Cryothalamectomy for Parkinson's Disease

In a review of 61 patients with Parkinson''s disease who were treated by cryothalamectomy, the technique of freezing a surgical target as compared with destroying it by alcohol or thermal heat was found effective and to a degree safer than other techniques. One patient died of unexpected cerebral hemorrhage. Of patients considered excellent candidates for the operation, 80 per cent had excellent and good results, while those considered good candidates showed 85 per cent excellent and good results. The results are more dependent on the selection of the patient as a candidate and the diffuseness of the pathophysiological circuits involved than on the technical factors of the cryogenic procedure.     

Development of an Alpha-synuclein Based Rat Model for Parkinson's Disease via Stereotactic Injection of a Recombinant Adeno-associated Viral Vector

In order to study the molecular pathways of Parkinson''s disease (PD) and to develop novel therapeutic strategies, scientific investigators rely on animal models. The identification of PD-associated genes has led to the development of genetic PD models. Most transgenic α-SYN mouse models develop gradual α-SYN pathology but fail to display clear dopaminergic cell loss and dopamine-dependent behavioral deficits. This hurdle was overcome by direct targeting of the substantia nigra with viral vectors overexpressing PD-associated genes. Local gene delivery using viral vectors provides an attractive way to express transgenes in the central nervous system. Specific brain regions can be targeted (e.g. the substantia nigra), expression can be induced in the adult setting and high expression levels can be achieved. Further, different vector systems based on various viruses can be used. The protocol outlines all crucial steps to perform a viral vector injection in the substantia nigra of the rat to develop a viral vector-based alpha-synuclein animal model for Parkinson''s disease.     

Cell Transplantation for Parkinson's Disease: Present Status

1. Parkinson's disease (PD) is a neurodegenerative disorder caused by the loss of neurons in the substantia nigra pars compacta and a striatal deficiency of dopamine. PD typically affects people in late middle age and progresses slowly. In the early stages of the disease, treatment targeting the dopaminergic network is effective. However, with disease progression, transplantation is an option for repairing and replacing missing dopaminergic neurons. 2. In this review, we evaluate the tissue grafts and cellular therapies that have and are being considered. Clinical trials were originally derived from transplants of adrenal medullary chromaffin cells and embryonic nigral dopaminergic neurons in patients with PD. 3. Recently, novel molecular and cellular treatments are being utilized in animals and these include embryonic stem cells, fetal cells from pigs, or transfected cells. In spite of new molecular techniques and some 20 years of experience, the transplantation therapy for PD has today the same problems and results as the first reports which used neural fetal tissue or adrenal grafts.     

Disease model: Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is primarily characterized by the degeneration of dopaminergic neurons in the nigrostriatal pathway. The pathology of PD is typified by the presence of cytoplasmic inclusions (Lewy bodies) containing alpha-synuclein and ubiquitin. The pathogenesis of PD is not completely understood but environmental and genetic factors are thought to play important roles. To understand the pathophysiology of PD, and to develop novel therapies for improved symptomatic management, it is important to have relevant disease models. In this review, we summarize the available in vivo and in vitro models of PD and discuss their value.     

Neural Transplantation for Parkinson's Disease

1. Neural transplantation is one promising approach for the treatment of Parkinson's disease. Fetal substantia nigra cells are a good source of dopamine, but in order to avoid ethical and immunological problems, adrenal medullary chromaffin cells have been investigated as an alternative source.2. Grafted adrenal medullary chromaffin cells can provide dopamine as well as several neurotrophic factors that affect dopaminergic neurons in the brain.3. We review experimental studies for application of neural transplantation techniques in Parkinson's disease, including immunological studies, cryopreservation, microvasculature, donor tissue, and direct gene delivery studies performed in our laboratory. Our clinical experience and new approach involving a polymer-encapsulated cell grafting procedure are also described.     

Results of Thalamotomy for Parkinson's Disease

Surgical destruction of a portion of the ventrolateral nucleus of the thalamus is currently the procedure of choice for the treatment of incapacitating tremor and rigidity of parkinsonism. Seventy-three patients were treated by 105 thalamotomies at the University of Alberta Hospital and assessed one to four years later for improvement of function in everyday activities. Fifty-six patients were improved, 12 were unchanged, and five had died. Only two of the deaths were related to the operation. Paresis was permanent in only one patient. Twenty-five patients had bilateral operations and 22 of these showed improvement of function. Contraindications to operation include serious cardiovascular disease, mental deterioration, and those parkinsonian patients whose disability is chiefly due to akinesia, oculogyric crisis, dysphasia or dysarthria.     

帕金森病和阿尔茨海默氏病的基因治疗研究进展

帕金森病和阿尔茨海默氏病是世界范围内最普遍的神经退行性疾病.常规药物和手术治疗只能缓解症状,不能推迟或者终止疾病进程.近年来分子生物学与医学研究进展促进了对帕金森病和阿尔茨海默氏病发病机制的深入了解,为其基因治疗策略提供了理论和实验依据.综述了目前帕金森病、阿尔茨海默氏病的基因治疗研究进展.基因治疗作为帕金森病和阿尔茨海默氏病的一种全新治疗手段,无疑对于了解帕金森病和阿尔茨海默氏病的病因及其全面治疗具有重要意义.     

Parkinson's Disease: Mechanisms of Neuronal Death

Based on the published data, the authors analyze in detail events resulting in the death of neurons in the substantia nigra (according to the apoptosis scenario) and in the development of Parkinson's disease (idiopathic parkinsonism).     

帕金森病的细胞治疗研究进展

干细胞为治疗帕金森病提供了新的希望.目前用于研究的干细胞主要有神经干细胞、胚胎干细胞、诱导多功能干细胞、间充质干细胞等.本文回顾了上述细胞在移植治疗帕金森病研究中的进展,并介绍了近期出现的将体细胞直接重编程为神经细胞或神经干细胞的新技术.     

An Objective Fluctuation Score for Parkinson's Disease

Introduction

Establishing the presence and severity of fluctuations is important in managing Parkinson’s Disease yet there is no reliable, objective means of doing this. In this study we have evaluated a Fluctuation Score derived from variations in dyskinesia and bradykinesia scores produced by an accelerometry based system.

Methods

The Fluctuation Score was produced by summing the interquartile range of bradykinesia scores and dyskinesia scores produced every 2 minutes between 0900-1800 for at least 6 days by the accelerometry based system and expressing it as an algorithm.

Results

This Score could distinguish between fluctuating and non-fluctuating patients with high sensitivity and selectivity and was significant lower following activation of deep brain stimulators. The scores following deep brain stimulation lay in a band just above the score separating fluctuators from non-fluctuators, suggesting a range representing adequate motor control. When compared with control subjects the score of newly diagnosed patients show a loss of fluctuation with onset of PD. The score was calculated in subjects whose duration of disease was known and this showed that newly diagnosed patients soon develop higher scores which either fall under or within the range representing adequate motor control or instead go on to develop more severe fluctuations.

Conclusion

The Fluctuation Score described here promises to be a useful tool for identifying patients whose fluctuations are progressing and may require therapeutic changes. It also shows promise as a useful research tool. Further studies are required to more accurately identify therapeutic targets and ranges.     

Prostaglandin H Synthetase-Mediated Metabolism of Dopamine: Implication for Parkinson's Disease

Abstract: Differences in prostaglandin H synthetase (PHS) activity in the substantia nigra of age- and post-mortem interval-matched parkinsonian, Alzheimer's, and normal control brain tissue were assessed. Prostaglandin E₂ (PGE₂, an index of PHS activity) was higher in substantia nigra of parkinsonian brain tissue than Alzheimer's or control tissue. Incubation of substantia nigra slices with arachidonic acid (AA) increased PGE₂ synthesis. Dopamine stimulated PHS synthesis of PGE₂. [³H]Dopamine was activated by PHS to electrophilic intermediate(s) that covalently bound to DNA, microtubulin protein, bovine serum albumin, and sulfhydryl reagents. When AA was replaced by hydrogen peroxide, PHS/H₂O₂-supported binding proceeded at rates similar to those observed with PHS/AA. Indomethacin and aspirin inhibited AA-mediated cooxidation of dopamine but not H₂O₂-mediated metabolism. PHS-mediated metabolism of dopamine was not affected by monoamine oxidase inhibitors. Substrate requirements and effects of specific inhibitors suggest cooxidation of dopamine is mediated by the hydroperoxidase activity of PHS. ³²P-postlabeling was used to detect dopamine-DNA adducts. PHS/AA activation of dopamine in the presence of DNA resulted in the formation of five dopamine-DNA adducts, i.e., 23, 43, 114, 70, and 270 amol/µg DNA. DNA adduct formation was PHS, AA, and dopamine dependent. PHS catalyzed cooxidation of dopamine in dopaminergic neuronal degeneration is discussed.     

Parkinson's Disease: From Genetics to Clinical Practice

Breakthroughs in genetics over the last decade have radically advanced our understanding of the etiological basis of Parkinson''s disease (PD). Although much research remains to be done, the main genetic causes of this neurodegenerative disorder are now partially unraveled, allowing us to feel more confident that our knowledge about the genetic architecture of PD will continue to increase exponentially. How and when these discoveries will be introduced into general clinical practice, however, remains uncertain. In this review, we provide a general summary of the progress in the genetics of PD and discuss how this knowledge will contribute to the diagnosis and clinical management of patients with, or at risk of this disorder.     

Stereotaxical Infusion of Rotenone: A Reliable Rodent Model for Parkinson's Disease

A clinically-related animal model of Parkinson''s disease (PD) may enable the elucidation of the etiology of the disease and assist the development of medications. However, none of the current neurotoxin-based models recapitulates the main clinical features of the disease or the pathological hallmarks, such as dopamine (DA) neuron specificity of degeneration and Lewy body formation, which limits the use of these models in PD research. To overcome these limitations, we developed a rat model by stereotaxically (ST) infusing small doses of the mitochondrial complex-I inhibitor, rotenone, into two brain sites: the right ventral tegmental area and the substantia nigra. Four weeks after ST rotenone administration, tyrosine hydroxylase (TH) immunoreactivity in the infusion side decreased by 43.7%, in contrast to a 75.8% decrease observed in rats treated systemically with rotenone (SYS). The rotenone infusion also reduced the DA content, the glutathione and superoxide dismutase activities, and induced alpha-synuclein expression, when compared to the contralateral side. This ST model displays neither peripheral toxicity or mortality and has a high success rate. This rotenone-based ST model thus recapitulates the slow and specific loss of DA neurons and better mimics the clinical features of idiopathic PD, representing a reliable and more clinically-related model for PD research.