Limitations of cellular models in Parkinson's disease research

Cell cultures for Parkinson's disease research have the advantage of virtually unlimited access, they allow rapid screening for disease pathogenesis and drug candidates, and they restrict the necessary number of animal experiments. Limitations of cell cultures, include that the survival of neurons is dependent upon the culture conditions; that the cells do not develop their natural neuronal networks. In most cases, neurons are deprived from the physiological afferent and efferent connections. In Parkinson's disease research, mesencephalic slice cultures, primary immature dopaminergic neurons and immortalized cell lines--either in a proliferating state or in a differentiated state--are used. Neuronal cultures may be plated in the presence or absence of glial cells and serum. These different culture conditions as well as the selection of outcome parameters (morphological evaluation, viability assays, biochemical assays, metabolic assays) have a strong influence on the results of the experiments and the conclusions drawn from them. A primary example is the question of whether L-Dopa is toxic to dopaminergic neurons or whether it provides neurotrophic effects: In pure, neuronal-like cultures, L-Dopa provides toxicity, whereas in the presence of glial cells, it provides trophic effects when applied. The multitude of factors that influence the data generated from cell culture experiments indicates that in order to obtain clear-cut and unambiguous results, investigators need to choose their model carefully and are encouraged to verify their main results with different models.     

Surgical therapy for Parkinson's disease

Surgical therapies for Parkinson's disease (PD) are now being performed with increasing frequency due to the limitations of conventional dopaminergic therapies, improvements in operative procedures, and increased information on the organization of the basal ganglia in normal and pathologic conditions. Ablation procedures have now been largely replaced with deep brain stimulation, which permits benefits to be obtained without the need to make a destructive brain lesion. Several studies now demonstrate the value of stimulating the subthalamic nucleus or the globus pallidus pars interna in patients with advanced PD. Nonetheless, there are limitations associated with these procedures and benefits do not exceed those obtained with levodopa, albeit with reduced motor complications. Fetal transplantation remains an experimental procedure that has shown limited benefits in a double‐blind trial and is complicated by persistent dyskinesia. Stem cell, trophic factor, and gene therapy approaches are promising and are currently under intensive investigation.     

Gene therapy for Parkinson's disease

Advances in molecular biology and virology in recent years have enabled the technology of gene transfer to proceed forward. Parkinson's disease (PD) is a particularly appropriate target for gene therapy since the brain pathology is fully characterized and relatively well circumscribed largely within the nigrostriatal dopaminergic neurons. In addition, the search for genetic mutations responsible for familial forms of PD has accelerated in recent years with several genes or loci already identified. Mutations in the parkin gene are linked to the autosomal recessive form known as autosomal recessive juvenile parkinsonism, park2. Therefore, parkin gene therapy can be effective in PD caused by parkin gene mutations, which are inherited as an autosomal recessive trait. Intriguingly, several studies, including our reports, have suggested the possibility that parkin gene therapy could treat a subset of patients with PD who have mutations in the alpha-synuclein gene. Furthermore, if indeed parkin overexpression broadly corrects anatomical degeneration in the substantia nigra and striatum, this might be a potential therapy for alpha-synucleinopathy.     

GDNF therapy for Parkinson's disease

With an increase in the aging population, the incidence of Parkinson's disease (PD), a disabling neurodegenerative disorder mainly affecting motor function, will inevitably present a challenge to an already overburdened healthcare system. Current medical and surgical therapies offer symptomatic relief but do not provide a cure. Experimental studies suggest that GDNF has the ability to protect degenerating dopamine neurons in PD as well as promote regeneration of the nigrostriatal dopamine system. However, clinical trials of GDNF infusion to date remain inconclusive. This review will examine the experimental and clinical evidence of GDNF use in PD with particular focus on its potential as an effective therapy in the treatment of PD.     

Drug therapy for Parkinson's disease

The fundamental concepts of the medical treatment of Parkinson's disease are simple, and remain based on the enhancement of dopaminergic transmission by means of levodopa and dopamine agonists. Recently published practice parameters from the American Academy of Neurology and an evidence-based review under the auspices of the Movement Disorder Society provide guidance on motor complications and also cognitive and psychiatric issues associated with Parkinson's disease. The choices of medications are increasing as are the routes of administration, with the arrival of injectable and transdermal dopamine agonists and a monoamine inhibitor absorbed via the buccal mucosa. Although simple conceptually, the actual care of patients with Parkinson's disease is often complex, requiring consideration of potential future complications and individualized medication regimens, and minimizing the adverse effects of medications that range from unpleasant to seriously disturbing.     

Isoniazid therapy in Parkinson's disease

The effect of isoniazid on levodopa-induced dyskinesias has been evaluated in 20 patients with Parkinson's disease, following a serendipitous observation that choreic dyskinesias induced by levodopa in one parkinsonian patient were markedly reduced during treatment with isoniazid for tuberculous infection. A mean average isoniazid dose of 290 mg was given without any change in current antiparkinsonian treatment. "Benefit of dose" choreic dyskinesias were markedly reduced in 18 patients within the first few weeks of treatment. This effect was accompanied by an intolerable worsening of parkinsonian signs. All patients returned to their basal situation after isoniazid interferes with the therapeutic action of levodopa and dopamine agonists. The precise mechanism by which this action occurred is not known, but several possible explanations are discussed.     

Ropinirole therapy for Parkinson's disease

Ropinirole (Requip, GlaxoSmithKline) is a novel nonergoline dopamine D2 agonist indicated for the treatment of early and advanced Parkinson's disease. It is mainly metabolized by the liver and its elimination half-life is approximately 5.8 h. When used as monotherapy in early Parkinson's disease, ropinirole improves signs and symptoms of the disorder. When used as an adjunct to levodopa in advanced Parkinson's disease patients with motor fluctuations, ropinirole reduces off time and allows a reduction of levodopa dose. The initial use of ropinirole in early Parkinson's disease to which levodopa is added when necessary, has been demonstrated to lead to a lower incidence of dyskinesias compared with treatment with levodopa alone. An 18F-dihydroxyphenylalanine positron emission tomography study suggested the possibility that ropinirole could slow the progression of loss of dopamine neurons compared with treatment with levodopa but this remains to be proven. Side effects of ropinirole include nausea, somnolence, edema, orthostatic hypotension, hallucinations and dyskinesia. A once-daily formulation of ropinirole is currently in development that has the potential for greater convenience, improved tolerability and greater efficacy.     

Art therapy for Parkinson's disease

ObjectiveTo explore the potential rehabilitative effect of art therapy and its underlying mechanisms in Parkinson's disease (PD).MethodsObservational study of eighteen patients with PD, followed in a prospective, open-label, exploratory trial. Before and after twenty sessions of art therapy, PD patients were assessed with the UPDRS, Pegboard Test, Timed Up and Go Test (TUG), Beck Depression Inventory (BDI), Modified Fatigue Impact Scale and PROMIS-Self-Efficacy, Montreal Cognitive Assessment, Rey-Osterrieth Complex Figure Test (RCFT), Benton Visual Recognition Test (BVRT), Navon Test, Visual Search, and Stop Signal Task. Eye movements were recorded during the BVRT. Resting-state functional MRI (rs-fMRI) was also performed to assess functional connectivity (FC) changes within the dorsal attention (DAN), executive control (ECN), fronto-occipital (FOC), salience (SAL), primary and secondary visual (V1, V2) brain networks. We also tested fourteen age-matched healthy controls at baseline.ResultsAt baseline, PD patients showed abnormal visual-cognitive functions and eye movements. Analyses of rs-fMRI showed increased functional connectivity within DAN and ECN in patients compared to controls. Following art therapy, performance improved on Navon test, eye tracking, and UPDRS scores. Rs-fMRI analysis revealed significantly increased FC levels in brain regions within V1 and V2 networks.InterpretationArt therapy improves overall visual-cognitive skills and visual exploration strategies as well as general motor function in patients with PD. The changes in brain connectivity highlight a functional reorganization of visual networks.     

Gene therapy for Parkinson's disease

Parkinson's disease is a chronic and progressive disorder whose treatment does not prevent middle term appearance of invalidating motor and psychic complications. Gene therapy techniques which are increasingly applied in the field of neurodegenerative diseases are added to the possibility of treatment of this disease. Among the existing modalities, the in vivo strategies that use potent viral vectors are those which have obtained the best results in the different existing models of the disease. This article aims to review the information regarding the use of these latter techniques, the therapeutic trials that have been conducted and the advantages and disadvantages that the use of the different vectors have.     

帕金森病的手术治疗

帕金森病(PD)为常见于中老年人群的中枢神经系统变性疾病,以震颤、肌强直和运动减少为典型临床表现,其主要病理特征为黑质-纹状体系统多巴胺能神经元进行性变性、死亡。左旋多巴尚未研制用于临床之前,外科手术曾经是治疗帕金森病的主要方法。早期手术靶点包括大脑皮质、大脑脚、皮质脊髓速等,这些手术靶点在部分缓解帕金森病症状的同时,必然导致患者肢体瘫痪。1940年以     

Vasopressin therapy in Parkinson's disease

A double-blind crossover pilot study was carried out in six patients with Parkinson's disease in order to test the possible therapeutic effect of L-vasopressin after treatment for 1 month with 30 I.U. intranasally daily. The investigation was completed in five cases. No effect was noticed after LVP treatment.     

Surgical therapy for Parkinson's disease

High frequency stimulation (HFS) has become the main alternative to medical treatment, due to its reversibility, adaptability, and low morbidity. Initiated in the thalamus (Vim) for the control of tremor, HFS has been applied to the Pallidum (GPi), and then to the subthalamic nucleus (STN), suggested by experiments in MPTP monkeys. STN-HFS is highly efficient on tremor, rigidity and bradykinesia and is now widely applied. Criteria for success are correct patient selection and precise electrode placement. The best outcome predictor is the response to Levodopa. The mechanisms of action might associate inhibition of cell firing, jamming of neuronal message and exhaustion of synaptic neurotransmitter release. The inhibition of glutamate STN release could be neuroprotective on nigral cells. Animal experiments support this hypothesis, not contradicted by the long-term follow up of patients. Neuroprotection might have considerable impact on the management of PD patient and warrants clinical trials.     

Gene therapy for Parkinson's disease

We review recent progress in gene therapy utilizing experimental parkinsonian models including our data. Investigation of ex vivo gene therapy for Parkinson's disease (PD) is to provide L-dopa by transplantation of genetically modified cells into the striatum. Recently, neuronal progenitor cells (NPC) are recognized as the most appropriate target population for such genetic and cellular therapy of PD. We have developed modified pseudo-typed retrovirus production system. Using this gene transfer system, it is easy and efficient to introduce the gene into NPC because high titer virus vector is easily obtained. For the in vivo gene therapy, adeno-associated virus (AAV) vector is best virus vector because it is easy to introduce gene into neurons without inflammatory reaction. We established in vivo models of the inhibition of the caspase-cascade by overexpression of apoptotic protease activating factor-1-dominant negative inhibitor (Apaf-1-DN) using AAV vector. We showed that Apaf-1-DN delivery using an AAV vector system could prevent nigrostriatal degeneration in MPTP mice, suggesting that it might be an anti-mitochondrial apoptotic gene therapy for PD.     

Physical therapy and occupational therapy in Parkinson's disease

Current medical management is only partially effective in controlling the symptoms of Parkinson's disease. As part of comprehensive multidisciplinary care, physical therapy and occupational therapy aim to support people with Parkinson's disease in dealing with the consequences of their disease in daily activities. In this narrative review, we address the limitations that people with Parkinson's disease may encounter despite optimal medical management, and we clarify both the unique and shared approaches that physical therapists and occupational therapists can apply in treating these limitations.