Cell reprogramming therapy for Parkinson’s disease

Parkinson’s disease is typically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta.Many studies have been performed based on the supplementation of lost dopaminergic neurons to treat Parkinson’s disease.The initial strategy for cell replacement therapy used human fetal ventral midbrain and human embryonic stem cells to treat Parkinson’s disease,which could substantially alleviate the symptoms of Parkinson’s disease in clinical practice.However,ethical issues and tumor formation were limitations of its clinical application.Induced pluripotent stem cells can be acquired without sacrificing human embryos,which eliminates the huge ethical barriers of human stem cell therapy.Another widely considered neuronal regeneration strategy is to directly reprogram fibroblasts and astrocytes into neurons,without the need for intermediate proliferation states,thus avoiding issues of immune rejection and tumor formation.Both induced pluripotent stem cells and direct reprogramming of lineage cells have shown promising results in the treatment of Parkinson’s disease.However,there are also ethical concerns and the risk of tumor formation that need to be addressed.This review highlights the current application status of cell reprogramming in the treatment of Parkinson’s disease,focusing on the use of induced pluripotent stem cells in cell replacement therapy,including preclinical animal models and progress in clinical research.The review also discusses the advancements in direct reprogramming of lineage cells in the treatment of Parkinson’s disease,as well as the controversy surrounding in vivo reprogramming.These findings suggest that cell reprogramming may hold great promise as a potential strategy for treating Parkinson’s disease.

The autophagy-lysosome pathway:a potential target in the chemical and gene therapeutic strategies for Parkinson’s disease

Parkinson’s disease is a common neurodegenerative disease with movement disorders associated with the intracytoplasmic deposition of aggregate proteins such asα-synuclein in neurons.As one of the major intracellular degradation pathways,the autophagy-lysosome pathway plays an important role in eliminating these proteins.Accumulating evidence has shown that upregulation of the autophagy-lysosome pathway may contribute to the clearance ofα-synuclein aggregates and protect against degeneration of dopaminergic neurons in Parkinson’s disease.Moreover,multiple genes associated with the pathogenesis of Parkinson’s disease are intimately linked to alterations in the autophagy-lysosome pathway.Thus,this pathway appears to be a promising therapeutic target for treatment of Parkinson’s disease.In this review,we briefly introduce the machinery of autophagy.Then,we provide a description of the effects of Parkinson’s disease–related genes on the autophagy-lysosome pathway.Finally,we highlight the potential chemical and genetic therapeutic strategies targeting the autophagy–lysosome pathway and their applications in Parkinson’s disease.

The pathogenesis of Parkinson’s disease and crosstalk with other diseases

In China,Parkinson’s disease(PD)is the second most prevalent central nervous system(CNS)degenerative illness affecting middle-aged and older persons.Movement disorders including resting tremor,bradykinesia,myotonia,postural instability,and gait instability are the predominant clinical symptoms.The two main types of PD are sporadic and familial,with sporadic PD being the more prevalent of the two.The environment,genetics,mitochondrial dysfunction,oxidative stress,inflammation,protein aggregation and misfolding,loss of trophic factors,cell death,and gut microbiota may all have a role in the etiology of PD.PD is inversely connected with other cancers and positively correlated with COVID-19,diabetes mellitus(DM),melanoma,and ischemic heart disease(IHD)risk.Delaying disease progression,managing motor and non-motor symptoms,and avoiding and controlling dysfunction in the middle and later phases of the disease are the key areas of research and development for its therapy.Presently,the development and progression of PD can be slowed down by using conventional pharmacology,natural items,and innovative technology.This article reviews the pathogenesis of PD,its correlations with other non-genetic diseases,and the research progress of drugs and technologies for alleviating PD.

Exercise and exerkine upregulation:Brain-derived neurotrophic factor as a potential non-pharmacological therapeutic strategy for Parkinson’s disease

Physical activity and exercise have several beneficial roles in enhancing both physiological and psychological well-being of an individual.In addition to aiding the regulation of aerobic and anaerobic metabolism,exercise can stimulate the synthesis of exerkine hormones in the circulatory system.Among several exerkines that have been investigated for their therapeutic potential,Brain-derived neurotrophic factor(BDNF)is considered the most promising candidate,especially in the management of neurodegenerative diseases.Owing to the ability of physical activity to enhance BDNF synthesis,several experimental studies conducted so far have validated this hypothesis and produced satisfactory results at the pre-clinical level.This review highlights some of the recent animal model studies that have evaluated the efficiency of exercise in enhancing BDNF synthesis and promoting neuroprotective effects.Further,this review focuses on understanding the therapeutic benefits of exercise-induced exerkine synthesis as a non-pharmacological strategy in Parkinson’s disease(PD).Regarding physical activity and exerkine induction,the neuromuscular electrical stimulation(NMES)strategy could be considered as an alternate treatment modality for patients affected with PD.

Future directions:combination of acupuncture with mesenchymal stem cells for Parkinson’s disease

Parkinson’s disease(PD)is a progressive chronic disease currently with no radical cure drugs and means due to the complex pathological mechanisms and limited regenerative capacity of neurons.Acupuncture aids in neuronal regeneration via various signaling routes like ROCK,Wnt,and Notch,safeguarding dopaminergic neurons against inflammation,oxidative stress,and cell death,which in turn enhances the progression of PD progression.Numerous research findings indicate that integrating acupuncture with mesenchymal stem cells(MSCs)transplantation is more effective than using either acupuncture or MSCs infusion alone.The combined treatment improves the survival rate of MSCs,promotes the generation of functional neural networks by stimulating the secretion of neurotrophic factors,and ultimately improves the disease microenvironment.In this review,we state the neuroprotective effects of acupuncture or MSCs treament alone in PD,then summarize the application of acupuncture combined with MSCs therapy in other diseases.Consequently,we anticipate that integrating acupuncture with MSCs transplantation may emerge as a novel and efficient approach for managing PD.This possibility needs to be verified through further basic and clinical research.

Design of a Biomedical Device to Reduce Anxiety Experienced by Patients Diagnosed with Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative disease that occurs due to loss of nerve cells that produce dopamine in the brain, affecting approximately 4 million people worldwide. PD patients often feel an increase in anxiety levels daily. While there are medications/exercises to help relieve anxiety, there are limited methods to reduce anxiety without the help of a caretaker. As a result, MEDIC Foundation, a non-profit organization in British Columbia, Canada, is designing an automated system that consists of a wristband and an application which uses vi-bration therapy to help reduce anxiety of PD patients. Literature reviews were conducted to document the project’s needs. Phase I of the project focused on de-veloping a prototype for the application and phase II on developing the wrist-band. The team developed prototypes of a wristband that automatically applies vibration near the median nerve as the heart rate variability (HRV) deviates away from the normal threshold of the user, and an application that displays real-time heart rate variability signals as well as provides for relaxation. The development of the prototype is still in early progress. By creating this automated system, we aim to provide a solution to senior PD patients to relieve anxiety independently. .

Depression in Patients with Parkinson’s Disease and the Associated Features

The study was aimed to examine the prevalence of depression in patients with Parkinson’s disease （PD） and identify its features. A total of 131 out-patients, diagnosed as having idiopathic PD in accordance with the United Kingdom Parkinson’s Disease Society Brain Bank criteria, were interviewed with questionnaire and evaluated by Mini-Mental State Examination （MMSE）, Unified Parkinson’s Disease Rating Scale （UPDRS）, Hohen ＆Yahr staging （H＆Y staging） and Hamilton Rating Scale for Depression （HRSD）. Patients were divided into three groups in terms of HRSD score： depression group, sub-threshold depression group and non-depression group. The clinical variables and symptom profiles were obtained and compared among the three groups. The results showed that 27 patients （20.6%） fell into the depression group, 71 （54.2%） into the sub-threshold depression group, and 33 （25.2%） into the non-depression group. There were no differences in age, gender or tremor score among the groups （P〉0.05）. Significant differences were found in duration of PD, UPDRS score, rigidity score and H＆Y stage between the sub-threshold depression group （or the depression group） and the non-depression group （P〈0.05）. Moreover, the clinical variables in the subthreshold depression group had the trend of increasing with the severity of PD and their values were similar to those in the depression group. Anhedonia, feeling of incapability, sleep disturbance, gastrointestinal symptoms and depressive moods were most common in the depression group. And these symptoms also were more common in the other two groups. It is concluded that depression and sub-threshold depression are common in PD and share similar clinical features. Furthermore, subthreshold depression might be the prodrome of depression and may develop into depression as the condition progresses.

Prevalence, clinical features and treatment of depression in Parkinson's disease: An update

Parkinson's disease(PD) is one of the most prevalent neurodegenerative diseases which typically affects individuals over 65 years. Although the symptomatology is predominantly motor, neuropsychiatric manifestations, e.g., depression, apathy, anxiety, and cognitive impairment occur in the course of the illness and can have a great impact on the quality of life in these patients. Parkinson's disease is commonly comorbid with depression with prevalence rates of depression, generally higher than those reported in general population. Depression in PD is frequently underestimated andconsequently undertreated, which have significant effects on the quality of life in these patients. The neurobiology of depression in PD is complex and involves alterations in dopaminergic, serotonergic, noradrenergic and possibly other neurotransmitter systems which are affected in the course of the disease. The tricyclic antidepressants and the selective serotonin reuptake inhibitors are the two classes of antidepressant drugs used for depressive symptoms in PD. Several published studies suggested that both classes are of comparable efficacy. Other serotonergic antidepressants, e.g., nefazodone and trazodone have also been of benefit. Meanwhile, there are limited data available on other drugs but these suggest a benefit from the serotonin and noradrenaline reuptake inhibitors such as mirtazapine, venlafaxine, atomoxetine and duloxetine. Some of the drugs used in symptomatic treatment of PD, e.g., the irreversible selective inhibitors of the enzyme monoamine oxidase-B, rasagiline and selegiline as well as the dopamine receptor agonist pramipexole are likely to have direct antidepressant activity independent of their motor improving action. This would make these drugs an attractive option in depressed subjects with PD. The aim of this review is to provide an updated data on the prevalence, clinical features of depression in subjects with PD. The effects of antiparkinsonian and antidepressant drugs on depressive symptoms in these patients are also discussed.

Neural stem cells for Parkinson’s disease management:Challenges,nanobased support,and prospects

Parkinson’s disease(PD),characterized by loss of nigrostriatal dopaminergic neurons,is one of the most predominant neurodegenerative diseases affecting the elderly population worldwide.The concept of stem cell therapy in managing neurodegenerative diseases has evolved over the years and has recently rapidly progressed.Neural stem cells(NSCs)have a few key features,including selfrenewal,proliferation,and multipotency,which make them a promising agent targeting neurodegeneration.It is generally agreed that challenges for NSC-based therapy are present at every stage of the transplantation process,including preoperative cell preparation and quality control,perioperative procedures,and postoperative graft preservation,adherence,and overall therapy success.In this review,we provided a comprehensive,careful,and critical discussion of experimental and clinical data alongside the pros and cons of NSC-based therapy in PD.Given the state-of-the-art accomplishments of stem cell therapy,gene therapy,and nanotechnology,we shed light on the perspective of complementing the advantages of each process by developing nano-stem cell therapy,which is currently a research hotspot.Although various obstacles and challenges remain,nano-stem cell therapy holds promise to cure PD,however,continuous improvement and development from the stage of laboratory experiments to the clinical application are necessary.

IMPACTS OF PENETRATION THERAPY WITH HEAD ELECTRICAL ACUPUNCTURE ON PROLIFERATION OF NEURAL STEM CELLS IN SUBSTANTIA NIGRA OF RAT MODEL OF PARKINSON'S DISEASE

Objective To probe into the function mechanism of penetration therapy with head electrical acupuncture on Parkinson＇s disease. Methods Microinjection of 6-hydroxydopamin （6-OHDA） on the left cor- pus striatum was adopted to prepare rotation model of Parkinson^s disease in rat. Penetration therapy with head electrical acupuncture was administered in treatment. Normal group, sham-operation group, model group and penetration therapy group were set up. （1）lmmunohistochemical （IHC） method was used to test the morphology and count of positive cell of tyrosine hydroxylase （TH）. （2）RT-PCR technology was used to detect the expression of nestin mRNA of neural stem cell （NSC）. Results （1）Compared with model group, in pene- tration therapy group, the expressions of TH-positive neurons in immune response were increased in areal density （AD）, numerical density （ND） and integrating optic density （P〈0.05）. （2）Compared with model group, in penetration therapy group, the expression of nestin mRNA was increased （P〈0. 05）. Conclusion Penetration therapy with head electrical acupuncture promotes the proliferation of endogenous neural stem cells in substantia nigra of rat model of Parkinson＇s disease.

Neurotrophic factor therapy for Parkinson's disease: past, present and future

One of the greatest unmet needs in the treatment of Parkinson’s disease（PD）is a disease-modifying therapy,which can halt the ongoing degeneration of dopaminergic neurons that is characteristic of this disorder.Current therapies focus on managing symptoms,rather than on addressing their cause.Promising candidates for disease-modifying therapies are the dopaminergic neurotrophic factors（NTFs）.

Gene therapy in Parkinson's disease: targeting the endplasmic reticulum proteostasis network

Parkinson’s disease（PD）is the second most common neurodegenerative disease affecting 1%of the population over 60 years of age.The progressive degeneration of dopaminergic neurons at the substantia nigra pars compacta（SNpc）results in a severe and gradual depletion of dopamine content in the striatum,a phenomena that is responsible for the characteristic motor symptoms of this disease.

Why and how does light therapy offer neuroprotection in Parkinson＇s disease？

Red and infrared light （X = 600-1,070 nm） therapy, known also as photobiomodulation, has been reported to offer neu-roprotection and to improve locomotor behaviour in animal models of Parkinson＇s disease, from rodents to non-human primates （Rojas and Gonzalez-Lima, 2011; Hamblin, 2016; Johnstone et al., 2016）. The neuroprotective aspect of this therapy is particularly relevant; the saving of neurons that would normally die as a result of the parkinsonian degeneration, is without doubt,

Preliminary Network Centric Therapy for Machine Learning Classification of Deep Brain Stimulation Status for the Treatment of Parkinson’s Disease with a Conformal Wearable and Wireless Inertial Sensor

The concept of Network Centric Therapy represents an amalgamation of wearable and wireless inertial sensor systems and machine learning with access to a Cloud computing environment. The advent of Network Centric Therapy is highly relevant to the treatment of Parkinson’s disease through deep brain stimulation. Originally wearable and wireless systems for quantifying Parkinson’s disease involved the use a smartphone to quantify hand tremor. Although originally novel, the smartphone has notable issues as a wearable application for quantifying movement disorder tremor. The smartphone has evolved in a pathway that has made the smartphone progressively more cumbersome to mount about the dorsum of the hand. Furthermore, the smartphone utilizes an inertial sensor package that is not certified for medical analysis, and the trial data access a provisional Cloud computing environment through an email account. These concerns are resolved with the recent development of a conformal wearable and wireless inertial sensor system. This conformal wearable and wireless system mounts to the hand with the profile of a bandage by adhesive and accesses a secure Cloud computing environment through a segmented wireless connectivity strategy involving a smartphone and tablet. Additionally, the conformal wearable and wireless system is certified by the FDA of the United States of America for ascertaining medical grade inertial sensor data. These characteristics make the conformal wearable and wireless system uniquely suited for the quantification of Parkinson’s disease treatment through deep brain stimulation. Preliminary evaluation of the conformal wearable and wireless system is demonstrated through the differentiation of deep brain stimulation set to “On” and “Off” status. Based on the robustness of the acceleration signal, this signal was selected to quantify hand tremor for the prescribed deep brain stimulation settings. Machine learning classification using the Waikato Environment for Knowledge Analysis (WEKA) was applied using the multilayer perceptron neural network. The multilayer perceptron neural network achieved considerable classification accuracy for distinguishing between the deep brain stimulation system set to “On” and “Off” status through the quantified acceleration signal data obtained by this recently developed conformal wearable and wireless system. The research achievement establishes a progressive pathway to the future objective of achieving deep brain stimulation capabilities that promote closed-loop acquisition of configuration parameters that are uniquely optimized to the individual through extrinsic means of a highly conformal wearable and wireless inertial sensor system and machine learning with access to Cloud computing resources.

Promising use of metformin in treating neurological disorders:biomarker-guided therapies

Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebrovascular conditions(stroke),and neurodevelopmental disorders(autism spectrum disorder).Although they affect millions of individuals around the world,only a limited number of effective treatment options are available today.Since most neurological disorders express mitochondria-related metabolic perturbations,metformin,a biguanide type II antidiabetic drug,has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism.However,controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders.Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging,lifestyle,genetics,and environment,it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders.These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment,ultimately developing targeted therapy.In this review,we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.

Real world studies are essential for drug therapy in Parkinson's disease

Prospective real-world data from large patient samples, which re- port on the long-term effectiveness of the employed different drug therapies, are rare in Parkinson＇s disease （PD）. The non interven- tional ＂Transdermal Rotigotine User Surveillance Study＂ （TRUST） trial represents such a real-world study. It investigated long-term treatment with different dopamine substituting treatment regimens in 2195 PD patients （Mfiller et al., 2018）. Participation in TRUST meant that the treating neurologists were only asked to document and modify the dopaminergic drug regimen without any prior PD patient selection criteria. Thus this unique trial design reflects the real world of patient maintenance.

Comparison of continuous versus pulsatile dopaminergic therapy in the erderly with Parkinson’s Disease

Objective: Levodopa is the gold-standard of therapy in Parkinson’s disease (PD), but it is associated with motor complications that affect 50% of patients after five years of treatment. Development of delirium and psychosis is the main limitation of dopaminergic treatment in older persons. These adverse effects may result from pulsatile stimulation of the dopamine receptors. Dopamine agonists with transdermal delivery that continuously stimulate the dopamine receptors may reduce these complications. The objective of this study was to evaluate the frequencies of acute delirium and psychosis in elderly patients treated with rotigotine vs. levodopa in a newly diagnosed drugnaive Parkinson’s disease (PD). Methods: Patients admitted to the Geriatric-Rehabilitation Department of the University-Hospital of Parma were screened for the presence of Parkinsonism. All subjects admitted with diagnosis of PD according to the UK Brain Bank Criteria were randomly treated with Rotigotine or levodopa. All subjects were assessed by Movement Disorder Society (MDS)-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III. Acute delirium was asessed by CAM Diagnostic Algorithm during the first week after admission. After six months, diagnosis of psychosis was performed according to pro posed diagnostic criteria by NINDS and NIMH. Patients with cognitive impairment (MMSE dementia with Lewy bodies (DLB), were excluded. Results: 60 consecutive newly diagnosed drugnaive PD patients were evaluated. No statistical significant difference between the two groups were observed in term of age, gender, MMSE score, severity of disease expressed by H&Y staging. 30 patients were treated with rotigotine (6 mg/daily) and 30 patients were treated with L-Dopa (250 mg/daily). All participants completed the study. UPDRS Part III was statistical significant lower in both groups after treatment from 26.4 to 18.3 (rotigotine group) and from 26.3 to 17.3 (levodopa group), but comparable within groups (p = 0.83). After 6-month follow-up, acute delirium and/ or psychosis were observed in two cases (6.6%) of patients treated with rotigotine and in three cases (10%) of those treated with levodopa (p = 0.54). Conclusions: Transdermal rotigotine seems comparable to levodopa in regard to motor skill efficacy and neuropsychiatric safety, because provides a more continuous delivery of drug. Dopamine agonists may represent a valid therapeutic option in newly diagnosed older PD patients.

Gene therapy for Parkinson's disease: a decade of progress supported by posthumous contributions from volunteer subjects

Over the past decade,nine separate gene therapy clinical trials for advanced Parkinson’s disease（PD）have been launched and completed,involving the dosing of nearly 12-dozen PD volunteers who incurred significant risks to hopefully reduce symptoms and gain a better life.

Characteristics and advantages of adeno-associated virus vector-mediated gene therapy for neurodegenerative diseases

Common neurodegenerative diseases of the central nervous system are characterized by progressive damage to the function of neurons, even leading to the permanent loss of function. Gene therapy via gene replacement or gene correction provides the potential for transformative therapies to delay or possibly stop further progression of the neurodegenerative disease in affected patients. Adeno-associated virus has been the vector of choice in recent clinical trials of therapies for neurodegenerative diseases due to its safety and efficiency in mediating gene transfer to the central nervous system. This review aims to discuss and summarize the progress and clinical applications of adeno-associated virus in neurodegenerative disease in central nervous system. Results from some clinical trials and successful cases of central neurodegenerative diseases deserve further study and exploration.

A novel method for evaluating brain function and microstructural changes in Parkinson's disease

In this study,microstructural brain damage in Parkinson＇s disease patients was examined using diffusion tensor imaging and tract-based spatial statistics.The analyses revealed the presence of neuronal damage in the substantia nigra and putamen in the Parkinson＇s disease patients.Moreover,disease symptoms worsened with increasing damage to the substantia nigra,confirming that the substantia nigra and basal ganglia are the main structures affected in Parkinson＇s disease.We also found that microstructural damage to the putamen,caudate nucleus and frontal lobe positively correlated with depression.Based on the tract-based spatial statistics,various white matter tracts appeared to have microstructural damage,and this correlated with cognitive disorder and depression.Taken together,our results suggest that diffusion tensor imaging and tract-based spatial statistics can be used to effectively study brain function and microstructural changes in patients with Parkinson＇s disease.Our novel findings should contribute to our understanding of the histopathological basis of cognitive dysfunction and depression in Parkinson＇s disease.