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.

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.

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.

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.

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.

Effects of psychological nursing in Parkinson's related depression patients undergoing functional magnetic resonance imaging:A randomized controlled trial

BACKGROUND Patients with Parkinson’s disease(PD)often experience depression,and some may require magnetic resonance imaging(MRI)for diagnosis,which can lead to MRI failure due to claustrophobia.AIM To explore the value of psychological interventions in successfully completing functional MRI scans of the brain for PD-related depression.METHODS Ninety-six patients with PD were randomly divided into two groups.The control group(47 patients)received general care,and the experimental group(49 patients)received general care combined with psychological care.The Unified Parkinson's Disease Assessment Scale(UPDRS),Hamilton Depression Scale(HAMD),and Geriatric Depression Scale(GDS)-15 scores,heart rate,systolic blood pressure,and MRI-Anxiety Questionnaire(MRI-AQ)scores before and after the scan were recorded.The completion rate of magnetic resonance(MR)scanning,scanning duration,and image quality scores were recorded.RESULTS Before scanning,no statistically significant difference was observed between the two groups in terms of heart rate,systolic blood pressure,and UPDRS,HAMD,GDS-15,and MRI-AQ scores.After scanning,systolic blood pressure,MRI-AQ score,and scan time in the experimental group were significantly lower than those in the control group,whereas the scan completion rate and image quality score were significantly higher than those in the control group.CONCLUSION Psychological nursing interventions are helpful in alleviating PD-related depression and assessing MR depression scores and may be helpful in the successful completion of functional MRI scans of the patient's brain.

Research Progress on Neuroprotective Effects of Salvianolic Acid B in an Animal Model of Parkinson's Disease

As an active ingredient extracted from Salvia miltiorrhiza,the neuroprotective effects of salvianolic acid B in Parkinson's disease include antioxidation,improvement of mitochondrial function,modulation of neuroinflammation,inhibition of apoptosis,promotion of neuronal differentiation and proliferation,and influence on intestinal flora.As an adjuvant drug,salbutamol B can be used in combination with conventional therapeutic drugs to enhance the efficacy and minimize the side effects,which provides a method and basis for the early diagnosis and treatment of Parkinson's disease in clinical practice.

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.

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.

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.

Oxidative stress factors in Parkinson's disease

Parkinson's disease(PD) is the second most common cause of neurodegeneration.Over the last two decades, various hypotheses have been proposed to explain the etiology of PD.Among these is the oxidant-antioxidant theory, which asserts that local and systemic oxidative damage triggered by reactive oxygen species and other free radicals may promote dopaminergic neuron degeneration.Excessive reactive oxygen species formation, one of the underlying causes of pathology in the course of PD has been evidenced by various studies showing that oxidized macromolecules including lipids, proteins, and nucleic acids accumulate in brain tissues of PD patients.DNA oxidation may produce various lesions in the course of PD.Mutations incurred as a result of DNA oxidation may further enhance reactive oxygen species production in the brains of PD patients, exacerbating neuronal loss due to defects in the mitochondrial electron transport chain, antioxidant depletion, and exposure to toxic oxidized dopamine.The protein products of SNCA, PRKN, PINK1, DJ1, and LRRK2 genes are associated with disrupted oxidoreductive homeostasis in PD.SNCA is the first gene linked with familial PD and is currently known to be affected by six mutations correlated with the disorder: A53T, A30P, E46K, G51D, H50Q and A53E.PRKN encodes Parkin, an E3 ubiquitin ligase which mediates the proteasome degradation of redundant and disordered proteins such as glycosylated α-synuclein.Over 100 mutations have been found among the 12 exons of PRKN.PINK1, a mitochondrial kinase highly expressed in the brain, may undergo loss of function mutations which constitute approximately 1–8% of early onset PD cases.More than 50 PD-promoting mutations have been found in PINK1.Mutations in DJ-1, a neuroprotective protein, are a rare cause of early onset PD and constitute only 1% of cases.Around 20 mutations have been found in DJ1 among PD patients thus far.Mutations in the LRRK2 gene are the most common known cause of familial autosomal dominant PD and sporadic PD.Treatment of PD patients, especially in the advanced stages of the disease, is very difficult.The first step in managing progressive PD is to optimize dopaminergic therapy by increasing the doses of dopamine agonists and L-dopa.The next step is the introduction of advanced therapies, such as deep brain stimulation.Genetic factors may influence the response to L-dopa and deep brain stimulation therapy and the regulation of oxidative stress.Consequently, research into minimally invasive surgical interventions, as well as therapies that target the underlying etiology of PD is warranted.

Signal Alteration of Substantia Nigra on 3.0T Susceptibility-weighted Imaging in Parkinson's Disease and Vascular Parkinsonism

Recent researches have found that 7 Tesla SWI can detect the alteration of substantia nigra hyperintensity in Parkinson's disease(PD),multiple system atrophy(MSA),and progressive supranuclear palsy(PSP).The aim of this study was to investigate whether 3 Tesla SWI(3T SWI)can visualize anatomical alterations occurring in a hyperintense structure of the substantia nigra in PD and vascular parkinsonism(VP),and whether the evaluation of abnormal signal can be used as a factor in the differential diagnosis of PD and VP.Using 3 Tesla MRI,we evaluated 38 healthy subjects,33 patients with PD and 34 patients with VP.Two blinded readers independently assessed the images.We found that the dorsolateral nigral hyperintensity was absent in 31 of 33 patients with PD and 15 of 34 patients with VP.The dorsolateral nigral hyperintensity was present in 19 of 34 patients with VP and 35 of 38 healthy controls.Group comparisons of absence of dorsolateral nigral hyperintensity revealed significant differences between the patients with PD and those with VP(P<0.001).The sensitivity of SWI for PD was 93.9%and the specificity was 92.1%.Visual assessment of dorsolateral nigral hyperintensity on high-field SWI scans may serve as a new simple diagnostic imaging marker for PD.And our study results indicate that 3T SWI can be used as a tool to identify PD and VP.

Neuroprotective mechanisms ofε-viniferin in a rotenone-induced cell model of Parkinson's disease:significance of SIRT3-mediated FOXO3 deacetylation

Trans-(-)-ε-viniferin(ε-viniferin)has antioxidative and anti-inflammatory effects.It also has neuroprotective effects in Huntington's disease by activating the SIRT3/LKB1/AMPK signaling pathway;however,it remains unknown whetherε-viniferin also has a neuroprotective role in Parkinson's disease.A Parkinson's disease cell model was induced by exposing SH-SY5 Y cells to 3.0μM rotenone for 24 hours,and cells were then treated with 1.0μMε-viniferin for 24 hours.Treatment withε-viniferin upregulated SIRT3 expression,which promoted FOXO3 deacetylation and nuclear localization.ε-Viniferin also increased ATP production and decreased reactive oxygen species production.Furthermore,ε-viniferin treatment alleviated rotenone-induced mitochondrial depolarization and reduced cell apoptosis,and restored the expression of mitochondrial homeostasis-related proteins.However,when cells were transfected with SIRT3 or FOXO3 shRNA prior to rotenone andε-viniferin treatment,these changes were reversed.The results from the present study indicate thatε-viniferin enhances SIRT3-mediated FOXO3 deacetylation,reduces oxidative stress,and maintains mitochondrial homeostasis,thus inhibiting rotenone-induced cell apoptosis.ε-Viniferin may therefore be a promising treatment strategy for 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.

Neuron-protective effect of subanesthestic-dosage ketamine on mice of Parkinson's disease

Objective: To discuss the neuron-protective effect and possible mechanism of subanesthestic-dosage ketamine on Parkinson's disease mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.Methods: A total of 30 mice were divided equally into three groups, model control group(MC group), ketamine treatment group(KT group), and blank control group(BC group), respectively.The Parkinson's disease mice of MC group and KT groups were established by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(20 mg/kg/d), while mice in KT group were treated by intraperitoneal injection of subanesthestic-dosage ketamine(8 mg/kg).Differences on behaviors and the number of nigra dopaminergic neurons of mice in each group were compared through the behavioral test and tyrosine hydroxylase immunohistochemistry experiments after the treatments.Furthermore, Western blot was used to test the expression of autophagy-related gene LC3-Ⅱ, Beclin1, Parkin, PINK1,and mTOR.Results: Compared with the BC group, the neuroethology scores were lower and the amount of TH positive cells were less both in MC and MT groups; In KT group, the neuroethology scores were higher and the amount of tyrosine hydroxylase positive cells were significantly more than that in MC group(P < 0.05).Moreover, expression levels of autophagy-related proteins LC3-II, Beclin1, Parkin, and PINK1 were higher, while the mTOR expression level was lower than that in MC group.Conclusions: The subanesthestic-dosage ketamine has some protective effects on the coordinating ability of movement and cognitive ability of Parkinson's disease mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.This is probably due to that the autophagy activity of cells is activated by subanesthestic-dosage ketamine and that the neurons are protected.

Gut-microbiome-brain axis:the crosstalk between the vagus nerve,alpha-synuclein and the brain in Parkinson's disease

This critical review of the literature shows that there is a close link between the microbiome,the gut,and the brain in Parkinson's disease.The vagus nerve,the main component of the parasympathetic nervous system,is involved in the regulation of immune response,digestion,heart rate,and control of mood.It can detect microbiota metabolites through its afferents,transferring this gut information to the central nervous system.Preclinical and clinical studies have shown the important role played by the gut microbiome and gut-related factors in disease development and progression,as well as treatment responses.These findings suggest that the gut microbiome may be a valuable target for new therapeutic strategies for Parkinson's disease.More studies are needed to better understand the underlying biology and how this axis can be modulated for the patient's benefit.