Michelle James - US grants

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is growing global health issue. At present, there are no drugs available to halt or reverse disease progression, and all efforts to create such therapies have failed. One reason for these failures is the lack of translatable biomarkers useful in both mouse models and humans, and the relatively small role that appropriate biomarkers have played in the drug discovery and development process. Identification of translatable biomarkers for non-invasive assessment of therapeutic outcomes is imperative to improving the treatment of AD. Here we propose the use of a new imaging strategy for monitoring treatment response in Alzheimer's disease. The strategy involves using a specific positron emission tomography (PET) radioligand ([18F]GE-180) for the translocator protein 18 kDa (TSPO). TSPO PET radioligands are used to non-invasively detect and track microglial activation (a marker of neuroinflammation) in a living subject. Evidence suggests that neuroinflammation takes place very early in the AD, even before the formation of amyloid plaques. In addition, early anti-inflammatory intervention appears to profoundly impact the onset and progression of AD. The early involvement of neuroinflammation in AD, and the fact that it persists throughout disease and contributes to neurodegeneration, make it an ideal candidate biomarker for tracking pathology and monitoring response to early therapeutic interventions. Although there are a number of available TSPO radioligands, [18F]GE-180 has superior binding affinity and in vivo properties for imaging neuroinflammation processes in vivo. And while this tracer has undergone first in-man evaluation with favorable results, it is yet to be studied for it ability to monitor treatment response in AD. Our immediate goal is to evaluate [18F]GE-180-PET for its ability to track AD progression and monitor response to drug therapies in AD mouse models. Following this, our long- term goal is to assess the utility of [18F]-GE180-PET as a biomarker of AD treatment response in clinical trials of novel disease-modifying drugs. Our preliminary studies show that [18F]GE-180-PET can detect microglial activation in a mouse model of AD (APPL/S) at early stages of disease. In this proposal we aim to further evaluate [18F]GE-180 in AD mouse models for its use as a surrogate marker of AD neuroinflammation, and for monitoring response to novel drugs currently under evaluation for AD treatment. We will achieve our goals through the following specific aims: 1) determine whether [18F]GE-180-PET signal correlates with the extent of microglial activation and disease progression in two mouse models of AD, and 2) assess the sensitivity and accuracy of [18F]GE-180-PET for imaging response to two AD therapeutics currently in clinical trials (i.e., LM11A-31 and minocycline). The use of [18F]GE-180 could be a `game-changing' approach with potential far- reaching advantages in the whole arena of biomarker driven diagnostics and therapeutics for AD.

Project Summary Multiple sclerosis (MS) is a chronic, demyelinating, neuroinflammatory disease typically affecting young adults, causing substantial morbidity and diminished quality of life. Although multiple disease-modifying immunomodulatory therapies are available for MS, disease manifestations and treatment response are highly variable and difficult to predict in patients. Current standard of care imaging techniques used to diagnose and monitor MS cannot provide early and specific molecular information regarding an individual?s immune signature in the central nervous system (CNS), thus limiting our ability to select the most appropriate therapy and obtain early predictors of response for any given patient. Hence there is a need for non-invasive molecular imaging strategies that provide real-time endpoints about specific immune cells and their functional phenotypes in MS patients. Myeloid cells are fundamental to the progression and remission of MS; activated macrophages and microglia are the predominant immune cells associated with acute and chronic-active CNS lesions. Unfortunately, existing imaging strategies for detecting activated microglia and macrophages lack specificity and cannot distinguish between beneficial (anti-inflammatory) and toxic (pro-inflammatory) immune responses. To address this limitation, we recently identified triggering receptor expressed on myeloid cells 1 (TREM1) as a highly specific, promising biomarker of toxic inflammation in a mouse model of MS, i.e., experimental autoimmune encephalomyelitis (EAE). TREM1 is a membrane receptor selectively expressed on myeloid lineage cells, known to exacerbate pro-inflammatory responses by synergizing with classical pattern recognition receptors. Our preliminary studies show elevated numbers of TREM1-expressing myeloid cells in the CNS of EAE mice (compared to controls) at very early stages of disease prior to the development of clinical symptoms. Moreover, the numbers of TREM1-positive myeloid cells are present at even higher levels in symptomatic mice, and appear to correlate with degrees of limb/tail paralysis. Here, we hypothesize that a novel positon emission tomography (PET) tracer we developed to target TREM1 can be used to detect and quantify in vivo myeloid-driven immune responses in rodent models of MS, and that TREM1-PET can accurately predict disease progression and response to therapies. We will test our hypothesis with the following specific aims: 1) To determine the relationship between TREM1-PET signal, disease severity, and peripheral markers of inflammation in two mouse models of MS, and 2) To assess the ability of TREM1-PET to predict and monitor outcomes after treatment with immunomodulatory therapeutics. We thus aim to establish the sensitivity and potential utility of our TREM1-PET tracer prior to clinical translation. This research promises to provide critical in vivo information about the role and time course of myeloid-driven immune responses in EAE and MS. Our proposed strategy using TREM1-PET could have far-reaching and significant impact as a molecular imaging technique for mapping toxic innate immune activation in a range of neurological diseases.

Project Summary Multiple sclerosis (MS) is the most common demyelinating central nervous system (CNS) disease affecting young adults, often resulting in irreversible neurological dysfunction. B lymphocytes play a complex and critical role in MS pathology and are the target of several therapeutics in clinical trials. While monoclonal antibodies targeting the B cell surface marker CD20 (i.e. Rituximab, Ocrelizumab) dramatically reduce the annualized relapse rate and delay disability progression, not all patients respond, likely due to the heterogenous nature of MS. Currently, there is no approved technique to noninvasively visualize B cells in the CNS in order to select MS patients for anti-B cell therapies and monitor treatment responses. Positron emission tomography (PET) imaging has enormous potential to fill these gaps by providing highly specific, quantitative information by tracking B cells. Notably, PET tracers targeting CD19 and/or CD20 markers could reveal dynamic information on the pathophysiology of a wide range of B cells, ultimately enabling quantification of therapeutic effects on B cell load in the CNS and peripheral organs in real time. To date, only one PET tracer for CD20+ B cells has undergone preliminary evaluation in MS, and no PET tracers have been developed for imaging CD19, expressed on a broader range of B cells (including suspected pathogenic antibody-secreting plasmablasts and circulating plasma cells). Here, we propose to develop novel immuno-PET tracers based on clinically approved CD19 and CD20 monoclonal antibody therapeutics. Such PET tracers could undergo relatively rapid clinical translation and have immediate impact on patient stratification, dosing, and real-time therapy monitoring. Our hypothesis is that CD19 and CD20-targeted PET tracers will enable non-invasive, sensitive, and specific detection of various B cell subsets in the CNS and periphery, in the context of MS. We have previously demonstrated the feasibility of B cell specific PET imaging with [64Cu]Rituximab, which enabled in vivo detection and quantification of B cells in CNS and peripheral tissues in a murine model of MS, known as experimental autoimmune encephalomyelitis (EAE). In this proposal, we will build on our published data in addition to developing the first reported human CD19-PET tracer. We will achieve our goals through the following specific aims: 1) Develop immuno-PET tracers for imaging different B cell-subsets, 2) Assess biological effects of CD19 and CD20 imaging agents in cells and mice, and 3) Evaluate the specificity and sensitivity of CD19/CD20 PET tracers for detecting B cells in the CNS and periphery of MS mouse models in addition to their ability to predict treatment response. Completing these experiments will provide invaluable information regarding which B cell PET tracers appear most promising for clinical translation while also shedding light on the in vivo pathophysiology of B cells in MS in the brain and beyond. This proposal addresses a significant unmet clinical need and our unique approach has high potential to impact the way we study, monitor, and treat MS.

Project Summary Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a highly debilitating disease affecting millions of people in the United States, yet very little is known about its underlying pathophysiology. The disease itself is exceedingly complex and characterized by variable clusters of incapacitating symptoms, including extreme fatigue, unrefreshing sleep, muscle pain, joint pain, headaches, and loss of memory or concentration. Preliminary theories suggest that an initial trigger, possibly viral, results in inflammation that chronically affects several parts the body, including the muscles, joints, lymphatic system, and central nervous system (CNS). Unfortunately, current standard of care techniques for diagnosing suspected ME/CFS (i.e., blood tests and structural brain imaging) do not provide direct measures of inflammation in the CNS or other organs and often afford results within normal range. Hence, there is a critical unmet need to develop more sensitive and specific tests that not only improve the accuracy of diagnosis but also provide a means to investigate specific immune responses and their role in the initiation and progression of ME/CFS in the brain and periphery of ME/CFS. Here, we propose for the first time to perform whole body position emission tomography (PET) imaging of ME/CFS patients using [11C]DPA-713, a highly sensitive and specific radiotracer for the translocator protein 18 kDa (TSPO). TSPO is an established imaging biomarker of inflammation that is predominately upregulated in activated innate immune cells including microglia in the CNS and other myeloid lineage cells (e.g., macrophages) in the periphery. We hypothesize that chronic, unresolved inflammation driven by innate immune cells underlies the central clinical problems of fatigue, pain, and cognitive dysfunction observed in ME/CFS. Our encouraging preliminary data shows increased [11C]DPA-713-PET signal in multiple brain regions of severe ME/CFS patients compared to healthy controls. We also demonstrate the feasibility of whole body PET/magnetic resonance (PET/MR) imaging using [11C]DPA-713. In this proposal, we will expand on this data by investigating the relationship between peripheral and central markers of inflammation, through the following aims: 1) Quantify [11C]DPA-713 uptake in the CNS and whole body of ME/CFS patients compared to healthy asymptomatic controls using PET/MRI, and 2) Correlate the extent and location of [11C]DPA-713-PET signal to clinical measures of disease severity and peripheral fluid-based biomarkers of inflammation and infection. Additionally, we will correlate PET findings with advanced multimodal MRI, including quantitative brain volumetry, diffusion tensor imaging, and quantitative susceptibility mapping (QSM). Completing these experiments will provide invaluable insights into the correspondence between myeloid cell activation in the CNS and whole body, with that of plasma cytokine signatures, herpesvirus shedding, blood brain barrier disruption, white matter changes, and disease severity in ME/CFS. Since [11C]DPA-713 is available for clinical use, this imaging tool has potential to immediately impact the way we study, monitor, and treat ME/CFS.