Elucidating the Role of Cholinergic Degeneration in Cognitive Fluctuations in Lewy Body Dementia

Cognitive fluctuations (CF) are a hallmark of Lewy body dementia (LBD), presenting as spontaneous, unpredictable episodes of reduced attention and alertness. In addition to being common, CF in LBD are associated with greater impairment in activities of daily living, worse quality of life, and greater healthcare costs. Despite their high prevalence and negative impact, the mechanisms underlying CF are poorly understood. This project aims to elucidate the role of central cholinergic degeneration in CF in LBD, addressing critical gaps in understanding. This project will also establish a paradigm for assessing CF in real-time and focus future therapeutic development. CF in LBD have been linked to alterations in resting-state EEG, specifically reduced dominant frequency and increased dominant frequency variability. Preliminary data suggest that these EEG alterations, reflecting dysregulated cortical rhythms, are associated with CF. Cholinergic degeneration, particularly in the basal forebrain and midbrain, is more pronounced in LBD compared to other dementias and is associated with various cognitive and motor symptoms. However, there is less evidence supporting the role of central cholinergic deficits in CF. Our central hypothesis is that cholinergic deficits in cortical and thalamic circuits lead to dysregulation of cortical states, manifesting as increased low- frequency EEG activity and clinically as CF. In Aim 1, we will determine the association between cholinergic degeneration and CF in LBD. This cross-sectional study will compare cholinergic degeneration in LBD patients with CF to a group of Lewy body disease patients without CF. We will use T1-weighted MRI, diffusion tensor imaging (DTI), and resting-state functional MRI (rs-fMRI) to assess cholinergic network dysfunction. CF will be evaluated using the Clinical Assessment of Fluctuations scale (CAF), the psychomotor vigilance task (PVT) administered over 48 hours, and quantitative analysis of EEG over 48 hours. In Aim 2, we will isolate the effects of cholinesterase inhibitors on CF in a pre-post interventional study. In LBD patients with CF, we will determine the effect of a cholinesterase inhibitor on CF as measured by the CAF, the PVT administered over 48 hours and the quantitative EEG features over 48 hours. We will also assess the relationship between changes in network connectivity using rs-fMRI and changes in CF. In Aim 3, we will examine the longitudinal association between cholinergic degeneration and CF progression. This 2-year cohort study will monitor LBD patients with CF and Lewy body disease patients without CF over 2 years with annual MRI, CAF, PVT over 48 hours, and EEG over 48 hours. Our approach, integrating MRI, EEG, and clinical assessments, aims to provide a comprehensive understanding of CF dynamics and establish relevant outcome measures of CF. This research will also guide the development of new therapeutic strategies targeting the cholinergic system. The anticipated impact includes establishing a paradigm for monitoring CF with EEG and repeated cognitive testing, ultimately leading to better treatments and enhanced quality of life for individuals with LBD.