Fiscal Year 2019 Tick-Borne Disease Research Program Focus Area: Pathogenesis

Background: Lyme disease (LD) is a bacterial infection in which inflammation plays a primary role in causing disease. Symptoms and signs of infection range from localized infection of the skin to widespread disease that can involve the brain and nerves, as well as the heart and musculoskeletal systems. After currently recommended standard of care antibiotic therapy, 10%-20% of patients treated for LD will go on to develop a persistent symptoms, known to patients as chronic Lyme disease. A research definition to study chronic Lyme disease called post-treatment Lyme disease syndrome (PTLDS) has been developed based on commonly reported symptoms that typically include severe fatigue and memory and concentration difficulties suggestive of neurocognitive dysfunction.

Little is known about the origin of neurocognitive symptoms in PTLDS. Importantly, clinicians cannot identify patients who go on to develop PTLDS, because there are currently no blood, cerebrospinal fluid, or brain imaging tests that can accurately diagnose PTLDS and its impact on the brain.

We have discovered intriguing evidence using functional Magnetic Resonance Imaging (MRI) and Diffusion Tensor Imaging (DTI) that the brain’s white matter may be particularly vulnerable to neurologic Lyme disease. The DTI visualizes the integrity of the brain’s fiber tracts, which allows doctors to isolate regions that are not functioning properly. Traditional MRI scans cannot detect these abnormalities, because they do not have the capability of visualizing fiber tracts in the same way

Moreover, our previous research has shown that this phenomenon may be mediated by inflammatory processes that impact neuron-supportive cells, known as glia. A systematic line of research is required in order to substantiate these findings and take a much-needed, deep investigation into the mechanisms involved.

Methodology:

Aim 1: To characterize patients reported symptoms, we will do cognitive testing to measure the speed of thinking as well as specific types of memory and recall.

Aim 2: To detect brain changes associated with PTLDS, we will examine the fibers that transmit electrical signals in the brain called white matter using DTI. We will examine the function of the brain while patients are performing memory tasks in the MRI scanner using functional MRI.

Aim 3:

Determine levels of serum and cerebrospinal fluid (CSF) inflammatory proteins that we hypothesize may be harming the brain’s glial cells in the setting of PTLDS.

Impact: If successful, results of this project will help to identify whether brain scanning using DTI methods can quantify central nervous system damage due to Lyme disease. This would have a direct impact on our understanding of the causes of neurologic symptoms in Lyme disease. There are currently no blood, cerebrospinal fluid tests, or imaging techniques to determine if the brain has been directly impacted in PTLDS. The ability to have an objective marker of neurologic symptoms would transform the field of Lyme disease. In addition, our investigation into inflammatory molecules has the potential to inform novel therapeutic targets and uncover factors to recognize patients who are at risk of developing PTLDS at the time of acute infection, thereby guiding early treatment interventions. DTI scanning could rapidly become in a matter of several years a clinical diagnostic test for neurologic involvement in later stages of Lyme disease.