Lack of regional selectivity during the progression of Parkinson disease: implications for pathogenesis

Dopamine terminal loss in the putamen of patients with Parkinson disease (PD) shows a regional heterogeneity, reflecting selective vulnerability of degenerating neurons to mechanisms of cell death.

If the same pathogenic mechanisms are responsible for the onset and progression of PD, the regional selectivity of dopamine cell loss will be the same throughout the course of the disorder.

To investigate the regional selectivity of dopamine terminal loss during the progression of PD.

We studied 67 patients with PD and 20 healthy subjects using positron emission tomography with [(11)C](+/-)dihydrotetrabenazine (DTBZ).

Regional values of DTBZ binding potential (calculated as maximum specific binding [B(max)] divided by the equilibrium dissociation constant K(d)) against disease duration in the putamen of PD patients were best described by a multivariate exponential model with distinct parallel asymptotic values that were significantly (P<.001) different across 4 regions of the putamen. The extent of loss of DTBZ binding potential with disease progression during the clinical stage of PD (early vs late PD) was similar between the anterior (-33%, using early PD as the baseline) and posterior (-29%) putamen. In contrast, the extent of loss of DTBZ binding potential in early PD, which reflects the cumulated loss of DTBZ binding potential from the onset of the disorder (in healthy subjects vs those with early PD), was significantly (P<.001) lower in the posterior (-58%, using healthy subjects as the baseline) than the anterior (-42%) putamen.

To the extent that DTBZ positron emission tomography provides an accurate estimate of loss of dopamine neurons, our findings suggest that the mechanisms responsible for the progression of PD may not be the same as those responsible for its onset.