Study on the characteristics of intestinal motility of constipation in patients with Parkinson's disease

BACKGROUND Constipation is one of the most important nonmotor symptoms in Parkinson's disease(PD)patients,and constipation of different severities is closely related to the pathogenesis of PD.PD with constipation(PDC)is considered a unique type of constipation,but its mechanism of formation and factors affecting its severity have been less reported.Understanding the gastrointestinal motility characteristics and constipation classification of PDC patients is essential to guide the treatment of PDC.In this study,the colonic transit test and high-resolution anorectal manometry were used to identify the intestinal motility of PDC to provide a basis for the treatment of PDC.AIM To investigate the clinical classification of PDC,to clarify its characteristics of colonic motility and rectal anal canal pressure,and to provide a basis for further research on the pathogenesis of PDC.METHODS Twenty PDC patients and 20 patients with functional constipation(FC)who were treated at Xuanwu Hospital of Capital Medical University from August 6,2018 to December 2,2019 were included.A colonic transit test and high-resolution anorectal manometry were performed to compare the differences in colonic transit time,rectal anal canal pressure,and constipation classification between the two groups.RESULTS There were no statistically significant differences in sex,age,body mass index,or duration of constipation between the two groups.It was found that more patients in the PDC group exhibited difficulty in defecating than in the FC group,and the difference was statistically significant.The rectal resting pressure,anal sphincter resting pressure,intrarectal pressure,and anal relaxation rate in the PDC group were significantly lower than those in the FC group.The proportion of paradoxical contractions in the PDC group was significantly higher than that in the FC group.There was a statistically significant difference in the type composition ratio of defecatory disorders between the two groups(P<0.05).The left colonic transit time,rectosigmoid colonic transit time(RSCTT),and total colonic transit time were prolonged in PDC and FC patients compared to normal values.The patients with FC had a significantly longer right colonic transit time and a significantly shorter RSCTT than patients with PDC(P<0.05).Mixed constipation predominated in PDC patients and FC patients,and no significant difference was observed.CONCLUSION Patients with PDC and FC have severe functional dysmotility of the colon and rectum,but there are certain differences in segmental colonic transit time and rectal anal canal pressure between the two groups.

Induced pluripotent stem cell-related approaches to generate dopaminergic neurons for Parkinson's disease

The progressive loss of dopaminergic neurons in affected patient brains is one of the pathological features of Parkinson's disease,the second most common human neurodegenerative disease.Although the detailed pathogenesis accounting for dopaminergic neuron degeneration in Parkinson's disease is still unclear,the advancement of stem cell approaches has shown promise for Parkinson's disease research and therapy.The induced pluripotent stem cells have been commonly used to generate dopaminergic neurons,which has provided valuable insights to improve our understanding of Parkinson's disease pathogenesis and contributed to anti-Parkinson's disease therapies.The current review discusses the practical approaches and potential applications of induced pluripotent stem cell techniques for generating and differentiating dopaminergic neurons from induced pluripotent stem cells.The benefits of induced pluripotent stem cell-based research are highlighted.Various dopaminergic neuron differentiation protocols from induced pluripotent stem cells are compared.The emerging three-dimension-based brain organoid models compared with conventional two-dimensional cell culture are evaluated.Finally,limitations,challenges,and future directions of induced pluripotent stem cell–based approaches are analyzed and proposed,which will be significant to the future application of induced pluripotent stem cell-related techniques for Parkinson's disease.

NOX4 exacerbates Parkinson's disease pathology by promoting neuronal ferroptosis and neuroinflammation

Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidation,plays a vital role in the death of dopaminergic neurons.However,the molecular mechanisms underlying ferroptosis in dopaminergic neurons have not yet been completely elucidated.NADPH oxidase 4 is related to oxidative stress,however,whether it regulates dopaminergic neuronal ferroptosis remains unknown.The aim of this study was to determine whether NADPH oxidase 4 is involved in dopaminergic neuronal ferroptosis,and if so,by what mechanism.We found that the transcriptional regulator activating transcription factor 3 increased NADPH oxidase 4 expression in dopaminergic neurons and astrocytes in an 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced Parkinson's disease model.NADPH oxidase 4 inhibition improved the behavioral impairments observed in the Parkinson's disease model animals and reduced the death of dopaminergic neurons.Moreover,NADPH oxidase 4 inhibition reduced lipid peroxidation and iron accumulation in the substantia nigra of the Parkinson's disease model animals.Mechanistically,we found that NADPH oxidase 4 interacted with activated protein kinase Cαto prevent ferroptosis of dopaminergic neurons.Furthermore,by lowering the astrocytic lipocalin-2 expression,NADPH oxidase 4 inhibition reduced 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced neuroinflammation.These findings demonstrate that NADPH oxidase 4 promotes ferroptosis of dopaminergic neurons and neuroinflammation,which contribute to dopaminergic neuron death,suggesting that NADPH oxidase 4 is a possible therapeutic target for Parkinson's disease.

Role of the globus pallidus in motor and non-motor symptoms of Parkinson's disease

The globus pallidus plays a pivotal role in the basal ganglia circuit. Parkinson's disease is characterized by degeneration of dopamine-producing cells in the substantia nigra, which leads to dopamine deficiency in the brain that subsequently manifests as various motor and non-motor symptoms. This review aims to summarize the involvement of the globus pallidus in both motor and non-motor manifestations of Parkinson's disease. The firing activities of parvalbumin neurons in the medial globus pallidus, including both the firing rate and pattern, exhibit strong correlations with the bradykinesia and rigidity associated with Parkinson's disease. Increased beta oscillations, which are highly correlated with bradykinesia and rigidity, are regulated by the lateral globus pallidus. Furthermore,bradykinesia and rigidity are strongly linked to the loss of dopaminergic projections within the cortical-basal ganglia-thalamocortical loop. Resting tremors are attributed to the transmission of pathological signals from the basal ganglia through the motor cortex to the cerebellum-ventral intermediate nucleus circuit. The cortico–striato–pallidal loop is responsible for mediating pallidi-associated sleep disorders. Medication and deep brain stimulation are the primary therapeutic strategies addressing the globus pallidus in Parkinson's disease. Medication is the primary treatment for motor symptoms in the early stages of Parkinson's disease, while deep brain stimulation has been clinically proven to be effective in alleviating symptoms in patients with advanced Parkinson's disease,particularly for the movement disorders caused by levodopa. Deep brain stimulation targeting the globus pallidus internus can improve motor function in patients with tremordominant and non-tremor-dominant Parkinson's disease, while deep brain stimulation targeting the globus pallidus externus can alter the temporal pattern of neural activity throughout the basal ganglia–thalamus network. Therefore, the composition of the globus pallidus neurons, the neurotransmitters that act on them, their electrical activity,and the neural circuits they form can guide the search for new multi-target drugs to treat Parkinson's disease in clinical practice. Examining the potential intra-nuclear and neural circuit mechanisms of deep brain stimulation associated with the globus pallidus can facilitate the management of both motor and non-motor symptoms while minimizing the side effects caused by deep brain stimulation.

Understanding the link between type 2 diabetes mellitus and Parkinson's disease:role of brain insulin resistance

Type 2 diabetes mellitus and Parkinson's disease are chronic diseases linked to a growing pandemic that affects older adults and causes significant socio-economic burden.Epidemiological data supporting a close relationship between these two aging-related diseases have resulted in the investigation of shared pathophysiological molecular mechanisms.Impaired insulin signaling in the brain has gained increasing attention during the last decade and has been suggested to contribute to the development of Parkinson's disease through the dysregulation of several pathological processes.The contribution of type 2 diabetes mellitus and insulin resistance in neurodegeneration in Parkinson's disease,with emphasis on brain insulin resistance,is extensively discussed in this article and new therapeutic strategies targeting this pathological link are presented and reviewed.

Prolonged intermittent theta burst stimulation restores the balance between A_(2A)R-and A_(1)R-mediated adenosine signaling in the 6-hydroxidopamine model of Parkinson's disease

An imbalance in adenosine-mediated signaling,particularly the increased A_(2A)R-mediated signaling,plays a role in the pathogenesis of Parkinson's disease.Existing therapeutic approaches fail to alter disease progression,demonstrating the need for novel approaches in PD.Repetitive transcranial magnetic stimulation is a non-invasive approach that has been shown to improve motor and non-motor symptoms of Parkinson's disease.However,the underlying mechanisms of the beneficial effects of repetitive transcranial magnetic stimulation remain unknown.The purpose of this study is to investigate the extent to which the beneficial effects of prolonged intermittent theta burst stimulation in the 6-hydroxydopamine model of experimental parkinsonism are based on modulation of adenosine-mediated signaling.Animals with unilateral 6-hydroxydopamine lesions underwent intermittent theta burst stimulation for 3 weeks and were tested for motor skills using the Rotarod test.Immunoblot,quantitative reverse transcription polymerase chain reaction,immunohistochemistry,and biochemical analysis of components of adenosine-mediated signaling were performed on the synaptosomal fraction of the lesioned caudate putamen.Prolonged intermittent theta burst stimulation improved motor symptoms in 6-hydroxydopamine-lesioned animals.A 6-hydroxydopamine lesion resulted in progressive loss of dopaminergic neurons in the caudate putamen.Treatment with intermittent theta burst stimulation began 7 days after the lesion,coinciding with the onset of motor symptoms.After treatment with prolonged intermittent theta burst stimulation,complete motor recovery was observed.This improvement was accompanied by downregulation of the e N/CD73-A_(2A)R pathway and a return to physiological levels of A_(1)R-adenosine deaminase 1 after 3 weeks of intermittent theta burst stimulation.Our results demonstrated that 6-hydroxydopamine-induced degeneration reduced the expression of A_(1)R and elevated the expression of A_(2A)R.Intermittent theta burst stimulation reversed these effects by restoring the abundances of A_(1)R and A_(2A)R to control levels.The shift in ARs expression likely restored the balance between dopamine-adenosine signaling,ultimately leading to the recovery of motor control.

Clinical features and relative factors of constipation in a cohort of Chinese patients with Parkinson's disease

BACKGROUND Constipation as a most common non-motor symptom of Parkinson's disease(PD),has a higher prevalence compared to the general population.The etiologies of constipation in PD are diverse.In addition to physical weakness and other factors of disease,the lifestyles and eating habits are also important factors.Therefore,the prevalence and influencing factors of constipation may vary among different populations.AIM To determine the prevalence of constipation and analyze relative factors in a cohort of Chinese patients with PD.METHODS All the patients diagnosed with PD according to the movement disorders society criteria were consecutively collected by a self-developed questionnaire.Rome III diagnostic criteria were used to assess functional constipation and Wexner score was used to estimate the severity of constipation.Non-motor symptoms(NMS)were assessed with the non-motor symptoms assessment scale(NMSS).Unified Parkinson's disease Rating Scale III(UPDRS III)was used to evaluate the severity of motor symptoms.The modified Hoehn-Yahr stage was used to evaluate the severity of PD.Cognitive function was assessed using Montreal cognitive assessment(MoCA).Depression and anxiety were rated with the Hamilton depression scale(HAMD)and the Hamilton anxiety scale(HAMA).Quality of life was assessed using the Parkinson’s disease Questionnaire-39 items(PDQ-39).RESULTS Of 166 patients enrolled,87(52.41%)were accompanied with constipation,and 30(34.48%)experienced constipation for 6.30±5.06 years before motor symptoms occurred.Age,Hoehn-Yahr stage,disease duration,levodopa medication times,incidence of motor complications,the scores of UPDRS total,UPDRS III,NMSS,HAMD,HAMA,and PDQ-39 in the constipation group were higher than those in the non-constipation group(P<0.05),but there was no difference in the scores of MoCA,clinical types,or medications between the two groups(P>0.05).There was a higher incidence of depression in patients with constipation(P<0.05),but there were no difference in the incidence of anxiety and cognitive impairment between the two groups(P>0.05).As Hoehn-Yahr stages increased,the severity of constipation increased(P<0.05),but not the incidence of constipation(P>0.05).Pearson correlation analysis showed that constipation was moderately positively correlated with age,Hoehn-Yahr stage,and scores of NMSS,UPDRS III,UPDRS total,PDQ-39,HAMD,and HAMA(r=0.255,0.172,0.361,0.194,0.221,0.237,0.238,and 0.207,P<0.05).Logistic regression analysis showed that only NMSS score was an independent risk factor for constipation(P<0.001).CONCLUSION Our findings confirm that constipation has a relatively high frequency in patients with PD.PD patients with constipation have a higher incidence of depression,which leads to worse quality of life.

Unraveling the gut-brain axis:the impact of steroid hormones and nutrition on Parkinson's disease

This comprehensive review explores the intricate relationship between nutrition,the gut microbiome,steroid hormones,and Parkinson's disease within the context of the gut-brain axis.The gut-brain axis plays a pivotal role in neurodegenerative diseases like Parkinson's disease,encompassing diverse components such as the gut microbiota,immune system,metabolism,and neural pathways.The gut microbiome,profoundly influenced by dietary factors,emerges as a key player.Nutrition during the first 1000 days of life shapes the gut microbiota composition,influencing immune responses and impacting both child development and adult health.High-fat,high-sugar diets can disrupt this delicate balance,contributing to inflammation and immune dysfunction.Exploring nutritional strategies,the Mediterranean diet's anti-inflammatory and antioxidant properties show promise in reducing Parkinson's disease risk.Microbiome-targeted dietary approaches and the ketogenic diet hold the potential in improving brain disorders.Beyond nutrition,emerging research uncovers potential interactions between steroid hormones,nutrition,and Parkinson's disease.Progesterone,with its anti-inflammatory properties and presence in the nervous system,offers a novel option for Parkinson's disease therapy.Its ability to enhance neuroprotection within the enteric nervous system presents exciting prospects.The review addresses the hypothesis thatα-synuclein aggregates originate from the gut and may enter the brain via the vagus nerve.Gastrointestinal symptoms preceding motor symptoms support this hypothesis.Dysfunctional gut-brain signaling during gut dysbiosis contributes to inflammation and neurotransmitter imbalances,emphasizing the potential of microbiota-based interventions.In summary,this review uncovers the complex web of interactions between nutrition,the gut microbiome,steroid hormones,and Parkinson's disease within the gut-brain axis framework.Understanding these connections not only offers novel therapeutic insights but also illuminates the origins of neurodegenerative diseases such as Parkinson's disease.

A systematic review of salivary biomarkers in Parkinson's disease

The search fo r reliable and easily accessible biomarkers in Parkinson's disease is receiving a growing emphasis,to detect neurodegeneration from the prodromal phase and to enforce disease-modifying therapies.Despite the need for non-invasively accessible biomarke rs,the majo rity of the studies have pointed to cerebrospinal fluid or peripheral biopsies biomarkers,which require invasive collection procedures.Saliva represents an easily accessible biofluid and an incredibly wide source of molecular biomarkers.In the present study,after presenting the morphological and biological bases for looking at saliva in the search of biomarkers for Parkinson's disease,we systematically reviewed the results achieved so far in the saliva of different cohorts of Parkinson's disease patients.A comprehensive literature search on PubMed and SCOPUS led to the discovery of 289articles.After screening and exclusion,34 relevant articles were derived fo r systematic review.Alpha-synuclein,the histopathological hallmark of Parkinson's disease,has been the most investigated Parkinson's disease biomarker in saliva,with oligomeric alphasynuclein consistently found increased in Parkinson's disease patients in comparison to healthy controls,while conflicting results have been reported regarding the levels of total alpha-synuclein and phosphorylated alpha-synuclein,and few studies described an increased oligomeric alpha-synuclein/total alpha-synuclein ratio in Parkinson's disease.Beyond alpha-synuclein,other biomarkers to rgeting diffe rent molecular pathways have been explored in the saliva of Parkinson's disease patients:total tau,phosphorylated tau,amyloid-β1-42(pathological protein aggregation biomarkers);DJ-1,heme-oxygenase-l,metabolites(alte red energy homeostasis biomarkers);MAPLC-3beta(aberrant proteostasis biomarker);cortisol,tumor necrosis factor-alpha(inflammation biomarkers);DNA methylation,miRNA(DNA/RNA defects biomarkers);acetylcholinesterase activity(synaptic and neuronal network dysfunction biomarkers);Raman spectra,proteome,and caffeine.Despite a few studies investigating biomarkers to rgeting molecular pathways different from alpha-synuclein in Parkinson's disease,these results should be replicated and observed in studies on larger cohorts,considering the potential role of these biomarkers in determining the molecular variance among Parkinson's disease subtypes.Although the need fo r standardization in sample collection and processing,salivary-based biomarkers studies have reported encouraging results,calling for large-scale longitudinal studies and multicentric assessments,given the great molecular potentials and the non-invasive accessibility of saliva.

Dysfunction of synaptic endocytic trafficking in Parkinson's disease

Parkinson's disease is characterized by the selective degeneration of dopamine neurons in the nigrostriatal pathway and dopamine deficiency in the striatum.The precise reasons behind the specific degeneration of these dopamine neurons remain largely elusive.Genetic investigations have identified over 20 causative PARK genes and 90 genomic risk loci associated with both familial and sporadic Parkinson's disease.Notably,several of these genes are linked to the synaptic vesicle recycling process,particularly the clathrinmediated endocytosis pathway.This suggests that impaired synaptic vesicle recycling might represent an early feature of Parkinson's disease,followed by axonal degeneration and the eventual loss of dopamine cell bodies in the midbrain via a"dying back"mechanism.Recently,several new animal and cellular models with Parkinson's disease-linked mutations affecting the endocytic pathway have been created and extensively characterized.These models faithfully recapitulate certain Parkinson's disease-like features at the animal,circuit,and cellular levels,and exhibit defects in synaptic membrane trafficking,further supporting the findings from human genetics and clinical studies.In this review,we will first summarize the cellular and molecular findings from the models of two Parkinson's disease-linked clathrin uncoating proteins:auxilin(DNAJC6/PARK19)and synaptojanin 1(SYNJ1/PARK20).The mouse models carrying these two PARK gene mutations phenocopy each other with specific dopamine terminal pathology and display a potent synergistic effect.Subsequently,we will delve into the involvement of several clathrin-mediated endocytosis-related proteins(GAK,endophilin A1,SAC2/INPP5 F,synaptotagmin-11),identified as Parkinson's disease risk factors through genome-wide association studies,in Parkinson's disease pathogenesis.We will also explore the direct or indirect roles of some common Parkinson's disease-linked proteins(alpha-synuclein(PARK1/4),Parkin(PARK2),and LRRK2(PARK8))in synaptic endocytic trafficking.Additionally,we will discuss the emerging novel functions of these endocytic proteins in downstream membrane traffic pathways,particularly autophagy.Given that synaptic dysfunction is considered as an early event in Parkinson's disease,a deeper understanding of the cellular mechanisms underlying synaptic vesicle endocytic trafficking may unveil novel to rgets for early diagnosis and the development of interventional therapies for Parkinson's disease.Future research should aim to elucidate why generalized synaptic endocytic dysfunction leads to the selective degeneration of nigrostriatal dopamine neurons in Parkinson's disease.

Efficacy of short-term multidisciplinary intensive rehabilitation in patients with different Parkinson's disease motor subtypes: a prospective pilot study with 3-month follow-up

Parkinson's disease(PD) can be classified into three motor-based subtypes: postural instability/gait difficulty(PIGD), tremor dominant(TD), and indeterminate.The neuropathophysiological mechanisms of the three motor subtypes are different, which may lead to different responses to therapy.Sixty-nine patients with idiopathic Parkinson's disease(Hoehn–Yahr stage ≤ 3) were screened from 436 patients with Parkinsonism recruited through outpatient services and the internet.According to the Movement Disorder Society Unified Parkinson's Disease Rating Scale(MDS-UPDRS) TD/PIGD ratio, the patients were divided into PIGD(TD/PIGD ≤ 0.09;n = 36), TD(TD/PIGD ≥1.15;n = 19), and indeterminate(TD/PIGD = 0.90–1.15;n = 14) groups.All patients received 2 weeks of multidisciplinary intensive rehabilitation treatment(MIRT) during hospitalization, as well as a remote home rehabilitation health education class.Compared with the scores at admission, all patients showed significant improvements in their MDS-UPDRS III score, walking ability, balance, and posture control at discharge.Moreover, the MDS-UPDRS III score improvement was greater in the PIGD group than in the TD group.The follow-up data, collected for 3 months after discharge, showed that overall symptom improvement in each group was maintained for 1–3 months.Furthermore, there were no significant differences in the duration or grade effects of symptom improvement among the three groups.These findings suggest that 2 weeks of MIRT is effective for improving motor performance in all three motor subtypes.Patients in the PIGD group had a better response after hospitalization than those in the TD group.This study was approved by the Institutional Ethics Committee of Beijing Rehabilitation Hospital of Capital Medical University of China(approval No.2018 bkky022) on May 7, 2018 and registered with the Chinese Clinical Trial Registry(registration No.Chi CTR1900020771) on January 19, 2019.

Aquatic exercise program-modulated oxidative stress markers in patients with Parkinson's disease

Parkinson's disease is a neurodegenerative disease.Oxidative stress,i.e.,the imbalance between the generation of reactive oxygen species and the antioxidant defense capacity of the body,plays an important role in the pathogenesis of this disease.Physical exercise can regulate oxidative stress.The purpose of this study was to analyze the short-and long-term effects of an aquatic exercise program on oxidative stress levels in patients with Parkinson's disease.The aquatic exercise program was carried out during 1 month with two sessions per week(1 hour/session).Blood samples were collected at four different time points:pre-intervention,immediately,48 hours,and 30 days after the first session of aquatic exercise program.Our results revealed that water-based programs modulated antioxidant enzyme activity,increased superoxide dismutase activity,reduced catalase activity,and increased the ratio of superoxide dismutase activity to catalase activity in patients with Parkinson's disease.Compared with pre-intervention and 48 hours after the first session of aquatic exercise program,superoxide dismutase activity was higher and catalase activity was lower immediately and 30 days after the first session.Our results demonstrated that aquatic exercise program could modulate oxidative stress,mainly by the effect of antioxidant enzyme activity.These results could better help understand the target of oxidative stress in Parkinson's disease.This study was approved by the Ethics Committee of Centro Universitário Metodista IPA(approval No.1.373.911)on August 9,2019 and registered with REBEC(registration number:RBR-6 NJ4 MK).

Neuropsychiatric Symptoms and Cognitive Impairment in Chinese Patients with Parkinson's Disease in Han and Hui Ethnicity

Nenropsychiatric symptoms are common in patients with Parkinson's disease(PD)and they are likely to outweigh the motor symptoms and become a major factor affecting the quality of life of PD patients.However,the studies focusing on the non-motor symptoms in Chinese PD patients from different ethnicity are scarce.The aim of this retrospective study was to investigate neuropsychiatric symptoms and cognitive impairment in Chinese PD patients from Han and Hui populations from central China.Seventy-two Han Chinese PD patients(Han PD group)and 71 age-and sex-matched Hui Chinese PD patients(Hui PD group)were enrolled from Zhongnan Hospital of Wuhan University between Sept.2011 and Aug.2014 in the study.The neuropsychiatric symptoms and cognitive impairment were assessed using Neuropsychiatric Inventory(NPI)and Mini Mental State Examination(MMSE).We found that the proportion of depression,anxiety,apathy,irritability,euphoria and night time behavior disturbances were higher in the Han PD group than in the Hui PD group(P<0.05 or P<0.01).But the proportion of delusion,hallucination,agitation,disinhibition,aberrant motor behavior and change in appetite were not significantly different between the Han PD group and the Hui PD group(P>0.05).The total mean scores of the MMSE from patients in the Han PD group were similar to those in the Hui PD group(P>0.05).However,the subscale scores of recall domain and language domain in the Han PD group were significantly different from those in the Hui PD group(P<0.05).No significant difference was noted in the orientation,memory and calculation domains between the two PD groups(P>0.05).This study first showed the recall domain and language domain were different between the Han PD patients and the Hui PD patients.Depression,anxiety,apathy,irritability,euphoria and night time behavior disturbances were less presented in the Hui PD patients.All these differences may be related to the different ethnicity,which would be helpful for clinical physicians to recognize the different non-motor symptoms in Chinese PD patients with different ethnicity.

Increased activation of the caudate nucleus and parahippocampal gyrus in Parkinson's disease patients with dysphagia after repetitive transcranial magnetic stimulation:a case-control study

Repetitive transcranial magnetic stimulation(r TMS)has been shown to effectively improve impaired swallowing in Parkinson's disease(PD)patients with dysphagia.However,little is known about how r TMS affects the corresponding brain regions in this patient group.In this casecontrol study,we examined data from 38 PD patients with dysphagia who received treatment at Beijing Rehabilitation Medicine Academy,Capital Medical University.The patients received high-frequency r TMS of the motor cortex once per day for 10 successive days.Changes in brain activation were compared via functional magnetic resonance imaging in PD patients with dysphagia and healthy controls.The results revealed that before treatment,PD patients with dysphagia showed greater activation in the precentral gyrus,supplementary motor area,and cerebellum compared with healthy controls,and this enhanced activation was weakened after treatment.Furthermore,before treatment,PD patients with dysphagia exhibited decreased activation in the parahippocampal gyrus,caudate nucleus,and left thalamus compared with healthy controls,and this activation increased after treatment.In addition,PD patients with dysphagia reported improved subjective swallowing sensations after r TMS.These findings suggest that swallowing function in PD patients with dysphagia improved after r TMS of the motor cortex.This may have been due to enhanced activation of the caudate nucleus and parahippocampal gyrus.The study protocol was approved by the Ethics Committee of Beijing Rehabilitation Hospital of Capital Medical University(approval No.2018 bkky017)on March 6,2018 and was registered with Chinese Clinical Trial Registry(registration No.Chi CTR 1800017207)on July 18,2018.

Relationship among Parkinson’s disease, constipation, microbes, and microbiological therapy

This comprehensive review elucidates the complex interplay between gut microbiota and constipation in Parkinson’s disease(PD),a prevalent non-motor symptom contributing significantly to patients’morbidity.A marked alteration in the gut microbiota,predominantly an increase in the abundance of Proteobacteria and Bacteroidetes,is observed in PD-related constipation.Conventional treatments,although safe,have failed to effectively alleviate symptoms,thereby necessitating the development of novel therapeutic strategies.Microbiological interventions such as prebiotics,probiotics,and fecal microbiota transplantation(FMT)hold therapeutic potential.While prebiotics improve bowel movements,probiotics are effective in enhancing stool consistency and alleviating abdominal discomfort.FMT shows potential for significantly alleviating constipation symptoms by restoring gut microbiota balance in patients with PD.Despite promising developments,the causal relationship between changes in gut microbiota and PD-related constipation remains elusive,highlighting the need for further research in this expanding field.

Significant improvement after sensory tricks and trunk strength training for Parkinson’s disease with antecollis and camptocormia:A case report

BACKGROUND Patients with Parkinson's disease(PD)exhibit symptoms such as antecollis(AC)and camptocormia(CC).The pathology of these two conditions is unclear.Additionally,standard treatment methods have not been established.The article reports the case of a 65-year-old female patient with AC and CC who was treated with central and peripheral interventions to alleviate symptoms.CASE SUMMARY We present the case of a 65-year-old female PD patient with AC and CC.The course of the disease was 5 years.She was treated with rehabilitation strategies such as sensory tricks and trunk strength training.During the inpatient period,we compared and analyzed the patient's gait,rehabilitation assessment scale score,and angles of her abnormal trunk posture in the first week,the third week,and the fifth week.The patient's stride length increased,indicating that the patient's walking ability was improved.The Unified Parkinson's Disease Scale Part Three score and CC severity score decreased.Furthermore,the score of the other scale increased.In addition,the patient showed significant improvements in AC,upper CC,and lower CC angles.CONCLUSION This case study suggested that sensory tricks and trunk strength training are beneficial and safe for patients with AC and CC.

Exploring the Mechanism of Action of Gastrodin in Parkinson's Disease Based on Network Pharmacology

[Objectives]To explore the mechanism of action of gastrodin in the treatment of Parkinson's disease(PD)by employing network pharmacology technology,and to provide a scientific theoretical basis for the rational clinical application of gastrodin.[Methods]The target of gastrodin was identified through a search of the SwissTargetPrediction database.The keyword"Parkinson Disease"was employed to identify the pertinent targets of PD in the GeneCards and OMIM databases.The relationship between gastrodin and PD was elucidated,and a Veen map was constructed to identify the genes that were common to both.A total of 52 common drug targets associated with PD as identified in the Wayne chart were imported into the String database(https://string-db.org/)for protein-protein interaction prediction.Subsequently,Cytoscape 3.9.1 software was employed to construct a"drug-target"network.The potential targets of gastrodin in the treatment of PD were then imported into the DAVID database,where GO analysis and KEGG enrichment results were obtained.[Results]A total of 22 core targets and 53 related pathways of gastrodin were identified as potentially beneficial for the treatment of PD.[Conclusions]Gastrodin may be a potential therapeutic agent for the treatment of PD by modulating the biological process of apoptosis,affecting the relevant pathways such as the IL-17 signaling pathway and the TNF signaling pathway,and acting on GAPDH,EGFR,CASP3,MMP9 and other targets.

CHCHD2 Thr61Ile mutation impairs F1F0-ATPase assembly in in vitro and in vivo models of Parkinson's disease

Mitochondrial dysfunction is a significant pathological alte ration that occurs in Parkinson's disease(PD),and the Thr61lle(T61I)mutation in coiled-coil helix coiled-coil helix domain containing 2(CHCHD2),a crucial mitochondrial protein,has been reported to cause Parkinson's disease.FIFO-ATPase participates in the synthesis of cellular adenosine triphosphate(ATP)and plays a central role in mitochondrial energy metabolism.However,the specific roles of wild-type(WT)CHCHD2 and T611-mutant CHCHD2 in regulating F1FO-ATPase activity in Parkinson's disease,as well as whether CHCHD2 or CHCHD2 T61I affects mitochondrial function through regulating F1FO-ATPase activity,remain unclea r.Therefore,in this study,we expressed WT CHCHD2 and T61l-mutant CHCHD2 in an MPP^(+)-induced SH-SY5Y cell model of PD.We found that CHCHD2 protected mitochondria from developing MPP^(+)-induced dysfunction.Under normal conditions,ove rexpression of WT CHCHD2 promoted F1FO-ATPase assembly,while T61I-mutant CHCHD2 appeared to have lost the ability to regulate F1FO-ATPase assembly.In addition,mass spectrometry and immunoprecipitation showed that there was an interaction between CHCHD2 and F1FO-ATPase.Three weeks after transfection with AAV-CHCHD2 T61I,we intraperitoneally injected 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into mice to establish an animal model of chronic Parkinson's disease and found that exogenous expression of the mutant protein worsened the behavioral deficits and dopaminergic neurodegeneration seen in this model.These findings suggest that WT CHCHD2 can alleviate mitochondrial dysfunction in PD by maintaining F1F0-ATPase structure and function.

Quantitative study of peripapillary retinal nerve fiber layer thickness and peripapillary vessel density in patients with different stages of Parkinson's disease

AIM: To observe the changes in the thickness of peripapillary retinal nerve fiber layer(p RNFL) and peripapillary vessel density(pVD) in patients with different stages of Parkinson's disease(PD).METHODS: Totally 47 patients(47 eyes) with primary PD were divided into the mild group and the moderateto-severe group according to Hoehn & Yahr(H&Y) stage. Among them, there were 27 cases(27 eyes) in mild group and 20 cases(20 eyes) in moderate-to-severe group. And 20 cases(20 eyes) who were included in the control group were healthy people who came to our hospital for health screening at the same time. All participants underwent optical coherence tomography angiography(OCTA) examinations. The pRNFL thickness, total vessel density(tVD) and capillary vessel density(cVD) of the optic disc in average, superior half, inferior half, superior nasal(SN), nasal superior(NS), nasal inferior(NI), inferior nasal(IN), inferior temporal(IT), temporal inferior(TI), temporal superior(TS), and superior temporal(ST) were measured. One-way ANOVA was used to compare the differences of optic disc parameters among the three groups, and Pearson and Spearman correlations were used to analyze the correlation between pRNFL, pVD and the disease duration, H&Y stage and UPDRS-Ⅲ score in patients with PD, respectively.RESULTS: There were significant differences in p RNFL thickness in average, superior half, inferior half, SN, NS, IN, IT and ST quadrants among the three groups(P<0.05). In PD group, the pRNFL thickness in average, superior half, inferior half, NS and IT quadrants were negatively correlated with H&Y stage and UPDRS-Ⅲ score, respectively(P<0.05). There were statistically significant differences in the cVD of whole image, inferior half, NI and TS quadrants, the tVD of the whole image, inferior half, and peripapillary among the three groups(P<0.05). In PD group, the tVD of whole image and the c VD of NI and TS quadrants were negatively correlated with the H&Y stage, respectively(P<0.05);the cVD of TS quadrant was negatively correlated with UPDRS-Ⅲ score(P<0.05).CONCLUSION: The thickness of pRNFL in PD patients is significantly decreased, and it is negatively correlated with H&Y stage and UPDRS-Ⅲ score. With the increase of the severity of the disease, the pVD parameters in PD patients increase at first in the mild group, and then decrease in the moderate-to-severe group, and negatively correlate with H&Y stage and UPDRS-Ⅲ score.

Advances in Research of Chinese Medicine Tianma in the Treatment of Parkinson's Disease

In this study,a systematic review was conducted on the experimental study as well as the clinical application of Tianma(Gastrodia elata Blume),a traditional Chinese medicine,in the prevention and treatment of Parkinson's disease(PD).On this basis,a summary and outlook were made,so as to provide ideas and theoretical basis for the study,development and utilization of Tianma PD field.