# Early Serotonin System Changes in prodromal DLB

> **NIH NIH R56** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $692,428

## Abstract

Abstract
Dementia with Lewy Bodies (DLB) is the second most common neurodegenerative dementia next to
Alzheimer’s disease. Compared to the robust family of imaging biomarkers that have facilitated prodromal trials
in Alzheimer’s disease, there is an absence of DLB biomarkers capable of identifying prodromal disease or
tracking its progression. In DLB, early cognitive decline and visuospatial cortex dysfunction mark the transition
from prodromal states to manifest disease. These features are present to a milder degree in other alpha-
synucleinopathies including Parkinson disease (PD) but are most aggressive in DLB and distinguish its early
natural history. Idiopathic Rapid Eye Movement Sleep Behavior Disorder (iRBD) is a risk factor for both PD and
DLB—two conditions with overlapping neuropathological features but differing natural histories. This proposal
seeks to characterize serotonin system changes as a distinctive risk factor predicting iRBDDLB progression.
Neuronal pathology in the serotoninergic raphe nucleus accrues in parallel to nigrostriatal degeneration in early
synucleinopathies but its exact role in disease progression is not well understood. Our central hypothesis is
that raphe serotonin transporter (SERT) elevations in iRBD are a marker of DLB risk by indicating early
serotoninergic system dysfunction linked to posterior cortical neurodegeneration and visuospatial cognitive
decline. We will test this hypothesis by evaluating serotonin transporter [11C]DASB PET and striatal
dopaminergic [11C]DTBZ PET imaging in subjects with DLB, iRBD, and older controls to characterize the
natural history of serotoninergic system impairments in subjects at risk for DLB and to determine whether
changes in the serotonergic system might serve as an imaging signature potentially capable of identifying
progression of prodromal DLB. In Aim 1, we will test whether raphe nucleus [11C]DASB PET elevations
distinguish iRBD subjects both from DLB subjects and from older controls. In Aim 2, we will evaluate the
natural history of [11C]DASB PET changes in iRBD over time both in the raphe nucleus itself (Aim 2A) and in its
relation to cortical serotoninergic denervation in the visuospatial cortex (Aim 2B). Aim 3 will validate a novel
cognitive marker of visuospatial navigation capable of tracking both prodromal DLB progression and
associated cortical serotoninergic neurodegeneration. This work will generate the first longitudinal PET studies
of serotoninergic and presynaptic dopaminergic PET in iRBD, closing a critical knowledge gap in Alzheimer’s
disease related dementias (ADRD) science while advancing both DLB biomarker development and the
characterization of the serotonin system as a potential therapeutic target in synucleinopathies.

## Key facts

- **NIH application ID:** 10230922
- **Project number:** 1R56AG065529-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Vikas Kotagal
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $692,428
- **Award type:** 1
- **Project period:** 2020-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10230922

## Citation

> US National Institutes of Health, RePORTER application 10230922, Early Serotonin System Changes in prodromal DLB (1R56AG065529-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10230922. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*