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Brännström, Thomas
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Publications (10 of 95) Show all publications
Forsberg, K., Graffmo, K. S., Pakkenberg, B., Weber, M., Nielsen, M., Marklund, S. L., . . . Munch Andersen, P. (2019). Misfolded SOD1 inclusions in patients with mutations in C9orf72 and other ALS/FTD-associated genes. Journal of Neurology, Neurosurgery and Psychiatry, 90(8), 861-869
Open this publication in new window or tab >>Misfolded SOD1 inclusions in patients with mutations in C9orf72 and other ALS/FTD-associated genes
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2019 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 90, no 8, p. 861-869Article in journal (Refereed) Published
Abstract [en]

Objective: A hallmark of amyotrophic lateral sclerosis (ALS) caused by mutations in superoxide dismutase-1 (SOD1) are inclusions containing SOD1 in motor neurons. Here, we searched for SOD1-positive inclusions in 29 patients carrying ALS-linked mutations in six other genes.

Methods: A panel of antibodies that specifically recognise misfolded SOD1 species were used for immunohistochemical investigations of autopsy tissue.

Results: The 18 patients with hexanucleotide-repeat-expansions in C9orf72 had inclusions of misfolded wild type (WT) SOD1(WT) in spinal motor neurons. Similar inclusions were occasionally observed in medulla oblongata and in the motor cortex and frontal lobe. Patients with mutations in FUS, KIF5A, NEK1, ALSIN or VAPB, carried similar SOD1(WT) inclusions. Minute amounts of misSOD1(WT) inclusions were detected in 2 of 20 patients deceased from non-neurological causes and in 4 of 10 patients with other neurodegenerative diseases. Comparison was made with 17 patients with 9 different SOD1 mutations. Morphologically, the inclusions in patients with mutations in C9orf72HRE, FUS, KIF5A, NEK1, VAPB and ALSIN resembled inclusions in patients carrying the wildtype-like SOD1(D90A) mutation, whereas patients carrying unstable SOD1 mutations (A4V, V5M, D76Y, D83G, D101G, G114A, G127X, L144F) had larger skein-like SOD1-positive inclusions.

Conclusions and relevance Abundant inclusions containing misfolded SOD1(WT) are found in spinal and cortical motor neurons in patients carrying mutations in six ALS-causing genes other than SOD1. This suggests that misfolding of SOD1(WT) can be part of a common downstream event that may be pathogenic. The new anti-SOD1 therapeutics in development may have applications for a broader range of patients.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
Keywords
amyotrophic lateral sclerosis, neuronal inclusions, C9orf72, KIF5A, superoxide dismutase-1
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:umu:diva-163689 (URN)10.1136/jnnp-2018-319386 (DOI)000482509400004 ()30992335 (PubMedID)
Available from: 2019-10-17 Created: 2019-10-17 Last updated: 2019-11-25Bibliographically approved
Brännström, T., Andersen, P. M., Bergh, J., Ekhtiari Bidhendi, E. & Marklund, S. M. (2019). Mutant SOD1 aggregates from human ventral horn transmit templated aggregation and fatal ALS-like disease. Paper presented at 19th International Congress of Neuropathology, SEP 23-27, 2018, Tokyo, JAPAN. Brain Pathology, 29, 90-90
Open this publication in new window or tab >>Mutant SOD1 aggregates from human ventral horn transmit templated aggregation and fatal ALS-like disease
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2019 (English)In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 29, p. 90-90Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
John Wiley & Sons, 2019
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:umu:diva-157592 (URN)000459814800279 ()
Conference
19th International Congress of Neuropathology, SEP 23-27, 2018, Tokyo, JAPAN
Note

Supplement: 1

Special Issue: SI

Meeting Abstract: P2-66

Available from: 2019-03-28 Created: 2019-03-28 Last updated: 2019-11-25Bibliographically approved
Ekhtiari Bidhendi, E., Bergh, J., Zetterström, P., Forsberg, K., Pakkenberg, B., Andersen, P. M., . . . Brännström, T. (2018). Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis. Acta Neuropathologica, 136(6), 939-953
Open this publication in new window or tab >>Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis
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2018 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 136, no 6, p. 939-953Article in journal (Refereed) Published
Abstract [en]

Motor neurons containing aggregates of superoxide dismutase 1 (SOD1) are hallmarks of amyotrophic lateral sclerosis (ALS) caused by mutations in the gene encoding SOD1. We have previously reported that two strains of mutant human (h) SOD1 aggregates (denoted A and B) can arise in hSOD1-transgenic models for ALS and that inoculation of such aggregates into the lumbar spinal cord of mice results in rostrally spreading, templated hSOD1 aggregation and premature fatal ALS-like disease. Here, we explored whether mutant hSOD1 aggregates with prion-like properties also exist in human ALS. Aggregate seeds were prepared from spinal cords from an ALS patient carrying the hSOD1G127Gfs*7 truncation mutation and from mice transgenic for the same mutation. To separate from mono-, di- or any oligomeric hSOD1 species, the seed preparation protocol included ultracentrifugation through a density cushion. The core structure of hSOD1G127Gfs*7 aggregates present in mice was strain A-like. Inoculation of the patient- or mouse-derived seeds into lumbar spinal cord of adult hSOD1-expressing mice induced strain A aggregation propagating along the neuraxis and premature fatal ALS-like disease (p < 0.0001). Inoculation of human or murine control seeds had no effect. The potencies of the ALS patient-derived seed preparations were high and disease was initiated in the transgenic mice by levels of hSOD1G127Gfs*7 aggregates much lower than those found in the motor system of patients carrying the mutation. The results suggest that prion-like growth and spread of hSOD1 aggregation could be the primary pathogenic mechanism, not only in hSOD1 transgenic rodent models, but also in human ALS.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Superoxide dismutase, prion-like, aggregation, propagation, motor neuron disease
National Category
Neurosciences
Research subject
Neurology; Pathology
Identifiers
urn:nbn:se:umu:diva-150909 (URN)10.1007/s00401-018-1915-y (DOI)000451952700008 ()30284034 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationTorsten Söderbergs stiftelseThe Swedish Brain FoundationThe Kempe FoundationsVästerbotten County Council
Note

Originally included in thesis in manuscript form.

Available from: 2018-08-18 Created: 2018-08-18 Last updated: 2019-09-12Bibliographically approved
Tjust, A. E., Danielsson, A., Andersen, P. M., Brännstrom, T. & Pedrosa-Domellöf, F. (2017). Impact of Amyotrophic Lateral Sclerosis on Slow Tonic Myofiber Composition in Human Extraocular Muscles. Investigative Ophthalmology and Visual Science, 58(9), 3708-3715
Open this publication in new window or tab >>Impact of Amyotrophic Lateral Sclerosis on Slow Tonic Myofiber Composition in Human Extraocular Muscles
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2017 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 58, no 9, p. 3708-3715Article in journal (Refereed) Published
Abstract [en]

PURPOSE. To analyze the proportion and cross-sectional area of myofibers containing myosin heavy chain slow-twitch (MyHCI) and myosin heavy chain slow tonic (MyHCsto) in extraocular muscles of autopsied amyotrophic lateral sclerosis (ALS) patients with either spinal or bulbar site of disease onset. METHODS. Whole-muscle cross sections from the middle portion of the medial rectus were labeled with antibodies against MyHCI or MyHCsto and laminin. Myofibers labeled with the MyHC antibodies (MyHCI+sto) and the total number of myofibers were quantified in the orbital and global layer of 6 control individuals and 18 ALS patients. The cross-sectional area of myofibers labeled for either MyHC was quantified in 130 to 472 fibers/individual in the orbital and in 180 to 573 fibers/individual in the global layer of each specimen. RESULTS. The proportion of MyHCI+sto myofibers was significantly smaller in the orbital and global layer of ALS compared to control individuals. MyHCI+sto myofibers were significantly smaller in the global layer than in the orbital layer of ALS, whereas they were of similar size in control subjects. The decreased proportion of MyHCI+sto fibers correlated significantly with the age of death, but not disease duration, in patients who had the bulbar-onset variant of ALS but not in patients with spinal variant. CONCLUSIONS. ALS, regardless of site of onset, involves a loss of myofibers containing MyHCI+sto. Only in bulbar-onset cases did aging seem to play a role in the pathophysiological processes underlying the loss of MyHCI+sto fibers.

Place, publisher, year, edition, pages
ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2017
Keywords
amyotrophic lateral sclerosis, extraocular muscles, MyH14, slow tonic, muscle fibers
National Category
Ophthalmology
Identifiers
urn:nbn:se:umu:diva-140482 (URN)10.1167/iovs.17-22098 (DOI)000410931200051 ()28738414 (PubMedID)
Available from: 2017-10-20 Created: 2017-10-20 Last updated: 2019-11-19Bibliographically approved
Johansson, G., Brannstrom, T., Andersson, U., Golovleva, I. & Melin, B. (2017). MOLECULAR CLASSIFICATION OF MALIGNANT GLIOMA. Paper presented at 5th Quadrennial Meeting of the World-Federation-of-Neuro-Oncology-Societies (WFNOS), MAY 04-07, 2017, Zurich, SWITZERLAND. Neuro-Oncology, 19(Supplement: 3), 88-88, Article ID Meeting Abstract: P10.15.
Open this publication in new window or tab >>MOLECULAR CLASSIFICATION OF MALIGNANT GLIOMA
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2017 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 19, no Supplement: 3, p. 88-88, article id Meeting Abstract: P10.15Article in journal, Meeting abstract (Refereed) Published
Place, publisher, year, edition, pages
OXFORD UNIV PRESS INC, 2017
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-136983 (URN)000402732900335 ()
Conference
5th Quadrennial Meeting of the World-Federation-of-Neuro-Oncology-Societies (WFNOS), MAY 04-07, 2017, Zurich, SWITZERLAND
Available from: 2017-06-30 Created: 2017-06-30 Last updated: 2019-05-10Bibliographically approved
Tabatabaei, P., Visse, E., Bergström, P., Brännström, T., Siesjö, P. & Bergenheim, A. T. (2017). Radiotherapy induces an immediate inflammatory reaction in malignant glioma: a clinical microdialysis study. Journal of Neuro-Oncology, 131(1), 83-92
Open this publication in new window or tab >>Radiotherapy induces an immediate inflammatory reaction in malignant glioma: a clinical microdialysis study
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2017 (English)In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 131, no 1, p. 83-92Article in journal (Refereed) Published
Abstract [en]

The knowledge of response to radiation in the immuno-microenvironment of high grade gliomas is sparse. In vitro results have indicated an inflammatory response of myeloid cells after irradiation. Therefore, microdialysis was used to verify whether this is operative in tumor tissue and brain adjacent to tumor (BAT) after clinical radiotherapy of patients with high grade glioma. Stereotactic biopsies and implantation of microdialysis catheters in tumor tissue and BAT were performed in eleven patients with high-grade glioma. The patients were given daily radiation fractions of 2-3.4 Gy. Microdialysis samples were collected before radiotherapy and during the first five days of radiation. Cytokines, glucose metabolites, glutamate and glycerol were analyzed. Immunohistochemistry was performed to detect macrophages (CD68) and monocytes (CD163) as well as IL-6, IL-8 and MCP-1. A significant increase of IL-8, MCP-1 and MIP-1a were detected in tumor tissue already after the first dose of radiation and increased further during 5 days of radiation. IL-6 did also increase but after five fractions of radiation. In BAT, the cytokine response was modest with significant increase of IL-8 after third dose of radiation. We found a positive correlation between baseline IL-8 and IL-6 microdialysis levels in tumor tissue and survival. Glucose metabolites or glycerol and glutamate did not change during radiation. In all tumors staining for macrophages was demonstrated. IL-6 was found in viable tumor cells while MCP-1 was demonstrated in macrophages or tumor matrix. Our findings suggest that radiation induces a rapid enhancement of the prevailing inflammation in high-grade glioma tissue. The microdialysis technique is feasible for this type of study and could be used to monitor metabolic changes after different interventions.

Place, publisher, year, edition, pages
Springer, 2017
Keywords
Cytokine, Glioblastoma, Radiotherapy, Microdialysis, Inflammation
National Category
Cancer and Oncology Neurology
Identifiers
urn:nbn:se:umu:diva-131132 (URN)10.1007/s11060-016-2271-1 (DOI)000393065400010 ()27664151 (PubMedID)
Available from: 2017-02-06 Created: 2017-02-06 Last updated: 2019-05-09Bibliographically approved
Nordin, A., Akimoto, C., Wuolikainen, A., Alstermark, H., Forsberg, K., Baumann, P., . . . Andersen, P. M. (2017). Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation: a large multinational screening study. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 18(3-4), 256-264
Open this publication in new window or tab >>Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation: a large multinational screening study
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2017 (English)In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, E-ISSN 2167-9223, Vol. 18, no 3-4, p. 256-264Article in journal (Refereed) Published
Abstract [en]

A large GGGGCC-repeat expansion mutation (HREM) in C9orf72 is the most common known cause of ALS and FTD in European populations. Sequence variations immediately downstream of the HREM region have previously been observed and have been suggested to be one reason for difficulties in interpreting RP-PCR data. Our objective was to determine the properties of these sequence variations with regard to prevalence, the range of variation, and effect on disease prognosis. We screened a multi-national cohort (n = 6981) for the HREM and samples with deviant RP-PCR curves were identified. The deviant samples were subsequently sequenced to determine sequence alteration. Our results show that in the USA and European cohorts (n = 6508) 10.7% carried the HREM and 3% had a sequence variant, while no HREM or sequence variants were observed in the Japanese cohort (n = 473). Sequence variations were more common on HREM alleles; however, certain population specific variants were associated with a non-expanded allele. In conclusion, we identified 38 different sequence variants, most located within the first 50 bp downstream of the HREM region. Furthermore, the presence of an HREM was found to be coupled to a lower age of onset and a shorter disease survival, while sequence variation did not have any correlation with these parameters.

Keywords
ALS, C9orf72, FTD, RP-PCR interpretation, variants
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-134981 (URN)10.1080/21678421.2016.1262423 (DOI)000400792800012 ()27936955 (PubMedID)
Available from: 2017-05-15 Created: 2017-05-15 Last updated: 2019-05-09Bibliographically approved
Andersson, U., Degerman, S., Dahlin, A., Brannstrom, T., Roos, G. & Melin, B. S. (2017). TELOMERE LENGTH, ALLERGIES AND RISK OF GLIOMA. Paper presented at 5th Quadrennial Meeting of the World-Federation-of-Neuro-Oncology-Societies (WFNOS), MAY 04-07, 2017, Zurich, SWITZERLAND. Neuro-Oncology, 19(Supplement: 3), 23-23, Article ID Meeting Abstract: P01.03.
Open this publication in new window or tab >>TELOMERE LENGTH, ALLERGIES AND RISK OF GLIOMA
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2017 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 19, no Supplement: 3, p. 23-23, article id Meeting Abstract: P01.03Article in journal, Meeting abstract (Refereed) Published
Place, publisher, year, edition, pages
OXFORD UNIV PRESS INC, 2017
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-136984 (URN)000402732900081 ()
Conference
5th Quadrennial Meeting of the World-Federation-of-Neuro-Oncology-Societies (WFNOS), MAY 04-07, 2017, Zurich, SWITZERLAND
Available from: 2017-06-30 Created: 2017-06-30 Last updated: 2018-06-09Bibliographically approved
Ghasimi, S., Wibom, C., Dahlin, A. M., Brännström, T., Golovleva, I., Andersson, U. & Melin, B. (2016). Genetic risk variants in the CDKN2A/B, RTEL1 and EGFR genes are associated with somatic biomarkers in glioma. Journal of Neuro-Oncology, 127(3), 483-492
Open this publication in new window or tab >>Genetic risk variants in the CDKN2A/B, RTEL1 and EGFR genes are associated with somatic biomarkers in glioma
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2016 (English)In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 127, no 3, p. 483-492Article in journal (Refereed) Published
Abstract [en]

During the last years, genome wide association studies have discovered common germline genetic variants associated with specific glioma subtypes. We aimed to study the association between these germline risk variants and tumor phenotypes, including copy number aberrations and protein expression. A total of 91 glioma patients were included. Thirteen well known genetic risk variants in TERT, EGFR, CCDC26, CDKN2A, CDKN2B, PHLDB1, TP53, and RTEL1 were selected for investigation of possible correlations with the glioma somatic markers: EGFR amplification, 1p/19q codeletion and protein expression of p53, Ki-67, and mutated IDH1. The CDKN2A/B risk variant, rs4977756, and the CDKN2B risk variant, rs1412829 were inversely associated (p = 0.049 and p = 0.002, respectively) with absence of a mutated IDH1, i.e., the majority of patients homozygous for the risk allele showed no or low expression of mutated IDH1. The RTEL1 risk variant, rs6010620 was associated (p = 0.013) with not having 1p/19q codeletion, i.e., the majority of patients homozygous for the risk allele did not show 1p/19q codeletion. In addition, the EGFR risk variant rs17172430 and the CDKN2B risk variant rs1412829, both showed a trend for association (p = 0.055 and p = 0.051, respectively) with increased EGFR copy number, i.e., the majority of patients homozygote for the risk alleles showed chromosomal gain or amplification of EGFR. Our findings indicate that CDKN2A/B risk genotypes are associated with primary glioblastoma without IDH mutation, and that there is an inverse association between RTEL1 risk genotypes and 1p/19q codeletion, suggesting that these genetic variants have a molecular impact on the genesis of high graded brain tumors. Further experimental studies are needed to delineate the functional mechanism of the association between genotype and somatic genetic aberrations.

Keywords
CDKN2A/B, EGFR, RTEL1, SNP, FISH, ASCAT
National Category
Cancer and Oncology Neurology
Identifiers
urn:nbn:se:umu:diva-121460 (URN)10.1007/s11060-016-2066-4 (DOI)000374463800009 ()26839018 (PubMedID)
Available from: 2016-06-22 Created: 2016-06-02 Last updated: 2018-06-07Bibliographically approved
Tokuda, E., Brännström, T., Andersen, P. M. & Marklund, S. L. (2016). Low autophagy capacity implicated in motor system vulnerability to mutant superoxide dismutase. Acta neuropathologica communications, 4, Article ID 6.
Open this publication in new window or tab >>Low autophagy capacity implicated in motor system vulnerability to mutant superoxide dismutase
2016 (English)In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 4, article id 6Article in journal (Refereed) Published
Abstract [en]

Introduction: The motor system is selectively vulnerable to mutations in the ubiquitously expressed aggregation-prone enzyme superoxide dismutase-1 (SOD1).

Results: Autophagy clears aggregates, and factors involved in the process were analyzed in multiple areas of the CNS from human control subjects (n = 10) and amyotrophic lateral sclerosis (ALS) patients (n = 18) with or without SOD1 mutations. In control subjects, the key regulatory protein Beclin 1 and downstream factors were remarkably scarce in spinal motor areas. In ALS patients, there was evidence of moderate autophagy activation and also dysregulation. These changes were largest in SOD1 mutation carriers. To explore consequences of low autophagy capacity, effects of a heterozygous deletion of Beclin 1 were examined in ALS mouse models expressing mutant SOD1s. This caused earlier SOD1 aggregation, onset of symptoms, motor neuron loss, and a markedly shortened survival. In contrast, the levels of soluble misfolded SOD1 species were reduced.

Conclusions: The findings suggest that an inherent low autophagy capacity might cause the vulnerability of the motor system, and that SOD1 aggregation plays a crucial role in the pathogenesis.

Keywords
Amyotrophic lateral sclerosis, Autophagy, Motor system vulnerability, Protein aggregates, Superoxide sumutase-1
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-116740 (URN)10.1186/s40478-016-0274-y (DOI)000368653000001 ()26810478 (PubMedID)
Available from: 2016-02-19 Created: 2016-02-11 Last updated: 2019-05-20Bibliographically approved
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