Longitudinal Imaging Biomarkers of Disease Progression in DLB (U01)

​​​​Dementia with Lewy bodies (DLB) is a clinical syndrome characterized by the presence of Lewy body disease (LBD), but additional Alzheimer’s disease (AD)-related pathology is also common in patients with DLB. Although the impact of each of these two pathologies on the clinical disease progression is not fully understood, many DLB patients may benefit from treatments that target both AD and LBD-related pathological processes. To prepare for these clinical trials in DLB, we need robust and reliable biomarkers that can track disease progression, particularly the progression of both LBD- and AD-related pathologies. We propose multi-modal imaging biomarkers of pathological processes commonly present in patients with DLB to detect disease progression. We propose to establish a longitudinal cohort of patients with DLB and acquire clinical and multi-modal imaging biomarker data to model the longitudinal imaging biomarker changes with respect to clinical disease progression in DLB. In Aim 1, we propose to determine whether LBD-related dopaminergic loss on SPECT, and AD pathophysiology measured with higher amyloid-β deposition on PET and AD-signature atrophy on MRI is associated with the rate of clinical disease progression, cognitive decline and survival in DLB; In Aim 2, we will determine whether these longitudinal changes in imaging biomarkers and clinical outcomes, and their associations are modified by genetic, sex based, and cerebrovascular disease-related features. In Aim 3, we will determine the pattern of a tau ligand AV-1451 uptake in DLB compared to controls and its relationship to the rate of change in imaging biomarkers and clinical disease progression. Finally, we will determine the pathologic basis of the biomarker changes in DLB in autopsied patients, which is the gold standard for validating imaging biomarkers in Aim 4. In addition to these aims that focus on hypothesis testing, we will collect whole blood, plasma, serum, CSF, and urine samples, clinical and harmonized neuroimaging data longitudinally; DNA and peripheral blood mononuclear cells from a prospective cohort of DLB patients.

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. 

PUBLIC HEALTH RELEVANCE: Dementia with Lewy bodies (DLB) is a dementia syndrome that is often influenced by both Lewy body disease (LBD) and Alzheimer's disease (AD) pathologies. Mild Cognitive Impairment (MCI) with DLB features is now recognized as an early stage of DLB. Determining the autopsy-confirmed multi-modal imaging biomarkers of MCI with DLB features that are associated with disease progression is critical for clinical trials that target specific pathologic components in DLB patients early in the disease process, when preventing or delaying or progression to dementia is possible.

Goals of the Project

• Enroll and follow 90 patients with Dementia with Lewy Bodies (DLB) over time with cognitive, motor, behavioral and imaging measures. Imaging measures include:
  • AV-1451 PET at baseline (tau pathology)
  • DaTscan SPECT annually (Dopamine transporter)
  • PiB or Florbetapir PET annually (amyloid pathology)
  • Structural MRI annually (ADNI-3 protocol)
• Perform brain autopsies on all deceased participants who consent to brain donation.
• Enrollment Goals
• 90 Dementia with Lewy Bodies (DLB) patients

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