Although the primary pathology and key defects of neurotransmission leading to the clinical picture of Parkinson's disease (PD) are known, initiation and nature of the neurodegenerative process are still obscure. However, it is becoming increasingly evident that the underlying pathophysiology is complex and in most cases probably multifactorial, differing among the individuals affected.

Only a very small percentage of Parkinsonian cases are caused by monogenic alterations (see Chapter 40). However, since the first description of a family in which 79 of 194 members suffered from PD (Mjörnes, 1949), it has become evident that the risk of developing the clinical picture of PD is three to four times higher in individuals with relatives with PD compared to those with a negative family history. Functional neuroimaging proved to be especially valuable for the detection of affected siblings: for monozygotic twins a concordance of 75% for PD or at least a subclinical dopaminergic deficit was detected by PET-studies, the rate for dizygotic was 22% (Piccini et al., 1999). These and other findings provide strong evidence of a genetic contribution to idiopathic PD (Gasser et al., 1998, 2001). However, only about 25% of PD patients report a relative affected by the same disease. Therefore, other factors are necessary to explain the selectivity and susceptibility of the disease on the basis of a genetic predisposition. Biochemical and histological investigations of the past decades have illuminated some of these factors.