Monoamine Oxidase-B Inhibitor Rasagiline Effects on Motor and Non-Motor Symptoms in Individuals with Parkinson’s Disease: A Systematic Review and Meta-Analysis

Objective: In the manuscript titled Monoamine Oxidase-B Inhibitor Rasagiline Effects on Motor and Non-Motor Symptoms in Individuals with Parkinsons Disease: A Systematic Review and Meta-Analysis, the objective was to conduct a systematic review with meta-analysis to investigate the effects that Rasagiline has on motor and non-motor symptoms in individuals with PD. Introduction: Rasagiline is a second-generation monoamine oxidase-B (MAO-B) inhibitor used both as monotherapy and adjunctive therapy for Parkinsons Disease (PD). Methods: A systematic literature search and meta-analysis were performed with randomized control trials that investigated the effects of Rasagiline on motor and non-motor symptoms in individuals with PD. The systematic search was conducted in PubMed, Cochrane, and EBSCO databases. Methodological quality was assessed using the Cochrane Grading Recommendations Assessment, Development and Evaluation approach. Results: Fourteen studies were included in our review. There were trivial to small and statistically significant improvements in motor symptoms for individuals with PD treated with Rasagiline compared to placebo. Non-motor symptoms showed no significant improvement with Rasagiline compared to placebo in five of six meta-analyses. Results were based on very low to moderate certainty of evidence. Conclusion: 1 mg/day Rasagiline significantly improved Parkinsonian motor symptoms in individuals with PD compared with placebo. For all outcomes, the 1 mg/day Rasagiline group was favored over the placebo group.

Liquid Subcutaneous Levodopa-Carbidopa ND0612 Effects on Motor Symptoms in Individuals with Parkinson’s Disease: A Systematic Review and Meta-Analysis

Objective: In the manuscript titled “Liquid subcutaneous Levodopa-Carbidopa ND0612 effects on motor symptoms in individuals with Parkinson’s Disease: A systematic review and meta-analysis”, the objective was to conduct a systematic review with meta-analysis to investigate the effects ND0612 24-hour dosing regimen has on motor symptoms in individuals with Parkinson’s Disease (PD). Introduction: ND0612 is a novel minimally invasive continuous subcutaneous delivery system of liquid Levodopa-Carbidopa being investigated for the treatment of PD in individuals experiencing motor symptoms. Methods: A systematic literature search was conducted in PubMed, Cochrane, and EBSCO databases to identify randomized controlled trials investigating the effects of ND0612 on motor symptoms in individuals with PD. Outcomes included the Unified Parkinson’s Disease Rating Scale (UPDRS) Part II and Part III scores. Methodological quality was assessed using the Cochrane Grading of Recommendations Assessment, Development, and Evaluation approach. Meta-analysis was performed using a random effects model with the DerSimonian and Laird method to estimate the effects of the ND0612 24-hour dosing regimen on UPDRS Part II and Part III scores. Results: Three studies were included in our review. There were statistically significant reductions in UPDRS Part II scores (mean difference (MD) −3.299;95% confidence interval (CI) −3.438, −3.159) and in UPDRS Part III scores (MD −12.695;95% CI −24.428, −0.962) in the ND0612 24-hour dosing regimen. Results were based on very low certainty of evidence. Conclusion: Based on very low certainty evidence, the ND0612 24-hour dosing regimen is effective at improving motor symptoms in individuals with PD. Our findings suggest that ND0612 is more effective at improving UPDRS Part II and Part III scores in individuals with PD than other pharmacological and non-pharmacological treatments, warranting further study.

Progression of motor symptoms in Parkinson’s disease

Parkinson＇s disease （PD） is a chronic progressive neurodegenerative disease that is clinically manifested by a triad of cardinal motor symptoms - rigidity, bradykinesia and tremor - due to loss of dopaminergic neurons. The motor symptoms of PD become progressively worse as the disease advances. PD is also a heterogeneous disease since rigidity and bradykinesia are the major complaints in some patients whereas tremor is predominant in others. In recent years, many studies have investigated the progression of the hallmark symptoms over time, and the cardinal motor symptoms have dif- ferent rates of progression, with the disease usually progressing faster in patients with rigidity and bradykinesia than in those with predominant tremor. The current treatment regime of dopamine-replacement therapy improves motor symptoms and alleviates disability. Increasing the dosage of dopaminergic medication is commonly used to combat the worsening symptoms. However, the drug-induced involuntary body movements and motor complications can significantly contribute to overall disability. Further, none of the currently-available therapies can slow or halt the disease progression. Significant research efforts have been directed towards developing neuroprotective or disease-modifying agents that are intended to slow the progression. In this article, the most recent clinical studies investigating disease progression and current progress on the development of disease-modifying drug trials are reviewed.

Glutamatergic Neurons in the Caudal Zona Incerta Regulate Parkinsonian Motor Symptoms in Mice

Parkinson’s disease(PD)is the second most common and fastest-growing neurodegenerative disorder.In recent years,it has been recognized that neurotransmitters other than dopamine and neuronal systems outside the basal ganglia are also related to PD pathogenesis.However,little is known about whether and how the caudal zona incerta(ZIc)regulates parkinsonian motor symptoms.Here,we showed that specific glutamatergic but not GABAergic ZIc^(VgluT2) neurons regulated these symptoms.ZIc^(VgluT2) neuronal activation induced time-locked parkinsonian motor symptoms.In mouse models of PD,the ZIc^(VgluT2) neurons were hyperactive and inhibition of their activity ameliorated the motor deficits.ZIc^(VgluT2) neurons monosynaptically projected to the substantia nigra pars reticulata.Incerta-nigral circuit activation induced parkinsonian motor symptoms.Together,our findings provide a direct link between the ZIc,its glutamatergic neurons,and parkinsonian motor symptoms for the first time,help to better understand the mechanisms of PD,and supply a new important potential therapeutic target for PD.

Sex modulates the outcome of subthalamic nucleus deep brain stimulation in patients with Parkinson's disease

There are many documented sex differences in the clinical course,symptom expression profile,and treatment response of Parkinson’s disease,creating additional challenges for patient management.Although subthalamic nucleus deep brain stimulation is an established therapy for Parkinson’s disease,the effects of sex on treatment outcome are still unclear.The aim of this retrospective observational study,was to examine sex differences in motor symptoms,nonmotor symptoms,and quality of life after subthalamic nucleus deep brain stimulation.Outcome measures were evaluated at 1 and 12 months post-operation in 90 patients with Parkinson’s disease undergoing subthalamic nucleus deep brain stimulation aged 63.00±8.01 years(55 men and 35 women).Outcomes of clinical evaluations were compared between sexes via a Student’s t-test and within sex via a paired-sample t-test,and generalized linear models were established to identify factors associated with treatment efficacy and intensity for each sex.We found that subthalamic nucleus deep brain stimulation could improve motor symptoms in men but not women in the on-medication condition at 1 and 12 months post-operation.Restless legs syndrome was alleviated to a greater extent in men than in women.Women demonstrated poorer quality of life at baseline and achieved less improvement of quality of life than men after subthalamic nucleus deep brain stimulation.Furthermore,Hoehn-Yahr stage was positively correlated with the treatment response in men,while levodopa equivalent dose at 12 months post-operation was negatively correlated with motor improvement in women.In conclusion,women received less benefit from subthalamic nucleus deep brain stimulation than men in terms of motor symptoms,non-motor symptoms,and quality of life.We found sex-specific factors,i.e.,Hoehn-Yahr stage and levodopa equivalent dose,that were related to motor improvements.These findings may help to guide subthalamic nucleus deep brain stimulation patient selection,prognosis,and stimulation programming for optimal therapeutic efficacy in Parkinson’s disease.

Mechanisms of motor symptom improvement by long-term Tai Chi training in Parkinson’s disease patients

Background:Tai Chi has been shown to improve motor symptoms in Parkinson’s disease(PD),but its long-term effects and the related mechanisms remain to be elucidated.In this study,we investigated the effects of long-term Tai Chi training on motor symptoms in PD and the underlying mechanisms.Methods:Ninety-five early-stage PD patients were enrolled and randomly divided into Tai Chi(n=32),brisk walk-ing(n=31)and no-exercise(n=32)groups.At baseline,6 months and 12 months during one-year intervention,all participants underwent motor symptom evaluation by Berg balance scale(BBS),Unified PD rating-scale(UPDRS),Timed Up and Go test(TUG)and 3D gait analysis,functional magnetic resonance imaging(fMRI),plasma cytokine and metabolomics analysis,and blood Huntingtin interaction protein 2(HIP2)mRNA level analysis.Longitudinal self-changes were calculated using repeated measures ANOVA.GEE(generalized estimating equations)was used to assess factors associated with the longitudinal data of rating scales.Switch rates were used for fMRI analysis.False discovery rate correction was used for multiple correction.Results:Participants in the Tai Chi group had better performance in BBS,UPDRS,TUG and step width.Besides,Tai Chi was advantageous over brisk walking in improving BBS and step width.The improved BBS was correlated with enhanced visual network function and downregulation of interleukin-1β.The improvements in UPDRS were asso-ciated with enhanced default mode network function,decreased L-malic acid and 3-phosphoglyceric acid,and increased adenosine and HIP2 mRNA levels.In addition,arginine biosynthesis,urea cycle,tricarboxylic acid cycle and beta oxidation of very-long-chain fatty acids were also improved by Tai Chi training.Conclusions:Long-term Tai Chi training improves motor function,especially gait and balance,in PD.The underlying mechanisms may include enhanced brain network function,reduced inflammation,improved amino acid metabolism,energy metabolism and neurotransmitter metabolism,and decreased vulnerability to dopaminergic degeneration.Trial registration This study has been registered at Chinese Clinical Trial Registry(Registration number:ChiCTR2000036036;Registration date:August 22,2020).

Deep Clinical Phenotyping of Parkinson’s Disease: Towards a New Era of Research and Clinical Care

Despite recent advances in technology,clinical phenotyping of Parkinson’s disease(PD)has remained relatively limited as current assessments are mainly based on empirical observation and subjective categorical judgment at the clinic.A lack of comprehensive,objective,and quantifiable clinical phenotyping data has hindered our capacity to diagnose,assess patients’conditions,discover pathogenesis,identify preclinical stages and clinical subtypes,and evaluate new therapies.Therefore,deep clinical phenotyping of PD patients is a necessary step towards understanding PD pathology and improving clinical care.In this review,we present a growing community consensus and perspective on how to clinically phenotype this disease,that is,to phenotype the entire course of disease progression by integrating capacity,performance,and perception approaches with state-of-the-art technology.We also explore the most studied aspects of PD deep clinical phenotypes,namely,bradykinesia,tremor,dyskinesia and motor fluctuation,gait impairment,speech impairment,and non-motor phenotypes.

Early morning off in patients with Parkinson's disease:a Chinese nationwide study and a 7-question screening scale

Background:Early morning off(EMO)is a common feature of Parkinson's disease(PD).This study aimed to characterize its clinical features and develop a convenient and pragmatic self-assessment instrument in a Chinese nationwide population.Methods:This study was conducted on 942 PD patients admitted to 55 clinic centers for movement disorders between June 2018 and May 2019 in China.Stepwise logistic regression analyses were performed to determine potential risk factors and the most predictive symptoms of EMO,as well as whether EMO was an independent risk factor of functional dependency in daily life.Based on this,a 7-question scale was derived for EMO screening.Diagnostic accuracy of this scale was assessed from the area under the receiver operative characteristic curve(AUROC)and its 95%confidence intervals(CIs).We further calculated sensitivity,specificity,positive predictive value(PPV),and negative predictive value(NPV)for the optimal cutoff point.Results:EMO occurred in 49.2%of PD patients across all disease stages.We identified 7 symptoms most predictive of EMO,including bradykinesia or rigidity,excessive sweating or salivation,ificulty in turning on or getting out of bed,muscle cramp,fatigue or sleepiness,frozen state or freezing gait,and tremor.The resulting 7-item scale was confirmed to be of good discrimination with a relatively large AUROC of 0.83,a relatively high sensitivity of 75.7%,specificity of 77.5%,PPV of 76.5%,and NPV of 76.7%.Nonideal nighttime sleep,long PD duration,advanced H&Y stages,posture instability gait difficulty-dominant or mixed subtypes,and high levodopa dose were independently associated with increased risk of EMO.EMO patients were at 87%higher(OR=1.87,95%C:1.07-3.32)risk of experiencing functional dependency in daily living compared with their counterparts.Conclusions:We demonstrated that EMO is a common feature for PD patients across all disease stages and put forward an EMO-specific screening card of sufficient accuracy and brevity.Meanwhile,we have thrown some light upon potential determinants and negative health effects of EMO.Our findings may exert great impact on improving the awareness,recognition and management of EMO in PD patients.

Effect of combined scalp and body acupuncture on Parkinson’s disease:A randomized clinical trial

Objective:To observe the therapeutic effect of combined scalp and body acupuncture on the motor symptoms in Parkinson’s disease(PD),and on the score of levodopa equivalent dose(LED).Methods:This is a randomized,single blind trial.Sixty-six patients with PD were randomized into an acupuncture+medication group(33 patients)and a medication group(33 patients).The patients were aware of allocation and the assessors were blinded to group assignment and therapeutic regimen.AntiPD drugs were administered in both groups.In the acupuncture+medication group,scalp and body acupuncture therapy was added.Treatments were applied for 8 weeks.In scalp acupuncture,the anterior oblique line of the vertex-temporal(MS6),lateral line 1 of the vertex(MS8),lateral line 2 of the vertex(MS9),and lower-lateral line of the occiput(MS14)were selected.In the body acupuncture,the acupoints included Bǎihuì(百会GV20),Sìshéncōng(四神聪EX-HN1),and Dàzhuī(大椎GV14),as well as the bilateral Fēngchí(风池GB20),Nèiguān(内关PC6),Hégǔ(合谷LI4),Gānshū(肝俞BL18),Shènshū(肾俞BL23),Yánglíngquán(阳陵泉GB34),Zúsānlǐ(足三里ST36),Fēnglóng(丰隆ST40),Sānyīnjiāo(三阴交SP6),Tàixī(太溪KI3),and Tàichōng(太冲LR3).Before and after treatments,the unified Parkinson’s disease rating scale(UPDRS),3section of the UPDRS(UPDRS-Ⅲ),and motor dysfunction rating scale for Parkinson’s disease(MDRSPD)were scored in the patients.The therapeutic effect of traditional Chinese medicine(TCM)and LED score were compared between both groups.Results:Thirty-three cases were included in data analysis in each group.After treatment,UPDRS scores were(28.77±8.85)and(36.58±10.16)points,UPDRS-Ⅲscores were(12.16±1.97)and(17.47±2.93)points and MDRSPD scores were(15.56±3.31)and(19.13±4.87)points in the acupuncture+medication and medication groups respectively.The UPDRS,UPDRS-Ⅲ,and MDRSPD scores all reduced after treatments in both groups(all P<0.05).All three scores were lower in the acupuncture+medication group than in the medication group(all P<0.05).When examining the therapeutic effects of TCM,the total effective rate was 87.88%in the acupuncture+medication group and 75.76%in the medication group(P<0.05).After treatment,the LED scores were(387.55±146.24)points and(437.42±183.16)points in the acupuncture+medication and medication groups,respectively.The LED dose differences before and after treatment for the acupuncture+medication and medication groups were(40.36±16.33)points and(95.88±35.79)points,respectively.The LED scores in both groups were higher than the pre-treatment scores(P<0.05).However,the post-treatment LED score was lower in the acupuncture+medication group than in the medication group(P<0.05),as was the dose difference before and after treatment(P<0.05).No relevant adverse reaction was found in each group.Conclusion:In addition to anti-PD medication,the scalp and body acupuncture may effectively relieve the motor symptoms of PD and improve the control of LED score.

Drug therapy in patients with Parkinson’s disease

Parkinson`s disease(PD)is a progressive,disabling neurodegenerative disorder with onset of motor and non-motor features.Both reduce quality of life of PD patients and cause caregiver burden.This review aims to provide a survey of possible therapeutic options for treatment of motor and non motor symptoms of PD and to discuss their relation to each other.MAO-B-Inhibitors,NMDA antagonists,dopamine agonists and levodopa with its various application modes mainly improve the dopamine associated motor symptoms in PD.This armentarium of PD drugs only partially influences the onset and occurrence of non motor symptoms.These PD features predominantly result from non dopaminergic neurodegeneration.Autonomic features,such as seborrhea,hyperhidrosis,orthostatic syndrome,salivation,bladder dysfunction,gastrointestinal disturbances,and neuropsychiatric symptoms,such as depression,sleep disorders,psychosis,cognitive dysfunction with impaired execution and impulse control may appear.Drug therapy of these non motor symptoms complicates long-term PD drug therapy due to possible occurrence of drug interactions,-side effects,and altered pharmacokinetic behaviour of applied compounds.Dopamine substituting compounds themselves may contribute to onset of these non motor symptoms.This complicates the differentiation from the disease process itself and influences therapeutic options,which are often limited because of additional morbidity with necessary concomitant drug therapy.