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Forsberg, Karin
Publications (10 of 15) Show all publications
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: 2018-06-09Bibliographically approved
Nordin, A., Akimoto, C., Wuolikainen, A., Alstermark, H., Jonsson, P., Birve, A., . . . Andersen, P. M. (2015). Extensive size variability of the GGGGCC expansion in C9orf72 in both neuronal and non-neuronal tissues in 18 patients with ALS or FTD. Human Molecular Genetics, 24(11), 3133-3142
Open this publication in new window or tab >>Extensive size variability of the GGGGCC expansion in C9orf72 in both neuronal and non-neuronal tissues in 18 patients with ALS or FTD
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2015 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 11, p. 3133-3142Article in journal (Refereed) Published
Abstract [en]

A GGGGCC-repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) among Caucasians. However, little is known about the variability of the GGGGCC expansion in different tissues and whether this correlates with the observed phenotype. Here, we used Southern blotting to estimate the size of hexanucleotide expansions in C9orf72 in neural and non-neural tissues from 18 autopsied ALS and FTD patients with repeat expansion in blood. Digitalization of the Southern blot images allowed comparison of repeat number, smear distribution and expansion band intensity between tissues and between patients. We found marked intra-individual variation of repeat number between tissues, whereas there was less variation within each tissue group. In two patients, the size variation between tissues was extreme, with repeat numbers below 100 in all studied non-neural tissues, whereas expansions in neural tissues were 20-40 times greater and in the same size range observed in neural tissues of the other 16 patients. The expansion pattern in different tissues could not distinguish between diagnostic groups and no correlation was found between expansion size in frontal lobe and occurrence of cognitive impairment. In ALS patients, a less number of repeats in the cerebellum and parietal lobe correlated with earlier age of onset and a larger number of repeats in the parietal lobe correlated with a more rapid progression. In 43 other individuals without repeat expansion in blood, we find that repeat sizes up to 15 are stable, as no size variation between blood, brain and spinal cord was found.

National Category
Medical Genetics Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-103256 (URN)10.1093/hmg/ddv064 (DOI)000355674000011 ()25712133 (PubMedID)
Available from: 2015-05-19 Created: 2015-05-19 Last updated: 2018-06-07Bibliographically approved
Liwing, J., Uttervall, K., Lund, J., Aldrin, A., Blimark, C., Carlson, K., . . . Nahi, H. (2014). Improved survival in myeloma patients: starting to close in on the gap between elderly patients and a matched normal population. British Journal of Haematology, 164(5), 684-693
Open this publication in new window or tab >>Improved survival in myeloma patients: starting to close in on the gap between elderly patients and a matched normal population
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2014 (English)In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 164, no 5, p. 684-693Article in journal (Refereed) Published
Abstract [en]

The outcome for multiple myeloma patients has improved since the introduction of bortezomib, thalidomide and lenalidomide. However, studies comparing new and conventional treatment include selected patient groups. We investigated consecutive patients (n = 1638) diagnosed in a defined period and compared survival with a gender- and age-matched cohort Swedish population (n = 9 340 682). Median overall survival for non-high-dose treated patients was 2.8 years. The use of bortezomib, thalidomide or lenalidomide in first line therapy predicted a significantly longer overall survival (median 4.9 years) compared to conventional treatment (2.3 years). Among non-high-dose treated patients receiving at least 2 lines with bortezomib, thalidomide or lenalidomide, 69% and 63% have survived at 3 and 5 years as compared to 48% and 22% with conventional drugs and 88% and 79% in the matched cohort populations, respectively. The median overall survival in high-dose treated patients was 6.9 years. Of these patients, 84% survived at 3 years and 70% at 5 years as compared to 98% and 95% in the matched cohort population. Overall survival in the best non-high-dose treated outcome group is closing the gap with the matched cohort. Upfront use of new drugs is clearly better than waiting until later lines of treatment.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2014
Keywords
myeloma; time to next treatment; progression-free survival; treatment sequencing; population based
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-87151 (URN)10.1111/bjh.12685 (DOI)000331354700009 ()
Available from: 2014-04-11 Created: 2014-03-24 Last updated: 2018-06-08Bibliographically approved
Lund, J., Gruber, A., Lauri, B., Blimark, C., Swedin, A., Hansson, M., . . . Nahi, H. (2014). THE REVII TRIAL: LENALIDOMIDE AND DEXAMETHASONE AS SECOND LINE TREATMENT IN MYELOMA FOLLOWED BY EXTENDED LENALIDOMID VS LEN/DEX. Haematologica (online), 99 (Suppl 1)(P352), 104-105
Open this publication in new window or tab >>THE REVII TRIAL: LENALIDOMIDE AND DEXAMETHASONE AS SECOND LINE TREATMENT IN MYELOMA FOLLOWED BY EXTENDED LENALIDOMID VS LEN/DEX
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2014 (English)In: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99 (Suppl 1), no P352, p. 104-105Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-96641 (URN)000342830900253 ()
Available from: 2014-11-28 Created: 2014-11-24 Last updated: 2018-06-07Bibliographically approved
Mellqvist, U.-H., Gimsing, P., Hjertner, O., Lenhoff, S., Laane, E., Remes, K., . . . Westin, J. (2013). Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial. Blood, 121(23), 4647-4654
Open this publication in new window or tab >>Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial
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2013 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 121, no 23, p. 4647-4654Article in journal (Refereed) Published
Abstract [en]

The Nordic Myeloma Study Group conducted an open randomized trial to compare bortezomib as consolidation therapy given after high-dose therapy and autologous stem cell transplantation (ASCT) with no consolidation in bortezomib-naive patients with newly diagnosed multiple myeloma. Overall, 370 patients were centrally randomly assigned 3 months after ASCT to receive 20 doses of bortezomib given during 21 weeks or no consolidation. The hypothesis was that consolidation therapy would prolong progression-free survival (PFS). The PFS after randomization was 27 months for the bortezomib group compared with 20 months for the control group (P = .05). Fifty-one of 90 patients in the treatment group compared with 32 of 90 controls improved their response after randomization (P = .007). No difference in overall survival was seen. Fatigue was reported more commonly by the bortezomib-treated patients in self-reported quality-of-life (QOL) questionnaires, whereas no other major differences in QOL were recorded between the groups. Consolidation therapy seemed to be beneficial for patients not achieving at least a very good partial response (VGPR) but not for patients in the >= VGPR category at randomization. Consolidation with bortezomib after ASCT in bortezomib-naive patients improves PFS without interfering with QOL. This trial was registered at www.clinicaltrials.gov as #NCT00417911.

National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-79913 (URN)10.1182/blood-2012-11-464503 (DOI)000321895700008 ()
Available from: 2013-09-06 Created: 2013-09-04 Last updated: 2018-06-08Bibliographically approved
Graffmo, K. S., Forsberg, K., Bergh, J., Birve, A., Zetterström, P., Andersen, P. M., . . . Brännström, T. (2013). Expression of wild-type human superoxide dismutase-1 in mice causes amyotrophic lateral sclerosis. Human Molecular Genetics, 22(1), 51-60
Open this publication in new window or tab >>Expression of wild-type human superoxide dismutase-1 in mice causes amyotrophic lateral sclerosis
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2013 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 22, no 1, p. 51-60Article in journal (Refereed) Published
Abstract [en]

A common cause of amyotrophic lateral sclerosis (ALS) is mutations in the gene encoding superoxide dismutase-1. There is evolving circumstantial evidence that the wild-type protein can also be neurotoxic and that it may more generally be involved in the pathogenesis of ALS. To test this proposition more directly, we generated mice that express wild-type human superoxide dismutase-1 at a rate close to that of mutant superoxide dismutase-1 in the commonly studied G93A transgenic model. These mice developed an ALS-like syndrome and became terminally ill after around 370 days. The loss of spinal ventral neurons was similar to that in the G93A and other mutant superoxide dismutase-1 models, and large amounts of aggregated superoxide dismutase-1 were found in spinal cords, but also in the brain. The findings show that wild-type human superoxide dismutase-1 has the ability to cause ALS in mice, and they support the hypothesis of a more general involvement of the protein in the disease in humans.

National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-63578 (URN)10.1093/hmg/dds399 (DOI)000312643400004 ()23026746 (PubMedID)
Available from: 2013-01-03 Created: 2013-01-03 Last updated: 2018-08-19Bibliographically approved
Nahi, H., Liwing, J., Aldrin, A., Andreasson, J., Blimark, C., Carlson, K., . . . Aschan, J. (2012). Is Multiple Myeloma a Chronic Disease?: A Population Based Study Comparing 1843 Patients to a Matched Swedish Population. Paper presented at 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), DEC 08-11, 2012, Atlanta, GA. Blood, 120(21)
Open this publication in new window or tab >>Is Multiple Myeloma a Chronic Disease?: A Population Based Study Comparing 1843 Patients to a Matched Swedish Population
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2012 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, no 21Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
American Society of Hematology, 2012
National Category
Hematology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-67074 (URN)000314049600162 ()
Conference
54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), DEC 08-11, 2012, Atlanta, GA
Available from: 2013-03-14 Created: 2013-03-12 Last updated: 2018-06-08Bibliographically approved
Forsberg, K., Andersen, P. M., Marklund, S. L. & Brännström, T. (2011). Glial nuclear aggregates of superoxide dismutase-1 are regularly present in patients with amyotrophic lateral sclerosis. Acta Neuropathologica, 121(5), 623-634
Open this publication in new window or tab >>Glial nuclear aggregates of superoxide dismutase-1 are regularly present in patients with amyotrophic lateral sclerosis
2011 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 121, no 5, p. 623-634Article in journal (Refereed) Published
Abstract [en]

The most common cause of amyotrophic lateral sclerosis (ALS) is mutations in superoxide dismutase-1 (SOD1). Since there is evidence for the involvement of non-neuronal cells in ALS we searched for signs of SOD1 abnormalities focusing on glia. Spinal cords from 9 ALS patients carrying SOD1 mutations, 51 patients with sporadic or familial ALS who lacked such mutations, and 46 controls were examined by immunohistochemistry. A set of anti-peptide antibodies with specificity for misfolded SOD1 species was used. Misfolded SOD1 in the form of granular aggregates was regularly detected in the nuclei of ventral horn astrocytes, microglia and oligodendrocytes in ALS patients carrying and as well as lacking SOD1 mutations. There was negligible staining in neurodegenerative and non-neurological controls. Misfolded SOD1 appeared occasionally also in nuclei of motoneurons of ALS patients. The results suggest that misfolded SOD1 present in glial and motoneuron nuclei may generally be involved in ALS pathogenesis.

Place, publisher, year, edition, pages
SpringerLink, 2011
Keywords
Amyotrophic lateral sclerosis, superoxide dismutase, motoneurons, intranuclear, glia
National Category
Neurosciences
Research subject
Pathology
Identifiers
urn:nbn:se:umu:diva-47510 (URN)10.1007/s00401-011-0805-3 (DOI)
Available from: 2011-09-22 Created: 2011-09-22 Last updated: 2018-06-08Bibliographically approved
Forsberg, K. (2011). Misfolded superoxide dismutase-1 in sporadic and familial Amyotrophic Lateral Sclerosis. (Doctoral dissertation). Umeå: Umeå Universitet
Open this publication in new window or tab >>Misfolded superoxide dismutase-1 in sporadic and familial Amyotrophic Lateral Sclerosis
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Felveckat superoxid dismutas-1 i sporadisk och familiär amyotrofisk lateralskleros
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative syndrome of unknown etiology that most commonly affects people in middle and high age. The hallmark of ALS is a progressive and simultaneous loss of upper and lower motor neurons in the central nervous system that leads to a progressive muscle atrophy, paralysis and death usually by respiratory failure. ALS is not a pure motor neuronal syndrome; it extends beyond the motor system and affects extramotor areas of the brain as well. The majority of the patients suffer from a sporadic ALS disease (SALS) while in at least ten percent the disease appears in a familial form (FALS). Mutations in the gene encoding the antioxidant enzyme superoxide dismutase-1 (SOD1) are the most common cause of FALS. More than 165 SOD1 mutations have been described, and these confer the enzyme a cytotoxic gain of function. Evidence suggests that the toxicity results from structural instability which makes the mutated enzyme prone to misfold and form aggregates in the spinal cord and brain motor neurons. Recent studies indicate that the wild-type human SOD1 protein (wt-hSOD1) has the propensity to develop neurotoxic features.

The aim of the present study was to investigate if wt-hSOD1 is involved in the pathogenesis of SALS and FALS patients lacking SOD1 mutations and to evaluate the neurotoxic effect of misfolded wt-hSOD1 protein in vivo by generating a transgenic wt-hSOD1 mice model. We produced specific SOD1-peptide-generated antibodies that could discriminate between the misfolded and native form of the enzyme and optimized a staining protocol for detection of misfolded wt-hSOD1 by immunohistochemistry and confocal microscopy of brain and spinal cord tissue. We discovered that aggregates of misfolded wt-hSOD1 were constitutively present in the cytoplasm of motor neurons in all investigated SALS patients and in FALS patients lacking SOD1 gene mutations. Interestingly, the misfolded wt-hSOD1 aggregates were also found in some motor neuron nuclei and in the nuclei of the surrounding glial cells, mainly astrocytes but also microglia and oligodendrocytes, indicating that misfolded wt-hSOD1 protein aggregates may exert intranuclear toxicity. We compared our findings to FALS with SOD1 mutations by investigating brain and spinal cord tissue from patients homozygous for the D90A SOD1 mutation, a common SOD1 mutation that encodes a stable SOD1 protein with a wild-type-like enzyme activity. We observed a similar morphology with a profound loss of motor neurons and aggregates of misfolded SOD1 in the remaining motor neuron. Interestingly, we found gliosis and microvacuolar degeneration in the superficial lamina of the frontal and temporal lobe, indicating a possible frontotemporal lobar dementia in addition to the ALS disorder.

Our morphological and biochemical findings were tested in vivo by generating homozygous transgenic mice that over expressed wt-hSOD1. These mice developed a fatal ALS-like disease, mimicking the one seen in mice expressing mutated hSOD1. The wt-hSOD1 mice showed a slower weight gain compared to non-transgenic mice and developed a progressive ALS-like hind-leg paresis. Aggregates of misfolded wt-hSOD1 were found in the brain and spinal cord neurons similar to those in humans accompanied by a loss of 41 % of motor neurons compared to non-transgenic litter mates.

In conclusion, we found misfolded wt-hSOD1 aggregates in the cytoplasm and nuclei of motor neurons and glial cells in all patients suffering from ALS syndrome. Notable is the fact that misfolded wt-hSOD1 aggregates were also detected in FALS patients lacking SOD1 mutations indicating a role for SOD1 even when other genetic mutations are present. The neurotoxicity of misfolded wt-hSOD1 protein was confirmed in vivo by wt-hSOD1 transgenic mice that developed a fatal ALS-like disease. Taken together, our results support the notion that misfolded wt-hSOD1 could be generally involved and play a decisive role in the pathogenesis of all forms of ALS.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2011. p. 78
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1438
Keywords
ALS, SOD-1 motor neuron, protein misfolding, intranuclear, antibodies, CNS, brain
National Category
Neurosciences
Research subject
Pathology
Identifiers
urn:nbn:se:umu:diva-47550 (URN)978-91-7459-256-6 (ISBN)
Public defence
2011-10-14, Betula, Umeå University, Norrlands Universitetssjukhus, byggnad 6M, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2011-09-23 Created: 2011-09-22 Last updated: 2018-06-08Bibliographically approved
Waage, A., Gimsing, P., Fayers, P., Abildgaard, N., Ahlberg, L., Björkstrand, B., . . . Turesson, I. (2010). Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood, 116(9), 1405-1412
Open this publication in new window or tab >>Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma
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2010 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 116, no 9, p. 1405-1412Article in journal (Refereed) Published
Abstract [en]

In this double-blind, placebo-controlled study, 363 patients with untreated multiple myeloma were randomized to receive either melphalan-prednisone and thalidomide (MPT) or melphalan-prednisone and placebo (MP). The dose of melphalan was 0.25 mg/kg and prednisone was 100 mg given daily for 4 days every 6 weeks until plateau phase. The dose of thalidomide/placebo was escalated to 400 mg daily until plateau phase and thereafter reduced to 200 mg daily until progression. A total of 357 patients were analyzed. Partial response was 34% and 33%, and very good partial response or better was 23% and 7% in the MPT and MP arms, respectively (P < .001). There was no significant difference in progression-free or overall survival, with median survival being 29 months in the MPT arm and 32 months in the MP arm. Most quality of life outcomes improved equally in both arms, apart from constipation, which was markedly increased in the MPT arm. Constipation, neuropathy, nonneuropathy neurologic toxicity, and skin reactions were significantly more frequent in the MPT arm. The number of thromboembolic events was equal in the 2 treatment arms. In conclusion, MPT had a significant antimyeloma effect, but this did not translate into improved survival. This trial was registered at www.clinicaltrials.gov as #NCT00218855.

Identifiers
urn:nbn:se:umu:diva-36855 (URN)10.1182/blood-2009-08-237974 (DOI)20448107 (PubMedID)
Available from: 2010-10-12 Created: 2010-10-12 Last updated: 2018-06-08Bibliographically approved
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