“We must believe that we are gifted for something, and that this thing, at whatever cost, must be attained.” ~Marie Curie (1867–1934)
Identifying Biomarkers of Immune Cell Functional State and Radiotracer Design
The overall utility and impact of any non-invasive imaging strategy is entirely dependent on the sensitivity, specificity, and functional relevance of the biomarker(s) being probed. Therefore, the foundation of our research approach is firmly grounded in first identifying and validating molecular targets/pathways that are intimately associated with the underlying biology driving the initiation and progression of specific neurological diseases. We are particularly interested in discovering biomarkers that reflect toxic functional phenotypes of immune cells (e.g., myeloid lineage cells and B cells) in the context of neurodegenerative diseases, including Alzheimer’s disease and multiple sclerosis. With human postmortem tissue, biological fluids, and rodent models of brain diseases, we use a variety of methods (i.e., immunological assays, transcriptomics, GWAS data) to identify and investigate candidate biomarkers for use as diagnostic and/or therapeutic targets.
After confirming the diagnostic/predictive potential of promising candidate imaging biomarkers, we synthesize highly specific positron emission tomography (PET) radiotracers to target these biomarkers. From small molecules to antibodies, we determine the most suitable imaging agent scaffold/type to interrogate the biological-process and disease of interest.
Early Detection of CNS Diseases and Predicting Therapeutic Response
Our work is mainly focused on designing and developing imaging agents that will enable early detection of brain diseases and accurate prediction/monitoring of response to therapies. After synthesizing a novel radiotracer, we first evaluate its specificity, selectivity, and sensitivity using in vitro tests. Such assays include cell binding studies and autoradiography using human and/or rodent CNS tissues. Upon successful in vitro validation, we perform preclinical imaging of various rodent models of neurological diseases e.g., cerebral ischemia models, experimental autoimmune encephalomyelitis (EAE), Alzheimer’s disease transgenic mice – using small animal PET, computed tomography (CT), and magnetic resonance imaging (MRI). Following confirmation of in vivo specificity of a novel radiotracer, we can use it to answer questions about underlying mechanisms of Alzheimer’s disease for example, depending on the target of the tracer. Our lab recently demonstrated the utility of PET tracers targeting the translocator protein 18 kDa (TSPO), a biomarker of glial activation, for non-invasively monitoring neuroinflammation in Alzheimer’s mouse models and response to a disease modifying therapeutic in Phase 2a clinical trials (i.e., LM11A-31).
Clinical Imaging of Neurodegenerative Diseases
Translation of radiotracers from preclinical to clinical imaging is no small task, but is something we consider high priority. The James lab has developed and translated a number of PET tracers for detecting underlying inflammatory processes in Alzheimer’s disease, traumatic brain injury, pain, and stroke. Currently, we are using the TSPO-PET tracer [11C]DPA-713, a radiotracer Dr. James developed with Prof. Michael Kassiou at the University of Sydney, to answer questions about
1. The spatiotemporal overlap between different pathological hallmarks of Alzheimer’s disease
2. the relationship between peripheral biomarkers of inflammation, cognitive status, and central innate immune activation in patients with multiple sclerosis
3. whether TSPO-PET can predict cognitive decline in the early stages of various CNS diseases.
We strongly believe that molecular imaging using PET has enormous potential to enhance our understanding of the in vivo role and spatiotemporal dynamics of neuroinflammation in the context of different diseases, and that this will lead to early detection/prevention strategies and precision therapy.
We are committed to developing a highly sensitive and specific toolkit of molecular imaging agents that will greatly improve the way we diagnose, care for, and treat patients with neurodegenerative diseases.