Zwagerman, Nathan T.; Richardson, R. Mark
Parkinson’s disease (PD) is characterized by dysfunction in the dopaminergic nigrostriatal system. It previously has been accepted that by the time of diagnosis, a significant amount of degeneration in dopaminergic fibers projecting from the substantia nigra pars compacta to the striatum has already occurred. However, surprisingly little is known about the extent and time course of this deterioration in humans. This information is important, as it has direct bearing on the optimal timing for interventions that aim to prevent further neuronal loss or to rescue neuronal dysfunctional.
In the recent report Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease, Kordower et al. (Brain 2013: 136; 2419-2431) evaluated the post-mortem brains of 28 patients who had been diagnosed with Parkinson’s disease over a range of 1-27 years before death. In each case, the diagnosis of PD had been made by a movement disorders neurologist and confirmed by a neuropathologist. The authors then studied brain sections using tyrosine hydroxylase and dopamine transporter immunostaining to investigate dopamine fiber density in the putamen, and stereology to estimate numbers of tyrosine hydroxylase expressing and melanin containing cells in the substantia nigra. Comparing these patients to age-matched controls, the investigators sequentially examined the extent of dopaminergic terminal degeneration and cell loss throughout the course of the disease. Their findings revealed a previously unreported substantial reduction in dopamine terminals early on in the disease.
Dopamine markers in the dorsal putamen of PD patients were significantly but variably reduced (35-75%) at 1-3 years after diagnosis, and severely reduced (70-90%) by 5 years after diagnosis, exhibiting stable levels thereafter. Similarly, profound loss of tyrosine hydroxylase expressing neurons was found in the pars compacta (50-90%) beginning at the earliest time points, suggesting that compensatory sprouting may transiently occur in the striatum during the earliest stage of the disease to offset neuronal loss in the nigra. Interestingly, at all time points there were more melanin-containing than tyrosine hydroxylase-expressing neurons, indicating that a window exists during which dopaminergic function is lost but cells survive.
Although previous studies have examined histologic changes in the nigrostriatal system of PD patients, this is the largest pathology study to date that examines multiple post-diagnosis time points using modern stereological technique. Several points are important for neurosurgeons interested in developing or implementing neurorestorative therapies, such as gene therapy, direct drug delivery of therapeutic molecules, or cell transplantation. In light of these data, neuroprotective therapies targeted to individuals with greater than 4 years of disease duration may have missed the optimal window for preventing loss of dopaminergic function in the majority of surviving neurons. On the other hand, trophic or regenerative therapies may still have value in later stages of the disease, due to the persistence of populations of melanin-containing neurons in which the dopaminergic phenotype potentially may be restored. This study also emphasizes the need to develop biomarkers that would allow the diagnosis of patients before the onset of motor symptoms, after which significant nigrostriatal degeneration has already occurred. Future restorative neurosurgical clinical trials, therefore, should consider enrolling patients earlier in the course of their disease, rather than as a “last resort” following long disease duration and failure of medical management.