Objective/Rationale:
Inflammatory activation has been a widely observed feature in the substantia nigra of Parkinson’s disease (PD) patients, and inflammatory stimuli can cause selective nigral cell loss in pre-clinical models of PD. These features have suggested that initial inflammatory events could be responsible for much of the cell death in PD. This makes inflammation an attractive target for treatment since inhibiting inflammation might slow down the progression of the disease.
The problem to be addressed is whether there are signs of increased inflammation early in PD, and if so what are the involved molecular pathways. Although the pre-clinical studies are convincing, there is insufficient data on what might be ongoing in human brain regions affected by or at risk from PD. This project will fill a significant gap in this knowledge by utilizing comprehensive methods to identify the major inflammatory mediators at early stages of PD.
Project Description:
Using the large tissue resources of the Banner Sun Health Research Institute Brain and Body Donation program, we will measure 120 significant inflammatory mediators in each tissue sample. We will utilize samples of substantia nigra and striatum, brain regions that are critical to clinical function and that are significantly affected by the specific neuropathological markers. Determination of whether changes occur early or later in disease will be made possible by analyzing brain tissue from normal control subjects as well as subjects with incidental Lewy body disease (a possible precursor to PD), and those with Symptoms & Side Effects PD. To complement these findings, we will also measure Th1/Th2 cytokine levels in the cerebral spinal fluid (CSF) of individuals from the three groups using high-sensitivity multiplexed immunoassays.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This project will assess to what extent specific inflammatory pathways are involved in the human disease and thereby what inflammation-related therapeutic targets would be most promising.
Anticipated Outcome:
Based on pre-clinical studies, there is a strong indication that inflammation is a significant pathological mechanism of PD. Additionally, the project will determine whether specific inflammatory pathways occur at an early stage of disease when counteractive measures would be most effective.
Progress Report
This project has profiled the levels of inflammatory-associated proteins and related growth factors in human brain tissue samples from control subjects, from subjects with incidental Lewy body disease (a pre-Parkinson’s disease [PD] syndrome) and from subjects with PD. We analyzed tissue samples from two key brain regions affected in PD, namely the substantia nigra and the striatum, for 160 different biological molecules. As inflammation has been widely suggested to be a factor in PD, we sought to address this issue in the most comprehensive way possible using high-quality human tissue. Our results have identified several molecules or groups of molecules, including interleukin-5, interleukin-15, platelet factor-4, interleukin-2 and the receptor tyrosine kinase ErbB3, as being associated with PD. We have generated a unique amount of data based on the large number of cases analyzed and the large number of molecules screened. Due to experimental difficulties, we cannot define how early the inflammatory changes occur, but we have identified a separate group of molecules whose expressions change with loss of tyrosine hydroxylase levels, a central measure of PD severity. Some of these molecules include those associated with maintaining the brain blood vessels. This research has identified some new molecules that can be applied not only as biomarkers for PD, but in studies on their involvement in disease mechanisms.
Final Outcome
This project has profiled the levels of inflammatory-associated proteins and related growth factors in human brain tissue samples from control subjects, from subjects with incidental Lewy body disease (a pre-Parkinson’s disease [PD] syndrome) and from subjects with PD. We analyzed tissue samples from two key brain regions affected in PD, namely the substantia nigra and the striatum, for 160 different biological molecules. As inflammation has been widely suggested to be a factor in PD, we sought to address this issue in the most comprehensive way possible using high-quality human tissue. Our results have identified several molecules or groups of molecules, including interleukin-5, interleukin-15, platelet factor-4, interleukin-2 and the receptor tyrosine kinase ErbB3, as being associated with PD. We have generated a unique amount of data based on the large number of cases analyzed and the large number of molecules screened. Due to experimental difficulties, we cannot define how early the inflammatory changes occur, but we have identified a separate group of molecules whose expressions change with loss of tyrosine hydroxylase levels, a central measure of PD severity. Some of these molecules include those associated with maintaining the brain blood vessels. This research has identified some new molecules that can be applied not only as biomarkers for PD, but in studies on their involvement in disease mechanisms.