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Title: The endocrine and metabolic factors influencing neuroinflammation and recovery following traumatic brain injury
Author: Feeney, Claire
ISNI:       0000 0004 5994 3089
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Background: Traumatic brain injury (TBI) is a major cause of psychological and cognitive disability in young adults in the developed world. The prognosis for these patients is uncertain. Neuroinflammation may be an important underlying mechanism. Growth hormone deficiency (GHD) is a recognised consequence of TBI and may influence recovery. The metabolic syndrome, a state of insulin resistance, may also influence outcome from TBI. Objectives: i) To study the prevalence and consequences of pituitary dysfunction in soldiers who have suffered a blast TBI (bTBI) ii) To investigate the effect of GH deficiency and serum IGF-I levels on recovery from TBI iii)To evaluate a new positron emission tomography (PET) radioligand [18F]GE-180 purported to measure TSPO neuroinflammation in the healthy human brain iv) To quantify neuroinflammation using [18F]GE-180 in patient following TBI and correlate with metabolic factors. Methods: i) Cross-sectional comparative study of 19 soldiers with bTBI vs. 39 civilians with non-blast TBI. Full endocrine testing, neuropsychological testing, diffusion tensor imaging (DTI) ii) Longitudinal study of 39 patients following TBI; IGF-I and GHD testing at baseline, DTI and neuropsychological testing at two study visits designed to be one year apart. Intervention study of 10 patients with GHD pre- and post- 1 year of GH replacement therapy iii) Cross-sectional PET study using [18F]GE-180 in 10 healthy volunteers iv) Longitudinal [18F]GE-180 PET study in 12 patients following TBI: MRI, PET, neuropsychological and metabolic testing at two visits 6 months apart. Results: i) Higher prevalence of pituitary dysfunction in bTBI (31.6%) compared to nbTBI (2.6%), P =0.004 ii) Greater improvement in fractional anisotropy (FA) in patients with a higher IGF-I at baseline, in the splenium of the corpus callosum (SPCC) and in logical memory scores; no effect of GH replacement per se seen on WM recovery or memory, but significant improvement in QoL and depression scores iii) Low brain uptake of [18F]GE-180 in healthy volunteers, two compartmental 4K-fix (2TC) model provided best fit of the data, no effect of TSPO polymorphism seen iv) no significant effect of genotype seen in TBI patients or in outcome measures between patients and controls. Conclusions i) Novel finding of greater prevalence of pituitary dysfunction in patients with bTBI ii) IGF-I, irrespective of the presence of GHD, improves WM recovery in the SPCC and memory iii) GH replacement does not influence cognition or brain structure in this study but did improve quality of life iv) The TSPO ligand [18F]GE-180 appears to be limited by poor brain uptake v) the 2TC-fix model provides the best model fit iv) distribution volumes are low and there appears to be no effect of the TSPO polymorphism on PET outcome measures in patients with TBI and controls.
Supervisor: Sharp, David ; Goldstone, Anthony Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral