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  • 1.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lannsjö, Marianne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Rehabilitation Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Howells, Tim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Extended anatomical grading in diffuse axonal injury using MRI: Hemorrhagic lesions in the substantia nigra and mesencephalic tegmentum indicate poor long-term outcome2017In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 5, no 34, p. 341-352Article in journal (Refereed)
    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).

  • 2.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Lewén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Howells, Tim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Intracranial pressure elevations in diffuse axonal injury: association with nonhemorrhagic MR lesions in central mesencephalic structures2019In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 131, no 2, p. 604-611Article in journal (Refereed)
    Abstract [en]

    Objective: Increased intracranial pressure (ICP) in patients with severe traumatic brain injury (TBI) 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 patients with DAI.

    Methods: Fifty-two patients with severe TBI (median age 24 years, range 9–61 years), who had undergone ICP monitoring and had DAI on MRI, as determined using T2*-weighted gradient echo, susceptibility-weighted imaging, and diffusion-weighted imaging (DWI) sequences, were enrolled. The proportion of good monitoring time (GMT) with ICP > 20 mm Hg during the first 120 hours postinjury was calculated and associations with clinical and MRI-related factors were evaluated using linear regression.

    Results: All patients had episodes of ICP > 20 mm Hg. The mean proportion of GMT with ICP > 20 mm Hg was 5%, and 27% of the patients (14/52) spent more than 5% of GMT with ICP > 20 mm Hg. The Glasgow Coma Scale motor score at admission (p = 0.04) and lesions on DWI sequences in the substantia nigra and mesencephalic tegmentum (SN-T, p = 0.001) were associated with the proportion of GMT with ICP > 20 mm Hg. In multivariable linear regression, lesions on DWI sequences in SN-T (8% of GMT with ICP > 20 mm Hg, 95% CI 3%–13%, p = 0.004) and young age (−0.2% of GMT with ICP > 20 mm Hg, 95% CI −0.07% to −0.3%, p = 0.002) were associated with increased ICP.

    Conclusions: Increased ICP occurs in approximately one-third of patients with severe TBI who have DAI. Age and lesions on DWI sequences in the central mesencephalon (i.e., SN-T) are associated with elevated ICP. These findings suggest that MR lesion localization may aid prediction of increased ICP in patients with DAI.

    Abbreviations: ADC = apparent diffusion coefficient; CPP = cerebral perfusion pressure; DAI = diffuse axonal injury; DWI = diffusion-weighted imaging; EVD = external ventricular drain; GCS = Glasgow Coma Scale; GMT = good monitoring time; GOSE = Glasgow Outcome Scale–Extended; ICC = intraclass correlation coefficient; ICP = intracranial pressure; MAP = mean arterial blood pressure; NICU = neurointensive care unit; SN-T = substantia nigra and mesencephalic tegmentum; SWI = susceptibility-weighted imaging; TBI = traumatic brain injury; T2*GRE = T2*-weighted gradient echo.

  • 3.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lewén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Howells, Timothy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Intracranial pressure elevations in diffuse axonal injury are associated with non-hemorrhagic MR lesions in central mesencephalic structuresIn: Article in journal (Other academic)
    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.

  • 4.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Rollman Waara, Erik
    BioArctic Neurosci AB, Stockholm, Sweden.
    Möller, Christer
    BioArctic Neurosci AB, Stockholm, Sweden.
    Söderberg, Linda
    BioArctic Neurosci AB, Stockholm, Sweden.
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. BioArctic Neuroscience AB, Stockholm, Sweden.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. BioArctic Neuroscience AB, Stockholm, Sweden.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Rapid amyloid-β oligomer and protofibril accumulation in traumatic brain injury2018In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 28, no 4, p. 451-462Article in journal (Refereed)
    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.

  • 5.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Musunuri, Sravani
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Proteomic differences between focal and diffuse traumatic brain injury in human brain tissue2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 6807Article in journal (Refereed)
    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.

  • 6.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Musunuri, Sravani
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Proteomic Differences Between Focal And Diffuse Traumatic Brain Injury In Human Brain Tissue2018In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 16, p. A238-A239Article in journal (Other academic)
  • 7.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Virhammar, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Cesarini, Kristina G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Brain tissue Aβ42 levels are linked to shunt response in idiopathic normal pressure hydrocephalus2018In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, p. 1-9Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE The authors conducted a study to test if the cortical brain tissue levels of soluble amyloid beta (Aβ) reflect the propensity of cortical Aβ aggregate formation and may be an additional factor predicting surgical outcome following idiopathic normal pressure hydrocephalus (iNPH) treatment. METHODS Highly selective ELISAs (enzyme-linked immunosorbent assays) were used to quantify soluble Aβ40, Aβ42, and neurotoxic Aβ oligomers/protofibrils, associated with Aβ aggregation, in cortical biopsy samples obtained in patients with iNPH (n = 20), sampled during ventriculoperitoneal (VP) shunt surgery. Patients underwent pre- and postoperative (3-month) clinical assessment with a modified iNPH scale. The preoperative CSF biomarkers and the levels of soluble and insoluble Aβ species in cortical biopsy samples were analyzed for their association with a favorable outcome following the VP shunt procedure, defined as a ≥ 5-point increase in the iNPH scale. RESULTS The brain tissue levels of Aβ42 were negatively correlated with CSF Aβ42 (Spearman's r = -0.53, p < 0.05). The Aβ40, Aβ42, and Aβ oligomer/protofibril levels in cortical biopsy samples were higher in patients with insoluble cortical Aβ aggregates (p < 0.05). The preoperative CSF Aβ42 levels were similar in patients responding (n = 11) and not responding (n = 9) to VP shunt treatment at 3 months postsurgery. In contrast, the presence of cortical Aβ aggregates and high brain tissue Aβ42 levels were associated with a poor outcome following VP shunt treatment (p < 0.05). CONCLUSIONS Brain tissue measurements of soluble Aβ species are feasible. Since high Aβ42 levels in cortical biopsy samples obtained in patients with iNPH indicated a poor surgical outcome, tissue levels of Aβ species may be associated with the clinical response to shunt treatment.

  • 8.
    Axelson, Hans
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Winkler, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Flygt, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Djupsjö, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hånell, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Plasticity of the contralateral motor cortex following focal traumatic brain injury in the rat2013In: Restorative Neurology and Neuroscience, ISSN 0922-6028, E-ISSN 1878-3627, Vol. 31, no 1, p. 73-85Article in journal (Refereed)
    Abstract [en]

    Purpose: Recovery is limited following traumatic brain injury (TBI) since injured axons regenerate poorly and replacement of lost cells is minimal. Behavioral improvements could instead be due to plasticity of uninjured brain regions. We hypothesized that plasticity of the uninjured hemisphere occurs contralateral to a focal TBI in the adult rat. Thus, we performed cortical mapping of the cortex contralateral to the TBI using intracortical microstimulation (ICMS). Methods: A focal TBI was induced using the weight-drop technique (n = 5) and sham-injured animals were used as controls (n = 4). At five weeks post-injury, ICMS was used to map the motor area contralateral to the injury. Motor responses were detected by visual inspection and electromyography (EMG). Results: In sham- and brain-injured animals, numerous fore- and hindlimb motor responses contralateral to the stimulation (ipsilateral to the injury) were obtained. Compared to sham-injured controls, there was a markedly increased (p < 0.05) number of fore- and hindlimb responses ipsilateral to the stimulation after TBI. Conclusion: Following focal TBI in the rat, our data suggest reorganization of cortical and/or subcortical regions in the uninjured hemisphere contralateral to a focal TBI leading to an altered responsiveness to ICMS. Although we cannot exclude that these changes are maladaptive, it is plausible that this plasticity process positively influences motor recovery after TBI.

  • 9.
    Bakalkin, Georgy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kononenko, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Stålhandske, Lada
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    TBI induced spinal cord plasticity: The endogenous opioid system mediates trauma effects on motor reflexes2016In: Brain Injury, ISSN 0269-9052, E-ISSN 1362-301X, Vol. 30, no 5-6, p. 712-712Article in journal (Other academic)
  • 10.
    Bartley, Andreas
    et al.
    Sahlgrens Univ Hosp, Dept Neurosurg, Bla Straket 5, S-41345 Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Dept Clin Neurosci, Inst Neurosci & Physiol, Box 430, S-40530 Gothenburg, Sweden..
    Jakola, Asgeir S.
    Sahlgrens Univ Hosp, Dept Neurosurg, Bla Straket 5, S-41345 Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Dept Clin Neurosci, Inst Neurosci & Physiol, Box 430, S-40530 Gothenburg, Sweden.;St Olavs Hosp, Dept Neurosurg, N-7006 Trondheim, Norway..
    Bartek, Jiri, Jr.
    Karolinska Univ Hosp, Dept Neurosurg, Solna, Sweden.;Karolinska Inst, Sect Neurosurg, Dept Clin Neurosci, Stockholm, Sweden.;Rigshosp, Dept Neurosurg, Copenhagen Univ Hosp, Copenhagen, Denmark..
    Sundblom, Jimmy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Förander, Petter
    Karolinska Univ Hosp, Dept Neurosurg, Solna, Sweden.;Karolinska Inst, Sect Neurosurg, Dept Clin Neurosci, Stockholm, Sweden..
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Tisell, Magnus
    Sahlgrens Univ Hosp, Dept Neurosurg, Bla Straket 5, S-41345 Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Dept Clin Neurosci, Inst Neurosci & Physiol, Box 430, S-40530 Gothenburg, Sweden..
    The Swedish study of Irrigation-fluid temperature in the evacuation of Chronic subdural hematoma (SIC!): study protocol for a multicenter randomized controlled trial2017In: Trials, ISSN 1745-6215, E-ISSN 1745-6215, Vol. 18, article id 471Article in journal (Refereed)
    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.

  • 11.
    Baunsgaard, Carsten Bach
    et al.
    Univ Copenhagen, Rigshosp, Clin Spinal Cord Injuries, Havnevej 25, DK-3100 Hornbaek, Denmark.
    Nissen, Ulla Vig
    Univ Copenhagen, Rigshosp, Clin Spinal Cord Injuries, Havnevej 25, DK-3100 Hornbaek, Denmark.
    Brust, Anne Katrin
    SPC, Nottwil, Switzerland.
    Frotzler, Angela
    SPC, Nottwil, Switzerland.
    Ribeill, Cornelia
    Ulm Univ, SCI Ctr Orthopaed Dept, Ulm, Germany.
    Kalke, Yorck-Bernhard
    Ulm Univ, SCI Ctr Orthopaed Dept, Ulm, Germany.
    Leon, Natacha
    FLM, Madrid, Spain.
    Gomez, Belen
    FLM, Madrid, Spain.
    Samuelsson, Kersti
    Linkoping Univ, Dept Rehabil Med, Linkoping, Sweden;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.
    Antepohl, Wolfram
    Linkoping Univ, Dept Rehabil Med, Linkoping, Sweden;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.
    Holmstrom, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery. Uppsala Univ Hosp, Spinal Cord Rehabil Unit, Uppsala, Sweden.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery. Uppsala Univ Hosp, Spinal Cord Rehabil Unit, Uppsala, Sweden.
    Glott, Thomas
    Sunnaas Rehabil Hosp, Nesoddtangen, Norway.
    Opheim, Arve
    Sunnaas Rehabil Hosp, Nesoddtangen, Norway;Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Rehabil Med, Gothenburg, Sweden;Reg Vastra Gotaland, Habilitat & Hlth, Gothenburg, Sweden.
    Benito Penalva, Jesus
    Neurorehabil Hosp, Inst Guttmann, Barcelona, Spain.
    Murillo, Narda
    Neurorehabil Hosp, Inst Guttmann, Barcelona, Spain.
    Nachtegaal, Janneke
    Heliomare Rehabil Ctr, Wijk Aan Zee, Netherlands.
    Faber, Willemijn
    Heliomare Rehabil Ctr, Wijk Aan Zee, Netherlands.
    Biering-Sorensen, Fin
    Univ Copenhagen, Rigshosp, Clin Spinal Cord Injuries, Havnevej 25, DK-3100 Hornbaek, Denmark.
    Exoskeleton Gait Training After Spinal Cord Injury: An Exploratory Study on Secondary Health Conditions2018In: Journal of Rehabilitation Medicine, ISSN 1650-1977, E-ISSN 1651-2081, Vol. 50, no 9, p. 806-813Article in journal (Refereed)
    Abstract [en]

    Objective: To explore changes in pain, spasticity, range of motion, activities of daily living, bowel and lower urinary tract function and quality of life of individuals with spinal cord injury following robotic exoskeleton gait training.

    Design: Prospective, observational, open-label multicentre study. Methods: Three training sessions per week for 8 weeks using an Ekso GT robotic exoskeleton (Ekso Bionics). Included were individuals with recent (<1 year) or chronic (>1 year) injury, paraplegia and tetraplegia, complete and incomplete injury, men and women.

    Results: Fifty-two participants completed the training protocol. Pain was reported by 52% of participants during the week prior to training and 17% during training, but no change occurred longitudinally. Spasticity decreased after a training session compared with before the training session (p< 0.001), but not longitudinally. Chronically injured participants increased Spinal Cord Independence Measure (SCIM III) from 73 to 74 (p= 0.008) and improved life satisfaction (p= 0.036) over 8 weeks of training. Recently injured participants increased SCIM III from 62 to 70 (p<0.001), but no significant change occurred in life satisfaction. Range of motion, bowel and lower urinary function did not change over time.

    Conclusion: Training seemed not to provoke new pain. Spasticity decreased after a single training session. SCIM III and quality of life increased longitudinally for subsets of participants.

  • 12.
    Baunsgaard, Carsten Bach
    et al.
    Univ Copenhagen, Rigshosp, Clin Spinal Cord Injuries, Copenhagen, Denmark..
    Nissen, Ulla Vig
    Univ Copenhagen, Rigshosp, Clin Spinal Cord Injuries, Copenhagen, Denmark..
    Brust, Anne Katrin
    SPC, Nottwil, Switzerland..
    Frotzler, Angela
    SPC, Nottwil, Switzerland..
    Ribeill, Cornelia
    Ulm Univ, SCI Ctr, Orthopaed Dept, Ulm, Germany..
    Kalke, Yorck-Bernhard
    Ulm Univ, SCI Ctr, Orthopaed Dept, Ulm, Germany..
    Leon, Natacha
    FLM, Madrid, Spain..
    Gomez, Belen
    FLM, Madrid, Spain..
    Samuelsson, Kersti
    Linkoping Univ, Dept Rehabil Med, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Antepohl, Wolfram
    Linkoping Univ, Dept Rehabil Med, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Holmström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Glott, Thomas
    Sunnaas Rehabil Hosp, Nesoddtangen, Norway..
    Opheim, Arve
    Sunnaas Rehabil Hosp, Nesoddtangen, Norway.;Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Rehabil Med, Gothenburg, Sweden..
    Benito, Jesus
    Neurorehabil Hosp, Inst Guttmann, Barcelona, Spain..
    Murillo, Narda
    Neurorehabil Hosp, Inst Guttmann, Barcelona, Spain..
    Nachtegaal, Janneke
    Heliomare Rehabil Ctr, Wijk Aan Zee, Netherlands..
    Faber, Willemijn
    Heliomare Rehabil Ctr, Wijk Aan Zee, Netherlands..
    Biering-Sorensen, Fin
    Univ Copenhagen, Rigshosp, Clin Spinal Cord Injuries, Copenhagen, Denmark..
    Gait training after spinal cord injury: safety, feasibility and gait function following 8 weeks of training with the exoskeletons from Ekso Bionics2018In: Spinal Cord, ISSN 1362-4393, E-ISSN 1476-5624, Vol. 56, no 2, p. 106-116Article in journal (Refereed)
    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.

  • 13.
    Clausen, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Dahlin, Andreas
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Chu, Jiangtao
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Kaller, Bodil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    During, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Novel Microdialysis Method to Study The Acute Cytokine Response to Diffuse Traumatic Brain Injury in the Rat2014In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 31, no 5, p. A19-A19Article in journal (Refereed)
  • 14.
    Clausen, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hansson, Hans-Arne
    Univ Gothenburg, Inst Biomed, Gothenburg, Sweden..
    Raud, Johan
    Lantmannen AS Faktor AB, Stockholm, Sweden..
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Intranasal Administration of the Antisecretory Peptide AF-16 Reduces Edema and Improves Cognitive Function Following Diffuse Traumatic Brain Injury in the Rat2017In: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 8, article id 39Article in journal (Refereed)
    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.

  • 15.
    Clausen, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hånell, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Björk, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Mir, Anis K.
    Gram, Hermann
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Neutralization of interleukin-1β modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice2009In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 30, no 3, p. 385-396Article in journal (Refereed)
    Abstract [en]

    Interleukin-1beta (IL-1beta) may play a central role in the inflammatory response following traumatic brain injury (TBI). We subjected 91 mice to controlled cortical impact (CCI) brain injury or sham injury. Beginning 5 min post-injury, the IL-1beta neutralizing antibody IgG2a/k (1.5 microg/mL) or control antibody was infused at a rate of 0.25 microL/h into the contralateral ventricle for up to 14 days using osmotic minipumps. Neutrophil and T-cell infiltration and microglial activation was evaluated at days 1-7 post-injury. Cognition was assessed using Morris water maze, and motor function using rotarod and cylinder tests. Lesion volume and hemispheric tissue loss were evaluated at 18 days post-injury. Using this treatment strategy, cortical and hippocampal tissue levels of IgG2a/k reached 50 ng/mL, sufficient to effectively inhibit IL-1betain vitro. IL-1beta neutralization attenuated the CCI-induced cortical and hippocampal microglial activation (P < 0.05 at post-injury days 3 and 7), and cortical infiltration of neutrophils (P < 0.05 at post-injury day 7). There was only a minimal cortical infiltration of activated T-cells, attenuated by IL-1beta neutralization (P < 0.05 at post-injury day 7). CCI induced a significant deficit in neurological motor and cognitive function, and caused a loss of hemispheric tissue (P < 0.05). In brain-injured animals, IL-1beta neutralizing treatment resulted in reduced lesion volume, hemispheric tissue loss and attenuated cognitive deficits (P < 0.05) without influencing neurological motor function. Our results indicate that IL-1beta is a central component in the post-injury inflammatory response that, in view of the observed positive neuroprotective and cognitive effects, may be a suitable pharmacological target for the treatment of TBI.

  • 16.
    Clausen, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Acute Inflammatory Biomarker Responses to Diffuse Traumatic Brain Injury in the Rat Monitored by a Novel Microdialysis Technique2019In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 36, no 2, p. 201-211Article in journal (Refereed)
    Abstract [en]

    Neuroinflammation is a major contributor to the progressive brain injury process induced by traumatic brain injury (TBI), and may play an important role in the pathophysiology of axonal injury. The immediate neuroinflammatory cascade cannot be characterized in the human setting. Therefore, we used the midline fluid percussion injury model of diffuse TBI in rats and a novel microdialysis (MD) method providing stable diffusion-driven biomarker sampling. Immediately post-injury, bilateral amphiphilic tri-block polymer coated MD probes (100 kDa cut off membrane) were inserted and perfused with Dextran 500 kDa-supplemented artificial cerebrospinal fluid (CSF) to optimize protein capture. Six hourly samples were analyzed for 27 inflammatory biomarkers (9 chemokines, 13 cytokines, and 5 growth factors) using a commercial multiplex biomarker kit. TBI (n = 6) resulted in a significant increase compared with sham-injured controls (n = 6) for five chemokines (eotaxin/CCL11, fractalkine/CX3CL1, LIX/CXCL5, monocyte chemoattractant protein [MCP]1α/CCL2, macrophage inflammatory protein [MIP]1α /CCL3), 10 cytokines (interleukin [IL]-1α, IL-1β, IL-4, IL-6, IL-10, IL-13, IL-17α, IL-18, interferon [IFN]-γ, tumor necrosis factor [TNF]-α), and four growth factors (epidermal growth factor [EGF], granulocyte-macrophage colony-stimulating factor [GM-CSF], leptin, vascular endothelial growth factor [VEGF]). Therefore, diffuse TBI was associated with an increased level of 18 of the 27 inflammatory biomarkers at one through six time points, during the observation period whereas the remaining 9 biomarkers were unaltered. The study shows that diffuse TBI induces an acute increase in a number of inflammatory biomarkers. The novel MD technique provides stable MD sampling suitable for further studies on the early neuroinflammatory cascade in TBI.

  • 17.
    Clausen, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lewén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Interstitial F2-Isoprostane 8-Iso-PGF As a Biomarker of Oxidative Stress after Severe Human Traumatic Brain Injury2012In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 29, no 5, p. 766-775Article in journal (Refereed)
    Abstract [en]

    Oxidative stress is a major contributor to the secondary injury process after experimental traumatic brain injury (TBI). The importance of oxidative stress in the pathobiology of human TBI is largely unknown. The F(2)-isoprostane 8-iso-prostaglandin F(2α) (8-iso-PGF(2α)), synthesized in vivo through non-enzymatic free radical catalyzed peroxidation of arachidonic acid, is a widely used biomarker of oxidative stress in multiple disease states, including TBI and cerebral ischemia/reperfusion. Our hypothesis is that harvesting of biomarkers directly in the injured brain by cerebral microdialysis (MD) is advantageous because of its high spatial and temporal resolution compared to blood or cerebrospinal fluid sampling. The aim of this study was to test the feasibility of measuring 8-iso-PGF(2α) in MD, ventricular cerebrospinal fluid (vCSF), and plasma samples collected from patients with severe TBI, and to compare the MD signals with MD-glycerol, implicated as a biomarker of oxidative stress, as well as MD-glutamate, a biomarker of excitotoxicity. Six patients (4 men, 2 women) were included in the study, three of whom had a focal/mixed TBI, and three a diffuse axonal injury (DAI). Following the bedside analysis of routine MD biomarkers (glucose, lactate:pyruvate ratio, glycerol, and glutamate), two 12-h MD samples per day were used to analyze 8-iso-PGF(2α) from 24 h up to 8 days post-injury. The interstitial levels of 8-iso-PGF(2α) were markedly higher than the levels obtained from plasma and vCSF (p<0.05), supporting our hypothesis. The MD-8-iso-PGF(2α) levels correlated strongly (p<0.05) with MD-glycerol and MD-glutamate, which are widely used biomarkers of membrane phospholipid degradation/oxidative stress and excitotoxicity, respectively. This study demonstrates the feasibility of analyzing 8-iso-PGF(2α) in MD samples from the human brain. Our results support a close relationship between oxidative stress and excitotoxicity following human TBI. MD-8-iso-PGF(2α) in combination with MD-glycerol may be useful biomarkers of oxidative stress in the neurointensive care setting.

  • 18.
    Clausen, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lewén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    The nitrone free radical scavenger NXY-059 is neuroprotective when administered after traumatic brain injury in the rat2008In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 25, no 12, p. 1449-1457Article in journal (Refereed)
    Abstract [en]

    Reactive oxygen species (ROS) are important contributors to the secondary injury cascade following traumatic brain injury (TBI), and ROS inhibition has consistently been shown to be neuroprotective following experimental TBI. NXY-059, a nitrone free radical trapping compound, has been shown to be neuroprotective in models of ischemic stroke but has not been evaluated in experimental TBI. In the present study, a continuous 24-h intravenous infusion of NXY-059 or vehicle was initiated 30min following a severe lateral fluid percussion brain injury (FPI) in adult rats (n=22), and histological and behavioral outcomes were evaluated. Sham-injured animals (n=22) receiving identical drug infusion were used as controls. Visuospatial learning was evaluated in the Morris water maze at post-injury days 11–14, followed by a probe trial (memory test) at day 18. The animals were sacrificed at day 18, and loss of hemispheric brain tissue was measured in microtubule-associated protein (MAP)–2stained sections. Brain-injured, NXY-059-treated animals showed a significant reduction of visuospatial learning deficits when compared to the brain-injured, vehicle-treated control animals (p<0.05). NXY-059-treated animals significantly reduced the loss of hemispheric tissue compared to brain-injured controls (43.0±11mm3 versus 74.4±19mm3, respectively; p<0.01). The results show that post-injury treatment with NXY-059 significantly attenuated the loss of injured brain tissue and improved cognitive outcome, suggesting a major role for ROS in the pathophysiology of TBI.

  • 19.
    Ekmark-Lewén, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Flygt, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fridgeirsdottir, Gudrun A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kiwanuka, Olivia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hanell, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Meyerson, Bengt J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mir, Anis K.
    Novartis Inst Biomed Res, Basel, Switzerland..
    Gram, Hermann
    Novartis Inst Biomed Res, Basel, Switzerland..
    Lewen, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Clausen, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Diffuse traumatic axonal injury in mice induces complex behavioural alterations that are normalized by neutralization of interleukin-1β2016In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 43, no 8, p. 1016-1033Article in journal (Refereed)
    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.

  • 20.
    Ekmark-Lewén, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Flygt, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Kiwanuka, Olivia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Meyerson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Lewén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Traumatic axonal injury in the mouse is accompanied by a dynamic inflammatory response, astroglial reactivity and complex behavioral changes2013In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 10, no 1, p. 44-Article in journal (Refereed)
    Abstract [en]

    Background

    Diffuse traumatic axonal injury (TAI), a common consequence of traumatic brain injury, is associated with high morbidity and mortality. Inflammatory processes may play an important role in the pathophysiology of TAI. In the murine central fluid percussion injury (cFPI) TAI model, the neuroinflammatory and astroglial response and behavioral changes are unknown.

    Methods

    Twenty cFPI-injured and nine sham-injured mice were used, and the neuroinflammatory and astroglial response was evaluated by immunohistochemistry at 1, 3 and 7 days post-injury. The multivariate concentric square field test (MCSF) was used to compare complex behavioral changes in mice subjected to cFPI (n = 16) or sham injury (n = 10). Data was analyzed using non-parametric statistics and principal component analysis (MCSF data).

    Results

    At all post-injury time points, beta-amyloid precursor protein (beta-APP) immunoreactivity revealed widespread bilateral axonal injury and IgG immunostaining showed increased blood--brain barrier permeability. Using vimentin and glial fibrillary acidic protein (GFAP) immunohistochemistry, glial cell reactivity was observed in cortical regions and important white matter tracts peaking at three days post-injury. Only vimentin was increased post-injury in the internal capsule and only GFAP in the thalamus. Compared to sham-injured controls, an increased number of activated microglia (MAC-2), infiltrating neutrophils (GR-1) and T-cells (CD3) appearing one day after TAI (P<0.05 for all cell types) was observed in subcortical white matter. In the MCSF, the behavioral patterns including general activity and exploratory behavior differed between cFPI mice and sham-injured controls.

    Conclusions

    Traumatic axonal injury in mice resulted in marked bilateral astroglial and neuroinflammatory responses and complex behavioral changes. The cFPI model in mice appears suitable for the study of injury mechanisms, including neuroinflammation, and the development of treatments targeting traumatic axonal injury.

  • 21.
    Fahlström, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Tobieson, Lovisa
    Linkoping Univ, Dept Neurosurg, Linkoping, Sweden;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Redebrandt, Henrietta Nittby
    Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Neurosurg, Lund, Sweden.
    Zeberg, Hugo
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden.
    Bartek, Jiri, Jr.
    Karolinska Inst, Dept Med & Clin Neurosci, Stockholm, Sweden;Karolinska Univ Hosp, Dept Neurosurg, Stockholm, Sweden;Rigshosp, Copenhagen Univ Hosp, Dept Neurosurg, Copenhagen, Denmark.
    Bartley, Andreas
    Univ Gothenburg, Sahlgrenska Univ Hosp, Sahlgrenska Acad, Dept Clin Neurosci,Neurosurg, Gothenburg, Sweden.
    Erkki, Maria
    Umea Univ, Umea Univ Hosp, Dept Clin Neurosci, Neurosurg, Umea, Sweden.
    Hessington, Amel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Troberg, Ebba
    Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Neurosurg, Lund, Sweden.
    Mirza, Sadia
    Karolinska Inst, Dept Med & Clin Neurosci, Stockholm, Sweden.
    Tsitsopoulos, Parmenion P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery. Linkoping Univ, Dept Neurosurg, Linkoping, Sweden;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden;Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Neurosurg, Lund, Sweden.
    Differences in neurosurgical treatment of intracerebral haemorrhage: a nation-wide observational study of 578 consecutive patients2019In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 161, no 5, p. 955-965Article in journal (Refereed)
    Abstract [en]

    Background

    Supratentorial intracerebral haemorrhage (ICH) carries an excessive mortality and morbidity. Although surgical ICH treatment can be life-saving, the indications for surgery in larger cohorts of ICH patients are controversial and not well defined. We hypothesised that surgical indications vary substantially among neurosurgical centres in Sweden.

    Objective

    In this nation-wide retrospective observational study, differences in treatment strategies among all neurosurgical departments in Sweden were evaluated.

    Methods

    Patient records, neuroimaging and clinical outcome focused on 30-day mortality were collected on each operated ICH patient treated at any of the six neurosurgical centres in Sweden from 1 January 2011 to 31 December 2015.

    Results

    In total, 578 consecutive surgically treated ICH patients were evaluated. There was a similar incidence of surgical treatment among different neurosurgical catchment areas. Patient selection for surgery was similar among the centres in terms of patient age, pre-operative level of consciousness and co-morbidities, but differed in ICH volume, proportion of deep-seated vs. lobar ICH and pre-operative signs of herniation (p<.05). Post-operative patient management strategies, including the use of ICP-monitoring, CSF-drainage and mechanical ventilation, varied among centres (p<.05). The 30-day mortality ranged between 10 and 28%.

    Conclusions

    Although indications for surgical treatment of ICH in the six Swedish neurosurgical centres were homogenous with regard to age and pre-operative level of consciousness, important differences in ICH volume, proportion of deep-seated haemorrhages and pre-operative signs of herniation were observed, and there was a substantial variability in post-operative management. The present results reflect the need for refined evidence-based guidelines for surgical management of ICH.

  • 22.
    Flygt, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Clausen, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Diffuse traumatic brain injury in the mouse induces a transient proliferation of oligodendrocyte progenitor cells in injured white matter tracts2016Conference paper (Refereed)
  • 23.
    Flygt, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Clausen, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Diffuse traumatic brain injury in the mouse induces a transient proliferation of oligodendrocyte progenitor cells in injured white matter tracts2017In: Restorative Neurology and Neuroscience, ISSN 0922-6028, E-ISSN 1878-3627, Vol. 35, no 2, p. 251-263Article in journal (Refereed)
    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.

  • 24.
    Flygt, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Djupsjö, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lenne, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Myelin loss and oligodendrocyte pathology in white matter tracts following traumatic brain injury in the rat2013In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 38, no 1, p. 2153-2165Article, review/survey (Refereed)
    Abstract [en]

    Axonal injury is an important contributor to the behavioral deficits observed following traumatic brain injury (TBI). Additionally, loss of myelin and/or oligodendrocytes can negatively influence signal transduction and axon integrity. Apoptotic oligodendrocytes, changes in the oligodendrocyte progenitor cell (OPC) population and loss of myelin were evaluated at 2, 7 and 21 days following TBI. We used the central fluid percussion injury model (n = 18 and three controls) and the lateral fluid percussion injury model (n = 15 and three controls). The external capsule, fimbriae and corpus callosum were analysed. With Luxol Fast Blue and RIP staining, myelin loss was observed in both models, in all evaluated regions and at all post-injury time points, as compared with sham-injured controls (P ≤ 0.05). Accumulation of β-amyloid precursor protein was observed in white matter tracts in both models in areas with preserved and reduced myelin staining. White matter microglial/macrophage activation, evaluated by isolectin B4 immunostaining, was marked at the early time points. In contrast, the glial scar, evaluated by glial fibrillary acidic protein staining, showed its highest intensity 21 days post-injury in both models. The number of apoptotic oligodendrocytes, detected by CC1/caspase-3 co-labeling, was increased in both models in all evaluated regions. Finally, the numbers of OPCs, evaluated with the markers Tcf4 and Olig2, were increased from day 2 (Olig2) or day 7 (Tcf4) post-injury (P ≤ 0.05). Our results indicate that TBI induces oligodendrocyte apoptosis and widespread myelin loss, followed by a concomitant increase in the number of OPCs. Prevention of myelin loss and oligodendrocyte death may represent novel therapeutic targets for TBI.

  • 25.
    Flygt, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Gumucio, Astrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala Univ, Dept Publ Hlth & Caring Sci, Geriatr, Uppsala, Sweden..
    Skoglund, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Holm, Jonatan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Human Traumatic Brain Injury Results in Oligodendrocyte Death and Increases the Number of Oligodendrocyte Progenitor Cells2016In: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 75, no 6, p. 503-515Article in journal (Refereed)
    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.

  • 26.
    Flygt, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Ruscher, Karsten
    Department of Neuroscience, unit of Neurosurgery, Lund University, Lund, Sweden..
    Norberg, Amanda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Mir, AK
    Novartis Institutes of Biomedical Research, Basel, Switzerland .
    Gram, Hermann
    Novartis Institutes of Biomedical Research, Basel, Switzerland .
    Clausen, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Reduced loss of mature Oligodendrocytes following Diffuse Traumatic Brain Injury in the mouse by Neutralization of Interleukin-1βManuscript (preprint) (Other academic)
    Abstract [en]

    Abstract

    Background: Traumatic brain injury (TBI) leads to several secondary consequences impairing patient outcome. Injury to the components of the white matter, the oligodendrocyte population, myelin and axons, associate with post-injury cognitive deficits. Oligodendrocytes (OLs), the myelin-producing cell, are highly vulnerable post-TBI. Lost OLs may be replaced by proliferating oligodendrocyte progenitor cells (OPCs). A complex inflammatory response is also initiated following TBI, which is an important therapeutic target in TBI. The cytokine, interleukin-1β (IL-1β), is a key mediator of the inflammatory response. When neutralized following experimental TBI, behavioral and histological outcome is improved by unknown mechanisms.

    Methods: The central fluid percussion injury (cFPI) and sham injury was used in mice at three survival end-points; 2, 7 and 14 days post-injury. Mice were, at 30 min post-injury, randomly administered a neutralizing IL-1β antibody or a control antibody.  OPC proliferation (5-ethynyl 2´- deoxyuridine (EdU)/Olig 2 co-labeling) and mature OL cell death was evaluated in injured white matter tracts. In situ hybridization for Olig2 transcripts in EdU positive cells and microglia ramification was also evaluated.

    Results: Attenuated cell death, indicated by cleaved caspase-3 expression, and OL cell loss was observed in brain-injured animals treated with the IL-1β neutralizing antibody without influencing proliferation of OPCs, the number of Olig2 transcript or the ramification of microglia. 

     

    Conclusion: Although OPC proliferation was not influenced, IL-1β neutralization reduced oligodendrocyte cell death in diffuse TBI which may partly explain the beneficial outcome observed using this anti-inflammatory treatment.   

     

  • 27.
    Flygt, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Ruscher, Karsten
    Novartis Inst Biomed Res, Basel, Switzerland.
    Norberg, Amanda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Mir, Anis
    Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Neurosurg, Lund, Sweden.
    Gram, Hermann
    Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Neurosurg, Lund, Sweden.
    Clausen, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery. Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Neurosurg, Lund, Sweden.
    Neutralization of Interleukin-1 beta following Diffuse Traumatic Brain Injury in the Mouse Attenuates the Loss of Mature Oligodendrocytes2018In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 23, p. 2837-2849Article in journal (Refereed)
    Abstract [en]

    Traumatic brain injury (TBI) commonly results in injury to the components of the white matter tracts, causing post-injury cognitive deficits. The myelin-producing oligodendrocytes (OLs) are vulnerable to TBI, although may potentially be replaced by proliferating oligodendrocyte progenitor cells (OPCs). The cytokine interleukin-1 beta (IL-1 beta) is a key mediator of the complex inflammatory response, and when neutralized in experimental TBI, behavioral outcome was improved. To evaluate the role of IL-1 beta on oligodendrocyte cell death and OPC proliferation, 116 adult male mice subjected to sham injury or the central fluid percussion injury (cFPI) model of traumatic axonal injury, were analyzed at two, seven, and 14 days post-injury. At 30 min post-injury, mice were randomly administered an IL-1 beta neutralizing or a control antibody. OPC proliferation (5-ethynyl 2 '- deoxyuridine (EdU)/Olig2 co-labeling) and mature oligodendrocyte cell loss was evaluated in injured white matter tracts. Microglia/macrophages immunohistochemistry and ramification using Sholl analysis were also evaluated. Neutralizing IL-1 beta resulted in attenuated cell death, indicated by cleaved caspase-3 expression, and attenuated loss of mature OLs from two to seven days post-injury in brain-injured animals. IL-1 beta neutralization also attenuated the early, two day post-injury increase of microglia/macrophage immunoreactivity and altered their ramification. The proliferation of OPCs in brain-injured animals was not altered, however. Our data suggest that IL-1 beta is involved in the TBI-induced loss of OLs and early microglia/macrophage activation, although not the OPC proliferation. Attenuated oligodendrocyte cell loss may contribute to the improved behavioral outcome observed by IL-1 beta neutralization in this mouse model of diffuse TBI.

  • 28.
    Hanell, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Clausen, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Djupsjö, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Vallstedt, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Patra, Kalicharan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Israelsson, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Larhammar, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Björk, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Paixao, Sonia
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Functional and Histological Outcome after Focal Traumatic Brain Injury Is Not Improved in Conditional EphA4 Knockout Mice2012In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 29, no 17, p. 2660-2671Article in journal (Refereed)
    Abstract [en]

    We investigated the role of the axon guidance molecule EphA4 following traumatic brain injury (TBI) in mice. Neutralization of EphA4 improved motor function and axonal regeneration following experimental spinal cord injury (SCI). We hypothesized that genetic absence of EphA4 could improve functional and histological outcome following TBI. Using qRT-PCR in wild-type (WT) mice, we evaluated the EphA4 mRNA levels following controlled cortical impact (CCI) TBI or sham injury and found it to be downregulated in the hippocampus (p < 0.05) but not the cortex ipsilateral to the injury at 24 h post-injury. Next, we evaluated the behavioral and histological outcome following CCI using WT mice and Emx1-Cre-driven conditional knockout (cKO) mice. In cKO mice, EphA4 was completely absent in the hippocampus and markedly reduced in the cortical regions from embryonic day 16, which was confirmed using Western blot analysis. EphA4 cKO mice had similar learning and memory abilities at 3 weeks post-TBI compared to WT controls, although brain-injured animals performed worse than sham-injured controls (p < 0.05). EphA4 cKO mice performed similarly to WT mice in the rotarod and cylinder tests of motor function up to 29 days post-injury. TBI increased cortical and hippocampal astrocytosis (GFAP immunohistochemistry, p < 0.05) and hippocampal sprouting (Timm stain, p < 0.05) and induced a marked loss of hemispheric tissue (p < 0.05). EphA4 cKO did not alter the histological outcome. Although our results may argue against a beneficial role for EphA4 in the recovery process following TBI, further studies including post-injury pharmacological neutralization of EphA4 are needed to define the role for EphA4 following TBI.

  • 29. Hanell, Anders
    et al.
    Hedin, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Clausen, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Facilitated assessment of tissue loss following experimental traumatic brain injury2012In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 29, no 10, p. A154-A154Article in journal (Other academic)
  • 30.
    Hessington, Amel
    et al.
    Uppsala Univ Hosp, Sect Neurosurg, Dept Neurosci, Uppsala, Sweden.
    Tsitsopoulos, Parmenion P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery. Aristotle Univ Thessaloniki, Hippokratio Gen Hosp, Thessaloniki, Greece.
    Fahlström, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery. Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Neurosurg, Lund, Sweden.
    Favorable clinical outcome following surgical evacuation of deep-seated and lobar supratentorial intracerebral hemorrhage: a retrospective single-center analysis of 123 cases2018In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 160, no 9, p. 1737-1747Article in journal (Refereed)
    Abstract [en]

    Background: In spontaneous supratentorial intracerebral hemorrhage (ICH), the role of surgical treatment remains controversial, particularly in deep-seated ICHs. We hypothesized that early mortality and long-term functional outcome differ between patients with surgically treated lobar and deep-seated ICH.

    Method: Patients who underwent craniotomy for ICH evacuation from 2009 to 2015 were retrospectively evaluated and categorized into two subgroups: lobar and deep-seated ICH. The modified Rankin Scale (mRS) was used to evaluate long-term functional outcome.

    Result: Of the 123 patients operated for ICH, 49.6% (n = 61) had lobar and 50.4% (n = 62) deep-seated ICH. At long-term follow-up (mean 4.2 years), 25 patients (20.3%) were dead, while 51.0% of survivors had a favorable outcome (mRS score <= 3). Overall mortality was 13.0% at 30 days and 17.9% at 6 months post-ictus, not influenced by ICH location. Mortality was higher in patients >= 65 years old (p = 0.020). The deep-seated group had higher incidence and extent of intraventricular extension, younger age (52.6 +/- 9.0 years vs. 58.5 +/- 9.8 years; p < 0.05), more frequently pupillary abnormalities, and longer neurocritical care stay (p < 0.05). The proportion of patients with good outcome was 48.0% in deep-seated vs. 54.1% in lobar ICH (p = 0.552). In lobar ICH, independent predictors of long-term outcome were age, hemorrhage volume, preoperative level of consciousness, and pupillary reaction. In deep-seated ICHs, only high age correlated significantly with poor outcome.

    Conclusions: At long-term follow-up, most ICH survivors had a favorable clinical outcome. Neither mortality nor long-term functional outcome differed between patients operated for lobar or deep-seated ICH. A combination of surgery and neurocritical care can result in favorable clinical outcome, regardless of ICH location.

  • 31.
    Holmström, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Tsitsopoulos, Parmenion P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery. Aristotle Univ Thessaloniki, Hippokratio Gen Hosp, Thessaloniki, Greece.
    Flygt, Hjalmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Holtz, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery. Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Neurosurg, Lund, Sweden.
    Neurosurgical untethering with or without syrinx drainage results in high patient satisfaction and favorable clinical outcome in post-traumatic myelopathy patients2018In: Spinal Cord, ISSN 1362-4393, E-ISSN 1476-5624, Vol. 56, no 9, p. 873-882Article in journal (Refereed)
    Abstract [en]

    Study design: Retrospective data collection and patient-reported outcome measures.

    Objectives: To investigate surgical outcome, complications, and patient satisfaction in patients with chronic SCI and symptomatic post-traumatic progressive myelopathy (PPM) who underwent neurosurgical untethering and/or spinal cord cyst drainage with the aim of preventing further neurological deterioration.

    Setting: Single-center study at an academic neurosurgery department.

    Methods: All SCI patients who underwent neurosurgery between 1996 and 2013 were retrospectively included. All medical charts and the treating surgeon's operative reports were reviewed to identify surgical indications, surgical technique, and post-operative complications. A questionnaire and an EQ-5D-instrument were used to assess patient's self-described health status and satisfaction at long-term follow-up.

    Results: Fifty-two patients (43 men, 9 women) were identified, of whom five were dead and one was lost to follow-up. Main indications for surgery were pain (54%), motor (37%), or sensory (8%) impairment, and spasticity (2.0%). Overall complications were rare (8%). At follow-up, the subjectively perceived outcome was improved in 24 and remained unchanged in 21 patients. Thus, the surgical aim was met in 87% of patients. Of the 46 eligible patients, 38 responded to the questionnaire of whom 65% were satisfied with the surgical results. Patients with cervical lesions were more satisfied with the surgical treatment than patients with thoracic/thoracolumbar lesions (p = 0.05).

    Conclusions: Neurosurgical untethering and/or cyst drainage in chronic SCI patients and PPM resulted in a high degree of patient satisfaction, particularly in cervical SCI patients with minimal complications.

  • 32.
    Hopp, Sarah
    et al.
    Univ Hosp Wurzburg, Dept Neurol, Josef Schneider Str 11, D-97080 Wurzburg, Germany.;Univ Hosp Wurzburg, Dept Neurosurg, D-97080 Wurzburg, Germany..
    Albert-Weissenberger, Christiane
    Univ Hosp Wurzburg, Dept Neurol, Josef Schneider Str 11, D-97080 Wurzburg, Germany.;Univ Hosp Wurzburg, Dept Neurosurg, D-97080 Wurzburg, Germany..
    Mencl, Stine
    Univ Hosp Wurzburg, Dept Neurol, Josef Schneider Str 11, D-97080 Wurzburg, Germany..
    Bieber, Michael
    Univ Hosp Wurzburg, Dept Neurol, Josef Schneider Str 11, D-97080 Wurzburg, Germany.;Univ Hosp Wurzburg, Comprehens Heart Failure Ctr DZHI, D-97080 Wurzburg, Germany..
    Schuhmann, Michael K.
    Univ Hosp Wurzburg, Dept Neurol, Josef Schneider Str 11, D-97080 Wurzburg, Germany..
    Stetter, Christian
    Univ Hosp Wurzburg, Dept Neurosurg, D-97080 Wurzburg, Germany..
    Nieswandt, Bernhard
    Univ Wurzburg, Rudolf Virchow Ctr, German Res Soc, Res Ctr Expt Biomed, D-97070 Wurzburg, Germany..
    Schmidt, Peter M.
    CSL Ltd, Mol Sci & Biotechnol Inst Bio21, Parkville, Vic, Australia..
    Monoranu, Camelia-Maria
    Univ Wurzburg, Comprehens Canc Ctr Mainfranken, Inst Pathol, Dept Neuropathol, D-97070 Wurzburg, Germany..
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Nolte, Marc W.
    CSL Behring, Marburg, Germany..
    Siren, Anna-Leena
    Univ Hosp Wurzburg, Dept Neurosurg, D-97080 Wurzburg, Germany..
    Kleinschnitz, Christoph
    Univ Hosp Wurzburg, Dept Neurol, Josef Schneider Str 11, D-97080 Wurzburg, Germany..
    Targeting Coagulation Factor XII as a Novel Therapeutic Option in Brain Trauma2016In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 79, no 6, p. 970-982Article in journal (Refereed)
    Abstract [en]

    Objective: Traumatic brain injury is a major global public health problem for which specific therapeutic interventions are lacking. There is, therefore, a pressing need to identify innovative pathomechanism-based effective therapies for this condition. Thrombus formation in the cerebral microcirculation has been proposed to contribute to secondary brain damage by causing pericontusional ischemia, but previous studies have failed to harness this finding for therapeutic use. The aim of this study was to obtain preclinical evidence supporting the hypothesis that targeting factor XII prevents thrombus formation and has a beneficial effect on outcome after traumatic brain injury.

    Methods: We investigated the impact of genetic deficiency of factor XII and acute inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused infestin-4 (rHA-Infestin-4) on trauma-induced microvascular thrombus formation and the subsequent outcome in 2 mouse models of traumatic brain injury.

    Results: Our study showed that both genetic deficiency of factor XII and an inhibition of activated factor XII in mice minimize trauma-induced microvascular thrombus formation and improve outcome, as reflected by better motor function, reduced brain lesion volume, and diminished neurodegeneration. Administration of human factor XII in factor XII-deficient mice fully restored injury-induced microvascular thrombus formation and brain damage.

    Interpretation: The robust protective effect of rHA-Infestin-4 points to a novel treatment option that can decrease ischemic injury after traumatic brain injury without increasing bleeding tendencies.

  • 33.
    Hånell, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Structured evaluation of rodent behavioral tests used in drug discovery research2014In: Frontiers in Behavioral Neuroscience, ISSN 1662-5153, E-ISSN 1662-5153, Vol. 8Article, review/survey (Refereed)
    Abstract [en]

    A large variety of rodent behavioral tests are currently being used to evaluate traits such as sensory-motor function, social interactions, anxiety-like and depressive-like behavior, substance dependence and various forms of cognitive function. Most behavioral tests have an inherent complexity, and their use requires consideration of several aspects such as the source of motivation in the test, the interaction between experimenter and animal, sources of variability, the sensory modality required by the animal to solve the task as well as costs and required work effort. Of particular importance is a test's validity because of its influence on the chance of successful translation of preclinical results to clinical settings. High validity may, however, have to be balanced against practical constraints and there are no behavioral tests with optimal characteristics. The design and development of new behavioral tests is therefore an ongoing effort and there are now well over one hundred tests described in the contemporary literature. Some of them are well established following extensive use, while others are novel and still unproven. The task of choosing a behavioral test for a particular project may therefore be daunting and the aim of the present review is to provide a structured way to evaluate rodent behavioral tests aimed at drug discovery research.

  • 34.
    Israelsson, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Flygt, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Astrand, Elaine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Kiwanuka, Olivia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Bengtsson, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Altered expression of myelin-associated inhibitors and their receptors after traumatic brain injury in the mouse2014In: Restorative Neurology and Neuroscience, ISSN 0922-6028, E-ISSN 1878-3627, Vol. 32, no 5, p. 717-731Article in journal (Refereed)
    Abstract [en]

    Purpose: When central nervous system axons are injured, regeneration is partly inhibited by myelin-associated inhibitors (MAIs). Following traumatic brain injury (TBI) in the rat, pharmacological neutralisation of the MAIs Nogo-A and myelin-associated glycoprotein (MAG) resulted in improved functional outcome. In contrast, genetic or pharmacological neutralization of the MAI receptors Nogo-66 receptor 1 (NgR1) or paired-immunoglobulin like receptor-B (PirB) showed an unaltered or impaired outcome following TBI in mice. The aim of the present study was thus to evaluate the MAI expression levels following TBI in mice. Methods: Quantitative reverse transcriptase PCR (qRT-PCR) was used to measure total RNA isolated from brains of young adult male C57BL/6 mice at one, three or seven days following controlled cortical impact TBI or sham injury. Hippocampal and neocortical tissue ipsi- and contralateral to the injury was analyzed for Nogo-A, oligodendrocyte-myelin glycoprotein (OMgp), MAG, and the MAI receptors PirB and NgR1, including its co-receptor Lingo1. Results: Compared to sham-injured controls, PirB neocortical expression was significantly upregulated at one day and NgR1 expression downregulated at seven days post-TBI. In the hippocampus, transcriptional upregulation was observed in Nogo-A (one day post-injury), MAG and PirB at seven days post-injury. In contrast, the hippocampal transcripts of NgR1 and Lingo1 were decreased at seven days post-injury. The expression of OMgp was unaltered at all time points post-injury. Conclusion: These results suggest that early dynamic changes in MAI gene expression occur following TBI in the mouse, particularly in the hippocampus, which may play an inhibitory role for post-injury regeneration and plasticity.

  • 35.
    Kononenko, Olga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Key State Laboratory, Bogomoletz Institute of Physiology, Kiev, Ukraine.
    Galatenko, Vladimir
    Moscow State University.
    Andersson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Zhou, Xingwu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Iatsyshyna, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Department of Human Genetics, Institute of Molecular Biology and Genetics, Kiev, Ukraine.
    Mityakina, Irina
    Moscow State University.
    Yakovleva, Tatiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sarkisyan, Daniil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ponomarev, Igor
    University of Texas.
    Krishtal, Oleg
    Bogomoletz Institute of Physiology, Kiev..
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Tonevitsky, Alex
    Moscow State University.
    Adkins, DeAnna L.
    Medical University of South Carolina.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Intra- and interregional coregulation of opioid genes: broken symmetry in spinal circuits2017In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 31, no 5, p. 1953-1963Article in journal (Refereed)
    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.

  • 36.
    Kononenko, Olga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Stålhandske, Lada
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Zarelius, Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Clausen, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Yakovleva, Tatiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery. Lund Univ, Dept Clin Sci Neurosurg, Skane Univ Hosp, EA Blocket,4th Floor,Box 188, S-22100 Lund, Sweden.
    Focal traumatic brain injury induces neuroplastic molecular responses in lumbar spinal cord2019In: Restorative Neurology and Neuroscience, ISSN 0922-6028, E-ISSN 1878-3627, Vol. 37, no 2, p. 87-96Article in journal (Refereed)
    Abstract [en]

    Background/Objectives: Motor impairment induced by traumatic brain injury (TBI) may be mediated through changes in spinal molecular systems regulating neuronal plasticity. We assessed whether a focal controlled cortical impact (CCI) TBI in the rat alters expression of the Tgfb1, c-Fos, Bdnf and Gap43 neuroplasticity genes in lumbar spinal cord.

    Approach/Methods: Adult male Sprague-Dawley rats (n = 8) were subjected to a right-side CCI over the anterior sensorimotor hindlimb representation area or sham-injury (n=8). Absolute expression levels of Tgfb1, c-Fos, Bdnf, and Gapd43 genes were measured by droplet digital PCR in ipsi- and contralesional, dorsal and ventral quadrants of the L4 and L5 spinal cord. The neuronal activity marker c-Fos was analysed by immunohistochemistry in the dorsal L4 and L5 segments. The contra- vs. ipsilesional expression pattern was examined as the asymmetry index, AI.

    Results: The Tgfb1 mRNA levels were significantly higher in the CCI vs. sham-injured rats, and in the contra- vs. ipsilesional dorsal domains in the CCI group. The number of c-Fos-positive cells was elevated in the L4 and L5 segments; and on the contralesional compared to the ipsilesional side in the CCI group. The c-Fos AI in the dorsal laminae was significantly increased by CCI.

    Conclusions: The results support the hypothesis that focal TBI induces plastic alterations in the lumbar spinal cord that may contribute to either motor recovery or maladaptive motor responses.

  • 37.
    Kunz, T
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Marklund, Niklas
    Faculty of Medicine, Department of Neuroscience. Neurokirurgi.
    Hillered, Lars
    Faculty of Medicine, Department of Neuroscience. Neurokirurgi.
    Oliw, EH
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Effects of the selective cyclooxygenase-2 inhibitor rofecoxib on cell death following traumatic brain injury in the rat2006In: Restor Neurol Neurosci, Vol. 24, no 1, p. 55-63Article in journal (Refereed)
  • 38.
    Lööv, Camilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Fernqvist, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Walmsley, Adrian
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Erlansson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Neutralization of LINGO-1 during In Vitro Differentiation of Neural Stem Cells Results in Proliferation of Immature Neurons2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 1, p. e29771-Article in journal (Refereed)
    Abstract [en]

    Identifying external factors that can be used to control neural stem cells division and their differentiation to neurons, astrocytes and oligodendrocytes is of high scientific and clinical interest. Here we show that the Nogo-66 receptor interacting protein LINGO-1 is a potent regulator of neural stem cell maturation to neurons. LINGO-1 is expressed by cortical neural stem cells from E14 mouse embryos and inhibition of LINGO-1 during the first days of neural stem cell differentiation results in decreased neuronal maturation. Compared to neurons in control cultures, which after 6 days of differentiation have long extending neurites, neurons in cultures treated with anti-LINGO-1 antibodies retain an immature, round phenotype with only very short processes. Furthermore, neutralization of LINGO-1 results in a threefold increase in βIII tubulin-positive cells compared to untreated control cultures. By using BrdU incorporation assays we show that the immature neurons in LINGO-1 neutralized cultures are dividing neuroblasts. In contrast to control cultures, in which no cells were double positive for βIII tubulin and BrdU, 36% of the neurons in cultures treated with anti-LINGO-1 antibodies were proliferating after three days of differentiation. TUNEL assays revealed that the amount of cells going through apoptosis during the early phase of differentiation was significantly decreased in cultures treated with anti-LINGO-1 antibodies compared to untreated control cultures. Taken together, our results demonstrate a novel role for LINGO-1 in neural stem cell differentiation to neurons and suggest a possibility to use LINGO-1 inhibitors to compensate for neuronal cell loss in the injured brain.

  • 39.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Cerebral amyloid angiopathy: a long-term consequence of traumatic brain injury?2017In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 159, no 1, p. 21-23Article in journal (Refereed)
  • 40.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery. Lund Univ, Lund, Sweden.
    The Neurological wake-up Test-A Role in Neurocritical Care Monitoring of Traumatic Brain injury Patients?2017In: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 8, article id 540Article, review/survey (Refereed)
    Abstract [en]

    The most fundamental clinical monitoring tool in traumatic brain injury (TBI) patients is the repeated clinical examination. In the severe TBI patient treated by continuous sedation in a neurocritical care (NCC) unit, sedation interruption is required to enable a clinical evaluation (named the neurological wake-up test; NWT) assessing the level of consciousness, pupillary diameter and reactivity to light, and presence of focal neurological deficits. There is a basic conflict regarding the NWT in the NCC setting; can the clinical information obtained by the NWT justify the risk of inducing a stress response in a severe TBI patient? Furthermore, in the presence of advanced multimodal monitoring and neuroimaging, is the NWT necessary to identify important clinical alterations? In studies of severe TBI patients, the NWT was consistently shown to induce a stress reaction including brief increases in intracranial pressure (ICP) and changes in cerebral perfusion pressure (CPP). However, it has not been established whether these short-lived ICP and CPP changes are detrimental to the injured brain. Daily interruption of sedation is associated with a reduced ventilator time, shorter hospital stay and reduced mortality in many studies of general intensive care unit patients, although such clinical benefits have not been firmly established in TBI. To date, there is no consensus on the use of the NWT among NCC units and systematic studies are scarce. Thus, additional studies evaluating the role of the NWT in clinical decision-making are needed. Multimodal NCC monitoring may be an adjunct in assessing in which TBI patients the NWT can be safely performed. At present, the NWT remains the golden standard for clinical monitoring and detection of neurological changes in NCC and could be considered in TBI patients with stable baseline ICP and CPP readings. The focus of the present review is an overview of the existing literature on the role of the NWT as a clinical monitoring tool for severe TBI patients.

  • 41.
    Marklund, Niklas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Bareyre, Florence M.
    Royo, Nicolas C.
    Thompson, Hilaire J.
    Mir, Anis K.
    Grady, Sean
    Schwab, Martin E.
    McIntosh, Tracy K.
    Cognitive outcome following brain injury and treatment with an inhibitor of Nogo-A in association with an attenuated downregulation of hippocampal growth-associated protein-43 expression2007In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 107, no 4, p. 844-853Article in journal (Refereed)
    Abstract [en]

    Object. Central nervous system axons regenerate poorly after traumatic brain injury (TBI), partly due to inhibitors such as the protein Nogo-A present in myelin. The authors evaluated the efficacy of anti-Nogo-A monoclonal antibody (mAb) 7B 12 administration on the neurobehavioral and cognitive outcome of rats following lateral fluid-percussion brain injury, characterized the penetration of the 7B 12 or control antibodies into target brain regions, and evaluated the effects of Nogo-A inhibition on hemispheric tissue loss and sprouting of uninjured motor tracts in the cervical cord. To elucidate a potential molecular response to Nogo-A inhibition, we evaluated the effects of 7B 12 on hippocampal GAP-43 expression. Methods. Beginning 24 hours after lateral fluid-percussion brain injury or sham injury in rats, the mAb 7B12 or control antibody was infused intracerebroventricularly over 14 days, and behavior was assessed over 4 weeks. Results. Immunoreactivity for 7B 12 or immunoglobulin G was detected in widespread brain regions at 1 and 3 weeks postinjury. The brain-injured animals treated with 7B12 showed improvement in cognitive function (p < 0.05) at 4 weeks but no improvement in neurological motor function from 1 to 4 weeks postinjury compared with brain-injured, vehicle-treated controls. The enhanced cognitive function following inhibition of Nogo-A was correlated with an attenuated postinjury downregulation of hippocampal GAP-43 expression (p < 0.05). Conclusions. Increased GAP-43 expression may be a novel molecular mechanism of the enhanced cognitive recovery mediated by Nogo-A inhibition after TBI in rats.

  • 42.
    Marklund, Niklas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Farrokhnia, Nina
    Hanell, Anders
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Zetterberg, Henrik
    Blennow, Kaj
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Monitoring of amyloid-beta dynamics after human traumatic brain injury2012In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 29, no 10, p. A185-A185Article in journal (Other academic)
  • 43.
    Marklund, Niklas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Farrokhnia, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hånell, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Vanmechelen, Eugeen
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Zetterberg, Henrik
    Blennow, Kaj
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Monitoring of beta-Amyloid Dynamics after Human Traumatic Brain Injury2014In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 31, no 1, p. 42-55Article in journal (Refereed)
    Abstract [en]

    Epidemiological evidence links severe or repeated traumatic brain injury (TBI) to the development of Alzheimer's disease (AD). Accumulation of amyloid precursor protein (APP) occurs with high frequency after TBI, particularly in injured axons, and APP may be cleaved to amyloid- (A) peptides playing key pathophysiological roles in AD. We used cerebral microdialysis (MD) to test the hypothesis that interstitial A levels are altered following TBI and are related to the injury type, cerebral energy metabolism, age of the patient, and level of consciousness. In the present report, we evaluated 10 mechanically ventilated patients (7 male, 3 female, ages 18-76 years) with a severe TBI, who had intracranial pressure and MD monitoring. Each MD sample was analyzed for hourly routine energy metabolic biomarkers (MD-lactate, MD-pyruvate, MD-glucose, and MD-lactate/pyruvate ratio), cellular distress biomarkers (MD-glutamate, MD-glycerol), and MD-urea. The remaining MD samples were analyzed for A1-40 (A40; n=765 samples) and A1-42 (A42; n=765 samples) in pooled 2h fractions up to 14 days post-injury, using the Luminex xMAP technique, allowing detection with high temporal resolution of the key A peptides A40 and A42. Data are presented using medians and 25th and 75th percentiles. Both A40 and A42 were consistently higher in patients with predominately diffuse axonal injury compared with patients with focal TBI at days 1-6 post- injury, A42 being significantly increased at 113-116h post-injury (p<0.05). The A levels did not correlate with the interstitial energy metabolic situation, age of the patient, or the level of consciousness. These results support that interstitial generation of potentially toxic A species may occur following human TBI, particularly related to axonal injury.

  • 44.
    Marklund, Niklas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Salci, Konstantin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Energy metabolic changes in the early post-injury period following traumatic brain injury in rats2006In: Neurochemical Research, ISSN 0364-3190, E-ISSN 1573-6903, Vol. 31, no 8, p. 1085-1093Article in journal (Refereed)
    Abstract [en]

    Impaired cerebral energy metabolism may be a major contributor to the secondary injury cascade that occurs following traumatic brain injury (TBI). To estimate the cortical energy metabolic state following mild and severe controlled cortical contusion (CCC) TBI in rats, ipsi-and contralateral cortical tissues were frozen in situ at 15 and 40 min post-injury and adenylate (ATP, ADP, AMP) levels were analyzed using high-performance liquid chromatography (HPLC) and the energy charge (EC) was calculated. At 15 min post-injury, mildly brain-injured animals showed a 43% decrease in cortical ATP levels and a 2.4-fold increase in AMP levels (P < 0.05), and there was a significant reduction of the ipsilateral cortical EC when compared to sham-injured animals (P < 0.05). At 40 min post-injury, the ipsilateral adenylate levels and EC had recovered to the values observed in the sham-injury group. In the severe CCC group, there was a 51% decrease in ipsilateral cortical ATP levels and a 5.3-fold increase in AMP levels with a significant reduction of cortical EC at 15 min post-injury (P < 0.05). At 40 min post-injury, a 2.6-fold ipsilateral increase in AMP levels and an 11% and 44% decrease in EC and ATP levels, respectively, remained (P < 0.05). A 37–38% reduction of the total adenylate pool was observed ipsilaterally in both CCC severity groups at the early time-point, and a 19% and 28% decrease remained in the mild and severe CCC groups, respectively, at 40 min post-injury. Significant contralateral ATP and EC changes were only observed in the severe CCC group at 40 min post-injury (P < 0.05). The energy-requiring secondary injury cascades that occur early post-injury do not challenge the brain tissue to the extent of ATP depletion and may provide a window of opportunity for therapeutic intervention.

  • 45.
    Rodriguez-Lorenzo, Andres
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Rydevik Mani, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Thor, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Gudjonsson, Olafur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Olerud, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ekberg, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Fibula osteo-adipofascial flap for reconstruction of a cervical spine and posterior pharyngeal wall defect2014In: Microsurgery, ISSN 0738-1085, E-ISSN 1098-2752, Vol. 34, no 4, p. 314-318Article in journal (Refereed)
    Abstract [en]

    When reconstructing combined defects of the cervical spine and the posterior pharyngeal wall the goals are bone stability along with continuity of the aerodigestive tract. We present a case of a patient with a cervical spine defect, including C1 to C3, associated with a posterior pharyngeal wall defect after excision of a chordoma and postoperative radiotherapy. The situation was successfully solved with a free fibula osteo-adipofascial flap. The reconstruction with a fibula osteo-adipofascial flap provided several benefits in comparison with a fibula osteo-cutaneous flap in our case, including an easier insetting of the soft tissue component at the pharyngeal level and less bulkiness of the flap allowing our patient to resume normal deglutition.

  • 46.
    Ronne-Engström, Elisabeth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Borota, Ljubisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Kothimbakam, Raj
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lewén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Outcome from spontaneous subarachnoid haemorrhage: results from 2007-2011 and comparison with our previous series2014In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 1, p. 38-43Article in journal (Refereed)
    Abstract [en]

    Objectives

    The management of patients with spontaneous subarachnoid haemorrhage (SAH) has changed, in part due to interventions now being extended to patients who are older and in a worse clinical condition. This study evaluates the effects of these changes on a complete 5-year patient material.

    Methods

    Demographic data and results from 615 patients with SAH admitted from 2007 to 2011 were put together. Aneurysms were found in 448 patients (72.8%). They were compared with the aneurysm group (n = 676) from a previously published series from our centre (2001-2006). Linear regression was used to determine variables predicting functional outcome in the whole aneurysm group (2001-2011).

    Results

    Patients in the more recent aneurysm group were older, and they were in a worse clinical condition on admission. Regarding younger patients admitted in World Federation of Neurosurgical Societies SAH grading (WFNS) 3, there were fewer with a good outcome. In the whole aneurysm group 2001-2011, outcome was best predicted by age, clinical condition at admission, and the size of the bleeding, and not by treatment mode or localization of aneurysm.

    Conclusion

    It seems important for the outcome that aneurysms are treated early. The clinical course after that depends largely on the condition of the patient on admission rather than on aneurysm treatment method. This, together with the fact that older patients and those in worse condition are now being admitted, increases demands on neurointensive care. Further improvement in patient outcome depends on better understanding of acute brain injury mechanisms and improved neurointensive care as well as rehabilitation measures.

  • 47.
    Samuelsson, Carolina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Zetterling, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Ryttlefors, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Lewén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Nilsson, Pelle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Salci, Konstantin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Ronne-Engström, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Cerebral glutamine and glutamate levels in relation to compromised energy metabolism: a microdialysis study in subarachnoid hemorrhage patients2007In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 27, no 7, p. 1309-1317Article in journal (Refereed)
    Abstract [en]

    Astrocytic glutamate (Glt) uptake keeps brain interstitial Glt levels low. Within the astrocytes Glt is converted to glutamine (Gln), which is released and reconverted to Glt in neurons. The Glt–Gln cycle is energy demanding and impaired energy metabolism has been suggested to cause low interstitial Gln/Glt ratios. Using microdialysis (MD) measurements from visually noninjured cortex in 33 neurointensive care patients with subarachnoid hemorrhage, we have determined how interstitial Glt and Gln, as a reflection of the Glt–Gln cycle turnover, relate to perturbed energy metabolism. A total of 3703 hourly samples were analyzed. The lactate/pyruvate (L/P) ratios correlated to the Gln/Glt ratios (r=-0.66), but this correlation was not stronger than the correlation between L/P and Glt (r=0.68) or the correlation between lactate and Glt (r=0.65). A novel observation was a linear relationship between interstitial pyruvate and Gln (r=0.52). There were 13 periods (404 h) of 'energy crisis', defined by L/P ratios above 40. All were associated with high interstitial Glt levels. Periods with L/P ratios above 40 and low pyruvate levels were associated with decreased interstitial Gln levels, suggesting ischemia and failing astrocytic Gln synthesis. Periods with L/P ratios above 40 and normal or high pyruvate levels were associated with increased interstitial Gln levels, which may represent an astrocytic hyperglycolytic response to high interstitial Glt levels. The results imply that moderately elevated L/P ratios cannot always be interpreted as failing energy metabolism and that interstitial pyruvate levels may discriminate whether or not there is sufficient astrocytic capacity for Glt–Gln cycling in the brain.

  • 48.
    Shahim, Pashtun
    et al.
    Gothenburg Univ, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, S-41124 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden..
    Tegner, Yelverton
    Lulea Univ Technol, Dept Hlth Sci, Div Med Sci, Lulea, Sweden..
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hoeglund, Kina
    Gothenburg Univ, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, S-41124 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden..
    Portelius, Erik
    Gothenburg Univ, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, S-41124 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden..
    Brody, David L.
    Washington Univ, Sch Med, St Louis, MO 63130 USA..
    Blennow, Kaj
    Gothenburg Univ, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, S-41124 Gothenburg, Sweden..
    Zetterberg, Henrik
    Gothenburg Univ, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, S-41124 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden.;UCL, Inst Neurol, Dept Mol Neurosci, Queen Sq, London, England..
    Astroglial activation and altered amyloid metabolism in human repetitive concussion2017In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 88, no 15, p. 1400-1407Article in journal (Refereed)
    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.

  • 49.
    Skoglund, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    The neurological wake-up test increases stress hormone levels in patients with severe traumatic brain injury2012In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 40, no 1, p. 216-222Article in journal (Refereed)
    Abstract [en]

    Objectives: The "neurological wake-up test" is needed to evaluate the level of consciousness in patients with severe traumatic brain injury. However, the neurological wake-up test requires interruption of continuous sedation and may induce a stress response and its use in neurocritical care is controversial. We hypothesized that the neurological wake-up test induces an additional biochemical stress response in patients with severe traumatic brain injury.

    Patients: Twenty-four patients who received continuous propofol sedation and mechanical ventilation after moderate to severe traumatic brain injury (Glasgow Coma Scale score <= 8; patient age 18-71 yrs old) were analyzed. Exclusion criteria were age <18 yrs old, ongoing pentobarbital infusion, or markedly increased intracranial pressure on interruption of continuous sedation.

    Design: Single-center prospective study. During postinjury days 1-8, 65 neurological wake-up tests were evaluated. Adrenocorticotrophic hormone, epinephrine, and norepinephrine levels in plasma and cortisol levels in saliva were analyzed at baseline (during continuous intravenous propofol sedation) and during neurological wake-up test. Data are presented using medians and 25th and 75th percentiles.

    Setting: The study was performed in a university hospital neurocritical care unit.

    Interventions: None.

    Measurements and Main Results: At baseline, adrenocorticotrophic hormone and cortisol levels were 10.6 (6.0-19.4) ng/L and 16.0 (10.7-31.8) nmol/L, respectively. Immediately after the neurological wake-up test, adrenocorticotrophic hormone levels increased to 20.5 (11.1-48.4) ng/L (p < .05) and cortisol levels in saliva increased to 24.0 (12.3-42.5) nmol/L (p < .05). The plasma epinephrine and norepinephrine levels increased from a baseline of 0.3 (0.3-0.6) and 1.6 (0.9-2.3) nmol/L, respectively, to 0.75 (0.3-1.4) and 2.8 (1.28-3.58) nmol/L, respectively (both p < .05).

    Conclusions: The neurological wake-up test induces a biochemical stress response in patients with severe traumatic brain injury. The clinical importance of this stress response remains to be established but should be considered when deciding the frequency and use of the neurological wake-up test during neurocritical care.

  • 50.
    Skoglund, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Wake-up test and stress hormone levels in patients with brain injury: A focus on mechanisms involved: Reply2012In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 40, no 6, p. 2002-2003Article in journal (Refereed)
12 1 - 50 of 67
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