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Title: Dopaminergic abnormalities following traumatic brain injury : a potential therapeutic target
Author: Jenkins, Peter
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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Cognitive problems are one of the main causes of ongoing disability after traumatic brain injury (TBI). There are currently no licensed medications for treatment of these cognitive impairments although numerous medications have been trialled with varying success. This is likely to be due to the heterogeneity of the injuries sustained and the variability of the resulting cognitive deficits. Identifying the underlying pathology allows a targeted treatment approach aimed at cognitive enhancement. For example, damage to neuromodulatory neurotransmitter systems (e.g. the dopamine and acetylcholine systems) is common after traumatic brain injury and is an important cause of cognitive impairment. The overarching aim of this thesis is to explore the effects of TBI on the dopaminergic system using a multi-modal imaging approach and to determine if these techniques can be used to predict who will respond to methylphenidate, a dopaminergic agonist. In the first experimental chapter, Chapter 3, I explore the effect of TBI on the dopamine transporter (DaT) in the striatum using single photon emission computed tomography (SPECT) imaging. In particular, I examine whether TBI produces a distinct pattern of DaT abnormalities, as the striatum is functionally sub-divided. Motor control is facilitated by the posterior striatum (putamen) and cognitive processes modulated by the anterior striatum (caudate). In the second experimental chapter, I use advanced magnetic resonance imaging (MRI) techniques to investigate the potential causes of disruption to the dopaminergic system following TBI. The dopaminergic cell bodies are housed in midbrain nuclei. From here, they project ascending fibres to the striatum through the nigro-striatal tract. Therefore, I explore whether damage to the midbrain nuclei or ascending fibres relates to changes in the striatum as both areas are potentially susceptible to damage caused by trauma. In the third experimental chapter, I report the results of a clinical trial assessing whether these advanced imaging techniques can be used to stratify TBI patients and predict who will respond to treatment with methylphenidate as a cognitive enhancer. My hypothesis is that patients with evidence of disruption to their dopaminergic system will benefit from the use of methylphenidate. In the final experimental chapter, I compare the SPECT scans in TBI patients to patients with newly diagnosed idiopathic Parkinson's disease. TBI patients rarely show evidence of motor parkinsonism but do have cognitive impairments in domains known to be modulated by the dopamine system. In Parkinson's disease the motor signs relate to loss of DaT in the putamen. As the disease advances the striatal abnormalities progress anteriorly to involve the caudate, at which time cognitive impairments become apparent. Therefore, I hypothesize that there is a differential impact on the striatal regions in TBI and Parkinson's disease to explain these phenotypes. As a whole, this thesis explores the proof-of-principle that treatment selection following traumatic brain injury requires stratification based on the underlying pathophysiology. Traumatic brain injury is a very heterogeneous process and therefore a 'one-size fits all' approach to treatment is unlikely to be successful. My hope is that this principle will be applied to future trials aimed at improving function following TBI.
Supervisor: Sharp, David ; Leech, Robert Sponsor: Guarantors of Brain
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral