Mapping Synaptic Density in Prodromal and Manifest Lewy Body Dementia

Project Summary Synaptic loss is theorized to occur early in the course of common neurodegenerative proteinopathies such as Alzheimer disease (AD) and Lewy body dementia (LBD). Until recently, the evaluation of synaptic loss in the human brain depended on the availability of pathologic/autopsy material, which inevitably did not represent early

stages of disease. In the past few years, development of radiopharmaceuticals that target SV2A, a ubiquitous synaptic protein, have made it possible to quantify synaptic density in the human brain in vivo. One long-term goal of the collaborative neuroimaging programs at UW-Madison is to use magnetic resonance imaging (MRI)

and Positron Emission Tomography (PET) to understand and detect preclinical stages of neurodegeneration in AD and ADRD. The objective of this proposal is to use SV2A PET, acquired simultaneously with diffusion and structural MRI, to evaluate the sequence and topography of synaptic, white matter microstructural, and

volumetric changes that correspond to prodromal and manifest stages of LBD. The central hypothesis is that lower synaptic density in neocortex and hippocampus will be detectable at earlier disease stages than reductions in white matter microstructural integrity and will correspond to or predict cognitive decline. The rationale for this

proposal is that participants selected and carefully characterized to represent the spectrum of disease stages from healthy aging to prodromal LBD will provide a representative cohort from which to draw conclusions regarding the sequence of brain changes that occur prior to clinical disease onset. For this project we will recruit

160 human research participants, 120 of whom have significant risk factors to develop LBD: Forty participants with rapid eye movement sleep behavior disorder and normal cognition (RBD-NC), 40 participants with early- stage Parkinsonism and normal cognition (PD-NC), and 40 participants who meet research criteria for mild

cognitive impairment with Lewy body (MCI-LB), as well as 40 age- and sex-matched healthy controls. We are experienced in and will perform extensive motor and cognitive characterization of these individuals at baseline and 2-year follow-up intervals. All participants will undergo structural and diffusion MRI as well as SV2A PET at

baseline; a subset of participants (~35) who show cognitive decline during the study will be re-imaged with SV2A PET/MRI at follow-up. Using the SV2A PET and MRI data, the specific aims will be to (1) map differences in synaptic density between control, RBD-NC, PD-NC, and MCI-LB at baseline, (2) determine the relationship

between synaptic density within prespecified neo and allocortical regions and cognitive decline, and (3) determine the degree to which reduced synaptic density occurs independent of microstructural and structural change prior to dementia. The significance of this project is that it evaluates important hypotheses regarding

the role of synaptic loss as an early event in and cause of cognitive change in LBD. This project is innovative because few studies have evaluated SV2A in prodromal stages of LBD, including RBD and MCI-LB. The positive impact of this work will be to develop biomarkers for the future evaluation of intervention therapies.