Penn ADCC-funded Pilot Awards
Announcement: The 2018-2019 IOA and ADCC Pilot Award RFA is now available! The submission deadline is February 2, 2018.
| For Fiscal Year 2018
Palliative Care Consultations for Persons with Advanced Dementia in the Medicare Skilled Nursing Setting
PI: Mary Ersek, PhD
Abstract: Palliative care is a patient and family-centered approach to care that is recommended for persons with advanced dementia (PWAD). Key components of this approach are:1) open discussion of the course of illness; 2) establishment and communication of patient- and family- directed goals that guide health care; 3) aggressive prevention, early identification and treatment of illness-related symptoms; and 4) identification of psycho-spiritual needs and approaches to mitigating suffering. Unfortunately, many PWAD, especially those who are cared for in nursing homes, lack access to palliative care. This is particularly concerning in post-acute (i.e., following hospitalization) nursing home care, where PWAD are likely to receive intensive physical rehabilitation services and treatments such as feeding tubes that are burdensome rather than beneficial for the person’s well-being. Our project’s goal is to refine and test a palliative care consultation intervention for PWADs who are receiving post-acute care in nursing homes. Our long-term goal is to shift the current models of dementia care in nursing homes to a person-centered model that results in better symptom control, enhanced communication, and enhanced quality of life for PWAD and their families.
Effects of episodic memory on economic decision-making in older adults with and without biological markers of preclinical Alzheimer's disease
PI: Joseph Kable, PhD
Abstract: Older adults often struggle with financial decision-making, and they are disproportionately exploited for financial gain. The consequences of this decline in decision-making capacity can be devastating, placing undue burdens on relatives and public entitlement programs. Decision-making difficulties in old age may stem primarily from difficulty in learning and acquiring values for later decisions. In particular, learning values from single experiences requires a functioning episodic memory system, a learning system that deteriorates rapidly as individuals age. It is unknown how well older adults can use episodic memories of single events to make adaptive decisions. Moreover, learning has never been investigated in older adults in the social domain, where appropriate learning about others is fundamental for avoiding financial fraud. Here we propose to test if older adults can learn to associate stimuli with rewards after one experience in order to make adaptive economic decisions, in both the social and non-social domain. We will also investigate the effects of preclinical Alzheimer’s disease (AD) and medial temporal lobe structural alterations, which are also related to episodic memory decline (but are usually unaccounted for in aging studies) on episodic memory-based decision-making. For this pilot study, we will recruit participants from the well- characterized cohort of older adults at the ADCC, many of whom have already undergone MRI and PET imaging to test for biological markers of AD. This pilot is the PI’s first foray into studying decision-making in health aging, as his research program to date has focued exclusively on the cognitive and neural bases of decision-making in young adults. We have consulted Dr. David Wolk, co-director of the Penn Memory Center and Clinical Core Leader and Associate Directory of the ADCC, and he supports this research as proposed. He will facilitate recruitment from and access to data from the ADCC cohort. This pilot study will serve as the basis for a joint NIH R01 application with Dr. Wolk, investigating the effects of multiple forms of memory on adaptive decision-making.
AD-related Penn Institute on Aging-funded Pilots
Elucidation of Cell-type Specific Transcriptomic Profiles in Neurodegenerative Brain
PI: Mingyao Li, PhD
Abstract: Alzheimer’s disease (AD), the most common cause of dementia, affects 5.2 million Americans and 35 million worldwide. Genome-wide association studies (GWAS) have identified susceptibility loci from AD patients that suggest multiple biological pathways contributing to its genetic architecture. However, most GWAS-identified variants are located in non-coding regions suggesting that dysregulation of RNA expression may determine AD susceptibility. Transcriptomics provides a promising avenue to assess GWAS regions that show altered gene expression. While many transcriptional changes in AD are likely due to dysfunctional cellular pathways, changes in the cellular composition of affected brain regions are also likely to impact gene expression levels, but dissection of the two confounding effects has been technically challenging. To gain a better understanding of the transcriptional changes in AD, we propose to characterize gene expression variations in single-cell RNA-seq data from human brains. Using cell type-specific gene expression from single-cell RNA-seq data as a reference, we will infer cell type-specific gene expression and alternative splicing in bulk RNA-seq data from AD and normal brains, and compare their cell type composition and cell type-specific gene expression and splicing profiles. Findings from this project will allow us to examine cell type- specific effect in AD.
Characterization of Alzheimer's disease-linked MHC Polymorphisms within the HLA-DRB Locus
PI: Dimitri Monos, PhD and Brad Johnson, MD, PhD
Abstract: Two recent, large and independent GWAS meta-analysis studies report that two intergenic SNPs, rs9271192 and rs2516049 in the class II region of the major histocompatibility complex (MHC), located centromeric to HLA-DRB5 gene, are associated with Alzheiemr’s disease (AD). These SNPs are located within a ~40Kbp linkage disequilibrium block (R2 0.8 within the CEU population) containing the HLA-DRB5 gene, which is found in approximately 15% of MHC haplotypes. Additionally regarding gene expression HLA-DRA transcript was significantly altered in AD brains as compared to control brains. Recent research from our group demonstrates that both the DRA and DRB5 genes encode additional genomic elements, including novel microRNAs, encoded within intron 5 of the HLA-DRB5 and intron 1 of DRA gene. Preliminary data suggests that these particular miRNAs is computationally predicted to target transcripts of genes that have been associated with AD pathogenesis through GWAS studies, including eQTL loci that have been associated with AD. Importantly, because of the complexity of the MHC locus, it has, until recently, been difficult to obtain full and accurate sequence information for MHC haplotypes. It is therefore likely that there are additional and as-yet uncharacterized sequence variations in linkage disequilibrium to the two SNPs that may explain the increased risk for AD. Identifying such variations should yield clues to which factors encoded within the region might contribute to pathogenesis. Our approach will involve the capture and sequencing by next generation sequencing (NGS) of the HLA-DR region, a 153kbp genomic fragment, including all the relevant DRA and DRB genes, using a NGS-based methodology developed in the Monos lab and shown to provide credible sequencing data of high coverage (92-97%) and accuracy (99.99%) for the whole MHC (4 Mbp). For this pilot study we will work with a limited number of subjects (40) to 1) demonstrate that our NGS approach can successfully characterize the region and 2) identify novel sequence variants that will provide candidates for future studies to explain how this region of the MHC contributes to AD pathogenesis.
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