Progress in defining the premotor phase of Parkinson's disease.

Several studies have suggested that a variety of non-motor symptoms (NMS) frequently antedate the development of the classical motor symptoms in Parkinson's disease (PD). Some of these premotor symptoms are well known, like REM sleep behaviour disorder, smell loss and constipation and can precede the motor symptoms by years or even decades. The appearance of these symptoms seems to correlate with the neuropathological changes occurring during Braaks stages I to III. Also studies of the nigrostriatal dopaminergic pathways with neuroimaging show that substantia nigra degeneration occurs before motor symptoms onset. Studies on the premotor phase of PD are important for our understanding of when and where does PD start and how it evolves in these initial stages. Several ongoing studies combine clinical, genetic and neuroimaging investigations to study the premotor phase in subjects at high risk for developing such as hyposmic individuals (PARS study) or nonmanifesting carriers of LRRK2 mutations (ASAP Study). The diagnosis of premotor PD remains still elusive but the information becoming available on premotor PD should guide the search for predictive biomarkers and the identification of risk or protective factors for PD.