Molecular and Network Analyses of Lewy Body Dementia Pathogenesis

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Project Summary / Abstract Lewy body dementia (LBD), which includes Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB), is a major form of Alzheimer disease (AD)-related dementia, accounting for up to 30% of all dementia cases. Patients with LBD suffer from cognitive impairment, neuropsychiatric symptoms, and a fraction of LBD patients have Parkinsonian motor symptoms. Clinical differentiation of DLB from PDD is based on an arbitrarily defined “one-year rule”, and whether DLB and PDD are the same or different clinical syndromes remains unclear. Our current knowledge of the molecular commonalities and differences in the pathogenesis of these two LBD subtypes is limited. Furthermore, LBD is underdiagnosed, due to the low sensitivity of the clinical diagnosis criteria and challenges in clinical differentiation of LBD from AD. Despite the overlap in clinical symptoms between LBD and AD, there are key differences between LBD and AD patients in the responses to antipsychotic drug treatment. The molecular basis of the phenotypic overlaps and dissimilarities between LBD and AD is unknown. Currently, there is no reliable biomarker for LBD diagnosis and no effective means of prevention or disease-modifying treatment, highlighting the need to better understand the pathogenesis of LBD. This project will use an innovative approach of integrative proteomics, glycoproteomics, and glycomics coupled with network analyses to address the following key questions: What are the molecular abnormalities that define LBD? Do the two LBD subtypes (PDD and DLB) have the same or different molecular abnormalities? How do PDD and DLB overlap with or differ from AD at the molecular level? The proposed research will determine disease-associated changes in human LBD brain proteome, glycoproteome, and glycome, identify molecular targets and pathways involved in LBD pathogenesis, and elucidate LBD pathogenic mechanisms that are similar to or distinct from those of AD. A variety of biochemical, cell biological, targeted glycoproteomics, and functional analyses as well as animal model studies will be performed to validate and study the identified LBD-associated targets and pathways. Findings from the proposed research will advance our knowledge of LBD pathogenesis and help accelerate the effort to discover curative therapies for LBD as well as AD.