Parkinson’s Disease (PD)

PD is a progressive neurodegenerative disorder in which the most prominent symptom is impairment of motor function, particularly gait, that eventually limits independence and quality of life. Patients can also suffer from mild cognitive impairment or dementia at more advanced stages of the disease. Dopaminergic signaling deficits driven by degeneration of the nigrostriatal pathway are the hallmark pathophysiological feature of PD.  The economic burden of PD is at least $14.4 billion a year in the United States, and the prevalence of Parkinson’s will more than double by the year 2040, according to the authors of “The Current and Projected Economic Burden of Parkinson’s Disease in the United States” published in the journal Movement Disorders in 2013.  The authors of a second study published in the same journal issue, “An Economic Model of Parkinson’s Disease:  Implications for Slowing Progression in the United States,” focused on the potential cost savings that could be realized through the development of a disease-modifying treatment for Parkinson’s. According to the authors, a treatment that could slow Parkinson’s progression by 50% would yield a 35% reduction in excess costs, representing a dramatic reduction in cost of care spread over a longer expected survival. Despite decades of research, there are no disease-modifying treatments currently available for PD.

While dopamine is progressively lost with age, in PD the loss occurs at a much greater rate and both biochemical measures and imaging studies suggest that there is a significant decrease in dopamine by the time motor symptoms occur.  In this view, PD is an accelerated version of cell death seen with normal aging in which oxidative stress and neuroinflammation are believed to be important contributory factors.  Degeneration of dopamine neurons is particularly evident in parts of the substantia nigra where the loss of dopamine increases the excitatory drive in the basal ganglia disrupting voluntary motor control and causing characteristic symptoms of PD.  Normalization of motor function can be achieved with levodopa but it’s benefits decrease over time.  As the severity of PD increases, the loss of dopaminergic neurons leads to further changes in the ganglia pathways, including altered function of other neurotransmitters such as glutamate, GABA and serotonin.

Inflammation and cellular immune responses are increasingly being considered as important mediators of dopaminergic neurodegeneration. Additionally, increasing evidence indicates that PD-associated genes, such as alpha-synuclein, LRRK2, Parkin and PINK1 are involved in the regulation of immune responses of microglia and astrocytes. Neuronal death further activates inflammatory mechanisms, resulting in a vicious cycle of inflammation and neuronal death. Inflammatory responses, although essential for tissue homeostasis, can contribute to neuronal injury. As neural tissues have a restricted cell renewal and regenerative capacity, the brain is extremely vulnerable to uncontrolled immune and inflammatory processes. Dopaminergic neurons from substantia nigra are particularly vulnerable to microglial-mediated neurotoxicity.