The Emory Udall Center administers a pilot grant program to encourage Parkinson's disease research at Emory which includes up to three grants annually for meritorious high-impact projects that generate preliminary data for larger grant applications. The Emory National Biomedical Research Center, Emory School of Medicine, The Jean and Paul Amos Parkinson’s Disease and Movement Disorders Program and Emory College provide financial support for this pilot program.
Past Awardees
Year 1
The link between purine metabolism and Parkinson’s Disease
Fatemeh Seifar, MD, Principal Investigator; HA Jinnah MD, PhD, Co-Principal Investigator
Purines are important components of DNA, ATP, GTP and are crucial for cell function and energy consumption. Cells use two main pathways to metabolize purines: de novo purine synthesis and recycling. Uric acid (UA) is the end-product of purine metabolism and is linked to incidence and progression of Parkinson’s disease (PD). The link between low UA and PD is quite strong and reproducible, however, the biological mechanism linking UA to PD is still undiscovered. Since UA level is closely linked to purine metabolic pathway, low UA could be due to lower purine production in PD. This project is aimed to discover the link between purines metabolism and PD. We will use human derived induced pluripotent stem cells (iPSC)s to develop an in vitro model of dopamine neurons, the most relevant cells to PD. We will measure purine pools in PD neurons relative to controls (aim 1) to determine whether low UA is due to low purine production. The results may show low purines or the opposite, but even if the levels of purines were normal, this doesn’t refute the low capacity to produce purines due to downstream and compensatory pathways. So, we will measure the expression of key enzymes in purine pathway (aim 2). Then, we will challenge purine metabolism to see how PD neurons respond to high purine demands (aim 3). Our findings will provide clues to determine the biological mechanisms that link low UA to PD.
Cortical activity underlying impaired reactive and anticipatory postural control in Parkinson’s disease
Lena H. Ting, PhD, Principal Investigator; Michael Borich, DPT, PhD, Co-Principal Investigator; J Lucas McKay, PhD, MSCR, Co-Investigator; Svjetlana Miocinovic, MD PhD, Co-Investigator
Interactions between balance and cognitive impairments in older adults with and without Parkinson’s disease (PD) lead to reduced mobility and falls, through unknown mechanisms. Our recent work showed that cognitive set-shifting impairment is associated with fall history in older adults with and without PD – even after controlling for overall cognitive impairment. We have developed expertise using high-resolution scalp electroencephalography (EEG) during reactive balance perturbations, revealing a number of associations between evoked cortical activity to cognitive set shifting and dual-task interference in older adults with and without PD. Here, we seek to identify cortical mechanisms underlying cognitive-motor interactions in more ecologically-relevant standing balance conditions that support upper-limb motor tasks. These are the first experiments we propose on our newly-acquired KinArm End-Point Lab™, a graspable robot that monitors and manipulates location of the hand in 2-dimensional space during standing or sitting. We will record EEG activity while participants stand and hold the hand within a target or reach to a target. In Aim 1, we will compare cortical activity during reactive versus anticipatory postural control in older adults (HOA) and older adults with PD. In Aim 2, we will test the hypothesis that cortical activity related to error assessment will be greater as the consequences of perturbations increase, and that this relationship will be impaired in PD. In Aim 3, we will compare spatiotemporal cortical activity during cognitive dual-task conditions using a robotic Trail Making Test (a test of cognitive set-shifting), conducted in the standing position in PD vs HOA. If successful, we will develop an initial set of instrumented tests to precisely and objectively probe cognitive-motor impairments in PD during coordinated upper and lower limb movements, time-locked to spatiotemporal cortical activity. We anticipate this research to lead to a number of externally-funded clinical and neurophysiological studies of PD pathophysiology and treatment.
Year 2
Influence of ovarian hormones on the expression of parkinsonism and LIDs
Ellen J. Hess, PhD, Principal Investigator
Biological sex is a risk factor in Parkinson’s disease (PD). Males are more likely to develop PD and have an earlier age of onset than females. Disease presentation also differs with males exhibiting more bradykinesia and rigidity than females whereas females tend to have tremor-predominant PD. In later stages, females exhibit more severe L-DOPA-induced dyskinesias (LIDs) than males. Although small clinical studies implicate estrogens in the sex-biased features of PD and LIDs, the findings are inconsistent. Because systematic clinical studies are lacking and little basic research has focused on the question, the mechanisms underlying sex differences in PD and LIDs are not understood. To begin to address this gap in knowledge, we will test the hypothesis that estradiol mediates parkinsonism and the pathogenesis and severity of LIDs in a mouse model of parkinsonism and LIDs by experimentally manipulating ovarian hormones. To accomplish this, 6OHDAtreated mice will be ovariectomized and challenged with estrogen or progesterone or vehicle before, during and after the induction of LIDs to identify the effect of each hormone on the severity parkinsonism and the severity and time course of the development of LIDs. Based on the very limited information available, we expect estrogen to reduce the severity of LIDs while progesterone may have little effect or exacerbate LIDs. Regardless of the results, the proposed work has immediate implications because it is not known if hormone replacement therapy in postmenopausal women is therapeutic or contraindicated for PD, particularly for the development of LIDs. Further, it is also critical to identify the role of both estrogen and progesterone since anecdotal evidence suggests that estrogen and progesterone may have opposing effects, which has implications for the specific formulation of hormone replacement therapy appropriate for females with PD.
Translation of LRRK2-specific PET radiopharmaceuticals in humans
Steven Liang, PhD, Principal Investigator; David Schuster, MD, Co-investigator
Mutations in LRRK2 are the most common cause of familial Parkinson’s disease (PD). The most common LRRK2 variant, G2019S, is present in more than 85% of PD patients carrying LRRK2 mutations. This mutation, which occurs within the LRRK2 kinase activation loop, leads to increased LRRK2 activity and expression. As a non-invasive imaging technology, PET is capable of quantifying biochemical processes in vivo, and a suitable PET ligand would substantially improve our understanding of LRRK2 signaling under disease conditions otherwise inaccessible by ex vivo (destructive) analysis. Furthermore, quantification of LRRK2 in living brain by PET would provide the assessment of distribution, target engagement and dose occupancy of novel LRRK2- targeted neurotherapeutics. In 2022, the PI developed the first and only validated LRRK2 PET ligand, namely [18F]PF-943, in crossspecies studies (transgenic LRRK2-G2019S mutant mouse models and nonhuman primates). The ligand is highly potent and selective among all the LRRK2 inhibitors reported to date. Preliminary PET imaging in NHPs confirmed that we have overcome the two major obstacles for LRRK2 ligand development by achieving high brain uptake and high target specificity. However, LRRK2-targeted PET imaging has not yet been conducted in humans (PD patients and age-matched healthy controls) and in vivo evidence in living Parkinson’s brain is still deficient in demonstrating the underlying mechanism between LRRK2 dysfunction and PD. The availability of [18F]PF-943 now provides a unique opportunity to address this unmet clinical need. Therefore, we will take advantage of Udall pilot grant support to complete key regulatory components, including radiation dosimetry, toxicological study and CMC production validation. The successful completion of this work will enable us to file an FDA IND Application under PET drug 21CFR212 and obtain IRB approval for first-in-human study, which ultimately serves as a molecular imaging tool for industry-sponsored trials and/or strong preliminary data for NIH applications. Novel lipid transfer pathway between erythrocytes and plasma Provides a Parkinson’s diagnostic strategy Fathima Shaima Muhammed Nazaar, PhD, Principal Investigator; Blaine R. Roberts, PhD, Co-Investigator Diagnosis of idiopathic Parkinson’s disease (PD) is a major challenge, and unlike Alzheimer’s disease, the field is still without accurate molecular diagnostic tools (e.g., blood tests and imaging). To address this gap, we recently completed a Michael J. Fox foundation-funded project to conduct lipidomic analysis on paired red blood cells and plasma from a cohort of PD and control cases (n=284). We discovered over 150 differentially expressed lipids, with approximately 10 that have the potential to serve as a lipid biomarker panel for PD. During this project, we made the surprising discovery that many of the lipids in red blood cells that accumulate in PD are depleted in plasma. This was contrary to the hypothesis that lipid signatures in the RBCs would be reflected in plasma. The discordance in the changes in lipid abundance between RBC and plasma suggests a novel active lipid transport or metabolic process. The purpose of this study is to determine if the proteins involved in lipid metabolism and transport are also differentially regulated in RBC. The results from this study, combined with data collected in our MJFOX grant, will be used to submit an RO1 application in 2023.