Amyloidopathy is an important feature of several dementias - Alzheimer disease (AD), Dementia with Lewy Bodies (DLB), and Parkinson disease dementia (PDD). Amyloid (Ab) peptide production is an important therapeutic target. Experimental in vitro and murine genetic model experiments indicate that Ab peptide production is reduced by activation of some G-protein coupled receptors, including serotonin receptors. Modest human data supports these interesting observations. Based on preliminary studies, our central hypothesis is that serotoninergic neurotransmission inhibits Ab amyloid production-deposition. An important corollary of this hypothesis is that diminished regional serotoninergic innervation should correlate inversely with Ab deposition. Parkinson disease (PD) - a disorder characterized by variable degeneration of serotoninergic projection systems and variable Ab peptide deposition - provides a model to evaluate this corollary prediction. In preliminary PET imaging studies of PD subjects, we found a strong inverse correlation between regional forebrain serotoninergic innervation and Ab deposition as measured with the serotonin transporter ligand [11C]DASB and the amyloid ligand [11C]PiB, respectively. These intriguing data are limited by relatively small sample size and cross-sectional study design. We propose a larger longitudinal study of PD subjects that will yield more specific assessments of the interactions between serotoninergic system changes and brain Ab amyloid deposition. To determine if the relationship between regional serotoninergic innervation and Ab amyloid deposition is generalizable, we will perform a parallel cross-sectional study in a sample of cognitively asymptomatic elderly controls. Validation of our predictions will strongly support the implementation of clinical investigations in PD and other pre-dementias aimed at using serotoninergic agents to modify the natural history of cerebral Ab peptide production-deposition. Falsification of our predictions will be equally valuable as it would undermine the central hypothesis and forestall the implementation of clinical trials of serotoninergic agents as disease modifying agents in MCI, AD, DLB, and PD.
Production of the abnormal protein Ab amyloid is a central feature of several dementias. Prior experimental animal work suggests that Ab amyloid production can be decreased by the neurotransmitter serotonin. We will test this idea in Parkinson disease (PD) subjects using positron emission tomography imaging of brain serotonin containing brain cells and correlate loss of these brain cells with brain Ab amyloid load. This work may suggest new treatment approaches for dementias.
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