The scientific and clinical basis for future therapies in Parkinson’s disease

More than 190 years have passed since James Parkinson wrote his Essay on the Shaking Palsy . Since then, huge effort has gone into the research and treatment of Parkinson s disease (PD). With time, our understanding of the condition has also evolved, as awareness of the psychiatric and non-motor aspects has grown. As a consequence, two of the most important challenges for the future management of PD are the need to treat non-motor symptoms and to slow or prevent disease progression. The key to development of any successful disease modifying therapy depends upon a comprehensive understanding of the pathogenesis of PD. Only by deciphering the molecular mechanisms that underlie neurodegeneration can we hope to find the means to intervene effectively upstream. Thus the question: Where does the pathological process of PD start , is one of vital importance. What mechanisms are responsible for a-synuclein aggregation? What role do central and peripheral autonomic structures play in PD? Alphonse Probst et al. broach these questions and challenge the traditional view that the substantia nigra pars compacta is the region that is affected predominantly and earliest in PD. Recent advances in our understanding of the molecular basis of PD provide additional targets for intervention to modify the progress of the disease. Attention has turned to the role of apoptosis and mitochondrial dysfunction in the aetiology of PD. Several agents have demonstrated potential neuroprotective qualities and studies have attempted to evaluate these properties. However, the results are not always easy to interpret. We review developments in trial design and drugs under investigation for possible neuroprotective effect. We also discuss early correction of the basal ganglia functional abnormalities as a means to support the intrinsic physiological compensatory mechanisms and both limit and delay the circuitry changes that evolve as PD progresses. The neuropathology underlying PD involves many brain areas beyond the dopaminergic nigrostriatal system. The non-motor symptoms of PD that become increasingly prevalent over the course of the illness and are a major determinant of quality of life are to a significant degree related to the degeneration of nondopaminergic pathways. Non-motor dysfunction antedates clinical manifestations of the motor symptoms of PD by years or even decades and may thus turn out to be a critical target for early diagnosis and identification of at-risk populations. Whilst awaiting effective neuroprotective therapies that will hopefully retard or prevent neural degeneration, the clinician is faced with the challenge of managing the variety of non-motor features that emerge in PD patients. Therefore, another major focus of this supplement will be to provide an overview of the clinical spectrum of non-motor symptoms in PD, and in particular depression, together with a brief review of treatment options. We hope that this supplement to the European Journal of Neurology will provide you with useful and practical information for the treatment of your patients, as well as important insights into the future direction of Parkinson s disease research and therapies.