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Proteomic differences between focal and diffuse traumatic brain injury in human brain tissue
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.ORCID-id: 0000-0001-6173-8357
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
Vise andre og tillknytning
2018 (engelsk)Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikkel-id 6807Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
2018. Vol. 8, artikkel-id 6807
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-341912DOI: 10.1038/s41598-018-25060-0ISI: 000431113100005PubMedID: 29717219OAI: oai:DiVA.org:uu-341912DiVA, id: diva2:1183199
Forskningsfinansiär
The Swedish Brain FoundationVINNOVASwedish Research CouncilLars Hierta Memorial FoundationStiftelsen Gamla TjänarinnorTilgjengelig fra: 2018-02-15 Laget: 2018-02-15 Sist oppdatert: 2018-07-13bibliografisk kontrollert
Inngår i avhandling
1. Clinical Consequences of Axonal Injury in Traumatic Brain Injury
Åpne denne publikasjonen i ny fane eller vindu >>Clinical Consequences of Axonal Injury in Traumatic Brain Injury
2018 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2018. s. 84
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1436
Emneord
Traumatic brain injury, diffuse axonal injury, intracranial pressure, magnetic resonance imaging, amyloid-beta, tau
HSV kategori
Forskningsprogram
Neurokirurgi
Identifikatorer
urn:nbn:se:uu:diva-341914 (URN)978-91-513-0251-5 (ISBN)
Disputas
2018-04-21, Auditorium minus, Gustavianum, Akademigatan 3, Uppsala, 09:15 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2018-03-28 Laget: 2018-02-19 Sist oppdatert: 2018-07-13

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