Therapeutic prospects for parkinson's disease

Ann Neurol. 2013 Aug 22. doi: 10.1002/ana.24011. [Epub ahead of print]

Olanow CW, Schapira A.

Source

Departments of Neurology and Neuroscience, Mount Sinai School of Medicine.

Abstract

INTRODUCTION:

Parkinson's disease (PD) affects approximately 5 million persons globally, and prevalence is expected to markedly increase in the coming decades due to aging of the population. The disease is characterized clinically by motor features (rest tremor, rigidity, bradykinesia) and pathologically by degeneration of nigrostriatal dopamine neurons. Current therapy is primarily based on a dopamine replacement strategy using the dopamine precursor levodopa. Levodopa is effective for virtually all patients, particularly in the early stages of the disease. However, chronic treatment is associated with the development of motor complications (fluctuations in motor response and dyskinesia) in the majority of patients. Additional classes of drugs have been developed to try and enhance dopaminergic tone. These include dopamine agonists which act directly on the dopamine receptor, monoamine oxidase-B (MAO-B) inhibitors which increase synaptic dopamine levels by blocking central dopamine oxidative metabolism, and catechol-O-methyltransferase (COMT) inhibitors which increase the elimination half-life and bioavailability of levodopa by blocking its peripheral metabolism1 . Surgical therapies such as deep brain stimulation (DBS) have proven valuable in treating motor complications that cannot be satisfactorily controlled with medical therapy. However, none of these treatments provide anti-parkinsonian benefits superior to levodopa and most patients eventually develop intolerable disability. Further, non-dopaminergic features emerge that are not adequately controlled by levodopa.1 Indeed, in the levodopa era, non-dopamine features such as gait disturbance, falls, and dementia represent the major source of disability for advanced PD patients. There remains a need for new therapies that a) provide symptomatic benefits that are not associated with motor complications, b) treat the non-dopaminergic features, and c) slow, stop, or reverse disease progression.