Study Rationale: Many people with Parkinson’s disease (PD) develop untreatable cognitive symptoms due to changes in the brain’s cerebral cortex. These symptoms, which include problems with attention and decision making, can progress to dementia in the late stages of the disease. Evidence suggests that aggregation of the protein alpha-synuclein in vulnerable nerve cells interferes with brain health. However, the relationships between alpha-synuclein, damaged brain cells and impaired brain cell connections are not understood. Understanding these relationships will enable the development of therapies that directly target the underlying mechanisms of cognitive impairment in PD.
Hypothesis: We hypothesize that networks of nerve cells in the cerebral cortex become dysfunctional because of damage caused by toxic deposits of the protein alpha-synuclein in vulnerable cells.
Study Design: We will assess how alpha-synuclein aggregation progressively damages brain cells and impairs communication between brain cells in the cortex, identifying key alterations that distinguish cells that are vulnerable from those that are resilient. We will employ innovative technologies, including high-resolution microscopy of neuronal connections, imaging of neural activity, profiling of different cell types and their molecular contents and integration of the results using advanced computational methods. Our studies will investigate the poorly understood cognitive changes in PD in an innovative manner that integrates multiple levels of approaches.
Impact on Diagnosis/Treatment of Parkinson’s disease: Our findings will reveal mechanisms of impaired brain function in PD and identify specific types of nerve cells suited for the development of new treatments. Understanding the disease process will also enable diagnostic tests to predict disease and therapeutic outcomes and to monitor the success of potential treatments.
Next Steps for Development: If we can restore cortical function in our preclinical PD models, the next steps would include studies in humanized mice and other preclinical models to optimize treatments that could be adapted for use in the clinic. These can include medications that modulate the activity of vulnerable neurons and new translational biomarkers.