The promise of neuroprotective agents in Parkinson's disease

http://www.ncbi.nlm.nih.gov/pubmed/22125548?dopt=Abstract

 

Front Neurol. 2011;2:68. Epub 2011 Nov 21.

Seidl SE, Potashkin JA.

 

Parkinson's disease (PD) is characterized by loss of dopamine neurons in the substantia nigra of the brain. Since there are limited treatment options for PD, neuroprotective agents are currently being tested as a means to slow disease progression. Agents targeting oxidative stress, mitochondrial dysfunction, and inflammation are prime candidates for neuroprotection. This review identifies Rasagiline, Minocycline, and creatine, as the most promising neuroprotective agents for PD, and they are all currently in phase III trials. Other agents possessing protective characteristics in delaying PD include stimulants, vitamins, supplements, and other drugs. Additionally, combination therapies also show benefits in slowing PD progression. The identification of neuroprotective agents for PD provides us with therapeutic opportunities for modifying the course of disease progression and, perhaps, reducing the risk of onset when preclinical biomarkers become available.

Markers of inflammation in prevalent and incident Parkinson's disease in the Cardiovascular Health Study.

http://www.ncbi.nlm.nih.gov/pubmed/22119505?dopt=Abstract

Parkinsonism Relat Disord. 2011 Nov 25. [Epub ahead of print]

Ton TG, Jain S, Biggs ML, Thacker EL, Strotmeyer ES, Boudreau R, Newman AB, Longstreth WT Jr, Checkoway H.

BACKGROUND:

Studies demonstrate existence of inflammation in prevalent Parkinson's disease (PD). We assessed associations of baseline levels of inflammatory markers with prevalent PD at baseline (1989) and incident PD identified over 13 years of follow-up of the Cardiovascular Health Study.

METHODS:

Blood samples at baseline were measured for fibrinogen, interleukin-6, tumor necrosis factor-α, C-reactive protein, albumin, and white blood cells. The analysis included 60 prevalent and 154 incident PD cases.

RESULTS:

Risk of prevalent PD was significantly higher per doubling of IL-6 among women (odds ratio [OR]=1.5, 95% confidence interval [CI]: 1.0, 2.4) and WBC among men (OR: 2.4, 95% CI: 1.2, 4.9) in multivariate models. Risk of incident PD was not associated with higher levels of any biomarker after adjusting for age, smoking, African American race, and history of diabetes. Inverse associations with incident PD were observed per doubling of C-reactive protein (OR=0.9; 95% CI: 0.8, 1.0) and of fibrinogen among women (OR=0.4; 95% CI: 0.2, 0.8).

CONCLUSIONS:

Although inflammation exists in PD, it may not represent an etiologic factor. Our findings suggest the need for larger studies that measure inflammatory markers before PD onset.

Sleep disorders in Parkinson's disease: Many causes, few therapeutic options.

http://www.ncbi.nlm.nih.gov/pubmed/22118862?dopt=Abstract

J Neurol Sci. 2011 Nov 24. [Epub ahead of print]

Diederich NJ, McIntyre DJ.

Abstract

Sleep symptoms in Parkinson's disease (PD) are frequent and have multifactorial and multilayered causes. Primary involvement of sleep/wake regulating centers in the brainstem, sleep problems caused by the nocturnal manifestation of motor and dysautonomic signs and medication-induced sleep problems are often impossible to disentangle in the individual patient. Two syndromes, hypersomnia and REM sleep behavior disorder (RBD), are increasingly recognized as harbingers of the core PD motor syndrome. RBD, associated with a panoply of other nonmotor symptoms, may predispose to a specific PD phenotype. Long-acting dopaminergic stimulation, when abating nocturnal akinesia, also improves subjective sleep quantity. While this strategy is backed up by several randomized controlled trials (RCT), other treatment recommendations are mostly based on case series or expert opinion. Thus we identified only two other RCT, one treating insomnia with eszopiclone, the other nocturnal behavioral abnormalities in demented PD patients with memantine. While the causal complexity of sleep problems in PD certainly hampers the design of therapeutic studies, multiple general treatment strategies against sleep disorders can however be applied efficiently in PD patients as well.

Changes in quality of life, burden and mood among spouses of Parkinson's disease patients receiving neurostimulation

http://www.ncbi.nlm.nih.gov/pubmed/22118900?dopt=Abstract

Parkinsonism Relat Disord. 2011 Nov 23. [Epub ahead of print]
Soulas T, Sultan S, Gurruchaga JM, Palfi S, Fénelon G.

BACKGROUND:

Deep brain stimulation improves motor function and quality of life in patients with Parkinson's disease. The impact of these changes on patients' spouses is largely unknown.

METHODS:

Twenty-six spouses of patients undergoing surgery were evaluated before and 12 months after surgery, using the 36-Item Short Form Health Survey for quality of life, the Beck Depression Inventory, and the Zarit Burden Inventory.

RESULTS:

The spouses' mean mood and quality of life scores changed little, while burden improved in younger spouses. There was no significant change in the spouses' overall status. However, at the individual level the effect of surgery was more frequently negative than positive. Changes in psychological status and quality of life in the spouses did not correlate with changes in the patients' motor status or quality of life.

CONCLUSIONS:

Spouses' experience of neurostimulation for Parkinson's disease is variable and complex. The improvement in burden experienced by younger spouses may reflect a greater capacity to cope with new situations.

Living with Parkinson's

http://www.parkinsons.org.au/media-advocacy/docs/AEReport_2011.pdf

Above is a link to the Deloitte Access Economics report for Parkinson's Australia. This is freely accessible on the Parkinson's Australia website.

Why Do We Need Multifunctional Neuroprotective and Neurorestorative Drugs for Parkinson's and Alzheimer's Diseases as Disease Modifying Agents.

http://www.ncbi.nlm.nih.gov/pubmed/22110336?dopt=Abstract

Parkinson's disease (PD) and Alzheimer's Disease (AD) are severe neurodegenerative disorders, with no drugs that are currently approved to prevent the neuronal cell loss characteristic in brains of patients suffering from PD and AD and all drug treatment are synptomactic. Due to the complex pathophysiology, including a cascade of neurotoxic molecular events that results in neuronal death and predisposition to depression and eventual dementia and etiology of these disorders, an innovative approach towards neuroprotection or neurorestoration (neurorescue) may be the development and use of multifunctional pharmaceuticals. Such drugs target an array of pathological pathways, each of which is believed to contribute to the cascades that ultimately lead to neuronal cell death. In this short review, we discuss examples of novel multifunctional ligands that may have potential as neuroprotective-neurorestorative therapeutics in PD and AD. The compounds discussed originate from synthetic chemistry as well as from natural sources.

Can nicotine be used medicinally in Parkinson's disease?

http://www.ncbi.nlm.nih.gov/pubmed/22114853?dopt=Abstract

The risk of Parkinson's disease is reduced by cigarette smoking, which raises some unanswered questions. Nicotine, a major component of tobacco smoke, could exert either non-receptor-mediated biological effects or, more importantly, act on the different subtypes of nicotinic brain receptors, in particular those associated with the nigrostriatal dopaminergic pathway. There is now robust experimental evidence for a neuroprotective effect of nicotine upon dopaminergic neurons. By contrast, in animal models of Parkinson's disease, nicotine alone has slight or no motor effects. However, nicotine may modulate dopamine transmission and has clear motor effects when associated with L-DOPA, reducing L-DOPA-induced dyskinesias. Clinical trials have yielded inconclusive results thus far and are hampered by different designs and small cohorts. Ongoing studies address either symptomatic motor or non-motor symptoms, or neuroprotection. There is still no agreement on the daily dosage of nicotine or the method of administration. Together, these data suggest that nicotine or nicotinic receptor drugs have therapeutic potential for Parkinson's disease, although the specific treatment regimens remain to be determined.

Intranasally applied l-DOPA alleviates parkinsonian symptoms in rats with unilateral nigro-striatal 6-OHDA lesions.

http://www.ncbi.nlm.nih.gov/m/pubmed/22108632/

Chao OY, et al. 

JournalBrain Res Bull. 2011 Nov 15. [Epub ahead of print]

Abstract

l-3,4-Dihydroxyphenylalanine (l-DOPA) remains the most effective drug for therapy of Parkinson's disease. However, the current clinical route of l-DOPA administration is variable and unreliable because of problems with drug absorption and first-pass metabolism. Administration of drugs via the nasal passage has been proven an effective alternate route for a number of medicinal substances. Here we examined the acute behavioral and neurochemical effects of intranasally (IN) applied l-DOPA in rats bearing unilateral lesions of the medial forebrain bundle, with severe depletion (97%) of striatal dopamine. Turning behavior in an open field, footslips on a horizontal grid and postural motor asymmetry in a cylinder were assessed following IN l-DOPA or vehicle administration with, or without, benserazide pre-treatment. IN l-DOPA without benserazide pre-treatment mildly decreased ipsilateral turnings and increased contralateral turnings 10-20min after the treatment. IN l-DOPA with saline pre-treatment reduced contralateral forelimb-slips on the grid while no effects were evident in the cylinder test. These results support the hypothesis that l-DOPA can bypass the blood-brain barrier by the IN route and alleviate behavioral impairments in the hemiparkinsonian animal model.

Controversies in Neurology: why monoamine oxidase B inhibitors could be a good choice for the initial treatment of Parkinson's disease

Abstract

BMC Neurology 2011, 11:112doi:10.1186/1471-2377-11-112

Background 

Early initiation of pharmacotherapy in Parkinson's disease (PD) is nowadays widely advocated by experts since the delay of treatment has shown to be associated with a significant deterioration of health related quality of life in affected patients. Due to marked advances in PD treatment during the last decades, physicians are nowadays fortunately equipped with a variety of substances that can effectively ameliorate emerging motor symptoms of the disease, among them levodopa, dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors. Despite numerous drug intervention trials in early PD, there is however still ongoing controversy among neurologists which substance to use for the initial treatment of the disease. 

Discussion 

In multiple studies, MAO-B inhibitors, such as selegiline and rasagiline, have shown to provide mild symptomatic effects, delay the need for levodopa, and to reduce the incidence of motor fluctuations. Although their symptomatic efficacy is inferior compared to dopamine agonists and levodopa, MAO-B inhibitors undoubtedly have fewer side effects and are easy to administer. In contrary to their competitors, MAO-B inhibitors may furthermore offer a chance for disease modification, which so far remains a major unmet need in the management of PD and eventually makes them ideal candidates for the early treatment of the disease. 

Summary 

MAO-B inhibitors may constitute a preferable therapeutic option for early PD, mainly due to their favourable safety profile and their putative neuroprotective capabilities. Since the symptomatic effects of MAO-B inhibitors are comparatively mild, dopamine agonists and levodopa should however be considered for initial treatment in those PD patients, in whom robust and immediate symptomatic relief needs to be prioritized.

Low BMI in people with Parkinson's

Abstract

"This meta-analysis supports the long-standing observation that people with Parkinson's tend to have lower BMI than members of the general population. BMI is a proxy for body fat in humans and is calculated using height and weight. This observation was not dependent on the duration of disease.


A number of studies have looked at whether changes in BMI occur prior to the movement features of Parkinson's. These studies are largely in disagreement with one another and differences in the BMI ranges used make them difficult to compare directly. As it stands, there is no compelling literature to suggest that changes in BMI predate the movement problems."

Passive smoking reduces Parkinson's risk

Abstract

"This case control study shows that passive smoking is associated with a reduced risk of Parkinson's. A previous study has shown similar reduction in risk if both parents smoked. Whilst a protective effect of cigarette smoke has long been suspected, this not yet prove. What is certain is that regardless of its role in Parkinson's, smoking causes a large number of other illnesses including heart disease, stroke and cancer."

Solvent exposure and risk of Parkinson's

Abstract

"This is a new report of a twin study from the US looking at the role that specific solvents/chemicals may have in causing Parkinson's. A number of other chemicals have also been suggested to increase individual risk of Parkinson's. The authors acknowledge the need for further work in this area."

Restless legs in Parkinson's

Abstract

"This is a new research article reporting on a case control study of the rate of restless legs syndrome (RLS) in early untreated Parkinson's and healthy controls. RLS is a diagnosis made on the basis of certain criteria and is not simply isolated leg restlessness. This is an important point because this study shows that isolated leg restlessness is more common in persons with early Parkinson's than healthy controls, but there is no difference in the rate of true RLS between these two groups."

Cochrane review on H.pylori and Parkinson's

Abstract


"A number of Predict PD participants have asked about the role of the bacteria H. pylori and Parkinson's following some publicity on the subject earlier this year. This Cochrane review looks at the current literature on how H. pylori may reduce response to treatment and concludes that at the moment there is insufficient evidence in this area. A further study is ongoing which may serve to answer this question."

A review of the role of the gut in Parkinson's

"An interesting 'Views and Reviews' article has just been published by Derkinderen et al in this week's Neurology journal. It outlines the evidence base for the gut as a window to the brain and it's potential role in Parkinson's diagnosis and monitoring.


I will post a link to the abstract as soon as it is available."