Arizona Parkinson Disease Center Prevention of Progression to Parkinson's Disease and Parkinson's Disease with Dementia: Development of Biomarkers and Novel Treatment Strategies

Principal Investigators:
Charles H. Adler, MD, PhD (Mayo Clinic) and Thomas Beach, MD, PhD (Sun Health Research Institute)

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is currently diagnosed clinically by finding slowness of movement along with either rest tremor or rigidity. The only definitive diagnosis for PD is by autopsy. While usually thought of as a motor disorder, 30-75% of patients with PD go on to develop dementia. As the disease progresses dementia is often more disabling than the motor symptoms leading to higher rates of nursing home placement and death. While there are treatments (medications and surgical procedures) that improve the motor symptoms, there are no treatments that slow or halt disease progression nor prevent dementia in PD.

We have designed our proposal to include cores and projects whose theme is the development of biomarkers and putative treatments for preventing the development of PD and progression of PD to PD with dementia. The work will be performed through the Arizona Parkinson Center, a consortium of investigators at multiple institutions throughout the state: Sun Health Research Institute, Mayo Clinic Scottsdale, Barrow Neurologic Institute, Banner Good Samaritan Medical Center, Arizona State University, and the Translational Genomics Research Institute.

Goals and Objectives of the Research: Provide a concise summary of the goals, objectives and the hypothesis to be tested.

This grant application is geared towards expanding the Arizona Parkinson Disease Center Brain Donor Program to develop biomarkers that have high predictive values for the development of both PD and PD with dementia (PD-D). The clinical data will be validated by autopsy confirmation, the “gold standard” for diagnosing PD. Multiple projects have been included that will investigate potential biomarkers in CSF and brain tissue for PD and PD-D. Additionally, studies will be undertaken investigating possible mechanisms for the development of PD and dementia in PD with the goal of finding new targets for treatment. This program will then utilize the antemortem data to predict the likelihood of individuals to progress to PD or PD-D.

The Clinical Core will enroll and longitudinally evaluate subjects in the Brain Donor Program categorizing them as being controls, PD, and PD-D. One main goal of the Clinical Core will be to determine clinical biomarkers that will be used to predict who will develop PD and PD-D. In addition the Clinical Core will provide the Neuropathology Core and projects with extensive clinical description obtained during life of the autopsy material. The Neuropathology Core will perform all autopsies, provide data on Lewy bodies and other markers to correlate with the clinical data, and provide brain tissue and CSF for the projects. One project will investigate whether a loss of brain-derived neurotrophic factor (BDNF) in the cortex of PD-D may lead to neuronal susceptibility to cell death. A second project will determine whether mitochondria from cases of PD-D have different levels of the TNF type 1 death receptor (TNFR1) and whether this influences changes in -synuclein and DJ-1. A third project will utilize microarray fingerprinting of neurons susceptible to cell death in PD-D to identify the genetic pathways leading to  -synulein/DJ-1 aggregation and cell death. The fourth project will utilize proteomics in CSF to investigate for biomarkers that distinguish PD without dementia from PD-D. As a whole, these projects will provide new biomarkers and new therapeutic targets for eventual testing with subjects at the Clinical Core sites.

At the completion of the three-year funding period we propose the submission of a NIH funded program project or center grant that will build on these themes. Additionally we will propose randomized controlled trials of treatments that will be designed to stop or slow the progression to PD or PD with dementia. The design of these clinical treatment trials will be a result of information gathered from the Clinical Core allowing us to choose enriched populations of subjects with high probability of developing PD or progressing to PD-D. Given the size of the Arizona Parkinson Disease Center clinical population, the controlled trials would be able to be performed here in Arizona by the consortium