David G. Standaert, M.D., Ph.D. - US grants

DESCRIPTION (provided by applicant): Glutamate is the principal excitatory neurotransmitter in the brain and has an important role in the regulation of movement. N-methyl-D-aspartate (NMDA) glutamate receptors are of particular interest because they are involved in long-term processes such as neural adaptation and memory. Drugs acting at NMDA receptors have important therapeutic potential in human Parkinson's disease. In particular, recent work has suggested that changes in NMDA receptor properties may be responsible for the development of the motor complications of levodopa therapy, such as wearing off and dyskinesias. Such motor complications occur in the majority of patients with Parkinson's disease and are frequently the principal cause of disability. NMDA receptors are assembled from proteins from two gene families, and receptors with different composition have distinct properties. The functions of the receptors are further regulated by differential trafficking and phosphorylation. Our investigations have revealed that neurons which serve different functions in the circuitry of the basal ganglia express different types of NMDA receptor subunits. In models of Parkinsonism, striatal NMDA receptors are modified. The most significant changes are not alterations in the level of gene expression, but rather are changes in the assembly, phosphorylation, and synaptic localization of the protein subunits. In this project, we will employ a variety of techniques to establish the nature and mechanisms of the modifications of basal ganglia NMDA receptors produced by chronic dopamine depletion and dopamine replacement therapy. The long term goal of this work is to gain insight into the cause of wearing off and dyskinesias in Parkinson's disease, and develop better treatments for this common and disabling neurological disorder.

dopamine agonists; human therapy evaluation; antiparkinson drugs; Parkinson's disease; dihydroxyphenylalanine; drug screening /evaluation; mental disorder chemotherapy; quality of life; mental health epidemiology; clinical trials; drug adverse effect; psychomotor function; neural degeneration; clinical research; vital statistics; questionnaires; blood chemistry; human subject;

Recent discoveries have pointed to a central role of the protein alpha-synuclein in the pathophysiology of Parkinson's disease. The mechanism by which alpha-synuclein exerts a toxic effect is unknown. One potentially crucial mechanism is transcriptional dysregulation, meaning interference with the expression of cellular genes essential for normal function. Transcriptional dysregulation has been shown to be a key mechanism in other neurodegenerative diseases including Alzheimer's and Huntington's diseases, and emerging evidence implicates similar mechanisms in PD. In the first two aims of this project we will address the question: Do alpha-synuclein aggregates in human disease or animal models lead to transcriptional dysregulation? We will use an array-based approach to perform a broad examination of this question, in addition, we will conduct a focused study of two processes that may underlie the selective vulnerability of dopamine neurons characteristic of the disease: i) mechanisms for protection against oxidative stress, and ii) chaperone mechanisms for the degradation and clearance of misfolded proteins (in collaboration with Projects by Young and Lindquist. In the third aim, we wilt use a transgenic model of synucleinopathy to determine whether restoring the expression of dysregulated genes can ameliorate the disease process. The fourth aim is directed at improving symptomatic therapy of the disease. The mainstay of existing therapies is dopaminergic replacement, but long term use of these drugs is associated with adverse motor effects (wearing off and dyskinesia). In collaboration with Project by Hyman, we will use gene expression studies to examine the striatal signaling pathways which lead to these adverse effects, in search a better understanding of the basic mechanisms responsible and new approaches to treatment.

Dystonia is a movement disorder characterized by sustained muscle contractions, frequently causing twisting and repetitive movements, or abnormal postures. Despite the recent progress in understanding how movements are controlled, the neural mechanisms of dystonia remain largely a mystery, and an adequate model is currently lacking. Potential mechanisms include abnormalities in dopamine metabolism, cholinergic function, and striatal dopamine/glutamate interactions. Mutations of the TOR1A gene cause DYT1 dystonia, a common early onset dystonia. This gene encodes torsinA, a member of the "AAA+" proteins. In studies conducted under the previous period of support, we have found that the mRNA for torsinA is expressed by neurons in several regions of normal adult human brain, including the dopamine neurons of the substantia nigra pars compacta. The expression of the encoded protein is widespread, but is found in presynaptic, putatively dopaminergic terminals in the striatum. In postmortem tissue from individuals with the DYT1 mutation, there are abnormalities of dopamine metabolism suggestive of a defect in dopamine release. We seek funding to extend our anatomical studies, and to investigate the localization and function of torsinA in genetically engineered rodent models. This data is essential to the construction of mechanistic models of the dysfunction, which produces dystonia in general, and DYT1 dystonia in particular.

Although the gene which causes DYT1 dystonia was discovered nearly a decade ago, the mechanism responsible for the symptoms in patients with this or many other forms of dystonia remains uncertain. This is a major obstacle to the rational design of effective therapies. During the prior period of support, we produced and characterized several mouse models of DYT1 in which there is expression of the abnormal torsinA protein throughout the brain, and found that these exhibit both behavioral as well as neurochemical abnormalities which appear to resemble aspects ofthe human disease. These have provided important insight into the effects of mutant torsinA on brain function. These models do not, however, resolve the question of how the abnormal protein leads to the phenotypic abnormalities, or identify the site of action. In this project, we will produce and study a novel series of mouse models with selective inactivation of torsinA, or knock-in ofthe DYT1 mutation. Using these, we will address the issue of whether selective inactivation in the cortex, striatum, or cerebellum is sufficient to produce behavioral and neurochemical abnormalities in the intact rodent. Given the strong evidence for involvement of the basal ganglia in many forms of dystonia, we will narrow the focus further by examining selective inactivation or knock-in ofthe DYT1 mutation in populations of striatal neurons, and within dopaminergic neurons. This project will also work closely with the other projects and cores, to identify opportunities to develop additional novel mouse models. Finally, we will seek to validate these models by assessing the effect of a drug treatment known to be effective in human dystonia, and establish a National Resource for distribution of these models to promote development of novel therapies. The overall goal of this work is to establish the anatomical site and mechanism of the dysfunction responsible for DYT1 and other dystonias, and enable targeted therapies for the disease.

DESCRIPTION (provided by applicant): This is a proposal for a new R25 research education award at the University of Alabama at Birmingham (UAB). This program will support residents in neurology, neurosurgery, and neuropathology who are pursuing careers combining clinical practice and research, and foster their development as physician-scientists. Over the past two decades, considerable efforts and resources have been devoted to understanding nervous system function in health and disease, and the result has been a vast expansion of knowledge encompassing fundamental discoveries in genetics, genomics, neurochemistry, synaptic plasticity, neural development, and behavior. It is clear, however, that there is an important gap between these advances and applications to human health. There is a pressing need for physician-scientists trained to: i) integrate discoveries about the nervous system from several domains into multi-modal and multi-dimensional frameworks; and ii) formulate translational pathways to apply this knowledge to important biomedical and behavioral problems. The Program Director and Associate Director are both physician-scientists with established track records in research and training. Residents supported by this program will initiate their research during their residency training, and continue it into a period of research fellowship following residency. Participants from all three disciplines (neurology, neurosurgery and neuropathology) will engage in a total of two years in full time research training. Their research experience will e supported by a structured mentoring program along with didactic teaching in professional skills training, grant writing, and responsible conduct of research. The goal of the program will be to enable residents and fellows to develop a career in neurological research, and to prepare them to successfully compete for individual fellowships or mentored career development awards. As an institution, UAB is exceptionally well positioned to undertake research education in the neurosciences, and to develop the physician-scientists who will apply today's discoveries to solve the challenges of the future.

DESCRIPTION (provided by applicant): Parkinson's Disease (PD) is a progressive, debilitating neurodegenerative disorder, which is characterized clinically by tremor, rigidity, bradykinesia and postural instability. Eventually, PD leads to profound functional disability in th areas of employability, ambulation and self-care. While current estimates indicate that approximately six million people worldwide (over 1/2 million Americans) have been diagnosed PD, there is neither a treatment to slow progression nor a cure. Morbidity and mortality associated with PD burden results in an estimated six billion dollars in healthcare costs in the United States annually. The NET-PD program established an innovative, evidence-based process by which potential therapies were selected and tested for slowing of PD progression. Operationally, NET-PD is organized into a Clinical Coordinating Center (CCC) at the University of Rochester, a Statistical Coordinating Center (SCC) at the University of Texas School of Public Health, and clinical sites (US and Canada). The NET-PD network is currently conducting a Phase 3 randomized, double-blinded and placebo-controlled clinical trial of creatine (LSI), and a futility trial of pioglitazone (FS-ZONE). FS-ZONE is fully funded by prior grants and is described in this application in order to provide a full view of NET-PD activities, but no additionl funds are being requested. LS-1 is an innovative trial which will test the utility of creatine in a real-world setting. At this point the trail is fully enrolled, and the most critical factor in the success of this trial is the retention of the subjects through the course of the study and accurate and complete data collection. UAB enrolled the largest single number of subjects in the LS-1 trial (61), and has 45 subjects currently active. Retaining this group in LS-1 will be highly significant in determining the success of the overall trial effort. UAB provides a unique and highly supportive environment for the continued success of the NET-PD program, and continued participation of UAB as a study site will help to ensure successful completion of this important effort.

Project Summary: Core A The Administrative Core provides for essential administration, communication, and compliance responsibilities of the Exploratory Grant. It acts to promote the integration, support the Program Director and Program Administrator, organizes meetings of the Program faculty and staff, and facilitate participation in national external activities. The Administrative Core is directed by the Program Director, Dr. Standaert. He is assisted by the Center Administrator, Ms. Katherine Belue. The Core will be responsible for the coordination of the Program. Although the investigators do have established collaborative interactions, achieving the integration needed for a successful P50 Udall application will require a higher level of integration and interaction among the PI?s, their laboratory trainees and staff, and the broader community of neuroscientists and immunologists who may participate in a P50 application. The approach to coordination will include electronic communication (video conferencing and a web-based content management system for document sharing, messaging, and calendaring) as well as in person meetings. These will include biweekly meetings of the project investigators and their team. The Core will support an annual ?mini-retreat? to assist in expanding collaborations beyond the initial Exploratory Grant investigators and achieving the scope required for a successful P50. The Core will oversee sharing, regulatory compliance, and financial management. The Core will establish a web site, to communicate the activities of the Exploratory Program and maintain ties with our community partners. Training is a key component of our plans for a future Udall Center plan. All three project PI?s have current pre- and post-doctoral fellows, and close relationships with important training. We will use the support from the Exploratory Grant to strengthen these connections and promote the participation of trainees and faculty at all levels in the activities of the Exploratory Grant.

Abstract Dopaminergic mechanisms, particularly the function of the nigrostriatal pathway, are strongly implicated in dystonia. Clinical studies and postmortem studies have shown reductions in dopamine receptor ligand binding. Acute treatment with dopamine antagonists can induce dystonia in normal individuals. Studies in animal models have shown diminished extracellular striatal dopamine and impaired dopamine release in response to sympathomimetic agents. Genetic defects in dopamine synthesis can also cause dystonia, and these rare forms often respond to dopamine replacement. In most forms of dystonia, however, simple dopamine replacement treatments are ineffective. From a clinical perspective, the most effective medications available for dystonia are anticholinergic drugs. These non-selective muscarinic receptor antagonists are clinically effective but produce a range of anticholinergic side effects and are not well tolerated. Studies in mouse models of DYT1 dystonia have provided experimental support for the concept that dystonia may be related to abnormalities of cholinergic transmission, with downstream effects on dopamine release and synaptic plasticity in the striatum. We have found that animals with transgenic expression of mutant torsinA have profound abnormalities of cholinergic neuron function, with paradoxical excitation in response to dopamine D2 activation. These same effects are reproduced in animals with selective deletion of torsinA from cholinergic cells, demonstrating that the effect is at least in part cell autonomous. Recently, two additional genes causing dystonia have been discovered by our P01 collaborators: mutations in the transcription factor THAP1 and heterozygous deletion of GNAL, encoding the G?olf regulatory G protein. All three genes produce a similar phenotype. Mechanistically, these may be related in that THAP1 may regulate torsinA expression and abnormal G protein signaling seems to be a downstream consequence of torsinA dysfunction. Our central hypothesis is that abnormal cholinergic function and downstream signaling is responsible for abnormal striatal signaling in dystonia, and that selective modulation of muscarinic and nicotinic receptors can normalize striatal physiology. We will explore this in mouse models of these three forms of genetic dystonia. Our studies will determine if DYT1, THAP1, and GNAL dystonia share common cholinergic mechanisms, whether this leads to disrupted dopaminergic function, and whether these abnormalities can be reversed by modulation of the cholinergic system and by modulation of downstream signaling. We incorporate studies of a novel series of cholinergic antagonists and modulators which provide a potential pathway to translate these findings into therapies for human dystonias.

? DESCRIPTION (provided by applicant): The development of neuroprotective strategies for PD is a vital unmet need. Despite remarkable advances in the last fifteen years in the understanding of pathobiological mechanisms in PD, there are no known therapies available that slow the progression or alter the course of PD. The systemic nature of PD suggests new pre-clinical approaches are needed in order to identify pathways and associated therapeutics that might slow the progression of disease. As stated in the Conference and Recommendations Report to NINDS Council (PD2014), the community of investigators focused on PD now strives to create therapies that meaningfully slow or stop the disease mechanisms that underlie all symptoms of PD. Neuroinflammation is increasingly recognized as a critically important element of PD pathogenesis. The vision for this P20 Exploratory Grant is to create the team, environment, and capability to explore innate and adaptive immunity in PD. Currently, there are no Udall Centers of Excellence that focus on understanding neuroinflammatory mechanisms in PD. These studies will require a team with a combination of specialized expertise in neuroimmunology and neurodegenerative disorders. We request support to foster the development of new collaborations and to develop critical data both in PD subjects as well as in recently developed pre-clinical models of PD. The investigative team includes two established investigators in PD (Drs. David Standaert and Andrew West), and an established investigator from the field of neuroimmunology (Dr. Etty Tika Benveniste). We will explore neuro-inflammatory signaling, particularly the actions of myeloid cells, in pre-clinical models of PD as well as early human disease. It is expected that success in these exploratory studies will lead to the development of a future Udall Center of Excellence dedicated to understanding the roles of the innate and adaptive immune system in PD, with emphasis on pursuing points of therapeutic mediation and novel neuroprotection strategies.

Project Summary: Project 3 Recent studies have begun to shed light on the complex interactions between the brain and body involved in Parkinson disease. Genetics, pathological studies, and model systems have highlighted the importance of cells of the myeloid lineage, particularly macrophages and other monocytes, in this brain/body interaction. In the brain, the resident myeloid cells are the microglia. Importantly, however, in several disease states it has been shown that circulating myeloid cells can infiltrate across the blood brain barrier in response to neuroinflammatory triggers and differentiate into macrophages and dendritic cells. Although the morphology of these ?invaders? may be similar to the resident microglia, their actions may be quite different, and they may be either pro-inflammatory, triggering neuron injury or death, or anti-inflammatory, contributing to resolution of local inflammation. While myeloid cells are conventionally dichotomized into M1 pro-inflammatory and M2 anti-inflammatory phenotypes, recent work has emphasized that these are extremes of a spectrum rather than discrete states. These activation states are the product of differential gene programs, and therefore, coding and non-coding RNA signatures are powerful tools for examining the functional states of myeloid cells. A key regulator of the activation of peripheral monocytes and their differentiation into pro-inflammatory macrophages and dendritic cells is microRNA 155 (miR-155). This project will employ recent advances in high-throughput genomic techniques to understand how peripheral myeloid cells function in PD. Based on our previous studies in mice, we will determine whether there is elevated miR-155 early in human disease. In addition, we will conduct transcriptional profiling of mRNAs and miRNAs in peripheral myeloid cells to identify important alterations in the gene programs regulating myeloid cell differentiation and activation, and assess the extent to which there is M1 polarization. All of the subjects recruited for this study will have early stage, untreated (?de novo?) Parkinson disease without chronic dopaminergic or anti-inflammatory treatment. This is a critically important patient population as it avoids issues arising from the effects of antiparkinsonian treatment. Together, these aims will provide an important test of the hypothesis that pro-inflammatory activation of peripheral myeloid cells occurs in early PD and that this activation is a critical part of the neurodegenerative process. It will also assist us in establishing the process and pathways needed for the future development of a Udall clinical core.

The Molecular Detection and Stereology Core (MDSC) provides the UAB Neuroscience community with cost- effective training and expertise in all aspects of immunohistochemistry (IHC) and in situ hybridization (ISH) procedures as applied to modern neuroscience research. For nearly ten years, the Core has focused on training technicians, undergraduate and graduate students, post-doctoral fellows, and faculty investigators in the theory and practice of IHC and ISH. This emphasis on education and hands on training facilitates the propagation of these techniques beyond the Core itself and allows integration of IHC and ISH into many of the NINDS funded laboratories at UAB. For experienced users, the Core directly assists with troubleshooting difficult antibodies, establishing advanced detection amplification techniques, such as tyramide signal amplification and Quantum Dots, and developing multi-label detection procedures. In this competitive renewal application, Dr. David Standaert has assumed the role of Principal Investigator of Core B. He is a clinician- scientist with a longstanding commitment to research and an excellent background in experimental neuroanatomy. Dr. Terry Lewis remains the Technical Director of the Core and has over ten years' experience in neuroscience related research. Dr. Lewis and Ms. Marissa Menard, a talented laboratory technician, work closely and directly with Core users throughout their training and experimental investigations. It is proposed to continue these services. It is proposed that the MDSC provide MicroBrightField stereology/morphometric systems which further enables UAB neuroscientists to accurately assess and quantitate the results of their IHC and ISH investigations. The additional stereology services to be offered in the MDSC uniquely positions the Core to train and assist UAB Neuroscience investigators with complete planning and performance of IHC and ISH experiments from fixation of tissue, section preparation, IHC/ISH protocol optimization, and final analysis utilizing the MicroBrightField systems. Over the previous nine years of funding, the MDSC has proven to be of great service to NINDS funded investigators and the entire UAB Neuroscience community. The Core consistently trains and assists over 50 students, postdocs, and investigators per year and is widely recognized as the ?go to? place for IHC, ISH and stereology expertise.. Of the 19 qualifying grants in the current application, 16 have utilized the MDSC emphasizing the Core's productivity and clear ongoing need for its services. By providing these services, the MDSC reduces startup time and redundant resources for laboratories wishing to incorporate IHC, ISH and stereology methods into their research as well as increasing productivity of more experienced investigators by expanding their capabilities to implement recently developed and powerful new sensitive detection methods.

Abstract This is a proposal for continuation of an R25 research education award at the University of Alabama at Birmingham (UAB). This program will support residents in neuroscience fields who are pursuing careers combining clinical practice and research, and foster their development as physician-scientists. Over the past two decades, considerable efforts and resources have been devoted to understanding nervous system function in health and disease, and the result has been a vast expansion of knowledge encompassing fundamental discoveries in genetics, genomics, neuro-oncology, neurochemistry, synaptic plasticity, neural development, and behavior. It is clear, however, that there remains an unmet gap between these advances and applications to human health. A pressing need for next-generation physician-scientists includes: i) integrate discoveries about the nervous system from several domains into multi-modal and multi- dimensional frameworks; and ii) formulate translational pathways to apply this knowledge to important biomedical and behavioral problems. The new and exciting initiatives in this renewal proposal are as follows: 1) Dr. David Standaert continues as Program Director, but he has been teamed with the new Associate Director, Dr. Ichiro Nakano; 2) the scope has been expanded and now includes not only neurology, neurosurgery, and neuropathology but also radiology and anesthesiology residents who are working areas consistent with the NINDS mission; 3) the mentors have been organized around the four themes, that is, neuro-oncology, neurodegeneration, synaptic plasticity, and cerebrovascular disease; 4) didactic components are strengthened, including a formal course in experimental rigor. The Program Director and Associate Director are both physician-scientists with established track records in research and training. Residents supported by this program will initiate their research during their residency training, and continue it into a period of research fellowship following residency. Participants from all disciplines will engage in a total of two years in full time research training. Their research experience will be supported by a structured mentoring program along with didactic teaching in experimental rigor, professional skills training, grant writing, and responsible conduct of research. The goal of the program will be to enable residents and fellows to develop a career in neurological research, and to prepare them to successfully compete for individual fellowships or mentored career development awards. As an institution, UAB is exceptionally well positioned to undertake research education in the neurosciences, and to develop the physician-scientists who will apply today?s discoveries to solve the challenges of tomorrow.

Abstract This is a proposal for a new T32 training program at the University of Alabama at Birmingham (UAB). This is a focused program for predoctoral students in basic and translational approaches to neurodegenerative disease. The rationale for establishing this new program is founded on three critical factors: 1) The aging of the US population, which will soon lead to growth in the numbers of patients affected by neurodegenerative disease, 2) Rapid advances in tools and technologies in the neurosciences, and 3) The increasing interest in neurosciences as a discipline by PhD students. A primary goal of this Training Program is to achieve cross- cultural training; we seek to expose students to the biological mechanisms and research approaches used across neurodegenerative disease, rather than the kind of single-disease training they might get working in an individual research laboratory. This program will provide support for advanced pre-doctoral students in the research phase of their training. Most students will enter the Neurodegeneration Training Program from the UAB Graduate Biomedical Science Program, which admits about 80 students annually, or the UAB Medical Scientist Training Program, which admits 8 students annually. Planned duration of appointment to the training program is two years for each student. A total of 2 slots are requested in Year 1, and 4 slots in subsequent years. Students will work under the supervision of one of 24 highly qualified mentors. Three of these are junior mentors, and there are plans for mentor development and co-mentoring. The program incorporates required didactic course work in neurodegeneration in both the first and second years, a newly developed formal course in experimental rigor, training in new tools and technologies, instruction in the translational pathway and drug development, a journal club on Neurodegeneration, an annual retreat, and mentor and outcomes evaluations. Our core philosophy is that we seek to enable the cures of the future by providing a robust training pathway in translational research. This unique emphasis will enable our students to take leading roles in therapeutic discovery across the spectrum of different skills sets and enterprises which are required to deliver the vitally needed treatments of the future.

Project Summary: Core A, Administrative Core The Administrative Core will serve as the organizational foundation for research activities of the Udall Center, and play a critical role in ensuring that the Center will be both a national leader in and local resource for PD research. The Core will ensure that the Udall Center is a resource for career enhancement of Udall Center investigators and an effective organizer of periodic, Udall Center-specific outreach activities for the local and national PD patient/advocacy community. The Administrative Core is directed by the Program Director, Dr. Standaert. He is assisted by the Program Administrator, Ms. Katherine Belue. The primary mission of the Administrative Core is to promote the integration and function of the Udall Center components and activities, and provide the infrastructure required for Center communication, decision- making and administration and the activities of the Program Director. The Core will support and organize periodic meetings of the Center Executive Committee, project staff, Internal Advisory Committee, External Advisory Committee, and collaborators. The Core will ensure that all components of the Alabama Udall Center maintain compliance with NIH policy requirements, and will prepare and submit annual progress reports for the Udall Center, and coordinate attendance of the Center Director, Center Administrator, and Project and Core Leads at the annual Udall Centers meeting. The Core is responsible for coordinating activities that fulfill the Udall Center Mission Statement for Training: ?Training for physicians, scientists and the community today to accelerate progress in PD research and treatment, and education to develop the scientific workforce and community partnerships of the future.? The Core seeks to enhance the integration of the Alabama Udall Center with UAB internal Parkinson disease research programs, promote the integration of the Alabama Udall Center with other Udall Centers and national programs in PD research, and develop and conduct outreach activities for the local and national Parkinson community, including an annual Udall Center symposium to present research results to the local community. The Core will support the Udall Center web site and social media outreach. The Core will maintain an accounting of resource generation and related utilization, and steps taken to maximize the research utilization of these resources within and beyond the Udall Center. The Core will coordinate data and resource sharing both between Udall Center investigators and with other Udall Centers and outside investigators and organizations. The Core will coordinate interactions of the Udall Center with NINDS staff, including providing advance notice of manuscripts and publications to the NINDS program officer and working with the NINDS Office of Communications and Public Liaison on press releases highlighting Center accomplishments.

Project Summary: Project 1 Although Parkinson disease (PD) is conventionally thought to be a condition primarily affecting the brain, recent studies have begun to shed light on the complex interactions between the brain and body involved in the disease, particularly the immune system. Innate immunity is mediated by cells of myeloid lineage: monocytes derived from bone marrow, tissue macrophages which arise from monocyte infiltration and differentiation, and the resident microglia of the brain which are independently derived from the embryonic yolk sac. Based on our preliminary data from the P20 Exploratory Grant Program, in this project our overarching hypothesis is that innate immune cells are activated towards a pro-inflammatory phenotype early in PD. We theorize that blocking this activation will protect from PD progression There are critical gaps in rigor of the available data which hinder the design and execution of future therapeutic trials of immunomodulation. These gaps include: 1) nearly all previous studies of inflammatory markers in PD have included heterogeneous groups of patients with a broad range of disease severity, durations and treatments; 2) there has been a lack of attention to sex as a biological variable; 3) there are no previous studies which directly examine monocytes populations in early PD, which we postulate to be critically important; 4) there is little information on longitudinal change in inflammatory markers; and 5) there is little data connecting brain and blood inflammatory markers to outcomes. Through the P20 program, we have established the ability to study a unique human subject cohort of early, de novo PD (a term meaning patients who have not yet received any anti-PD drug therapy) which will allow us to address these critical issues. Here we propose three aims which will directly address these critical knowledge gaps. In Aim 1, we will study a cohort of 60 patients with de novo PD and 60 age- and sex-matched controls recruited by the clinical core. We will determine whether peripheral immune activation or differentiation is associated with CNS inflammation in early PD through integrated analysis of blood monocytes, blood and CSF cytokines and chemokines, and brain imaging with the TSPO ligand 18F-DPA-714. In Aim 2, we will determine whether there is change over time in monocytes populations assessed by flow cytometry or in blood cytokines and chemokines. In Aim 3, we will examine the relationship between baseline measures of inflammation and longitudinal clinical outcomes, particularly cognition, in this population of early de novo PD subjects These Aims are closely integrated with other components of the Alabama Udall Center. All of the human data and biospecimens are drawn from the Clinical Research Core and will be studied in Project 2 (Benveniste, focused on JAK/STAT signaling) and Project 3 (West, focused on LRRK2). Together, these studies should provide a comprehensive view of the role of immune cells in PD, and identify targets for therapy.