Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease

Abstract

Objective: To investigate the degree of nigrostriatal degeneration in Parkinson disease (PD) patients at different disease durations following diagnosis. Method: Brains of PD patients (n=28) with disease durations of 1-27 years from the time of diagnosis and normal elderly controls (n=7) were examined. Sections of the putamen and SNc were processed for tyrosine hydroxylase and dopamine transporter immunohistochemistry. Stereological quantitative assessments of putaminal dopaminergic fiber density and estimates of the number of melanin-containing and tyrosine hydroxylase immunoreactive neurons in the SNc were performed by blinded investigators. Results: There was only modest loss of staining for dopaminergic markers in the dorsal putamen at 1 year after diagnosis and variable loss (moderate to marked) at 3 years. By 4 years post-diagnosis and thereafter, there was consistent and severe loss of staining in the dorsal putamen with only an occasional individual abnormal dopaminergic fiber detected. Some dopaminergic fibers were detected in the ventral and medial aspects of the putamen, presumably en route to the caudate nucleus. Stereological estimates of striatal dopaminergic fibers and SNc neurons demonstrated modest reductions at 1-3 years followed by an exponential decline that was largely complete by 5-7 years from the time of diagnosis. Interpretation: Degeneration of nigrostriatal dopaminergic terminals is relatively modest in years 1-3, but is virtually complete by 5 years after diagnosis. Loss of nigral neurons lags behind striatal denervation, consistent with the possibility that nigrostriatal degeneration begins as an axonopathy. These findings have important implications for studies of putative neuroprotective therapies.