Molecular imaging of neuroinflammation in repetitive mild traumatic brain injury

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Candidate: This Career Development Award (CDA2) describes research and training activities for Garth Terry, MD, PhD, a psychiatrist and clinical neuroscientist in the Mental Illness Research, Education, and Clinical Center at VA Puget Sound. His immediate career goal is to combine his established training in positron emission tomography (PET) with newly acquired and ongoing training in the pathobiology and translational research of mild traumatic brain injury (mTBI) and strengthen his training in group-wise neuroimage statistical analysis. Long- term, he intends to establish an independent research program focused on using molecular neuroimaging to enhance understanding and guide therapeutic development for neuropsychiatric disorders. Research: Approximately 20% of service members returning from Iraq have experienced mTBI resulting in somatic, cognitive, and behavioral symptoms leading to substantial disability and interference with job and family relationships. Neuroinflammation has been implicated as an important contributor to the acute and chronic effects of blast mTBI, and is associated with subsequent neurodegeneration. Both Veterans with history of blast- related mTBI and a battlefield-relevant mouse model of repetitive blast mTBI demonstrate persistently elevated IL-6. Furthermore, blast-exposed mice demonstrate persistent microglial pathology that is strikingly similar to the neuropathology very recently identified in Veterans with blast-induced mTBI. This proposal specifically addresses the need to understand if neuroinflammation is persistent following blast mTBI by imaging the translocator protein kDa 18 (TSPO), a well-validated biomarker of neuroinflammation and a protein associated with microglial activation. Using PET and the TSPO selective radioligand [18F]DPA-714, Dr. Terry will image mice following blast mTBI (SA1), which provides a unique opportunity to control injury repetition and acuity, and to characterize in vivo imaging results against ex vivo histopathological evidence of neuroinflammation and neurodegeneration. Second, Dr. Terry will image TSPO using PET in Veterans with a history of blast mTBI (SA2) to demonstrate the presence of chronic neuroinflammation. Resulting quantitative images of neuroinflammation will be correlated against clinical measures and other biomarkers already collected from those Veterans. Career Development Plan: This proposal serves Dr. Terry's short- and long-term goals by building his translational and clinical research expertise in three critical areas: 1) translational application of PET neuroimaging, 2) translational biomarker study and clinical assessments of blast mTBI, and 3) become an independent researcher-clinician within VHA. Professional development activities include: routinely scheduled meetings with career mentors, formal graduate coursework in statistics, neuroinflammation, and PET analysis; regular participation and presentation for local seminars in mTBI and neuroimaging; and presentation of research at national scientific conferences. By virtue of these goals, Dr. Terry will seek to clearly differentiate himself as an independent VA investigator who is both unique from his mentors and complementary to their efforts in helping Veterans with blast mTBI. Environment: Dr. Terry's training will be guided by an exceptionally multidisciplinary mentoring team comprised of senior faculty who are experts in blast mTBI, human biomarker collection and study, mouse blast mTBI pathobiology, and PET image research and analysis. His primary mentor, Dr. Peskind, is recognized as a leader in the field of blast mTBI and has successfully mentored multiple trainees through CDA to independent faculty position. Co-mentors Drs. Cook, Innis, and Mr. Muzi are fully-funded research faculty with expertise in mouse models of disease, molecular biology, neuroinflammation, and PET neuroimaging and analysis. His consultants include experts in in statistical analysis (Dr. Millard), PET imaging (Drs. Kinahan and Miyaoka), and radiochemistry (Drs. Grierson and Kassiou). These investigators have established professional collaborations with Dr. Terry and are invested in the success of the aims outlined herein.