Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial parkinsonism associated with mutations in the parkin gene

A kindred from South Tyrol (northern Italy) with familial, adult-onset park insonism of pseudo-dominant inheritance and mutations in the parkin gene wa s recently described. To gain insight into basal ganglia dysfunction in thi s form of hereditary parkinsonism, positron emission tomography (PET) with 18-fluorodopa (FDOPA) and C-11-raclopride (RAC) was performed in 5 affected family members and 5 asymptomatic relatives with proven compound heterozyg ous or heterozygous parkin mutations. Results were compared to findings in healthy control subjects and patients with typical sporadic, idiopathic Par kinson's disease. Similar to findings in the sporadic Parkinson's disease g roup, presynaptic striatal FDOPA storage was decreased in patients with com pound heterozygous parkin mutations, with the most prominent reduction in t he posterior part of the putamen. Along with the presynaptic lowered FDOPA uptake, we found a uniform reduction of the striatal C-11-raclopride bindin g index in all affected family members as compared to asymptomatic family m embers carrying a heterozygous parkin mutation, sporadic Parkinson's diseas e, and control subjects. Our PET data provide evidence that parkinsonism in this family is associated with presynaptic dopaminergic dysfunction simila r to idiopathic Parkinson's disease pathophysiology, along with alterations at the postsynaptic D2 receptor level. In asymptomatic carriers of a singl e parkin mutation with an apparently normal allele, we found a mild but sta tistically significant decrease of mean FDOPA uptake compared to control su bjects in all striatal regions. These data indicate a preclinical disease p rocess in these subjects.