Lewy body dementia pathway and biomarker discovery

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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 common form of Alzheimer disease (AD)-related dementia that accounts for up to 30% of all dementia cases. The pathological hallmarks of LBD are cortical α-synuclein aggregates in neuronal cell body and neuronal processes termed Lewy bodies and Lewy neurites, respectively. Patients with LBD suffer from cognitive impairment, neuropsychiatric symptoms, and Parkinsonian motor symptoms. Clinical differentiation of DLB from PDD is based on an arbitrarily defined “one-year rule”: patients who develop dementia before or within one year after the onset of motor symptoms are defined as DLB, whereas patients who develop dementia after one year of the original diagnosis of Parkinson disease (PD) are classified as PDD. Whether DLB and PDD are the same or different clinical syndromes remains hotly debated, and our 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. Currently, there is no reliable biomarker for LBD diagnosis and no effective means of prevention or disease-modifying treatment, highlighting the need to better understanding the pathogenesis of LBD. This project will address an important yet understudied area of dementia research and use an innovative multiplex platform of integrative proteomics, glycoproteomics, and glycomics to discover pathogenic pathways and molecular targets for LBD diagnostic and therapeutic development. The proposed research will investigate and uncover useful biological information stored in virtually unexplored, human LBD brain proteome, glycoproteome, and glycome and identify molecules and pathways involved in LBD pathogenesis. Furthermore, this project will use a systems biology approach to determine if the identified LBD-associated molecules, networks, and pathways are similar to or distinct from those of Alzheimer disease. Results from the proposed research will advance our knowledge of LBD pathogenesis and help accelerate the effort to discover curative therapies for LBD and other neurodegenerative dementia including Alzheimer disease.