Oxidative stress plays an important role in the degeneration of dopaminergic neurons in Parkinson's disease (PD). Disruptions in the physiologic maintenance of the redox potential in neurons interfere with several biological processes, ultimately leading to cell death. Evidence has been developed for oxidative and nitrative damage to key cellular components in the PD substantia nigra. A number of sources and mechanisms for the generation of reactive oxygen species (ROS) are recognized including the metabolism of dopamine itself, mitochondrial dysfunction, iron, neuroinflammatory cells, calcium, and aging. PD causing gene products including DJ-1, PINK1, parkin, alpha-synuclein and LRRK2 also impact in complex ways mitochondrial function leading to exacerbation of ROS generation and susceptibility to oxidative stress. Additionally, cellular homeostatic processes including the ubiquitin-proteasome system and mitophagy are impacted by oxidative stress. It is apparent that the interplay between these various mechanisms contributes to neurodegeneration in PD as a feed forward scenario where primary insults lead to oxidative stress, which damages key cellular pathogenetic proteins that in turn cause more ROS production. Animal models of PD have yielded some insights into the molecular pathways of neuronal degeneration and highlighted previously unknown mechanisms by which oxidative stress contributes to PD. However, therapeutic attempts to target the general state of oxidative stress in clinical trials have failed to demonstrate an impact on disease progression. Recent knowledge gained about the specific mechanisms related to PD gene products that modulate ROS production and the response of neurons to stress may provide targeted new approaches towards neuroprotection.

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The Role of Oxidative Stress in Parkinson’s Disease

Statistical Methods in Medical Research.

Meta-analysis in epidemiology, with special reference to studies of the association between exposure to environmental tobacco smoke and lung cancer: A critique

OBJECTIVES To report on a 10 year follow up of patients with idiopathic Parkinson’s disease, particularly with respect to mortality and the effect of early treatment with bromocriptine. METHODS The patients are from the 149 new patients recruited for a double blind, randomised study of low dose levodopa-carbidopa versus low dose bromocriptine. Patients were examined neurologically at least yearly. Neuropsychological examinations were performed at 0, 3, 5, and 10 years. Mortality and cause of death in these patients were compared with the Australian population using standardised mortality ratios (SMRs). Mortality and disease progression were compared by sex and treatment group. Predictors of death within 10 years, nursing home admission, and progression in Columbia score of ⩾20 points were examined by logistic regression analysis. RESULTS Thirteen patients were excluded as having atypical Parkinsonism and six were lost to follow up. All available patients have been followed up for 10 years. Fifty patients (38%) were dead by 10 years and 63 by the last follow up. The SMR was 1.58 for all patients (p CONCLUSIONS Mortality in Parkinson’s disease remains increased despite low dose levodopa-carbidopa therapy and no additional benefit was gained from early use of bromocriptine. Duration of disease was similar to that in the era before levodopa.

https://jnnp.bmj.com/content/jnnp/67/3/300.full.pdf

The sydney multicentre study of Parkinson's disease: progression and mortality at 10 years.

The aim of the study was to provide evidence-based recommendations for the management of early (uncomplicated) Parkinson's disease (PD), based on a review of the literature. Uncomplicated PD refers to patients suffering from the classical motor syndrome of PD only, without treatment-induced motor complications and without neuropsychiatric or autonomic problems. MEDLINE, Cochrane Library and International Network of Agencies for Health Technology Assessment (INAHTA) database literature searches were conducted. National guidelines were requested from all European Federation of Neurological Societies (EFNS) societies. Non-European guidelines were searched for using MEDLINE. Part I of the guidelines deals with prevention of disease progression, symptomatic treatment of motor features (parkinsonism), and prevention of motor and neuropsychiatric complications of therapy. For each topic, a list of therapeutic interventions is provided, including classification of evidence. Following this, recommendations for management are given, alongside ratings of efficacy. Classifications of evidence and ratings of efficacy are made according to EFNS guidance. In cases where there is insufficient scientific evidence, a consensus statement (good practice point) is made.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1468-1331.2006.01548.x

Review of the therapeutic management of Parkinson's disease. Report of a joint task force of the European Federation of Neurological Societies and the Movement Disorder Society–European Section. Part I: early (uncomplicated) Parkinson's disease

Long-term levodopa treatment in Parkinson's disease is typically associated with “motor side effects” consisting in dyskinesias and/or fluctuations in motility referred to as the on-off phenomena. The main objective of this prospective, randomized, multi-centre study was to determine to what extent the development of such complications could be prevented by partial substitution of levodopa monotherapy (L-DOPA/benserazide) by bromocriptine in patients with early symptoms of the disease. The basic trial population included 674 newly diagnosed Parkinsonian patients that were randomly allocated to monotherapy with levodopa or a combination therapy based upon a nearly 40% replacement of levodopa by bromocriptine. The two target regimens had to be consistently maintained for 42 months. Parkinsonian symptoms were assessed by means of the Webster rating scale, the Hoehn and Yahr scale, and the Zung Self-Rating Depression scale. Motor side effects and adverse events were recorded at each regular clinic visit. Neurological symptoms improved and stabilized in a similar manner during treatment with both regimens throughout the study period. Motor side effects were observed in more patients on levodopa alone than on combination therapy (28.8 vs 20%; p=0.008). According to Kaplan-Meier estimates the cumulative probability of experiencing motor side effects was 0.43 on monotherapy, compared to 0.28 on combination therapy, which was equal to a one third reduction of risk (p=0.025). In regard to motor side effects, the degree of substitution of levodopa proved relevant: patients with >50% substitution by bromocriptine exhibited half the risk observed in those with 30%) as first-line treatment of Parkinson's disease proves active in the prophylaxis of levodopa associated motor side effects. Early combination therapy therefore extends the period of optimal disease control.

Early institution of bromocriptine in Parkinson's disease inhibits the emergence of levodopa-associated motor side effects. Long-term results of the PRADO study.

L-Dopa supplemented by a peripheral decarboxylase inhibitor is considered the most potent therapeutic regimen prolonging active life in Parkinsonian patients. The long-term benefit of therapy is limited by adverse effects, such as dyskinesia and on-off phenomena, which can be mitigated by the concomitant administration of dopamine agonists, such as bromocriptine. In order to quantify the beneficial impact of early combination therapy, a controlled clinical trial (PRADO:PRA vi-del1 +DOpa) in patients with early Parkinson's disease was carried out, whereby L-Dopa monotherapy (in a fixed combination with benserazide (DoBe) was being compared with the same combination plus bromocriptine (DoBeBro). Patients were recruited and treated by 101 practising neurologists in the Federal Republic of Germany and in Hungary. 'Twenty seven clinical university centers cross-checked the patients at regular intervals. The trial started with 3 months of DoBe monotherapy (median dose of 375 mg L-Dopa for both randomized groups) followed by gradual substitution of DoBe by bromocriptine over 3 months in one of the groups (250 mg L-Dopa/10 mg bromocriptine). The target medication was maintained from study months 6 to 54.

Bromocriptine lessens the incidence of mortality in L-dopa-treated parkinsonian patients: prado-study discontinued.

Meta‐analyses of studies on lung cancer and passive smoking both by WALD and the authors have shown greater differences in the pooled relative risk. In our paper three scenarios with conservative rates of misclassification are assumed and their effect on individual and pooled relative risks are examined. All the results of 27 meta‐analyses are not statistically different from unity with the exception of 4 results, 3 of which are occurring if one selects only 4 case control studies with minor quality. Considering 10 case control studies alone 24 out of 1,023 possible meta‐analyses are technically significant. These are dominated by 3 studies of lower quality. Our results lead to the conclusion that based on meta‐analyses with proper correction for misclassification the null hypothesis has to be further accepted.

E. Blümner

Papers

Early institution of bromocriptine in Parkinson's disease inhibits the emergence of levodopa-associated motor side effects. Long-term results of the PRADO study.

Bromocriptine lessens the incidence of mortality in L-dopa-treated parkinsonian patients: prado-study discontinued.

Meta‐analyses on passive smoking and lung cancer effects of study selection and misclassification of exposure