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Clinical Consequences of Axonal Injury in Traumatic Brain Injury
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.ORCID iD: 0000-0001-6173-8357
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Traumatic brain injury (TBI), mainly caused by road-traffic accidents and falls, is a leading cause of mortality. Survivors often display debilitating motor, sensory and cognitive symptoms, leading to reduced quality of life and a profound economic burden to society. Additionally, TBI is a risk factor for future neurodegenerative disorders including Alzheimer’s disease (AD). Commonly, TBI is categorized into focal and diffuse injuries, and based on symptom severity into mild, moderate and severe TBI. Diffuse axonal injury (DAI), biomechanically caused by rotational acceleration-deceleration forces at impact, is characterized by widespread axonal injury in superficial and deep white substance. DAI comprises a clinical challenge due to its variable course and unreliable prognostic methods. Furthermore, axonal injury may convey the link to neurodegeneration since molecules associated with neurodegenerative events aggregate in injured axons.

The aim of this thesis was to study clinical consequences of axonal injury, its detection and pathological features, and potential link to neurodegeneration in severe TBI patients treated at the neurointensive care unit at Uppsala University Hospital. In paper I and IV DAI patients were studied for the relation of elevated intracranial pressure (ICP) and poor outcome to axonal injury on magnetic resonance imaging. In paper II, soluble amyloid-beta aggregates (oligomers and protofibrils), characteristic of AD pathology, were investigated in surgically resected brain tissue from severe TBI patients, using highly-selective Enzyme-Linked ImmunoSorbent Assays. In paper III, brain tissue biopsy samples from TBI patients with either focal injury or DAI were examined for differential proteome profiles using mass spectrometry-based proteomics.

The results provide evidence that axonal injury, located in the central brain stem, in substantia nigra and the mesencephalic tegmentum, is particularly related to poor outcome and increased ICP during neurointensive care of DAI patients. A novel classification system for prognostication after DAI is proposed. Furthermore, the thesis shows that severe TBI induces rapid accumulation of neurotoxic soluble amyloid-beta oligomers and protofibrils. In addition, DAI initiates unique proteome profiles different from that of focal TBI in structurally normal-appearing brain. These findings have implication for the clinical management of DAI patients, and provide new insight in the neuropathological consequences of axonal injury.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. , p. 84
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1436
Keywords [en]
Traumatic brain injury, diffuse axonal injury, intracranial pressure, magnetic resonance imaging, amyloid-beta, tau
National Category
Medical and Health Sciences
Research subject
Neurosurgery
Identifiers
URN: urn:nbn:se:uu:diva-341914ISBN: 978-91-513-0251-5 (print)OAI: oai:DiVA.org:uu-341914DiVA, id: diva2:1183939
Public defence
2018-04-21, Auditorium minus, Gustavianum, Akademigatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2018-03-28 Created: 2018-02-19 Last updated: 2018-07-13
List of papers
1. Extended anatomical grading in diffuse axonal injury using MRI: Hemorrhagic lesions in the substantia nigra and mesencephalic tegmentum indicate poor long-term outcome
Open this publication in new window or tab >>Extended anatomical grading in diffuse axonal injury using MRI: Hemorrhagic lesions in the substantia nigra and mesencephalic tegmentum indicate poor long-term outcome
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2017 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 5, no 34, p. 341-352Article in journal (Refereed) Published
Abstract [en]

Clinical outcome after traumatic diffuse axonal injury (DAI) is difficult to predict. In this study, three magnetic resonance imaging (MRI) sequences were used to quantify the anatomical distribution of lesions, to grade DAI according to the Adams grading system, and to evaluate the value of lesion localization in combination with clinical prognostic factors to improve outcome prediction. Thirty patients (mean 31.2 years ±14.3 standard deviation) with severe DAI (Glasgow Motor Score [GMS] <6) examined with MRI within 1 week post-injury were included. Diffusion-weighted (DW), T2*-weighted gradient echo and susceptibility-weighted (SWI) sequences were used. Extended Glasgow outcome score was assessed after 6 months. Number of DW lesions in the thalamus, basal ganglia, and internal capsule and number of SWI lesions in the mesencephalon correlated significantly with outcome in univariate analysis. Age, GMS at admission, GMS at discharge, and low proportion of good monitoring time with cerebral perfusion pressure <60 mm Hg correlated significantly with outcome in univariate analysis. Multivariate analysis revealed an independent relation with poor outcome for age (p = 0.005) and lesions in the mesencephalic region corresponding to substantia nigra and tegmentum on SWI (p  = 0.008). We conclude that higher age and lesions in substantia nigra and mesencephalic tegmentum indicate poor long-term outcome in DAI. We propose an extended MRI classification system based on four stages (stage I—hemispheric lesions, stage II—corpus callosum lesions, stage III—brainstem lesions, and stage IV—substantia nigra or mesencephalic tegmentum lesions); all are subdivided by age (≥/<30 years).

Keywords
adult brain injury, axonal injury, head trauma, MRI, susceptibility weighted imaging
National Category
Clinical Medicine Neurology
Identifiers
urn:nbn:se:uu:diva-309038 (URN)10.1089/neu.2016.4426 (DOI)000391754800009 ()27356857 (PubMedID)
Available from: 2016-12-01 Created: 2016-12-01 Last updated: 2018-07-13Bibliographically approved
2. Rapid amyloid-β oligomer and protofibril accumulation in traumatic brain injury
Open this publication in new window or tab >>Rapid amyloid-β oligomer and protofibril accumulation in traumatic brain injury
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2018 (English)In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 28, no 4, p. 451-462Article in journal (Refereed) Published
Abstract [en]

Deposition of amyloid-β (Aβ) is central to Alzheimer's disease (AD) pathogenesis and associated with progressive neurodegeneration in traumatic brain injury (TBI). We analyzed predisposing factors for Aβ deposition including monomeric Aβ40, Aβ42 and Aβ oligomers/protofibrils, Aβ species with pronounced neurotoxic properties, following human TBI. Highly selective ELISAs were used to analyze N-terminally intact and truncated Aβ40 and Aβ42, as well as Aβ oligomers/protofibrils, in human brain tissue, surgically resected from severe TBI patients (n = 12; mean age 49.5 ± 19 years) due to life-threatening brain swelling/hemorrhage within one week post-injury. The TBI tissues were compared to post-mortem AD brains (n = 5), to post-mortem tissue of neurologically intact (NI) subjects (n = 4) and to cortical biopsies obtained at surgery for idiopathic normal pressure hydrocephalus patients (iNPH; n = 4). The levels of Aβ40 and Aβ42 were not elevated by TBI. The levels of Aβ oligomers/protofibrils in TBI were similar to those in the significantly older AD patients and increased compared to NI and iNPH controls (P < 0.05). Moreover, TBI patients carrying the AD risk genotype Apolipoprotein E epsilon3/4 (APOE ε3/4; n = 4) had increased levels of Aβ oligomers/protofibrils (P < 0.05) and of both N-terminally intact and truncated Aβ42 (P < 0.05) compared to APOE ε3/4-negative TBI patients (n = 8). Neuropathological analysis showed insoluble Aβ aggregates (commonly referred to as Aβ plaques) in three TBI patients, all of whom were APOE ε3/4 carriers. We conclude that soluble intermediary Aβ aggregates form rapidly after TBI, especially among APOE ε3/4 carriers. Further research is needed to determine whether these aggregates aggravate the clinical short- and long-term outcome in TBI.

Keywords
Alzheimer's disease, amyloid β oligomers, amyloid-β, traumatic brain injury
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-341911 (URN)10.1111/bpa.12532 (DOI)000439749700001 ()28557010 (PubMedID)
Funder
The Swedish Brain FoundationSwedish Research CouncilSwedish Institute
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2018-02-15 Created: 2018-02-15 Last updated: 2019-07-03Bibliographically approved
3. Proteomic differences between focal and diffuse traumatic brain injury in human brain tissue
Open this publication in new window or tab >>Proteomic differences between focal and diffuse traumatic brain injury in human brain tissue
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 6807Article in journal (Refereed) Published
Abstract [en]

The early molecular response to severe traumatic brain injury (TBI) was evaluated using biopsies of structurally normal-appearing cortex, obtained at location for intracranial pressure (ICP) monitoring, from 16 severe TBI patients. Mass spectrometry (MS; label free and stable isotope dimethyl labeling) quantitation proteomics showed a strikingly different molecular pattern in TBI in comparison to cortical biopsies from 11 idiopathic normal pressure hydrocephalus patients. Diffuse TBI showed increased expression of peptides related to neurodegeneration (Tau and Fascin, p < 0.05), reduced expression related to antioxidant defense (Glutathione S-transferase Mu 3, Peroxiredoxin-6, Thioredoxin-dependent peroxide reductase; p < 0.05) and increased expression of potential biomarkers (e.g. Neurogranin, Fatty acid-binding protein, heart p < 0.05) compared to focal TBI. Proteomics of human brain biopsies displayed considerable molecular heterogeneity among the different TBI subtypes with consequences for the pathophysiology and development of targeted treatments for TBI.

National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:uu:diva-341912 (URN)10.1038/s41598-018-25060-0 (DOI)000431113100005 ()29717219 (PubMedID)
Funder
The Swedish Brain FoundationVINNOVASwedish Research CouncilLars Hierta Memorial FoundationStiftelsen Gamla Tjänarinnor
Available from: 2018-02-15 Created: 2018-02-15 Last updated: 2018-07-13Bibliographically approved
4. Intracranial pressure elevations in diffuse axonal injury are associated with non-hemorrhagic MR lesions in central mesencephalic structures
Open this publication in new window or tab >>Intracranial pressure elevations in diffuse axonal injury are associated with non-hemorrhagic MR lesions in central mesencephalic structures
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(English)In: Article in journal (Other academic) Submitted
Abstract [en]

Objective: Increased intracranial pressure (ICP) in severe traumatic brain injury (TBI) patients with diffuse axonal injury (DAI) is not well defined. This study investigated the occurrence of increased ICP and whether clinical factors and lesion localization on MRI were associated with increased ICP in DAI patients.

Methods: Fifty-two severe TBI patients (median 24, range 9-61 years), with ICP-monitoring and DAI on MRI, using T2*-weighted gradient echo, susceptibility-weighted and diffusion-weighted (DW) sequences, were enrolled. Proportion of good monitoring time (GMT) with ICP>20 mmHg during the first 120 hours post-injury was calculated and associations with clinical and MRI-related factors were evaluated using linear regression. 

Results: All patients had episodes of ICP>20 mmHg. The mean proportion of GMT with ICP>20 mmHg was 5% and 27% of the patients (14/52) had more than 5% of GMT with ICP>20 mmHg. Glasgow Coma Scale motor score at admission (P=0.04) and lesions on DW images in the substantia nigra and mesencephalic tegmentum (SN-T, P=0.001) were associated with the proportion of GMT with ICP>20 mmHg. In multivariate linear regression, lesions on DW images in SN-T (8% of GMT with ICP>20 mmHg, 95% CI 3–13%, P=0.004) and young age (-0.2% of GMT with ICP>20 mmHg, 95% CI -0.07–-0.3%, P=0.0008) were associated with increased ICP.   

Conclusions: Increased ICP occurs in ~1/3 of severe TBI patients with DAI. Age and lesions on DW images in the central mesencephalon (SN-T) associate with elevated ICP. These findings suggest that MR lesion localization may aid prediction of increased ICP in DAI patients.

National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-341913 (URN)
Available from: 2018-02-15 Created: 2018-02-15 Last updated: 2018-07-13

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