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

Abstract

The pace of nigrostriatal degeneration, both with regards to striatal denervation and loss of melanin and tyrosine hydroxylase-positive neurons, is poorly understood especially early in the Parkinson's disease process. This study investigated the extent of nigrostriatal degeneration in patients with Parkinson's disease at different disease durations from time of diagnosis. Brains of patients with Parkinson's disease (n=28) with post-diagnostic intervals of 1-27 years and normal elderly control subjects (n=9) were examined. Sections of the post-commissural putamen and substantia nigra pars compacta were processed for tyrosine hydroxylase and dopamine transporter immunohistochemistry. The post-commissural putamen was selected due to tissue availability and the fact that dopamine loss in this region is associated with motor disability in Parkinson's disease. Quantitative assessments of putaminal dopaminergic fibre density and stereological estimates of the number of melanin-containing and tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta (both in total and in subregions) were performed by blinded investigators in cases where suitable material was available (n=17). Dopaminergic markers in the dorsal putamen showed a modest loss at 1 year after diagnosis in the single case available for study. There was variable (moderate to marked) loss, at 3 years. At 4 years post-diagnosis and thereafter, there was virtually complete loss of staining in the dorsal putamen with only an occasional abnormal dopaminergic fibre detected. In the substantia nigra pars compacta, there was a 50-90% loss of tyrosine hydroxylase-positive neurons from the earliest time points studied with only marginal additional loss thereafter. There was only a ∼10% loss of melanized neurons in the one case evaluated 1 year post-diagnosis, and variable (30 to 60%) loss during the first several years post-diagnosis with more gradual and subtle loss in the second decade. At all time points, there were more melanin-containing than tyrosine hydroxylase-positive cells. Loss of dopaminergic markers in the dorsal putamen occurs rapidly and is virtually complete by 4 years post-diagnosis. Loss of melanized nigral neurons lags behind the loss of dopamine markers. These findings have important implications for understanding the nature of Parkinson's disease neurodegeneration and for studies of putative neuroprotective/restorative therapies.

Longitudinal Change of Clinical and Biological Measures in Early Parkinson's Disease: Parkinson's Progression Markers Initiative Cohort

“…These data also demonstrate that the annualized change in DAT binding was greatest at year 1 when compared with years 2 and 4. These data may be consistent with recent pathology data suggesting that DAT terminal have largely disappeared by year 4 of diagnosis,23 again creating a floor effect for change in DAT binding. These data also suggest the limitations of the linear change analysis for DAT binding.…”

The Parkinson's progression markers initiative (PPMI) – establishing a PD biomarker cohort

“…The study demographics are consistent with age, gender, education, and ethnicity typical of large PD clinical trials 35, 36, 37. There was no difference in demographics between US and European participants.…”

“…There are both scientific and practical reasons why an early PD cohort would likely have the best chance of success in demonstrating the effects of potential disease‐modifying therapeutics. First, there is increasing evidence that ongoing progression may lessen any potential therapeutic effect, as pathologic studies indicate significant dopaminergic degeneration present already at 4 years postdiagnosis 35. Second, studies designed to evaluate disease‐modifying therapeutics are limited by the slow change in MDS‐UPDRS following treatment with dopaminergic PD medications, as even subjects early in disease may require treatment.…”

Propagated but topologically distributed forebrain neurons expressing alpha-synuclein in aged macaques

“…The present results have demonstrated that throughout all ages, the dopaminergic neurons in the lateral SNc are affected more severely than those in the medial SNc. In favor of these findings, it has been reported in human PD cases that the pathological change in the SNc is the most prominently observed in the ventrolateral tier [41][42][43][44]. The age-related distribution pattern of α-syn-positive neurons in the SNc is reversed.…”