Disturbance of iron metabolism in Parkinson's disease -- ultrasonography as a biomarker.

A central role of iron in the pathogenesis of Parkinson's disease (PD) has been discussed for many years. So far, however, a biomarker indicating increased iron levels in the substantia nigra (SN) in PD patients has been missing. Performing transcranial ultrasound we detected an increased area of SN echogenicity as a typical echofeature in PD, visible already in the early stages of the disease and in subjects with subclinical impairment of the nigrostriatal system. Animal studies and post mortem analyses of human brain tissue revealed that this echofeature is associated with increased iron levels of the substantia nigra as well as a reduced neuromelanin content. The apparently autosomal dominant inheritance of this echofeature in relatives of patients with idiopathic PD indicates a primary role of disturbances of iron metabolism in PD. Consequently performed mutation analyses in genes involved in brain iron metabolism lead to the discovery of specific mutations in the ferritin-H, IRP2 and HFE gene in single PD patients. Moreover, variations in the ceruloplasmin gene were found to be associated with PD or SN hyperechogenicity. Functional relevance of some of these mutations for iron metabolism could be proven. Therefore, SN hyperechogenicity can be regarded as biomarker for both: impairment of the nigrostriatal system and increased iron levels of the SN. Future studies aim at substantiating the hypothesis that healthy subjects with SN hyperechogenicity indeed represent a population at risk for nigrostriatal degeneration, which would have a significant impact on therapeutical options.