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Title: Exploring microglial activation and neurodegeneration following traumatic brain injury
Author: Scott, Gregory
ISNI:       0000 0004 6496 0828
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Traumatic brain injury (TBI) patients may deteriorate months and years after injury, developing unforeseen consequences such as dementia. However, the mechanisms relating acute injury to later neurodegeneration are unclear. The positron emission tomography (PET) ligand [11C]-Pittsburgh compound B ([11C]PIB) detects Aβ plaques, a hallmark of Alzheimer’s disease. I found [11C]PIB binding in long-term survivors of moderate-severe TBI was increased in posterior cingulate cortex (PCC) and cerebellum. PCC binding increased with damage in white matter (WM) tracts connected to the region, measured using diffusion MRI. These findings suggest a link between TBI and development of dementia. Previously, using [11C]PK11195 PET, which binds the translocator protein (TSPO) up-regulated by activated microglia, we observed increased thalamic binding years after TBI. I found [11C]PK11195 binding in the thalamus was correlated with damage in thalamo-cortical WM tracts, supporting a link between axonal damage and microglial activation. In fifteen patients at least six months after injury, I found binding of [11C]PBR28, a second-generation TSPO ligand, was increased in WM. WM damage was higher in areas of increased [11C]PBR28 binding. The antibiotic minocycline is neuroprotective in models of acute TBI, through microglial inhibition. Patients received either minocycline 100mg twice daily or no drug for 12 weeks, followed by repeat PET. [11C]PBR28 binding post-minocycline was reduced (WM VT=-23.3%) compared to no drug. Neurofilament light chain (NFL) is a neuronal protein, elevated in the CSF acutely after TBI. I found plasma NFL was increased in patients, negatively correlated with time since injury, and positively correlated with [11C]PBR28 WM binding. These findings suggest NFL has promise as a marker of progressive damage in chronic TBI. However, minocycline increased NFL levels and reduced corpus callosal WM integrity. Together, these findings suggest minocycline inhibits chronic microglial activation, which is greater in areas of WM damage, but may impede recovery after brain trauma.
Supervisor: Sharp, David ; Matthews, Paul Sponsor: Wellcome Trust ; GlaxoSmithKline ; National Institute for Health Research ; Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral