Validation of the Dopamine-depleted CHT Hemizygous Pre-Clinical Model as an Animal Model of Parkinson's Disease with Dementia

Objective/Rationale:
Parkinson’s disease is traditionally thought of as a motor disorder. However, in addition to problems with movements, patients frequently develop cognitive problems leading to dementia as the disease progresses. Dementia strongly influences the quality of life of Parkinson’s patients. Currently, we know very little about the causes of dementia in Parkinson’s disease. One of the main reasons for this is the lack of animal models that reproduce essential cognitive deficits seen in patients with the Parkinson’s diseaseassociated dementia.

Project Description:
The project is aimed at developing an animal model of the Parkinson’s disease with dementia. Parkinson’s disease is caused by the loss of dopaminergic cells, but cholinergic neurons also suffer. Thus, many people with Parkinson’s disease, in addition to low concentration of dopamine, have low concentration of acetylcholine, which is known to cause cognitive problems. The project will use genetically engineered mice that have lower concentration of acetylcholine. The mice will be treated with the neurotoxin MPTP causing them to loose dopaminergic neurons, similarly to that happens in Parkinson’s disease. The mice then will be tested for their ability to learn, remember, and adapt their behavior to current situation based on what they have learned previously. These are the abilities known to be disturbed in Parkinson’s patients with dementia.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Currently, there are drugs that help with cognitive problems in patients with Parkinson’s disease, but there is no cure for dementia. A valid animal model would enable scientists to better understand the causes of dementia and to develop and test new therapies.

Anticipated Outcome:
We expect that the mice that have low concentrations of both dopamine and acetylcholine will have specific cognitive problems not seen in mice with low dopamine or acetylcholine. In particular, we expect these mice to perform poorly when cognitive flexibility is required. These results would provide evidence whether combined reduction in acetylcholine and dopamine impairs cognition in a specific way similar to that observed in human patients. Drugs currently used to improve cognition in Parkinson’s patients may prove effective in these mice, which would suggest that these animals are suitable for testing new therapies for Parkinson’s disease-associated dementia.