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Thelin, E. P., Helmy, A., Nelson, D. W. & Marklund, N. (2018). Editorial: Monitoring Pathophysiology in the injured Brain. Frontiers in Neurology, 9, Article ID 193.
Open this publication in new window or tab >>Editorial: Monitoring Pathophysiology in the injured Brain
2018 (English)In: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 9, article id 193Article in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2018
Keywords
traumatic brain injury, subarachnoid hemorrhage, monitoring, biomarkers, neurocritical care
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-356893 (URN)10.3389/fneur.2018.00193 (DOI)000428278500001 ()
Available from: 2018-08-10 Created: 2018-08-10 Last updated: 2018-08-10Bibliographically approved
Baunsgaard, C. B., Nissen, U. V., Brust, A. K., Frotzler, A., Ribeill, C., Kalke, Y.-B., . . . Biering-Sorensen, F. (2018). Gait training after spinal cord injury: safety, feasibility and gait function following 8 weeks of training with the exoskeletons from Ekso Bionics. Spinal Cord, 56(2), 106-116
Open this publication in new window or tab >>Gait training after spinal cord injury: safety, feasibility and gait function following 8 weeks of training with the exoskeletons from Ekso Bionics
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2018 (English)In: Spinal Cord, ISSN 1362-4393, E-ISSN 1476-5624, Vol. 56, no 2, p. 106-116Article in journal (Refereed) Published
Abstract [en]

Study design: Prospective quasi-experimental study, pre-and post-design.

Objectives: Assess safety, feasibility, training characteristics and changes in gait function for persons with spinal cord injury (SCI) using the robotic exoskeletons from Ekso Bionics.

Setting: Nine European rehabilitation centres.

Methods: Robotic exoskeleton gait training, three times weekly over 8 weeks. Time upright, time walking and steps in the device (training characteristics) were recorded longitudinally. Gait and neurological function were measured by 10 Metre Walk Test (10 MWT), Timed Up and Go (TUG), Berg Balance Scale (BBS), Walking Index for Spinal Cord Injury (WISCI) II and Lower Extremity Motor Score (LEMS).

Results: Fifty-two participants completed the training protocol. Median age: 35.8 years (IQR 27.5-52.5), men/women: N = 36/16, neurological level of injury: C1-L2 and severity: AIS A-D (American Spinal Injury Association Impairment Scale). Time since injury (TSI) < 1 year, N = 25; > 1 year, N = 27. No serious adverse events occurred. Three participants dropped out following ankle swelling (overuse injury). Four participants sustained a Category II pressure ulcer at contact points with the device but completed the study and skin normalized. Training characteristics increased significantly for all subgroups. The number of participants with TSI < 1 year and gait function increased from 20 to 56% (P=0.004) and 10MWT, TUG, BBS and LEMS results improved (P < 0.05). The number of participants with TSI > 1 year and gait function, increased from 41 to 44% and TUG and BBS results improved (P < 0.05).

Conclusions: Exoskeleton training was generally safe and feasible in a heterogeneous sample of persons with SCI. Results indicate potential benefits on gait function and balance.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-347086 (URN)10.1038/s41393-017-0013-7 (DOI)000424686800003 ()29105657 (PubMedID)
Available from: 2018-03-26 Created: 2018-03-26 Last updated: 2018-03-26Bibliographically approved
Abu Hamdeh, S., Shevchenko, G., Mi, J., Musunuri, S., Bergquist, J. & Marklund, N. (2018). Proteomic differences between focal and diffuse traumatic brain injury in human brain tissue. Scientific Reports, 8, Article ID 6807.
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
Shahim, P., Tegner, Y., Marklund, N., Hoeglund, K., Portelius, E., Brody, D. L., . . . Zetterberg, H. (2017). Astroglial activation and altered amyloid metabolism in human repetitive concussion. Neurology, 88(15), 1400-1407
Open this publication in new window or tab >>Astroglial activation and altered amyloid metabolism in human repetitive concussion
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2017 (English)In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 88, no 15, p. 1400-1407Article in journal (Refereed) Published
Abstract [en]

Objective: To determine whether postconcussion syndrome (PCS) due to repetitive concussive traumatic brain injury (rcTBI) is associated with CSF biomarker evidence of astroglial activation, amyloid deposition, and blood-brain barrier (BBB) impairment. Methods: A total of 47 participants (28 professional athletes with PCS and 19 controls) were assessed with lumbar puncture (median 1.5 years, range 0.25-12 years after last concussion), standard MRI of the brain, and Rivermead Post-Concussion Symptoms Questionnaire (RPQ). The main outcome measures were CSF concentrations of astroglial activation markers (glial fibrillary acidic protein [GFAP] and YKL-40), markers reflecting amyloid precursor protein metabolism (A beta 38, A beta 40, A beta 42, sAPPa, and sAPPb), and BBB function (CSF: serum albumin ratio). Results: Nine of the 28 athletes returned to play within a year, while 19 had persistent PCS.1 year. Athletes with PCS.1 year had higher RPQ scores and number of concussions than athletes with PCS,1 year. Median concentrations of GFAP and YKL-40 were higher in athletes with PCS.1 year compared with controls, although with an overlap between the groups. YKL-40 correlated with RPQ score and the lifetime number of concussions. Athletes with rcTBI had lower concentrations of A beta 40 and A beta 42 than controls. The CSF: serum albumin ratio was unaltered. Conclusions: This study suggests that PCS may be associated with biomarker evidence of astroglial activation and b-amyloid (A beta) dysmetabolism in the brain. There was no clear evidence of Ab deposition as A beta 40 and A beta 42 were reduced in parallel. The CSF: serum albumin ratio was unaltered, suggesting that the BBB is largely intact in PCS.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-320627 (URN)10.1212/WNL.0000000000003816 (DOI)000398674100008 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationTorsten Söderbergs stiftelseEU, Horizon 2020
Available from: 2017-08-17 Created: 2017-08-17 Last updated: 2017-08-17Bibliographically approved
Marklund, N. (2017). Cerebral amyloid angiopathy: a long-term consequence of traumatic brain injury?. Acta Neurochirurgica, 159(1), 21-23
Open this publication in new window or tab >>Cerebral amyloid angiopathy: a long-term consequence of traumatic brain injury?
2017 (English)In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 159, no 1, p. 21-23Article in journal (Refereed) Published
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-317505 (URN)10.1007/s00701-016-3005-z (DOI)000393022000008 ()27796651 (PubMedID)
Available from: 2017-04-13 Created: 2017-04-13 Last updated: 2017-11-29Bibliographically approved
Tsitsopoulos, P. P., Abu Hamdeh, S. & Marklund, N. (2017). Current Opportunities for Clinical Monitoring of Axonal Pathology in Traumatic Brain injury. Frontiers in Neurology, 8, Article ID 599.
Open this publication in new window or tab >>Current Opportunities for Clinical Monitoring of Axonal Pathology in Traumatic Brain injury
2017 (English)In: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 8, article id 599Article, review/survey (Refereed) Published
Abstract [en]

Traumatic brain injury (TBI) is a multidimensional and highly complex disease commonly resulting in widespread injury to axons, due to rapid inertial acceleration/deceleration forces transmitted to the brain during impact. Axonal injury leads to brain network dysfunction, significantly contributing to cognitive and functional impairments frequently observed in TBI survivors. Diffuse axonal injury (DAI) is a clinical entity suggested by impaired level of consciousness and coma on clinical examination and characterized by widespread injury to the hemispheric white matter tracts, the corpus callosum and the brain stem. The clinical course of DAI is commonly unpredictable and it remains a challenging entity with limited therapeutic options, to date. Although axonal integrity may be disrupted at impact, the majority of axonal pathology evolves over time, resulting from delayed activation of complex intracellular biochemical cascades. Activation of these secondary biochemical pathways may lead to axonal transection, named secondary axotomy, and be responsible for the clinical decline of DAI patients. Advances in the neurocritical care of TBI patients have been achieved by refinements in multimodality monitoring for prevention and early detection of secondary injury factors, which can be applied also to DAI. There is an emerging role for biomarkers in blood, cerebrospinal fluid, and interstitial fluid using microdialysis in the evaluation of axonal injury in TBI. These biomarker studies have assessed various axonal and neuroglial markers as well as inflammatory mediators, such as cytokines and chemokines. Moreover, modern neuroimaging can detect subtle or overt DAI/white matter changes in diffuse TBI patients across all injury severities using magnetic resonance spectroscopy, diffusion tensor imaging, and positron emission tomography. Importantly, serial neuroimaging studies provide evidence for evolving axonal injury. Since axonal injury may be a key risk factor for neurodegeneration and dementias at long-term following TBI, the secondary injury processes may require prolonged monitoring. The aim of the present review is to summarize the clinical short-and long-term monitoring possibilities of axonal injury in TBI. Increased knowledge of the underlying pathophysiology achieved by advanced clinical monitoring raises hope for the development of novel treatment strategies for axonal injury in TBI.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2017
Keywords
traumatic brain injury, diffuse axonal injury, monitoring, neurocritical care, neuroimaging, biomarkers, microdialysis
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-345831 (URN)10.3389/fneur.2017.00599 (DOI)000415706700001 ()29209266 (PubMedID)
Available from: 2018-03-12 Created: 2018-03-12 Last updated: 2018-07-13Bibliographically approved
Flygt, J., Clausen, F. & Marklund, N. (2017). Diffuse traumatic brain injury in the mouse induces a transient proliferation of oligodendrocyte progenitor cells in injured white matter tracts. Restorative Neurology and Neuroscience, 35(2), 251-263
Open this publication in new window or tab >>Diffuse traumatic brain injury in the mouse induces a transient proliferation of oligodendrocyte progenitor cells in injured white matter tracts
2017 (English)In: Restorative Neurology and Neuroscience, ISSN 0922-6028, E-ISSN 1878-3627, Vol. 35, no 2, p. 251-263Article in journal (Refereed) Published
Abstract [en]

Background: Injury to the white matter may lead to impaired neuronal signaling and is commonly observed following traumatic brain injury (TBI). Although endogenous repair of TBI-induced white matter pathology is limited, oligodendrocyte progenitor cells (OPCs) may be stimulated to proliferate and regenerate functionally myelinating oligodendrocytes. Even though OPCs are present throughout the adult brain, little is known about their proliferative activity following axonal injury caused by TBI.

Objective: We hypothesized that central fluid percussion injury (cFPI) in mice, a TBI model causing wide-spread axonal injury, results in OPC proliferation.

Methods: Proliferation of OPCs was evaluated in 27 cFPI mice using 5-ethynyl-2-deoxyuridine (EdU) labeling and a cell proliferation assay at 2 (n=9), 7 (n = 8) and 21 (n = 10) days post injury (dpi). Sham-injured mice (n = 14) were used as controls. OPC proliferation was quantified by immunohistochemistry using the OPC markers NG2 and Olig2 in several white matter loci including the corpus callosum, external capsule, fimbriae, the internal capsule and cerebral peduncle.

Results: The number of EdU/DAPI/Olig2-positive cells were increased in the cFPI group compared to sham-injured animals at 7 days post-injury (dpi; p≤0.05) in the majority of white matter regions. The OPC proliferation had subsided by 21 dpi. The number of EdU/DAPI/NG2 cells was also increase at 7 dpi in the external capsule and fimbriae.

Conclusion: These results suggest that traumatic axonal injury in the mouse induces a transient proliferative response of residing OPCs. These proliferating OPCs may replace dead oligodendrocytes and contribute to remyelination, which needs evaluation in future studies.

Keywords
traumatic brain injury, proliferation, axonal injury, EdU, oligodendrocyte progenitor cell, white matter, myelin, central fluid percussion injury
National Category
Neurology
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-316586 (URN)10.3233/RNN-160675 (DOI)000398131700009 ()27768001 (PubMedID)
Funder
The Swedish Brain FoundationSwedish Research Council
Available from: 2017-03-03 Created: 2017-03-03 Last updated: 2018-09-04Bibliographically approved
Abu Hamdeh, S., Marklund, N., Lannsjö, M., Howells, T., Raininko, R., Wikström, J. & Enblad, P. (2017). Extended anatomical grading in diffuse axonal injury using MRI: Hemorrhagic lesions in the substantia nigra and mesencephalic tegmentum indicate poor long-term outcome. Journal of Neurotrauma, 5(34), 341-352
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
Wicher, G. K., Wallenquist, U., Lei, Y., Enoksson, M., Li, X., Fuchs, B., . . . Forsberg Nilsson, K. (2017). Interleukin-33 Promotes Recruitment of Microglia/Macrophages in Response to Traumatic Brain Injury. Journal of Neurotrauma, 34(22), 3173-3182
Open this publication in new window or tab >>Interleukin-33 Promotes Recruitment of Microglia/Macrophages in Response to Traumatic Brain Injury
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2017 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 34, no 22, p. 3173-3182Article in journal (Refereed) Published
Abstract [en]

Traumatic brain injury (TBI) is a devastating condition, often leading to life-long consequences for patients. Even though modern neurointensive care has improved functional and cognitive outcomes, efficient pharmacological therapies are still lacking. Targeting peripherally derived, or resident inflammatory, cells that are rapid responders to brain injury is promising, but complex, given that the contribution of inflammation to exacerbation versus improved recovery varies with time post-injury. The injury-induced inflammatory response is triggered by release of alarmins, and in the present study we asked whether interleukin-33 (IL-33), an injury-associated nuclear alarmin, is involved in TBI. Here, we used samples from human TBI microdialysate, tissue sections from human TBI, and mouse models of central nervous system injury and found that expression of IL-33 in the brain was elevated from nondetectable levels, reaching a maximum after 72 h in both human samples and mouse models. Astrocytes and oligodendrocytes were the main producers of IL-33. Post-TBI, brains of mice deficient in the IL-33 receptor, ST2, contained fewer microglia/macrophages in the injured region than wild-type mice and had an altered cytokine/chemokine profile in response to injury. These observations indicate that IL-33 plays a role in neuroinflammation with microglia/macrophages being cellular targets for this interleukin post-TBI.

Keywords
alarmin, glia, microglia, traumatic brain injury, neuroinflammation
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-341988 (URN)10.1089/neu.2016.4900 (DOI)000414560000013 ()28490277 (PubMedID)
Funder
Swedish Research Council
Available from: 2018-02-16 Created: 2018-02-16 Last updated: 2018-07-13Bibliographically approved
Kononenko, O., Galatenko, V., Andersson, M., Bazov, I., Watanabe, H., Zhou, X., . . . Bakalkin, G. (2017). Intra- and interregional coregulation of opioid genes: broken symmetry in spinal circuits. The FASEB Journal, 31(5), 1953-1963
Open this publication in new window or tab >>Intra- and interregional coregulation of opioid genes: broken symmetry in spinal circuits
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2017 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 31, no 5, p. 1953-1963Article in journal (Refereed) Published
Abstract [en]

Regulation of the formation and rewiring of neural circuits by neuropeptides may require coordinated production of these signaling molecules and their receptors that may be established at the transcriptional level. Here, we address this hypothesis by comparing absolute expression levels of opioid peptides with their receptors, the largest neuropeptide family, and by characterizing coexpression (transcriptionally coordinated) patterns of these genes. We demonstrated that expression patterns of opioid genes highly correlate within and across functionally and anatomically different areas. Opioid peptide genes, compared with their receptor genes, are transcribed at much greater absolute levels, which suggests formation of a neuropeptide cloud that covers the receptor-expressed circuits. Surprisingly, we found that both expression levels and the proportion of opioid receptors are strongly lateralized in the spinal cord, interregional coexpression patterns are side specific, and intraregional coexpression profiles are affected differently by left-and right-side unilateral body injury. We propose that opioid genes are regulated as interconnected components of the same molecular system distributed between distinct anatomic regions. The striking feature of this system is its asymmetric coexpression patterns, which suggest side-specific regulation of selective neural circuits by opioid neurohormones.

Keywords
neuropeptides, spinal cord, lateralization
National Category
Natural Sciences Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-314798 (URN)10.1096/fj.201601039R (DOI)000399195500017 ()28122917 (PubMedID)
Funder
Swedish Research CouncilForte, Swedish Research Council for Health, Working Life and WelfareSwedish Research Council FormasSwedish InstituteThe Swedish Brain Foundation
Note

De 3 första författarna delar förstaförfattarskapet.

Available from: 2017-02-06 Created: 2017-02-06 Last updated: 2017-05-23Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-9797-5626

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