Preclinical Solutions for Insight in Premotor Parkinson

Abstract

Parkinson’s disease is second only to Alzheimer’s disease, among the main chronic and progressive neurodegenerative disorders. Although neurodegenerative disease may appear at any age, the risk increases with ageing. Therefore, the increasing prevalence of neurodegenerative diseases is an increasing concern for ageing western societies. The problem has been well-recognized and triggered research efforts to develop strategies to limit the progression of neurodegenerative diseases, such as Parkinson’s disease. The clinical features of Parkinson’s disease were first described by the English surgeon James Parkinson in his “Essay on the shaking palsy” in 1817. Notably, it took another hundred years after Parkinson’s publication before the first Parkinson’s disease brain pathology was described. The great breakthrough in Parkinson’s disease started in the 1950s by the Swedish scientist Carlsson (Fahn, 2008) who recognized dopamine as the neurotransmitter involved in the pathological process. This subsequently led to research into parkinsonian brains by the Austrian scientists Ehringer and Hornykiewicz. They demonstrated that the level of the neurotransmitter dopamine in parkinsonian brains was dramatically reduced (Ehringer & Hornykiewicz, 1960). This reduction was caused by the degeneration of dopamine neurons in the substantia nigra. Only one year later the first patients were treated with the dopamine replacement drug L-dihydroxy-phenylalanine (LDOPA) (Birkmayer & Hornykiewicz, 1961). L-DOPA therapy for Parkinson’s disease was designed and described by the English physician Cotzias (Fahn, 2008). Nowadays, treatment is still heavily dependent on dopamine replacement therapy, which is primarily aimed at symptom control and can be associated with severe side effects. Furthermore, with this treatment approach there is no prevention or retardation of dopaminergic neuron degeneration. Therefore, it would be a better approach to focus on a medical intervention in the cell death processes to stop or slow down progression in order to increase the quality of life of these patients. This strategy has been well-recognized (Jankovic, 2005; Philippens et al., 2010; Tolosa et al., 2009) and research efforts to develop neuroprotective treatment strategies is the current focus of both clinicians and basic scientists. To achieve this strategy, early identification of individuals at risk and an early start of neuroprotective treatment to prevent the progressive loss of neurons are important. Once it is established that a person is at risk of developing Parkinson’s disease, progressive loss of neurons must be prevented.