{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/390201"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/390201","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"From Acute to Chronic: Outcomes and Diagnostics in Traumatic Brain Injury","abstract":"Traumatic brain injury (TBI) is the most common neurological disorder worldwide and is a leading cause of morbidity and mortality. Despite growing evidence of its short- and long-term effects, even following a so called “mild” injury, understanding the intricate relationship between injury mechanisms, patient phenotypes, and clinical outcomes remains a significant challenge for researchers and clinicians. The advent of blood-based biomarkers has been an exciting recent development in TBI research, providing objective evidence of the degree of brain injury through a simple blood test, with the potential to aid in both diagnosis and prognostication following injury. This thesis has employed diverse analytical approaches across multiple datasets, moving from the acute to the chronic phase of illness in order to examine the incidence and determinants of selected patient outcomes following mild TBI, whilst exploring the role of blood-based biomarkers in TBI management. Beginning in the acute phase of injury, using the highly granular data from the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) core-study dataset, the thesis explored two key questions concerning the acute determinants of 6-month patient outcomes following mild TBI, focussing on the association between acute serum proteomic biomarker levels and patient outcomes. Initially, the association between a participant’s acute proteomic biomarker profile and a range of patient-reported outcomes, including functional status, symptomatic recovery, quality of life, and mental health were examined. Higher biomarker levels were observed in patients with a worse functional outcome, although, in general, little association was seen in relation to a participant’s quality of life or mental health. However, in participants with mild TBI and no traumatic findings on acute computed tomography (CT) brain scan (CT-negative mild TBI), unexpected associations were found, whereby higher levels of certain biomarkers were associated with improved patient-reported outcomes. Next, the examination of the acute phase determinants of patient outcomes continued, exploring the impact of care pathway (discharged from the Emergency Department (ED), admitted to hospital or admitted to intensive care) on 6-month cognitive performance following CT-negative mild TBI, alongside examination of the association between cognitive performance and the day of injury serum proteomic biomarker levels within the same population. CT-negative mild TBI patients demonstrated worse cognitive performance at 6-months following injury as compared to healthy controls although, overall, little association was seen between care pathway and cognitive performance. Of note, however, worse performance was seen specifically regarding a measure of attentional capacity in participants admitted to ICU. Minimal association was observed between the acute biomarker levels and 6-month cognitive test performance, indicating a lack of association between degree of neuronal injury and cognitive performance within the population studied. Next, the potential for diagnostic biomarkers to be integrated within current UK health systems for CT decision-making following TBI was explored in a targeted assessment of the CENTER-TBI dataset. A population of TBI patients was identified where clinical equipoise remained concerning the requirement for acute CT imaging, termed medium-risk. In this population, the targeted use of biomarkers to act as a screen for the neuroimaging may reduce CT scan requirements in these medium-risk patients by up to a quarter, reducing unnecessary investigation and expediting discharge from the ED. The thesis then moved to two smaller scale experimental studies. Firstly, correlation was observed between a novel point-of-care lateral flow test (LFT) and a gold-standard lab assay for Glial Fibrillary Acidic Protein (GFAP) in the first examination of the device in a TBI population. This indicated potential utility in the test, pending further validation, to offer fast and reliable biomarker testing applicable in a range of testing environments. Secondly, biomarkers that are sensitive to the presence of neuronal injury may have broader applications outside of trauma, particularly in the acute care setting. To explore this, severe infection/sepsis was used as an exemplar condition, with the acute profile of brain injury biomarkers examined in patients presenting to the ED with suspected sepsis. Elevated biomarker levels were observed in patients with suspected sepsis, including, of note, the Alzheimer’s disease biomarker p-tau-217, indicating potential reliability issues with this diagnostic biomarker when sampled in the context of acute illness. For the final section of the thesis, the focus was moved to the chronic phase of TBI. The long-term effects of head injury were explored using linked healthcare data contained within the UK Biobank study. An increased risk of neurodegenerative diseases, and worse performance in neurocognitive tests, was observed in those with a history of head injury, with a dose-response effect observed whereby a participant with a history of multiple head injuries had an increased risk of neurodegenerative disease and a worse performance across several neurocognitive tests. The levels of selected proteomic brain-injury biomarkers were then examined in the UK Biobank participants with a prior history of head injury. Although there was no association between a history of head injury and biomarker levels, a significant association was identified between biomarker levels and both contemporaneous cognitive performance and future dementia risk. This indicated the potential utility of the biomarkers for identification of patients in the preclinical phase of dementia, specifically in the head injured population who are at higher clinical risk compared to the general population. In conclusion, this thesis provides evidence of both short- and long-term harms following mild TBI, alongside identifying factors influencing recovery in both the acute and chronic phases of mild TBI. Additionally, evidence is provided demonstrating the utility of acute blood biomarkers for both diagnosis and prognosis following mild TBI and the potential pathways for integration of biomarkers into current UK healthcare systems","abstract_html":"Traumatic brain injury (TBI) is the most common neurological disorder worldwide and is a leading cause of morbidity and mortality. Despite growing evidence of its short- and long-term effects, even following a so called “mild” injury, understanding the intricate relationship between injury mechanisms, patient phenotypes, and clinical outcomes remains a significant challenge for researchers and clinicians. The advent of blood-based biomarkers has been an exciting recent development in TBI research, providing objective evidence of the degree of brain injury through a simple blood test, with the potential to aid in both diagnosis and prognostication following injury. This thesis has employed diverse analytical approaches across multiple datasets, moving from the acute to the chronic phase of illness in order to examine the incidence and determinants of selected patient outcomes following mild TBI, whilst exploring the role of blood-based biomarkers in TBI management. Beginning in the acute phase of injury, using the highly granular data from the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) core-study dataset, the thesis explored two key questions concerning the acute determinants of 6-month patient outcomes following mild TBI, focussing on the association between acute serum proteomic biomarker levels and patient outcomes. Initially, the association between a participant’s acute proteomic biomarker profile and a range of patient-reported outcomes, including functional status, symptomatic recovery, quality of life, and mental health were examined. Higher biomarker levels were observed in patients with a worse functional outcome, although, in general, little association was seen in relation to a participant’s quality of life or mental health. However, in participants with mild TBI and no traumatic findings on acute computed tomography (CT) brain scan (CT-negative mild TBI), unexpected associations were found, whereby higher levels of certain biomarkers were associated with improved patient-reported outcomes. Next, the examination of the acute phase determinants of patient outcomes continued, exploring the impact of care pathway (discharged from the Emergency Department (ED), admitted to hospital or admitted to intensive care) on 6-month cognitive performance following CT-negative mild TBI, alongside examination of the association between cognitive performance and the day of injury serum proteomic biomarker levels within the same population. CT-negative mild TBI patients demonstrated worse cognitive performance at 6-months following injury as compared to healthy controls although, overall, little association was seen between care pathway and cognitive performance. Of note, however, worse performance was seen specifically regarding a measure of attentional capacity in participants admitted to ICU. Minimal association was observed between the acute biomarker levels and 6-month cognitive test performance, indicating a lack of association between degree of neuronal injury and cognitive performance within the population studied. Next, the potential for diagnostic biomarkers to be integrated within current UK health systems for CT decision-making following TBI was explored in a targeted assessment of the CENTER-TBI dataset. A population of TBI patients was identified where clinical equipoise remained concerning the requirement for acute CT imaging, termed medium-risk. In this population, the targeted use of biomarkers to act as a screen for the neuroimaging may reduce CT scan requirements in these medium-risk patients by up to a quarter, reducing unnecessary investigation and expediting discharge from the ED. The thesis then moved to two smaller scale experimental studies. Firstly, correlation was observed between a novel point-of-care lateral flow test (LFT) and a gold-standard lab assay for Glial Fibrillary Acidic Protein (GFAP) in the first examination of the device in a TBI population. This indicated potential utility in the test, pending further validation, to offer fast and reliable biomarker testing applicable in a range of testing environments. Secondly, biomarkers that are sensitive to the presence of neuronal injury may have broader applications outside of trauma, particularly in the acute care setting. To explore this, severe infection/sepsis was used as an exemplar condition, with the acute profile of brain injury biomarkers examined in patients presenting to the ED with suspected sepsis. Elevated biomarker levels were observed in patients with suspected sepsis, including, of note, the Alzheimer’s disease biomarker p-tau-217, indicating potential reliability issues with this diagnostic biomarker when sampled in the context of acute illness. For the final section of the thesis, the focus was moved to the chronic phase of TBI. The long-term effects of head injury were explored using linked healthcare data contained within the UK Biobank study. An increased risk of neurodegenerative diseases, and worse performance in neurocognitive tests, was observed in those with a history of head injury, with a dose-response effect observed whereby a participant with a history of multiple head injuries had an increased risk of neurodegenerative disease and a worse performance across several neurocognitive tests. The levels of selected proteomic brain-injury biomarkers were then examined in the UK Biobank participants with a prior history of head injury. Although there was no association between a history of head injury and biomarker levels, a significant association was identified between biomarker levels and both contemporaneous cognitive performance and future dementia risk. This indicated the potential utility of the biomarkers for identification of patients in the preclinical phase of dementia, specifically in the head injured population who are at higher clinical risk compared to the general population. In conclusion, this thesis provides evidence of both short- and long-term harms following mild TBI, alongside identifying factors influencing recovery in both the acute and chronic phases of mild TBI. Additionally, evidence is provided demonstrating the utility of acute blood biomarkers for both diagnosis and prognosis following mild TBI and the potential pathways for integration of biomarkers into current UK healthcare systems","abstract_has_math":false,"creators":["Whitehouse, Daniel"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Newcombe, Virginia FJ"],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-04-29","date_published":"2025-04-29","updated_at":"2026-07-24T01:33:25Z","subjects":["traumatic brain injury"],"languages":["eng"],"rights":[],"rights_urls":["https://www.repository.cam.ac.uk/bitstreams/14401279-75a8-438a-8c85-4fcd369b858b/download","http://purl.org/NET/rdflicense/allrightsreserved"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.121827","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Newcombe, Virginia FJ"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["This Doctor of Philosophy (PhD) project is funded by the Royal College of Emergency Medicine (RCEM) via the RCEM PhD Doctoral Research Fellowship. 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Beginning in the acute phase of injury, using the highly granular data from the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) core-study dataset, the thesis explored two key questions concerning the acute determinants of 6-month patient outcomes following mild TBI, focussing on the association between acute serum proteomic biomarker levels and patient outcomes. Initially, the association between a participant’s acute proteomic biomarker profile and a range of patient-reported outcomes, including functional status, symptomatic recovery, quality of life, and mental health were examined. Higher biomarker levels were observed in patients with a worse functional outcome, although, in general, little association was seen in relation to a participant’s quality of life or mental health. However, in participants with mild TBI and no traumatic findings on acute computed tomography (CT) brain scan (CT-negative mild TBI), unexpected associations were found, whereby higher levels of certain biomarkers were associated with improved patient-reported outcomes. Next, the examination of the acute phase determinants of patient outcomes continued, exploring the impact of care pathway (discharged from the Emergency Department (ED), admitted to hospital or admitted to intensive care) on 6-month cognitive performance following CT-negative mild TBI, alongside examination of the association between cognitive performance and the day of injury serum proteomic biomarker levels within the same population. CT-negative mild TBI patients demonstrated worse cognitive performance at 6-months following injury as compared to healthy controls although, overall, little association was seen between care pathway and cognitive performance. Of note, however, worse performance was seen specifically regarding a measure of attentional capacity in participants admitted to ICU. Minimal association was observed between the acute biomarker levels and 6-month cognitive test performance, indicating a lack of association between degree of neuronal injury and cognitive performance within the population studied. Next, the potential for diagnostic biomarkers to be integrated within current UK health systems for CT decision-making following TBI was explored in a targeted assessment of the CENTER-TBI dataset. A population of TBI patients was identified where clinical equipoise remained concerning the requirement for acute CT imaging, termed medium-risk. In this population, the targeted use of biomarkers to act as a screen for the neuroimaging may reduce CT scan requirements in these medium-risk patients by up to a quarter, reducing unnecessary investigation and expediting discharge from the ED. The thesis then moved to two smaller scale experimental studies. Firstly, correlation was observed between a novel point-of-care lateral flow test (LFT) and a gold-standard lab assay for Glial Fibrillary Acidic Protein (GFAP) in the first examination of the device in a TBI population. This indicated potential utility in the test, pending further validation, to offer fast and reliable biomarker testing applicable in a range of testing environments. Secondly, biomarkers that are sensitive to the presence of neuronal injury may have broader applications outside of trauma, particularly in the acute care setting. To explore this, severe infection/sepsis was used as an exemplar condition, with the acute profile of brain injury biomarkers examined in patients presenting to the ED with suspected sepsis. Elevated biomarker levels were observed in patients with suspected sepsis, including, of note, the Alzheimer’s disease biomarker p-tau-217, indicating potential reliability issues with this diagnostic biomarker when sampled in the context of acute illness. For the final section of the thesis, the focus was moved to the chronic phase of TBI. The long-term effects of head injury were explored using linked healthcare data contained within the UK Biobank study. An increased risk of neurodegenerative diseases, and worse performance in neurocognitive tests, was observed in those with a history of head injury, with a dose-response effect observed whereby a participant with a history of multiple head injuries had an increased risk of neurodegenerative disease and a worse performance across several neurocognitive tests. The levels of selected proteomic brain-injury biomarkers were then examined in the UK Biobank participants with a prior history of head injury. Although there was no association between a history of head injury and biomarker levels, a significant association was identified between biomarker levels and both contemporaneous cognitive performance and future dementia risk. This indicated the potential utility of the biomarkers for identification of patients in the preclinical phase of dementia, specifically in the head injured population who are at higher clinical risk compared to the general population. In conclusion, this thesis provides evidence of both short- and long-term harms following mild TBI, alongside identifying factors influencing recovery in both the acute and chronic phases of mild TBI. 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The advent of blood-based biomarkers has been an exciting recent development in TBI research, providing objective evidence of the degree of brain injury through a simple blood test, with the potential to aid in both diagnosis and prognostication following injury. This thesis has employed diverse analytical approaches across multiple datasets, moving from the acute to the chronic phase of illness in order to examine the incidence and determinants of selected patient outcomes following mild TBI, whilst exploring the role of blood-based biomarkers in TBI management. Beginning in the acute phase of injury, using the highly granular data from the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) core-study dataset, the thesis explored two key questions concerning the acute determinants of 6-month patient outcomes following mild TBI, focussing on the association between acute serum proteomic biomarker levels and patient outcomes. Initially, the association between a participant’s acute proteomic biomarker profile and a range of patient-reported outcomes, including functional status, symptomatic recovery, quality of life, and mental health were examined. Higher biomarker levels were observed in patients with a worse functional outcome, although, in general, little association was seen in relation to a participant’s quality of life or mental health. However, in participants with mild TBI and no traumatic findings on acute computed tomography (CT) brain scan (CT-negative mild TBI), unexpected associations were found, whereby higher levels of certain biomarkers were associated with improved patient-reported outcomes. Next, the examination of the acute phase determinants of patient outcomes continued, exploring the impact of care pathway (discharged from the Emergency Department (ED), admitted to hospital or admitted to intensive care) on 6-month cognitive performance following CT-negative mild TBI, alongside examination of the association between cognitive performance and the day of injury serum proteomic biomarker levels within the same population. CT-negative mild TBI patients demonstrated worse cognitive performance at 6-months following injury as compared to healthy controls although, overall, little association was seen between care pathway and cognitive performance. Of note, however, worse performance was seen specifically regarding a measure of attentional capacity in participants admitted to ICU. Minimal association was observed between the acute biomarker levels and 6-month cognitive test performance, indicating a lack of association between degree of neuronal injury and cognitive performance within the population studied. Next, the potential for diagnostic biomarkers to be integrated within current UK health systems for CT decision-making following TBI was explored in a targeted assessment of the CENTER-TBI dataset. A population of TBI patients was identified where clinical equipoise remained concerning the requirement for acute CT imaging, termed medium-risk. In this population, the targeted use of biomarkers to act as a screen for the neuroimaging may reduce CT scan requirements in these medium-risk patients by up to a quarter, reducing unnecessary investigation and expediting discharge from the ED. The thesis then moved to two smaller scale experimental studies. Firstly, correlation was observed between a novel point-of-care lateral flow test (LFT) and a gold-standard lab assay for Glial Fibrillary Acidic Protein (GFAP) in the first examination of the device in a TBI population. This indicated potential utility in the test, pending further validation, to offer fast and reliable biomarker testing applicable in a range of testing environments. Secondly, biomarkers that are sensitive to the presence of neuronal injury may have broader applications outside of trauma, particularly in the acute care setting. To explore this, severe infection/sepsis was used as an exemplar condition, with the acute profile of brain injury biomarkers examined in patients presenting to the ED with suspected sepsis. Elevated biomarker levels were observed in patients with suspected sepsis, including, of note, the Alzheimer’s disease biomarker p-tau-217, indicating potential reliability issues with this diagnostic biomarker when sampled in the context of acute illness. For the final section of the thesis, the focus was moved to the chronic phase of TBI. The long-term effects of head injury were explored using linked healthcare data contained within the UK Biobank study. An increased risk of neurodegenerative diseases, and worse performance in neurocognitive tests, was observed in those with a history of head injury, with a dose-response effect observed whereby a participant with a history of multiple head injuries had an increased risk of neurodegenerative disease and a worse performance across several neurocognitive tests. The levels of selected proteomic brain-injury biomarkers were then examined in the UK Biobank participants with a prior history of head injury. Although there was no association between a history of head injury and biomarker levels, a significant association was identified between biomarker levels and both contemporaneous cognitive performance and future dementia risk. This indicated the potential utility of the biomarkers for identification of patients in the preclinical phase of dementia, specifically in the head injured population who are at higher clinical risk compared to the general population. In conclusion, this thesis provides evidence of both short- and long-term harms following mild TBI, alongside identifying factors influencing recovery in both the acute and chronic phases of mild TBI. 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