Serotonin and Amyloidopathy (R56)

Roger Albin
PI:
Roger Albin
University of Michigan (Ann Arbor, MI)

Summary

Aβ amyloidopathy is a significant feature of Alzheimer disease (AD), Dementia with Lewy Bodies (DLB), and Parkinson disease dementia (PDD). Modulation of amyloid Aβ peptide production is an important target for development of therapies to slow progression or delay the onset of amyloidopathies. In several experimental systems, stimulation of the neurotransmitter receptor for serotonin has been shown to reduce Aβ peptide production. To determine if there is a relationship between the amount of serotonin receptor present and the amount of Aβ peptide plaque accumulation in the brains of individuals with Parkinson’s disease, this study will use a non-invasive imaging technique to measure, at two time points, the amount of both the serotonin receptor load and Aβ peptide in the brains of PD patients and compare these results with the serotonin receptor load and Aβ peptide present in the brains of cognitively normal elderly subjects. If the data from this study strongly supports the relationship between serotonin receptor load and Aβ peptide levels, this could in turn lead to the development and implementation of clinical trials to determine the ability of serotonergic agents to prevent Aβ production and deposition in parkinsonian disorders.

Abstract

Amyloidopathy is an important feature of several dementias - Alzheimer disease (AD), Dementia with Lewy Bodies (DLB), and Parkinson disease dementia (PDD). Amyloid (Aβ peptide production is an important therapeutic target. Experimental in vitro and murine genetic model experiments indicate that Aβ 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 Aβ amyloid production-deposition. An important corollary of this hypothesis is that diminished regional serotoninergic innervation should correlate inversely with Aβ deposition. Parkinson disease (PD) - a disorder characterized by variable degeneration of serotoninergic projection systems and variable Aβ 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 Aβ 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 Aβ amyloid deposition. To determine if the relationship between regional serotoninergic innervation and Aβ 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 Aβ 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.

Goals

Goals of Project

  • Discovery: Determine the relationship between regional forebrain AŒ≤ deposition (PiB-PET DVR) and regional forebrain serotonin terminal integrity (DASB-PET DVR) in a 2 year longitudinal study of 75 Parkinson's disease subjects.
  • Discovery: Determine the relationship between regional forebrain AŒ≤ deposition (PiB-PET DVR) and regional forebrain serotonin terminal density (DASB-PET DVR) in a cross-sectional study of 30 cognitively asymptomatic elderly control subjects.
  • Resource Building: Obtain blood and plasma from all participants in a systematic manner in accordance with guidelines for PDBP. Blood and plasma will be correlated with clinical, cognitive and imaging data to further enable biomarker identification.

Enrollment Goals

  • 75 Parkinson's disease participants (varying stages of disease)
  • 30 Healthy participants (cognitively normal elderly)