The genetically-defined Parkinson's disease. A study of biomarkers in patients and healthy carriers of the Park8 G2019S mutation.

The mechanisms behind the development of PD are still obscure, but it is clear that PD is heterogeneous both in terms of cause, phenotype, progression, and response to treatment. Reproducible biomarkers for PD susceptibility and/or progression that are se nsitive and specific have long been sought, but have yet to be defined. Several genetic causes for PD have now been determined and the G2019S LRRK2 (Park8) gene, which codes for leucine-rich repeat kinase 2 (Lrrk2), a large, multidomain protein with unkno wn function has also been found in Norwegian patients. This gene accounts for over 3% of all PD patients in Central Norway (Aasly et al. 2005) with an avarage start of disease of 58 years. In February 2007 there are between 60 and 100 known cases in this area carrying this mutation and about two third are so-called presymptomatic individuals. In addition there are also a large group of family members followed who do not carry the mutation. All known Park8 patients in Norway are followed clinically by one neurologist (Dr. Aasly). The patients are seen twice yearly (or more frequent if necessary), the asymptomatic family members are seen once a year. The annual screening includes: - Longitudinal study of healthy carriers of Lrrk2 G2019S. - Regular clinical monitoring (Aasly) - Updating of database, recording environmental criteria possibly relevant for PD onset and progression - Regular blood sampling (every year In addition, done once: - Cerebrospinal fluid (CSF) sample (by dr. Aasly) - Regular brain MRI In case of adequate funding: - volumetric MRI - cerebral SPECT or PET Two control groups (50 sporadic PD cases and 25 healthy controls) are also included. The blood and CSF samples will be analyzed with metabolomics and proteomics methods. - CSF a-s ynuclein and filaments will be analyzed. - The MAPK-pathway in leukocytes will be used. These parameters will probably in combination give important clues to the pathogenesis of PD.