Abstract
Converging evidence implicates inflammation in the pathophysiology of depression. This has fuelled the development/ repurposing of novel and established immune-targeted agents as potential anti-depressant therapies. However, methods for assessing CNS target engagement for immunotherapeutics are currently limited. In this thesis, I aimed to determine whether an experimental model of acute inflammation (intravenous endotoxin) coupled with two different imaging modalities (MRI and PET), behavioural, physiological and immunological data could serve as a potential in-vivo model for assessing ‘target engagement’ for therapies targeting microglia.To do this, participants (healthy young males) underwent two experimental sessions in which they received Lipopolysaccharide (LPS) (1 ng/kg) or saline in randomised order. Half received minocycline (a putative microglial inhibitor) prior to each session, and half an identical looking placebo. The primary neuroimaging technique used to assess effects on the brain was Positron Emission Tomography (PET) targeting the microglial marker 18-kDa Translocator Protein (TSPO). Diffusion-Weighted Magnetic Resonance Spectroscopy (DW-MRS), was later added for a subset of participants to investigate whether this novel MRI-based method was sensitivity to ‘neuroinflammation’. Mood questionnaires and a reward/ punishment reinforcement learning task were used to assess psychological changes. Serial blood-draws and continuous physiological monitoring was used to assess physiological/ immunological responses.
Key findings include demonstrating that DWMRS is sensitive to LPS-induced changes in glial morphometry and showing that a simpler quantification of TSPO (using a 3 supervised clustering algorithm (SVCA) based pseudo-reference region) is sensitive to LPS-induced microglial activity. Though neither technique was significantly influenced by minocycline. Behavioural performance on the reward/punishment reinforcement learning task was also modulated by inflammation (LPS), replicating findings observed using a milder inflammation model (Typhoid vaccination). Interestingly this LPS-induced motivational reorientation (increased sensitivity to punishments versus rewards) was significantly attenuated by minocycline.
Together, these data provide tentative support for LPS coupled with a reward/punishment reinforcement learning task as a potential method for assessing target engagement for novel neuroimmune therapeutics. They show that a simpler pseudo-reference region approach is suitable for TSPO PET using the [ 18F]-DPA-714 tracer and provide proof-of concept data for DWMRS as a potentially important new MRI based tool for quantifying neuroinflammation. Future studies will be required to further validate each of these approaches before they are considered for wider adoption.
| Date of Award | Feb 2023 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Alessandro Colasanti (Supervisor), Neil A. Harrison (Supervisor) & Mara Cercignani (Supervisor) |