Objective/Rationale:
Parkinson’s disease causes neurodegeneration in multiple subcortical nuclei, including substantia nigra, locus coeruleus, dorsal raphe nucleus, and nucleus basalis. Each of these affected brain regions has connections to other brain regions. Subcortical nuclei regulate activity in these brain regions by releasing specific chemicals called neurotransmitters. We hypothesize that regional deficits in the release of the neurotransmitters dopamine, norepinephrine, serotonin and acetylcholine account for specific types of cognitive impairment in PD.
Project Description:
Our center is enrolling and following patients in a prospective study of cognitive impairment in Parkinson’s disease that includes regular cognitive evaluations and donation of brain tissue at the time of death. We will measure levels of individual neurotransmitters and corresponding protein markers for these neurotransmitters in nine different brain regions. Levels in PD patients will be compared to age-matched controls. Our analysis will determine whether specific neurotransmitter deficits correlate with specific cognitive phenotypes, including problems with memory, visuospatial function, executive function, fluctuating attention, and visual hallucinations.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Identification of specific neurotransmitter phenotypes underlying cognitive deficits in PD will define therapeutic targets for Symptoms & Side Effects and disease modifying treatments in PD. This could include approaches to increase the levels of a specific neurotransmitter as well as approaches to improve the function of subcortical nuclei associated with the neurotransmitter deficits.
Anticipated Outcome:
By determining whether changes in neurotransmitter release correlate with cognitive deficits, we expect to improve our understanding of how neurodegeneration in these subcortical nuclei impacts cognitive function in PD.
Final Outcome
We developed methods to measure neurotransmitters and corresponding protein markers in brain tissue donated at the time of death. We used these methods to perform measurements with brain tissue samples from 17 people with PD and 6 control participants in our study. We found that PD participants had significantly lower levels of dopamine, serotonin and norepinephrine in many of the brain regions we analyzed. PD participants also had significantly lower levels of the protein markers for the neurons that produce dopamine and serotonin. Lower levels of dopamine in cerebral cortex samples correlated with a greater degree of cognitive impairment in PD participants, the majority of who had significant cognitive impairment at the time of death. We also detected an association between serotonin deficits and two specific cognitive phenotypes, hallucinations and fluctuating attention. These finding support our hypothesis that regional deficits in the release of neurotransmitters contribute to cognitive impairment in PD. However, measurements in additional participants will be needed to confirm these associations and identify further relationships between neurotransmitter deficits and cognitive phenotypes in PD.
March 2014