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Clausen, Fredrik, Docent
Publications (10 of 38) Show all publications
Ozen, I., Ruscher, K., Nilsson, R., Flygt, J., Clausen, F. & Marklund, N. (2020). Interleukin-1 Beta Neutralization Attenuates Traumatic Brain Injury-Induced Microglia Activation and Neuronal Changes in the Globus Pallidus. International Journal of Molecular Sciences, 21(2), Article ID 387.
Open this publication in new window or tab >>Interleukin-1 Beta Neutralization Attenuates Traumatic Brain Injury-Induced Microglia Activation and Neuronal Changes in the Globus Pallidus
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2020 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 21, no 2, article id 387Article in journal (Refereed) Published
Abstract [en]

Traumatic brain injury (TBI) increases the risk of delayed neurodegenerative processes, including Parkinson's disease (PD). Interleukin-1beta (IL-1 beta), a key pro-inflammatory cytokine, may promote secondary injury development after TBI. Conversely, neutralizing IL-1 beta was found to improve functional recovery following experimental TBI. However, the mechanisms underlying the behavioral improvements observed by IL-1 beta neutralization are still poorly understood. The present study investigated the role of IL-1 beta on the microglia response and neuronal changes in the globus pallidus in response to diffuse TBI. Mice were subjected to sham injury or the central fluid percussion injury (cFPI) (a model of traumatic axonal injury), and were randomly administered an IL-1 beta neutralizing or a control antibody at 30 min post-injury. The animals were analyzed at 2, 7, or 14 days post-injury. When compared to controls, mice subjected to cFPI TBI had increased microglia activation and dopaminergic innervation in the globus pallidus, and a decreased number of parvalbumin (PV) positive interneurons in the globus pallidus. Neutralization of IL-1 beta attenuated the microglia activation, prevented the loss of PV+ interneurons and normalized dopaminergic fiber density in the globus pallidus of brain-injured animals. These findings argue for an important role for neuro-inflammation in the PD-like pathology observed in TBI.

Place, publisher, year, edition, pages
MDPI, 2020
Keywords
traumatic brain injury, interleukin-1 beta, inflammation, Parkinson's disease, globus pallidus, axonal injury
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-407617 (URN)10.3390/ijms21020387 (DOI)000515380000017 ()31936248 (PubMedID)
Funder
Swedish Research Council
Available from: 2020-03-31 Created: 2020-03-31 Last updated: 2020-03-31Bibliographically approved
Clausen, F., Marklund, N. & Hillered, L. (2019). Acute Inflammatory Biomarker Responses to Diffuse Traumatic Brain Injury in the Rat Monitored by a Novel Microdialysis Technique. Journal of Neurotrauma, 36(2), 201-211
Open this publication in new window or tab >>Acute Inflammatory Biomarker Responses to Diffuse Traumatic Brain Injury in the Rat Monitored by a Novel Microdialysis Technique
2019 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 36, no 2, p. 201-211Article in journal (Refereed) Published
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.

Keywords
diffuse axonal injury, inflammatory biomarkers, MD, rat, TBI
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-378744 (URN)10.1089/neu.2018.5636 (DOI)000459444800003 ()29790398 (PubMedID)
Funder
Swedish Research CouncilVINNOVAErik, Karin och Gösta Selanders Foundation
Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-11Bibliographically approved
Kononenko, O., Watanabe, H., Stålhandske, L., Zarelius, A., Clausen, F., Yakovleva, T., . . . Marklund, N. (2019). Focal traumatic brain injury induces neuroplastic molecular responses in lumbar spinal cord. Restorative Neurology and Neuroscience, 37(2), 87-96
Open this publication in new window or tab >>Focal traumatic brain injury induces neuroplastic molecular responses in lumbar spinal cord
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2019 (English)In: Restorative Neurology and Neuroscience, ISSN 0922-6028, E-ISSN 1878-3627, Vol. 37, no 2, p. 87-96Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
IOS PRESS, 2019
Keywords
Traumatic brain injury, Tgfb1, c-Fos, spinal cord, plasticity
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:uu:diva-383037 (URN)10.3233/RNN-180882 (DOI)000464944000001 ()30856132 (PubMedID)
Funder
Swedish Research CouncilSwedish Institute
Note

De tre första författarna delar förstaförfattarskapet.

de två sista författarna delar sistaförfattarskapet.

Available from: 2019-05-08 Created: 2019-05-08 Last updated: 2019-05-08Bibliographically approved
Zysk, M., Clausen, F., Aguilar, X., Sehlin, D., Syvänen, S. & Erlandsson, A. (2019). Long-Term Effects of Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease. Journal of Alzheimer's Disease, 72(1), 161-180
Open this publication in new window or tab >>Long-Term Effects of Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease
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2019 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 72, no 1, p. 161-180Article in journal (Refereed) Published
Abstract [en]

Alzheimer's disease (AD) is the leading cause of dementia worldwide, affecting over 10% of the elderly population. Epidemiological evidence indicates that traumatic brain injury (TBI) is an important risk factor for developing AD later in life. However, which injury-induced processes that contribute to the disease onset remains unclear. The aim with the present study was to identify cellular processes that could link TBI to AD development, by investigating the chronic impact of two different injury models, controlled cortical impact (CCI) and midline fluid percussion injury (mFPI). The trauma was induced in 3-month-old tg-ArcSwe mice, carrying the Arctic mutation along with the Swedish mutation, and the influence of TBI on AD progression was analyzed at 12- and 24-weeks post-injury. The long-term effect of the TBI on memory deficiency, amyloid-beta (A beta) pathology, neurodegeneration and inflammation was investigated by Morris water maze, PET imaging, immunohistochemistry, and biochemical analyses. Morris water maze analysis demonstrated that mice subjected to CCI or mFPI performed significantly worse than uninjured tg-ArcSwe mice, especially at the later time point. Moreover, the injured mice showed a late upregulation of reactive gliosis, which concurred with a more pronounced A beta pathology, compared to uninjured AD mice. Our results suggest that the delayed glial activation following TBI may be an important link between the two diseases. However, further studies in both experimental models and human TBI patients will be required to fully elucidate the reasons why TBI increases the risk of neurodegeneration.

Place, publisher, year, edition, pages
IOS PRESS, 2019
Keywords
Alzheimer's disease, amyloid-beta, inflammation, Morris water maze, neurodegeneration astrocytes, PET, traumatic brain injury
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-400408 (URN)10.3233/JAD-190572 (DOI)000500780700014 ()31561367 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationThe Swedish Brain Foundation
Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2020-01-02Bibliographically approved
Dyhrfort, P., Shen, Q., Clausen, F., Eriksson, M., Enblad, P., Kamali-Moghaddam, M., . . . Hillered, L. (2019). Monitoring of Protein Biomarkers of Inflammation in Human Traumatic Brain Injury Using Microdialysis and Proximity Extension Assay Technology in Neurointensive Care. Journal of Neurotrauma, 36(20), 2872-2885
Open this publication in new window or tab >>Monitoring of Protein Biomarkers of Inflammation in Human Traumatic Brain Injury Using Microdialysis and Proximity Extension Assay Technology in Neurointensive Care
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2019 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 36, no 20, p. 2872-2885Article in journal (Refereed) Published
Abstract [en]

Traumatic brain injury (TBI) is followed by secondary injury mechanisms strongly involving neuroinflammation. To monitor the complex inflammatory cascade in human TBI, we used cerebral microdialysis (MD) and multiplex proximity extension assay (PEA) technology and simultaneously measured levels of 92 protein biomarkers of inflammation in MD samples every three hours for five days in 10 patients with severe TBI under neurointensive care. One mu L MD samples were incubated with paired oligonucleotide-conjugated antibodies binding to each protein, allowing quantification by real-time quantitative polymerase chain reaction. Sixty-nine proteins were suitable for statistical analysis. We found five different patterns with either early (<48 h; e.g., CCL20, IL6, LIF, CCL3), mid (48-96 h; e.g., CCL19, CXCL5, CXCL10, MMP1), late (>96 h; e.g., CD40, MCP2, MCP3), biphasic peaks (e.g., CXCL1, CXCL5, IL8) or stable (e.g., CCL4, DNER, VEGFA)/low trends. High protein levels were observed for e.g., CXCL1, CXCL10, MCP1, MCP2, IL8, while e.g., CCL28 and MCP4 were detected at low levels. Several proteins (CCL8, -19, -20, -23, CXCL1, -5, -6, -9, -11, CST5, DNER, Flt3L, and SIRT2) have not been studied previously in human TBI. Cross-correlation analysis revealed that LIF and CXCL5 may play a central role in the inflammatory cascade. This study provides a unique data set with individual temporal trends for potential inflammatory biomarkers in patients with TBI. We conclude that the combination of MD and PEA is a powerful tool to map the complex inflammatory cascade in the injured human brain. The technique offers new possibilities of protein profiling of complex secondary injury pathways.

Place, publisher, year, edition, pages
MARY ANN LIEBERT, INC, 2019
Keywords
biomarkers, inflammation, microdialysis, molecular tools, neurointensive care, proteomics, traumatic brain injury
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-396069 (URN)10.1089/neu.2018.6320 (DOI)000472621900001 ()31017044 (PubMedID)
Funder
Swedish Research CouncilVinnova
Available from: 2019-10-30 Created: 2019-10-30 Last updated: 2020-04-08Bibliographically approved
Lewén, A., Dyhrfort, P., Clausen, F., Enblad, P. & Hillered, L. (2018). A Dedicated 21-Plex Pea Panel For High-Sensitive Protein Biomarker Detection Using Micro-Dialysis In Traumatic Brain Injury. Paper presented at 3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA. Journal of Neurotrauma, 35(16), A130-A130
Open this publication in new window or tab >>A Dedicated 21-Plex Pea Panel For High-Sensitive Protein Biomarker Detection Using Micro-Dialysis In Traumatic Brain Injury
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2018 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 16, p. A130-A130Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
MARY ANN LIEBERT, INC, 2018
Keywords
Biomarker, Inflammation / Immune Function, Monitoring, Neurocritical Care
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-363876 (URN)000441527400353 ()
Conference
3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA
Available from: 2018-11-12 Created: 2018-11-12 Last updated: 2018-11-12Bibliographically approved
Watanabe, H., Zhang, M., Sarkisyan, D., Kononenko, O., Clausen, F., Iakovleva, T., . . . Bakalkin, G. (2018). Asymmetric Hindlimb Motor Response To Focal Traumatic Brain Injury Is Controlled By Side-Specific Opioid Mechanism. Paper presented at 3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA. Journal of Neurotrauma, 35(16), A79-A79
Open this publication in new window or tab >>Asymmetric Hindlimb Motor Response To Focal Traumatic Brain Injury Is Controlled By Side-Specific Opioid Mechanism
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2018 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 16, p. A79-A79Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
MARY ANN LIEBERT, INC, 2018
Keywords
Therapeutics / Drug Discovery, Rehabilitation, Receptor Mediated / Signaling, Neuropathology
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-363881 (URN)000441527400221 ()
Conference
3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA
Available from: 2018-11-12 Created: 2018-11-12 Last updated: 2018-11-12Bibliographically approved
Mao, H., Lu, L., Bian, K., Clausen, F., Colgan, N. & Gilchrist, M. (2018). Biomechanical analysis of fluid percussion model of brain injury. Journal of Biomechanics, 77, 228-232
Open this publication in new window or tab >>Biomechanical analysis of fluid percussion model of brain injury
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2018 (English)In: Journal of Biomechanics, ISSN 0021-9290, E-ISSN 1873-2380, Vol. 77, p. 228-232Article in journal (Refereed) Published
Abstract [en]

Fluid percussion injury (FPI) is a widely used experimental model for studying traumatic brain injury (TBI). However, little is known about how the brain mechanically responds to fluid impacts and how the mechanical pressures/strains of the brain correlate to subsequent brain damage for rodents during FPI. Hence, we developed a numerical approach to simulate FPI experiments on rats and characterize rat brain pressure/strain responses at a high resolution. A previous rat brain model was improved with a new hexahedral elements-based skull model and a new cerebrospinal fluid (CSF) layer. We validated the numerical model against experimentally measured pressures from FPI. Our results indicated that brain tissues under FPI experienced high pressures, which were slightly lower (10-20%) than input saline pressure. Interestingly, FPI was a mixed focus- and diffuse-type injury model with highest strains (12%) being concentrated in the ipsilateral cortex under the fluid-impact site and diffuse strains (5-10%) being spread to the entire brain, which was different from controlled cortical impact in which high strains decreased gradually away from the impact site.

Place, publisher, year, edition, pages
ELSEVIER SCI LTD, 2018
Keywords
Fluid percussion injury, Finite element, Brain injury, Intracranial pressure, Strain
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-363930 (URN)10.1016/j.jbiomech.2018.07.004 (DOI)000442060100032 ()30031650 (PubMedID)
Available from: 2018-10-24 Created: 2018-10-24 Last updated: 2018-10-24Bibliographically approved
Flygt, J., Ruscher, K., Norberg, A., Mir, A., Gram, H., Clausen, F. & Marklund, N. (2018). Neutralization of Interleukin-1 beta following Diffuse Traumatic Brain Injury in the Mouse Attenuates the Loss of Mature Oligodendrocytes. Journal of Neurotrauma, 35(23), 2837-2849
Open this publication in new window or tab >>Neutralization of Interleukin-1 beta following Diffuse Traumatic Brain Injury in the Mouse Attenuates the Loss of Mature Oligodendrocytes
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2018 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 23, p. 2837-2849Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
MARY ANN LIEBERT, INC, 2018
Keywords
fluid percussion injury, inflammation, IL-1 beta, microglia, oligodendrocyte, oligodendrocyte progenitor cells, Olig2, traumatic brain injury
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-371120 (URN)10.1089/neu.2018.5660 (DOI)000450819000010 ()29690837 (PubMedID)
Available from: 2018-12-21 Created: 2018-12-21 Last updated: 2018-12-21Bibliographically approved
Clausen, F. & Hansson, H.-A. (2018). Reduced Intracranial Pressure After Treatment With Anti-Secretory Factor 16 In A Rat Model Of Traumatic Brain Injury. Paper presented at 3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA. Journal of Neurotrauma, 35(16), A195-A196
Open this publication in new window or tab >>Reduced Intracranial Pressure After Treatment With Anti-Secretory Factor 16 In A Rat Model Of Traumatic Brain Injury
2018 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 16, p. A195-A196Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
MARY ANN LIEBERT, INC, 2018
Keywords
Edema, Secondary Injury, Neuroprotection, Intracranial Pressure
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-363874 (URN)000441527400526 ()
Conference
3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA
Available from: 2018-11-14 Created: 2018-11-14 Last updated: 2018-11-14Bibliographically approved
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