The scientific and clinical basis for the treatment of Parkinson disease (2009)

Abstract

Parkinson disease (PD) is an age-related neurodegenerative disorder that affects as many as 1-2% of persons aged 60 years and older. With the aging of the population, the frequency of PD is expected to increase dramatically in the coming decades. Current therapy is largely based on a dopamine replacement strategy, primarily using the dopamine precursor levodopa. However, chronic treatment is associated with the development of motor complications, and the disease is inexorably progressive. Further, advancing disease is associated with the emergence of features such as freezing, falling, and dementia which are not adequately controlled with dopaminergic therapies. Indeed, it is now appreciated that these nondopaminergic features are common and the major source of disability for patients with advanced disease. Many different therapeutic agents and treatment strategies have been evaluated over the past several years to try and address these unmet medical needs, and many promising approaches are currently being tested in the laboratory and in the clinic. As a result, there are now many new therapies and strategic approaches available for the treatment of the different stages of PD, with which the treating physician must be familiar in order to provide patients with optimal care. This monograph provides an overview of the management of PD patients, with an emphasis on pathophysiology, and the results of recent clinical trials. It is intended to provide physicians with an understanding of the different treatment options that are available for managing the different stages of the disease and the scientific rationale of the different approaches. 1 PD is the second most common neurodegenerative disorder, with an average age at onset of about 60 years. An estimated 5 million people throughout the world have PD, with 1 million individuals each in the United States and in Europe with the disorder. PD affects approximately 0.3% of the population and 1% to 2% of those older than 60 years.2 With the aging of the population and the substantial increase in the number of at-risk individuals older than 60 years, it is anticipated that the prevalence of PD will increase dramatically in the coming decades.

Manganese-Enhanced Magnetic Resonance Imaging for Detection of Vasoactive Intestinal Peptide Receptor 2 Agonist Therapy in a Model of Parkinson's Disease

“…Progressive neuronal degeneration underlies the pathobiology of a broad range of neurodegenerative diseases that include PD [42]. While the causes of most neurodegenerative diseases are not known, the relationship between neurodegeneration and immune system activation is clear.…”

A Progressive Mouse Model of Parkinson's Disease: The Thy1-aSyn (“Line 61”) Mice

“…In fact, the predictive validity of a model can only be established when effective therapies exist for the particular disorder that is being modeled. In the case of PD, models that reproduce the loss of dopaminergic neurons have demonstrated predictive validity for symptomatic treatments that have changed the lives of patients [6]. However, the same models have not yet proven predictive for neuroprotective treatments [7].…”

Opposite Effects of Stimulant and Antipsychotic Drugs on Striatal Fast-Spiking Interneurons

“…It has especially high concentrations of the neurotransmitter dopamine, and dopamine receptors (Boyson et al, 1986). Alterations in striatal dopamine neurotransmission are a major mechanism of action of many widely used drugs, including both psychiatric/neurological therapies and drugs of abuse (Hyman et al, 1995;Berke and Hyman, 2000;Olanow et al, 2009). Psychomotor stimulants such as amphetamine can cause large increases in striatal dopamine release, with accompanying behavioral activation (Lyon and Robbins, 1975).…”