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.
Changes in serotonin system biology may play a role in the development of Dementia with Lewy Bodies (DLB) but are not well understood. We propose to study the serotonin system using unique imaging methods in DLB subjects, healthy controls, and subjects at risk for developing DLB. These aims are relevant to the goal of reducing Alzheimer?s disease and related dementias (ADRDs) and to the overall goal of advancing DLB science towards the goal of preventative clinical trials.
