Longitudinal Imaging Biomarkers of Prodromal DLB

PROJECT SUMMARY / ABSTRACT Mild Cognitive Impairment (MCI) with core clinical features of dementia with Lewy bodies (DLB) is recognized as the prodromal stage of DLB (MCI-LB). Patients with MCI-LB frequently progress to DLB, but a subset may have a range of additional AD pathology. Rapid advances in the development of protein-specific disease- modifying therapies highlight a critical need for biomarkers in MCI-LB, because clinical trials will need to be sufficiently powered to detect changes in disease progression during the prodromal phase, when the disease- modifying therapies would be most effective. During the initial cycle of this project, we determined the cross- sectional and longitudinal imaging biomarkers of DLB with pathologic confirmation. The current cycle of the U01 project is designed to identify cross-sectional and longitudinal multi-modal biomarkers of prodromal DLB in MCI-LB, and prepare for protein-specific disease-modifying clinical trials that will need these biomarkers for selection of participants and to track outcomes in MCI-LB. The rationale for a multi-modal biomarker approach stems from the multi-factorial and co-existing LBD and AD pathology in DLB and similarly in MCI-LB. We will determine the cross-sectional and longitudinal PET, SPECT, MRI, and polysomnogram (PSG) biomarkers of MCI-LB compared to cognitively unimpaired controls. We will also determine whether age, sex as a biological variable, APOE ε4 status, and cerebrovascular disease lesions on MRI modulate these differences. In a pilot analysis, we will compare protein misfolding cyclic amplification (PMCA) and real-time quaking-induced conversion (RT-QuIC) assays for α-synuclein in CSF for differentiating MCI-LB from controls. Finally, we will correlate our findings with pathologic outcomes. Inclusion of MCI-LB patients in the current cycle will be based on the presence of one or more core clinical features of DLB and not on biomarker findings. This will provide the opportunity to validate the use of proposed and novel biomarkers in the diagnosis of MCI-LB and to determine which biomarkers predict progression from MCI-LB to DLB. All samples, clinical, imaging, and autopsy data from MCI-LB cases and controls will be collected and shared according to the Parkinson's Disease Biomarkers Program guidelines.