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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, 1400-1407 p.Article 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, 21-23 p.Article 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
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, 341-352 p.Article 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).

Keyword
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: 2017-11-29Bibliographically 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, 1953-1963 p.Article 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.

Keyword
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
Clausen, F., Hansson, H.-A., Raud, J. & Marklund, N. (2017). Intranasal Administration of the Antisecretory Peptide AF-16 Reduces Edema and Improves Cognitive Function Following Diffuse Traumatic Brain Injury in the Rat. Frontiers in Neurology, 8, Article ID 39.
Open this publication in new window or tab >>Intranasal Administration of the Antisecretory Peptide AF-16 Reduces Edema and Improves Cognitive Function Following Diffuse Traumatic Brain Injury in the Rat
2017 (English)In: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 8, 39Article in journal (Refereed) Published
Abstract [en]

A synthetic peptide with antisecretory activity, antisecretory factor (AF)-16, improves injury-related deficits in water and ion transport and decreases intracranial pressure after experimental cold lesion injury and encephalitis although its role in traumatic brain injury (TBI) is unknown. AF-16 or an inactive reference peptide was administrated intranasally 30 min following midline fluid percussion injury (mFPI; n = 52), a model of diffuse mild-moderate TBI in rats. Sham-injured (n = 14) or naive (n = 24) animals were used as controls. The rats survived for either 48 h or 15 days post-injury. At 48 h, the animals were tested in the Morris water maze (MWM) for memory function and their brains analyzed for cerebral edema. Here, mFPI-induced brain edema compared to sham or naive controls that was significantly reduced by AF-16 treatment (p < 0.05) although MWM performance was not altered. In the 15-day survival groups, the MWM learning and memory abilities as well as histological changes were analyzed. AF-16-treated brain-injured animals shortened both MWM latency and swim path in the learning trials (p < 0.05) and improved probe trial performance compared to brain-injured controls treated with the inactive reference peptide. A modest decrease by AF-16 on TBI-induced changes in hippocampal glial acidic fibrillary protein (GFAP) staining (p = 0.11) was observed. AF-16 treatment did not alter any other immunohistochemical analyses (degenerating neurons, beta-amyloid precursor protein (beta-APP), and Olig2). In conclusion, intranasal AF-16-attenuated brain edema and enhanced visuospatial learning and memory following diffuse TBI in the rat. Intranasal administration early post-injury of a promising neuroprotective substance offers a novel treatment approach for TBI.

Keyword
cerebral edema, traumatic brain injury, intranasal, neuroprotection, AF-16, cognition
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-317585 (URN)10.3389/fneur.2017.00039 (DOI)000394282300001 ()28261150 (PubMedID)
Funder
The Swedish Brain FoundationSwedish Research Council
Available from: 2017-03-24 Created: 2017-03-24 Last updated: 2017-11-29Bibliographically approved
Bartley, A., Jakola, A. S., Bartek, J. J., Sundblom, J., Förander, P., Marklund, N. & Tisell, M. (2017). The Swedish study of Irrigation-fluid temperature in the evacuation of Chronic subdural hematoma (SIC!): study protocol for a multicenter randomized controlled trial. Trials, 18, Article ID 471.
Open this publication in new window or tab >>The Swedish study of Irrigation-fluid temperature in the evacuation of Chronic subdural hematoma (SIC!): study protocol for a multicenter randomized controlled trial
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2017 (English)In: Trials, ISSN 1745-6215, E-ISSN 1745-6215, Vol. 18, 471Article in journal (Refereed) Published
Abstract [en]

Background: Chronic subdural hematoma (cSDH) is one of the most common conditions encountered in neurosurgical practice. Recurrence, observed in 5-30% of patients, is a major clinical problem. The temperature of the irrigation fluid used during evacuation of the hematoma might theoretically influence recurrence rates since irrigation fluid at body temperature (37 degrees C) may beneficially influence coagulation and cSDH solubility when compared to irrigation fluid at room temperature. Should no difference in recurrence rates be observed when comparing irrigation-fluid temperatures, there is no need for warmed fluids during surgery. Our main aim is to investigate the effect of irrigation-fluid temperature on recurrence rates and clinical outcomes after cSDH evacuation using a multicenter randomized controlled trial design.

Methods: The study will be conducted in three neurosurgical departments with population-based catchment areas using a similar surgical strategy. In total, 600 patients fulfilling the inclusion criteria will randomly be assigned to either intraoperative irrigation with fluid at body temperature or room temperature. The power calculation is based on a retrospective study performed at our department showing a recurrence rate of 5% versus 12% when comparing irrigation fluid at body temperature versus fluid at room temperature (unpublished data). The primary endpoint is recurrence rate of cSDH analyzed at 6 months post treatment. Secondary endpoints are mortality rate, complications and health-related quality of life.

Discussion: Irrigation-fluid temperature might influence recurrence rates in the evacuation of chronic subdural hematomas. We present a study protocol for a multicenter randomized controlled trial investigating our hypothesis that irrigation fluid at body temperature is superior to room temperature in reducing recurrence rates following evacuation of cSDH.

Place, publisher, year, edition, pages
BIOMED CENTRAL LTD, 2017
Keyword
Chronic subdural hematoma, Surgical evacuation, Recurrence, Irrigation fluid, Temperature
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-338514 (URN)10.1186/s13063-017-2194-y (DOI)000412904300001 ()29021000 (PubMedID)
Funder
Region Västra Götaland
Available from: 2018-01-15 Created: 2018-01-15 Last updated: 2018-01-15Bibliographically approved
Ekmark-Lewén, S., Flygt, J., Fridgeirsdottir, G. A., Kiwanuka, O., Hanell, A., Meyerson, B. J., . . . Marklund, N. (2016). Diffuse traumatic axonal injury in mice induces complex behavioural alterations that are normalized by neutralization of interleukin-1β. European Journal of Neuroscience, 43(8), 1016-1033.
Open this publication in new window or tab >>Diffuse traumatic axonal injury in mice induces complex behavioural alterations that are normalized by neutralization of interleukin-1β
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2016 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 43, no 8, 1016-1033 p.Article in journal (Refereed) Published
Abstract [en]

Widespread traumatic axonal injury (TAI) results in brain network dysfunction, which commonly leads to persisting cognitive and behavioural impairments following traumatic brain injury (TBI). TBI induces a complex neuroinflammatory response, frequently located at sites of axonal pathology. The role of the pro-inflammatory cytokine interleukin (IL)-1 has not been established in TAI. An IL-1-neutralizing or a control antibody was administered intraperitoneally at 30min following central fluid percussion injury (cFPI), a mouse model of widespread TAI. Mice subjected to moderate cFPI (n=41) were compared with sham-injured controls (n=20) and untreated, naive mice (n=9). The anti-IL-1 antibody reached the target brain regions in adequate therapeutic concentrations (up to similar to 30g/brain tissue) at 24h post-injury in both cFPI (n=5) and sham-injured (n=3) mice, with lower concentrations at 72h post-injury (up to similar to 18g/g brain tissue in three cFPI mice). Functional outcome was analysed with the multivariate concentric square field (MCSF) test at 2 and 9days post-injury, and the Morris water maze (MWM) at 14-21days post-injury. Following TAI, the IL-1-neutralizing antibody resulted in an improved behavioural outcome, including normalized behavioural profiles in the MCSF test. The performance in the MWM probe (memory) trial was improved, although not in the learning trials. The IL-1-neutralizing treatment did not influence cerebral ventricle size or the number of microglia/macrophages. These findings support the hypothesis that IL-1 is an important contributor to the processes causing complex cognitive and behavioural disturbances following TAI.

Keyword
axonal injury, behavioural outcome, central fluid percussion injury, interleukin-1, traumatic brain injury
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-297130 (URN)10.1111/ejn.13190 (DOI)000374645700004 ()27091435 (PubMedID)
Funder
Swedish Research Council
Available from: 2016-06-22 Created: 2016-06-21 Last updated: 2017-11-28Bibliographically approved
Flygt, J., Clausen, F. & Marklund, N. (2016). Diffuse traumatic brain injury in the mouse induces a transient proliferation of oligodendrocyte progenitor cells in injured white matter tracts. Restorative Neurology and Neuroscience.
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
2016 (English)In: Restorative Neurology and Neuroscience, ISSN 0922-6028, E-ISSN 1878-3627Article 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.

Keyword
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)
Available from: 2017-03-03 Created: 2017-03-03 Last updated: 2017-11-29Bibliographically approved
Flygt, J., Clausen, F. & Marklund, N. (2016). Diffuse traumatic brain injury in the mouse induces a transient proliferation of oligodendrocyte progenitor cells in injured white matter tracts. In: : . Paper presented at 12th European Meeting on Glial Cell Function in Health and Disease, Bilbao, SPAIN, JUL 15-18, 2015 (pp. E182-E183). , 63.
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
2016 (English)Conference paper, Poster (with or without abstract) (Refereed)
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-258909 (URN)000356386700316 ()
Conference
12th European Meeting on Glial Cell Function in Health and Disease, Bilbao, SPAIN, JUL 15-18, 2015
Available from: 2015-07-22 Created: 2015-07-21 Last updated: 2018-01-11Bibliographically approved
Flygt, J., Gumucio, A., Ingelsson, M., Skoglund, K., Holm, J., Alafuzoff, I. & Marklund, N. (2016). Human Traumatic Brain Injury Results in Oligodendrocyte Death and Increases the Number of Oligodendrocyte Progenitor Cells. Journal of Neuropathology and Experimental Neurology, 75(6), 503-515.
Open this publication in new window or tab >>Human Traumatic Brain Injury Results in Oligodendrocyte Death and Increases the Number of Oligodendrocyte Progenitor Cells
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2016 (English)In: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 75, no 6, 503-515 p.Article in journal (Refereed) Published
Abstract [en]

Oligodendrocyte (OL) death may contribute to white matter pathology, a common cause of network dysfunction and persistent cognitive problems in patients with traumatic brain injury (TBI). Oligodendrocyte progenitor cells (OPCs) persist throughout the adult CNS and may replace dead OLs. OL death and OPCs were analyzed by immunohistochemistry of human brain tissue samples, surgically removed due to life-threatening contusions and/or focal brain swelling at 60.6 +/- 75 hours (range 4-192 hours) postinjury in 10 severe TBI patients (age 51.7 +/- 18.5 years). Control brain tissue was obtained postmortem from 5 age-matched patients without CNS disorders. TUNEL and CC1 co-labeling was used to analyze apoptotic OLs, which were increased in injured brain tissue (p < 0.05), without correlation with time from injury until surgery. The OPC markers Olig2, A2B5, NG2, and PDGFR-alpha were used. In contrast to the number of single-labeled Olig2, A2B5, NG2, and PDGFR-alpha-positive cells, numbers of Olig2 and A2B5 co-labeled cells were increased in TBI samples (p < 0.05); this was inversely correlated with time from injury to surgery (r = -0.8, p < 0.05). These results indicate that severe focal human TBI results in OL death and increases in OPCs postinjury, which may influence white matter function following TBI.

Keyword
Apoptosis, Human, Immunohistochemistry, Oligodendrocyte, Oligodendrocyte progenitor cells, Traumatic brain injury
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-299587 (URN)10.1093/jnen/nlw025 (DOI)000377665000003 ()27105664 (PubMedID)
Available from: 2016-07-22 Created: 2016-07-22 Last updated: 2017-11-28Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-9797-5626

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