X3-C motif)ligand 1(CX3CL1),which mediates microglial activation via interacting with its sole receptor CX3CR1 in microglia.In the present study,we aimed to investigate the dynamic changes of CX3CL1/CX3CR1 axis during microglial activation and MNs loss in SOD1G93A mouse model of ALS.Methods:qPCR,western blot and immunofluorescent staining were used to examine the mRNA and protein levels and localization of CX3CL1/CX3CR1 in the anterior horn region of spinal cord in both SOD1G93A mice and their agematched wild type(WT)littermates at 40,60,90 and 120 days of age.The M1/M2 microglial activation in the spinal cord tissues of SOD1G93A mice and WT mice were evaluated by immunofluorescent staining of M1/M2 markers and further confirmed by qPCR analysis of M1/M2-related cytokines.Results:The immunofluorescent staining revealed that CX3CL1 was predominately expressed in MNs,while CX3CR1 was highly expressed in microglia in the anterior horn region of spinal cord.Compared with age-matched WT mice,CX3CL1 mRNA level was elevated at 40 days but decreased at 90 and 120 days in the anterior horn region of spinal cords in ALS mice.Consistently,CX3CR1 mRNA level was increased at 90 and 120 days.Western blot assay further confirmed the dynamic changes of CX3CL1/CX3CR1 axis in ALS mice.Additionally,the levels of M1/M2 markers of microglia and their related cytokines in the anterior horn region of spinal cord in ALS mice were increased at 90 and 120 days.Moreover,while M1-related cytokines in ALS mice were persistently increased at 120 days,the upregulated M2-related cytokines started to decline at 120 days,suggesting an altered microglial activation.Conclusions:Our data revealed the dynamic changes of CX3CL1/CX3CR1 axis and an imbalanced M1/M2 microglial activation during ALS pathological progression.These findings may help identify potential molecular targets for ALS therapy.

Increased prediction value of biomarker combinations for the conversion of mild cognitive impairment to Alzheimer's dementia

Background:Progression of mild cognitive impairment(MCI)to Alzheimer's disease(AD)dementia can be predicted by clinical features and a combination of biomarkers may increase the predictive power.In the present study,we investigated whether the combination of olfactory function and plasma neuronal-derived exosome(NDE)Aβ1-42 can best predict progression to AD dementia.Methods:Eighty-seven MCI patients were enrolled and received cognitive assessment at 2-year and 3-year follow-up to reevaluate cognition.In the meanwhile,80 healthy controls and 88 AD dementia patients were enrolled at baseline as well to evaluate the diagnose value in cross-section.Olfactory function was evaluated with the sniffin sticks(SS-16)and Aβ142 levels in NDES were determined by ELISA.Logistic regression was performed to evaluate the risk factors for cognitive decline in MCI at 2-year and 3-year revisits.Results:In the cross cohort,lower SS-16 scores and higher AB142 levels in NDES were found in MCI and AD dementia compared to healthy controls.For the longitudinal set,8 MCI individuals developed AD dementia within 2 years,and 16 MCI individuals developed AD dementia within 3 years.The two-parameter combination of SS-16 scores and Aβ1-42 level in NDEs showed better prediction in the conversion of MCI to AD dementia at 2-year and 3-year revisits.Moreover,after a 3-year follow-up,SS-16 scores also significantly predicted the conversion to AD dementia,where lower scores were associated with a 10-fold increased risk of developing AD dementia(p=0.006).Similarly,higher AB1-42 levels in NDES in patients with MCI increased the risk of developing AD dementia by 8.5-fold(p=0.002).Conclusion:A combination of two biomarkers NDE AB1-42 and SS-16 predicted the conversion of MCI to AD dementia more accurately.These findings have critical implications for understanding the pathophysiology of AD dementia and for developing preventative treatments for cognitive decline.

Subthalamic nucleus deep brain stimulation for Parkinson’s disease: 8 years of follow-up

Objective:The short-term benefits of bilateral stimulation of the subthalamic nucleus(STN)in patients with advanced Parkinson’s disease(PD)are well documented,but long-term benefits are still uncertain.The aim of this study is to evaluate the outcome of 8 years of bilateral STN stimulation to PD patients.Methods:In this study,31 consecutive PD patients were treated with bilateral STN stimulation.Their functional status was measured using the Activities of Daily Living section of the Unified Parkinson’s Disease Rating Scale(UPDRS-ADL)at drug on(with medication)and drug off(without medication)states preoperatively and at 1,5,and 8 years postoperatively.In addition,Levodopa equivalent doses and stimulation parameters were also assessed.Results:After 8 years of STN stimulation,the UPDRS-ADL scores were improved by 4%at drug off status(P>0.05)and 22%at drug on status(P<0.05)compared with baseline;the levodopa daily doses were reduced by 28%(P<0.05)compared with baseline;the stimulation voltage and pulse width were not changed,but the stimulation frequency was decreased remarkably compared with the 5 years of follow-up.Adverse events were observed in 6 patients,including misplacement of the electrode and skin erosion requiring further surgery.All events were resolved without permanent sequelae.2 patients died of aspiration pneumonia 6 and 7 years after surgery.Conclusions:The marked improvement in UPDRS-ADL scores were still observed after 8 years of bilateral STN stimulation with medication.

Objective assessment of bradykinesia in Parkinson’s disease using evolutionary algorithms:clinical validation

Background:There is an urgent need for developing objective,effective and convenient measurements to help clinicians accurately identify bradykinesia.The purpose of this study is to evaluate the accuracy of an objective approach assessing bradykinesia in finger tapping(FT)that uses evolutionary algorithms(EAs)and explore whether it can be used to identify early stage Parkinson’s disease(PD).Methods:One hundred and seven PD,41 essential tremor(ET)patients and 49 normal controls(NC)were recruited.Participants performed a standard FT task with two electromagnetic tracking sensors attached to the thumb and index finger.Readings from the sensors were transmitted to a tablet computer and subsequently analyzed by using EAs.The output from the device(referred to as"PD-Monitor")scaled from−1 to+1(where higher scores indicate greater severity of bradykinesia).Meanwhile,the bradykinesia was rated clinically using the Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale(MDS-UPDRS)FT item.Results:With an increasing MDS-UPDRS FT score,the PD-Monitor score from the same hand side increased correspondingly.PD-Monitor score correlated well with MDS-UPDRS FT score(right side:r=0.819,P=0.000;left side:r=0.783,P=0.000).Moreover,PD-Monitor scores in 97 PD patients with MDS-UPDRS FT bradykinesia and each PD subgroup(FT bradykinesia scored from 1 to 3)were all higher than that in NC.Receiver operating characteristic(ROC)curves revealed that PD-Monitor FT scores could detect different severity of bradykinesia with high accuracy(≥89.7%)in the right dominant hand.Furthermore,PD-Monitor scores could discriminate early stage PD from NC,with area under the ROC curve greater than or equal to 0.899.Additionally,ET without bradykinesia could be differentiated from PD by PD-Monitor scores.A positive correlation of PD-Monitor scores with modified Hoehn and Yahr stage was found in the left hand sides.Conclusions:Our study demonstrated that a simple to use device employing classifiers derived from EAs could not only be used to accurately measure different severity of bradykinesia in PD,but also had the potential to differentiate early stage PD from normality.

Therapeutic application of exosomes in ischaemic stroke

Ischaemic stroke is a leading cause of long-term disability in the world,with limited effective treatments.Increasing evidence demonstrates that exosomes are involved in ischaemic pathology and exhibit restorative therapeutic effects by mediating cell–cell communication.The potential of exosome therapy for ischaemic stroke has been actively investigated in the past decade.In this review,we mainly discuss the current knowledge of therapeutic applications of exosomes from different cell types,different exosomal administration routes,and current advances of exosome tracking and targeting in ischaemic stroke.We also briefly summarised the pathology of ischaemic stroke,exosome biogenesis,exosome profile changes after stroke as well as registered clinical trials of exosome-based therapy.

Functional Connectivity-Based Modelling Simulates SubjectSpecific Network Spreading Effects of Focal Brain Stimulation

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.

The predictive value of SS-16 in clinically diagnosed Parkinson’s disease patients:comparison with ^(99m)Tc-TRODAT-1 SPECT scans

Background:Dopamine transporter based imaging has high diagnostic performance in distinguishing patients with Parkinson’s disease(PD)from patients with non-Parkinsonian syndromes.Our previous study indicated that the“Sniffin’Sticks”odor identification test(SS-16)acts as a valid instrument for olfactory assessment in Chinese PD patients.The aim of the study was to compare the efficacy of the two methods in diagnosing PD.Methods:Fifty-two PD patients were involved in this study and underwent single photon emission computed tomography(SPECT)imaging using the labeled dopamine transporter radiotracer ^(99)mTc-TRODAT-1 to assess nigrostriatal dopaminergic function.Olfactory function was assessed with the“Sniffin’Sticks”odor identification test(SS-16)in all patients who received DAT-SPECT scanning.Statistical analysis(SPSS version 21)was carried out to determine the diagnostic accuracy of SS-16 as well as its correlation with ^(99)mTc-TRODAT-1 SPECT,its positive predictive value(PPV),and negative predictive value(NPV).Results:We identified a negative correlation between SS-16 and DAT SPECT(Kappa=0.269,p=0.004).By using the ^(99)mTc-TRODAT-1 uptake results as the gold standard,the sensitivity and specificity of SS-16 was 56.8 and 37.5%,respectively.Furthermore,the negative and positive predictive values were calculated as 13.6 and 83.3%,respectively.Conclusions:SS-16 would not be used as a diagnostic tool for early stage PD patients.Negative results of SS-16 would not exclude the diagnosis of PD.Further tests are needed for validation.

The efficacy and safety of pramipexole ER versus IR in Chinese patients with Parkinson’s disease: a randomized, double-blind, double-dummy, parallel-group study

Objective:To evaluate the non-inferiority of pramipexole extended-release(ER)versus immediate-release(IR)in Chinese patients with Parkinson’s disease(PD)in a double-blind,randomized,parallel-group study.Methods:Subjects were Chinese patients with idiopathic PD with diagnosis≥2 years prior to trial,age≥30 years old at diagnosis,and Modified Hoehn and Yahr score 2-4 during‘on’-time.Subjects received treatment with pramipexole ER(n=234)or IR(n=239).Non-inferiority was based on the primary endpoint,the change from baseline to end of maintenance(week 18)in the UPDRS(Parts II+III)total score.Results:For the primary endpoint,the adjusted mean changes(standard error)of UPDRS Parts II+III at week 18 were−13.81(0.655)and−13.05(0.643)for ER and IR formulations,respectively,using ANCOVA adjusted for treatment and centre(fixed effect)and baseline(covariate).The adjusted mean between group difference was 0.8 for the 2-sided 95%CI(−1.047,2.566).Since the lower limit of the 2-sided 95%CI(−1.047)for treatment difference was higher than the non-inferiority margin of−4,non-inferiority between pramipexole ER and IR was demonstrated.The incidence of adverse events(AEs)was 68.8%in the ER arm and 73.6%in the IR arm with few severe AEs(ER:2.1%;IR:3.8%).Conclusion:Based on the UPDRS II+III score,pramipexole ER was non-inferior to pramipexole IR.The safety profiles of pramipexole ER and IR were similar.These results were based on comparable mean daily doses and durations of treatment for both formulations.

Dopamine Agonists Exert Nurrl-inducing Effect in Peripheral Blood Mononuclear Cells of Patients with Parkinson＇s Disease

Background： Nurrl plays an essential role in the development, survival, and function maintenance ofmidbrain dopaminergic （DA） neurons, and it is a potential target for Parkinson＇s disease （PD）. Nurrl mRNA can be detected in peripheral blood mononuclear cells （PBMCs）, but whether there is any association of altered Nurrl expression in PBMC with the disease and DA drug treatments remains elusive. This study aimed to measure the Nurrl mRNA level in PBMC and evaluate the effect of Nurrl expression by DA agents in vivo and in vitro. Methods： The mRNA levels of Nurrl in PBMC of four subgroups of 362 PD patients and 193 healthy controls （HCs） using real-time polymerase chain reaction were measured. The nonparametric Mann-Whitney U-test and Kruskal-Wallis test were performed to evaluate the differences between PD and HC, as well as the subgroups of PD. Multivariate linear regression analysis was used to evaluate the independent association of Nurrl expression with Hoehn and Yahr scale, age, and drug treatments. Besides, the Nurrl expression in cultured PBMC was measured to determine whether DA agonist pramipexole affects its mRNA level. Results： The relative Nurrl mRNA levels in DA agonists treated subgroup were significant higher than those in recent-onset cases without any anti-PD treatments （de novo） （P 〈 0.001 ） and HC groups （P 〈 0.010）, respectively. Furthermore, the increase in Nurr I mRNA expression was seen in DA agonist and L-dopa group. Multivariate linear regression showed DA agonists, L-dopa, and DA agonists were independent predictors correlated with Nurrl mRNA expression level in PBMC. In vitlv, in the cultured PBMC treated with 10 μmol/L pramipexole, the Nurrl mRNA levels were significantly increased by 99.61%, 71.75%, 73.16% in 2, 4, and 8 h, respectively （P 〈 0.001 ）. Conclusions： DA agonists can induce Nurrl expression in PBMC, and such effect may contribute to DA agonists-mediated neuroprotection on DA neurons.