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Rapid amyloid-β oligomer and protofibril accumulation in traumatic brain injury
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.ORCID-id: 0000-0001-6173-8357
BioArctic Neurosci AB, Stockholm, Sweden.
BioArctic Neurosci AB, Stockholm, Sweden.
BioArctic Neurosci AB, Stockholm, Sweden.
Vise andre og tillknytning
2018 (engelsk)Inngår i: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 28, nr 4, s. 451-462Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
2018. Vol. 28, nr 4, s. 451-462
Emneord [en]
Alzheimer's disease, amyloid β oligomers, amyloid-β, traumatic brain injury
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-341911DOI: 10.1111/bpa.12532ISI: 000439749700001PubMedID: 28557010OAI: oai:DiVA.org:uu-341911DiVA, id: diva2:1183197
Forskningsfinansiär
The Swedish Brain FoundationSwedish Research CouncilSwedish Institute
Merknad

De två första författarna delar förstaförfattarskapet.

Tilgjengelig fra: 2018-02-15 Laget: 2018-02-15 Sist oppdatert: 2019-07-03bibliografisk 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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