Predictors and Neuropsychiatric Profile of Nucleus Basalis of Meynert Degeneration in Parkinson Disease
Abstract
As Parkinson disease (PD) progresses, the non-motor symptoms of dementia, psychosis, and apathy become major sources of morbidity. All of these symptoms are associated with reduced quality of life. Considering the increasing public health burden of PD, there is an urgent need to develop improved treatments for dementia, psychosis, and apathy. The long-term goal of this research proposal is to contribute to the development of improved therapies for non-motor symptoms in PD, specifically the neuropsychiatric symptoms of dementia, psychosis, and apathy. The nucleus basalis of Meynert is a small region at the base of the brain that provides stimulation to the entire cortex via release of the chemical acetylcholine. In individuals with PD, the nucleus basalis of Meynert degenerates. This results in dementia via loss of acetylcholine stimulation to the cortex. Researchers are considering simulating the nucleus basalis of Meynert directly using brain electrodes (deep brain stimulation). There is evidence this surgical intervention stimulates neurons of the nucleus basalis of Meynert to release acetylcholine, and it may protect the nucleus basalis of Meynert from further degeneration. Before this procedure is tested in PD, it is important to identify which PD patients would most likely benefit. The next logical step is to identify predictors of nucleus basalis of Meynert degeneration and to fully understand the symptoms associated with nucleus basalis of Meynert degeneration. The objectives of this proposal are to (1) identify a genetic alteration and molecular marker that predict greater nucleus basalis of Meynert degeneration in PD and (2) to expand the neuropsychiatric symptom profile associated with nucleus basalis of Meynert degeneration in PD. Degeneration of the nucleus basalis of Meynert is the focus of this proposal because it is associated with dementia in PD and it has been identified as a potential therapeutic intervention point to treat dementia in PD. The proposal objectives address the Areas of Emphasis by seeking to identify predictors of nucleus basalis of Meynert degeneration and by aiming to show that the nucleus basalis of Meynert is also a therapeutic intervention point for the treatment of psychosis and apathy in PD. This proposal will investigate whether a genetic alteration and a molecular marker are associated with greater degeneration of the nucleus basalis of Meynert. We chose to investigate a genetic alteration in the MAPT gene, the H1 haplotype, because it is associated with greater risk of dementia in PD and is associated with PD pathology. We chose to investigate the molecular marker alpha-synclein protein in the cerebrospinal fluid because elevated alpha-synuclein in the cerebrospinal fluid of PD patients is associated with greater cognitive decline. We expect this proposal to have an impact on the treatment of dementia, psychosis, and apathy in PD. If we show that psychosis and apathy are associated with nucleus basalis of Meynert degeneration, it will demonstrate that targeting a therapy to the nucleus basalis of Meynert, such as deep brain stimulation, may improve these symptoms. If we identify markers associated with nucleus basalis of Meynert degeneration, it will help researchers select patients who are more likely to benefit from interventions that target this brain region. By allowing selection of patients who are more similar in regard to nucleus basalis of Meynert degeneration, this proposal will allow for smaller numbers of patients to be recruited into future treatment trials. Considering that the currently proposed intervention is an invasive procedure, this would be a major advantage. This research proposal will move the field forward by laying the groundwork for a first study to evaluate deep brain stimulation of the nucleus basalis of Meynert to treat neuropsychiatric symptoms in PD, specifically dementia, psychosis, and apathy. The outcomes of this researc
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610768
Entities
People
- Matthew J Barrett
Organizations
- United States Army
- University of Virginia