PROJECTSUMMARY/ABSTRACT Lyme disease is an inflammatory disease, transmitted by ticks that are infected with the bacterium Borrelia bugdorferi. Despite treatment with antibiotics, 10-20% of patients develop post-treatment Lyme disease (PTLD) that often includes neurocognitive symptoms. The mechanisms underlying this are not well understood. Prior published and preliminary data from our research group suggests that cognitive performance is impaired in PTLD and that white matter (WM) changes on functional MRI (fMRI) are part of this process. WM changes are also, however, associated with better patient-reported outcomes. Thus, WM changes during Lyme disease may be part of a healing process following injury that comes at a cost to cognition, but more information is needed. In this study, we will draw upon a unique longitudinal cohort of patients with early Lyme disease and erythema migrans who will be studied longitudinally for 12 months. Their data will be compared to that of healthy controls without a history of Lyme disease. Our overall objective is to study the underlying mechanism of neurologic symptoms in PTLD. We will test the overarching hypothesis that WM changes reflect an adaptive response, and these changes predict better outcomes after treatment of early Lyme disease. To accomplish this goal, we will track WM activity immediately after initial antibiotic therapy and longitudinally 6 and 12 months later. Functional MRI (fMRI) will be used to measure WM activity that will be compared to outcomes, which will be measured using clinical scales and cognitive testing (AIM 1). We will also address the underlying neurobiological basis of WM changes by determining whether the myelin sheath or the underlying axon, both of which comprise WM, are affected in PTLD. To do so, we will use multimodal neuroimaging measures including diffusion tensor imaging (DTI), QSM and 𝜒-separation to understand axon and myelin integrity and health. A blood plasma marker, neurofilament light chain (NfL), will be used to quantify axonal injury. These variables will be correlated with cognitive performance, clinical scales, and blood inflammation markers, which, if successful, would provide simple prognostic indicators. (AIM 2) Finally, we will examine inflammatory markers including the chemokine ligand 19 (CCL19), which has been associated with increased risk of developing PTLD, and Interleukin-6 (IL-6), which plays a role in mediating inflammation and demyelination. These have not been shown to correspond with central nervous system markers in Lyme disease thus far, but they may correspond with MRI WM values, which has never been tested. (AIM 3). Collectively, our studies represent a rigorous approach by including multimodal neuroimaging combined with blood biomarker measurement towards elucidating determinants that are associated with the cognitive and clinical outcomes of PTLD. The long-term goal is to generate insights that may lay the foundation for new diagnostic, prognostic, and therapeutic approaches to the cognitive manifestations of PTLD.

PROJECT NARRATIVE The proposed study aims to elucidate the neurobiology of neurocognitive symptoms associated with post- treatment Lyme disease (PTLD). Our goal is to generate fundamental knowledge about the activity and health of the brain, and to do so, this study will examine how white matter changes in structure and function throughout the course of Lyme disease. These findings may lead to the development of innovative prognostic and diagnostic tools as well as novel interventions to prevent or reduce the often significant cognitive symptom burden and functional impact of PTLD.