Targeting Lewy Body Specific Pathology Using Biomarkers (U01)

DLB is particularly problematic since it is often not appreciated until late stages, and often is admixed pathologically with concomitant Alzheimer’s disease (AD). Clinical care and the design of symptomatic and disease modifying trials for DLB would benefit from earlier diagnosis and reduced pathological heterogeneity. Thus, it is important to identify the extent to which Lewy Body versus AD pathology contributes to the phenotype and underlying biology of DLB, and to discover new molecular targets that specific to DLB. Clinically, we are uniquely poised to recruit a multiethnic cohort of DLB patients derived from both the local /metropolitan community, the Alzheimer’s Disease Research Center [ADRC], and the broader practice settings of the Aging and Dementia, Movement Disorders, and primary care programs at Columbia University. We will capture the continuum of cognitive impairment and extrapyramidal signs that exist in DLB. In Aim 1, we will identify and recruit an ethnically diverse (White, Hispanic, African American) cohort of 40 DLB patients per year for years 1-4, who will be followed semi-annually. We will administer the NINDS Parkinson’s Disease Biomarkers Program (PDBP) battery, the NIA National Alzheimer Coordinating Center (NACC) UDS3 with the new DLB module. In Aim 2, we will perform RNA gene expression and epigenetic (DNA methylation) profiling on dissected brain tissue from our Columbia University brain bank including cases with pathologically defined Lewy Body Disease with AD pathology (DLB/AD) and without significant AD (DLB), cases with AD, and controls to identify Lewy body specific differences primarily by comparing DLB/AD and AD. In Aim 3, we will use expression data from Aim 2, to develop biomarker assays in blood and CSF, including at RNA and protein levels. This aim will first utilize plasma from cases who have autopsy proven diagnosis, and will then be expanded to samples with clinical diagnoses. PUBLIC HEALTH RELEVANCE: /Relevance This project is designed to discover biomarkers specific for Dementia with Lewy Bodies (DLB). We will recruit a diverse cohort with DLB for longitudinal study as part of a national effort. We will use our extensive brain bank resources to analyze Lewy body specific gene expression to develop biomarkers for early diagnosis and identification of therapeutic targets.

Goals of Project

• Recruitment: We will identify and recruit an ethnically diverse (White, Hispanic, and African American) Columbia University cohort of 40 Dementia with Lewy Bodies (DLB) patients each year for years 1-4, who will be followed on an annual basis.
   
  • Assessment: The cohort will be evaluated using the NINDS Parkinson’s Disease Biomarkers Program (PDBP) battery of tests and the NIA/National Alzheimer Coordinating Center (NACC) new Uniform Data Set DLB module.
  • Resource Building: Each member of the cohort will be co-enrolled in the ADRC to leverage evaluation resources, and promote participation in brain autopsy through our already well-established ADRC methodology.

• Discovery: We will perform RNA gene expression and DNA methylation (epigenetic) profiling on brain tissues and purified neurons from 100 cases with Lewy Body Disease with Alzheimer’s Disease pathology (DLB/AD), 50 without significant AD (DLB only), 100 cases with AD only and 50 controls, in order to develop biomarkers for diagnostic and discriminatory purposes, and identify possible targets for therapeutic intervention in DLB.
   
  • Discovery: We will identify DLB specific differential expression using RNA-seq (RNA gene expression analysis) by comparing DLB/AD vs AD and, then secondarily DLB/AD and DLB vs control brains.
  • Discovery: We will examine each of the brain samples and purified neurons using epigenetic analyses to pinpoint DNA sequences that underlie DLB (by identifying marker loci that may show differential methylation specific to Lewy Body pathology and correlating methylation with genome-wide association study data)

• Resource Building: We will use this information to develop biomarker assays in blood and cerebrospinal fluid (CSF), including at RNA and protein levels.

Enrollment Goals

• 40 Dementia with Lewy Bodies (DLB) patients (varying stages of disease)

To participate in this study, please contact one of the following: