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Herman, S., Niemelä, V., Emami Khoonsari, P., Sundblom, J., Burman, J., Landtblom, A.-M., . . . Kultima, K. (2019). Alterations in the tyrosine and phenylalanine pathways revealed by biochemical profiling in cerebrospinal fluid of Huntington's disease subjects. Scientific Reports, 9, Article ID 4129.
Open this publication in new window or tab >>Alterations in the tyrosine and phenylalanine pathways revealed by biochemical profiling in cerebrospinal fluid of Huntington's disease subjects
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 4129Article in journal (Refereed) Published
Abstract [en]

Huntington's disease (HD) is a severe neurological disease leading to psychiatric symptoms, motor impairment and cognitive decline. The disease is caused by a CAG expansion in the huntingtin (HTT) gene, but how this translates into the clinical phenotype of HD remains elusive. Using liquid chromatography mass spectrometry, we analyzed the metabolome of cerebrospinal fluid (CSF) from premanifest and manifest HD subjects as well as control subjects. Inter-group differences revealed that the tyrosine metabolism, including tyrosine, thyroxine, L-DOPA and dopamine, was significantly altered in manifest compared with premanifest HD. These metabolites demonstrated moderate to strong associations to measures of disease severity and symptoms. Thyroxine and dopamine also correlated with the five year risk of onset in premanifest HD subjects. The phenylalanine and the purine metabolisms were also significantly altered, but associated less to disease severity. Decreased levels of lumichrome were commonly found in mutated HTT carriers and the levels correlated with the five year risk of disease onset in premanifest carriers. These biochemical findings demonstrates that the CSF metabolome can be used to characterize molecular pathogenesis occurring in HD, which may be essential for future development of novel HD therapies.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-379886 (URN)10.1038/s41598-019-40186-5 (DOI)000460754600020 ()30858393 (PubMedID)
Funder
Åke Wiberg FoundationEU, Horizon 2020, 654241
Available from: 2019-03-25 Created: 2019-03-25 Last updated: 2019-10-23Bibliographically approved
Herman, S., Åkerfeldt, T., Spjuth, O., Burman, J. & Kultima, K. (2019). Biochemical Differences in Cerebrospinal Fluid between Secondary Progressive and Relapsing-Remitting Multiple Sclerosis. Cells, 8(2), Article ID 84.
Open this publication in new window or tab >>Biochemical Differences in Cerebrospinal Fluid between Secondary Progressive and Relapsing-Remitting Multiple Sclerosis
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2019 (English)In: Cells, ISSN 2073-4409, Vol. 8, no 2, article id 84Article in journal (Refereed) Published
Abstract [en]

To better understand the pathophysiological differences between secondary progressive multiple sclerosis (SPMS) and relapsing-remitting multiple sclerosis (RRMS), and to identify potential biomarkers of disease progression, we applied high-resolution mass spectrometry (HRMS) to investigate the metabolome of cerebrospinal fluid (CSF). The biochemical differences were determined using partial least squares discriminant analysis (PLS-DA) and connected to biochemical pathways as well as associated to clinical and radiological measures. Tryptophan metabolism was significantly altered, with perturbed levels of kynurenate, 5-hydroxytryptophan, 5-hydroxyindoleacetate, and N-acetylserotonin in SPMS patients compared with RRMS and controls. SPMS patients had altered kynurenine compared with RRMS patients, and altered indole-3-acetate compared with controls. Regarding the pyrimidine metabolism, SPMS patients had altered levels of uridine and deoxyuridine compared with RRMS and controls, and altered thymine and glutamine compared with RRMS patients. Metabolites from the pyrimidine metabolism were significantly associated with disability, disease activity and brain atrophy, making them of particular interest for understanding the disease mechanisms and as markers of disease progression. Overall, these findings are of importance for the characterization of the molecular pathogenesis of SPMS and support the hypothesis that the CSF metabolome may be used to explore changes that occur in the transition between the RRMS and SPMS pathologies.

Keywords
cerebrospinal fluid, mass spectrometry, metabolomics, multiple sclerosis, pyrimidine, tryptophan
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-375564 (URN)10.3390/cells8020084 (DOI)000460896000006 ()30678351 (PubMedID)
Funder
Åke Wiberg FoundationEU, Horizon 2020, 654241
Available from: 2019-01-31 Created: 2019-01-31 Last updated: 2019-04-11Bibliographically approved
Novella, J. A., Emami Khoonsari, P., Herman, S., Whitenack, D., Capuccini, M., Burman, J., . . . Spjuth, O. (2019). Container-based bioinformatics with Pachyderm. Bioinformatics, 35, 839-846
Open this publication in new window or tab >>Container-based bioinformatics with Pachyderm
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2019 (English)In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 35, p. 839-846Article in journal (Refereed) Published
National Category
Bioinformatics and Systems Biology
Identifiers
urn:nbn:se:uu:diva-371628 (URN)10.1093/bioinformatics/bty699 (DOI)000467227300015 ()30101309 (PubMedID)
Projects
eSSENCE
Available from: 2018-08-08 Created: 2018-12-21 Last updated: 2019-09-26Bibliographically approved
Bridel, C., van Wieringen, W. N., Zetterberg, H., Tijms, B. M., Teunissen, C. E., Alvarez-Cermeno, J. C., . . . Wild, E. J. (2019). Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology: A Systematic Review and Meta-analysis. JAMA Neurology, 76(9), 1035-1048
Open this publication in new window or tab >>Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology: A Systematic Review and Meta-analysis
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2019 (English)In: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157, Vol. 76, no 9, p. 1035-1048Article, review/survey (Refereed) Published
Abstract [en]

Importance  Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.

Objectives  To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.

Data Sources  PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.

Study Selection  Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.

Data Extraction and Synthesis  Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.

Main Outcome and Measure  The cNfL levels adjusted for age and sex across diagnoses.

Results  Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.

Conclusions and Relevance  These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.

National Category
Psychiatry Neurology
Identifiers
urn:nbn:se:uu:diva-395752 (URN)10.1001/jamaneurol.2019.1534 (DOI)000486895500008 ()31206160 (PubMedID)
Funder
Swedish Research CouncilEU, European Research CouncilKnut and Alice Wallenberg FoundationSwedish Research Council, K2014-62X-14647-12-51Swedish Research Council, K2010-61P-21568-01-4Swedish Foundation for Strategic Research , KF10-0039The Swedish Brain Foundation
Available from: 2019-10-24 Created: 2019-10-24 Last updated: 2019-10-24Bibliographically approved
Burt, R. K., Balabanov, R., Burman, J., Sharrack, B., Snowden, J. A., Oliveira, M. C., . . . Helenowski, I. B. (2019). Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial. Journal of the American Medical Association (JAMA), 321(2), 165-174
Open this publication in new window or tab >>Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial
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2019 (English)In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 321, no 2, p. 165-174Article in journal (Refereed) Published
Abstract [en]

IMPORTANCE Hematopoietic stem cell transplantation (HSCT) represents a potentially useful approach to slow or prevent progressive disability in relapsing-remitting multiple sclerosis (MS).

OBJECTIVE To compare the effect of nonmyeloablative HSCT vs disease-modifying therapy (DMT) on disease progression.

DESIGN, SETTING, AND PARTICIPANTS Between September 20, 2005, and July 7, 2016, a total of 110 patients with relapsing-remitting MS, at least 2 relapses while receiving DMT in the prior year, and an Expanded Disability Status Scale (EDSS; score range, 0-10 [10 = worst neurologic disability]) score of 2.0 to 6.0 were randomized at 4 US, European, and South American centers. Final follow-up occurred in January 2018 and database lock in February 2018.

INTERVENTIONS Patients were randomized to receive HSCT along with cyclophosphamide (200mg/kg) and antithymocyte globulin (6mg/kg) (n = 55) or DMT of higher efficacy or a different class than DMT taken during the previous year (n = 55).

MAIN OUTCOMES AND MEASURES The primary end point was disease progression, defined as an EDSS score increase after at least 1 year of 1.0 point or more (minimal clinically important difference, 0.5) on 2 evaluations 6 months apart, with differences in time to progression estimated as hazard ratios. RESULTS Among 110 randomized patients (73 [66%] women; mean age, 36 [SD, 8.6] years), 103 remained in the trial, with 98 evaluated at 1 year and 23 evaluated yearly for 5 years (median follow-up, 2 years; mean, 2.8 years). Disease progression occurred in 3 patients in the HSCT group and 34 patients in the DMT group. Median time to progression could not be calculated in the HSCT group because of too few events; it was 24 months (interquartile range, 18-48 months) in the DMT group (hazard ratio, 0.07; 95% CI, 0.02-0.24; P < .001). During the first year, mean EDSS scores decreased (improved) from 3.38 to 2.36 in the HSCT group and increased (worsened) from 3.31 to 3.98 in the DMT group (between-group mean difference,-1.7; 95% CI,-2.03 to -1.29; P < .001). There were no deaths and no patients who received HSCT developed nonhematopoietic grade 4 toxicities (such as myocardial infarction, sepsis, or other disabling or potential life-threatening events).

CONCLUSIONS AND RELEVANCE In this preliminary study of patients with relapsing-remitting MS, nonmyeloablative HSCT, compared with DMT, resulted in prolonged time to disease progression. Further research is needed to replicate these findings and to assess long-term outcomes and safety.

Place, publisher, year, edition, pages
AMER MEDICAL ASSOC, 2019
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-375869 (URN)10.1001/jama.2018.18743 (DOI)000455606300015 ()30644983 (PubMedID)
Available from: 2019-02-04 Created: 2019-02-04 Last updated: 2019-02-04Bibliographically approved
Feresiadou, A., Nilsson, K., Ingelsson, M., Press, R., Kmezic, I., Nygren, I., . . . Burman, J. (2019). Measurement of sCD27 in the cerebrospinal fluid identifies patients with neuroinflammatory disease. Journal of Neuroimmunology, 332, 31-36
Open this publication in new window or tab >>Measurement of sCD27 in the cerebrospinal fluid identifies patients with neuroinflammatory disease
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2019 (English)In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 332, p. 31-36Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Laboratory tests to assist in the diagnosis and monitoring of neuroinflammatory diseases are scarce. The soluble form of the CD27 molecule (sCD27) is shed in high concentrations by activated T cells and can be detected in the cerebrospinal fluid. The aim of this study was to investigate whether CSF quantitation of sCD27 could discriminate between inflammatory and non-inflammatory neurological diseases.

METHODS: The concentration of sCD27 was measured using a commercially available ELISA in 803 well-defined subjects from a study cohort comprised of 338 patients with neuroinflammatory disease, 338 with non-inflammatory neurological disease and 127 controls without neurological disease.

RESULTS: The median value of cerebrospinal fluid sCD27 was 64 pg/mL (IQR 0-200) in controls, 58 pg/mL (IQR 0-130) in patients with non-inflammatory disease and 740 pg/mL (IQR 230-1800) in patients with inflammatory disease. The likelihood ratio of having an inflammatory disease was 10 (sensitivity 74% and specificity 93%) if the sCD27 concentration was >250 pg/mL. In patients with a known inflammatory condition, the likelihood ratio of having an infection was 10 (sensitivity 40% and specificity 96%) if the sCD27 concentration was >2500 pg/mL.

CONCLUSIONS: The likelihood of having an inflammatory neurological condition is increased with elevated concentrations of sCD27 in cerebrospinal fluid. Rapid tests of sCD27 should be developed to assist clinicians in diagnosis of neuroinflammatory disease.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-381319 (URN)10.1016/j.jneuroim.2019.03.015 (DOI)000470940600004 ()30928869 (PubMedID)
Available from: 2019-04-26 Created: 2019-04-26 Last updated: 2019-07-05Bibliographically approved
Tolf, A., Fagius, J., Carlson, K., Åkerfeldt, T., Granberg, T., Larsson, E.-M. & Burman, J. (2019). Sustained remission in multiple sclerosis after hematopoietic stem cell transplantation. Acta Neurologica Scandinavica, 140(5), 320-327
Open this publication in new window or tab >>Sustained remission in multiple sclerosis after hematopoietic stem cell transplantation
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2019 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 140, no 5, p. 320-327Article in journal (Refereed) Published
Abstract [en]

Objectives: To determine whether treatment with autologous hematopoietic stem cell transplantation (HSCT) can induce sustained complete remission in patients with multiple sclerosis (MS).

Material and methods: Case series of patients with relapsing‐remitting MS (n = 10) treated at a single center between 2004 and 2007 and followed up for 10 years. The patients were treated with a BEAM/ATG conditioning regimen (n = 9) or a cyclophosphamide/ATG conditioning regimen (n = 1) followed by infusion of unmanipulated autologous hematopoietic stem cells. The primary endpoint was sustained complete remission. Sustained complete remission was defined as “no evidence of disease activity‐4,” sustained for a period of at least 5 years without any ongoing disease‐modifying treatment. Furthermore, MS was considered as “resolved” if intrathecal IgG production and cerebrospinal fluid neurofilament light levels were normalized as well.

Results: Five out of 10 patients were in sustained complete remission at the end of the study. In three of them, MS was resolved.

Conclusions: Our data demonstrate that sustained complete remission after autologous HSCT for MS is possible.

 

Keywords
cerebrospinal fluid, hematopoietic stem cell transplantation, magnetic resonance imaging, multiple sclerosis
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-390961 (URN)10.1111/ane.13147 (DOI)000479109700001 ()31297793 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)
Available from: 2019-08-16 Created: 2019-08-16 Last updated: 2019-10-30Bibliographically approved
Alping, P., Piehl, F., Langer-Gould, A., Frisell, T., Burman, J., Fink, K., . . . Vrethem, M. (2019). Validation of the Swedish Multiple Sclerosis Register: Further Improving a Resource for Pharmacoepidemiologic Evaluations. Epidemiology, 30(2), 230-233
Open this publication in new window or tab >>Validation of the Swedish Multiple Sclerosis Register: Further Improving a Resource for Pharmacoepidemiologic Evaluations
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2019 (English)In: Epidemiology, ISSN 1044-3983, E-ISSN 1531-5487, Vol. 30, no 2, p. 230-233Article in journal (Refereed) Published
Abstract [en]

The Swedish Multiple Sclerosis Register is a national register monitoring treatment and clinical course for all Swedish multiple sclerosis (MS) patients, with high coverage and close integration with the clinic. Despite its great value for epidemiologic research, it has not previously been validated. In this brief report, we summarize a large validation of >3,000 patients in the register using clinical chart review in the context of the COMBAT-MS study. While further improving the data quality for a central cohort of patients available for future epidemiologic research, this study also allowed us to estimate the accuracy and completeness of the register data.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2019
Keywords
Multiple sclerosis, Pharmacoepidemiology, Register, Validation
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-378625 (URN)10.1097/EDE.0000000000000948 (DOI)000458417200017 ()30721167 (PubMedID)
Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-11Bibliographically approved
Demirbuker, S. S., Kagström, S., Fält, A., Berglund, A., Hillert, J., Nilsson, P., . . . Olsson, T. (2018). A Swedish nationwide pharmaco-epidemiological and genetic study of the long-term safety and effectiveness of dimethyl fumarate (IMSE 5). Paper presented at 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), OCT 10-12, 2018, Berlin, GERMANY. Multiple Sclerosis, 24, 701-702
Open this publication in new window or tab >>A Swedish nationwide pharmaco-epidemiological and genetic study of the long-term safety and effectiveness of dimethyl fumarate (IMSE 5)
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2018 (English)In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 24, p. 701-702Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Sage Publications, 2018
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-369957 (URN)000446861401580 ()
Conference
34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), OCT 10-12, 2018, Berlin, GERMANY
Funder
Swedish Research CouncilThe Swedish Brain Foundation
Available from: 2018-12-17 Created: 2018-12-17 Last updated: 2018-12-17Bibliographically approved
Kagström, S., Fält, A., Demirbuker, S. S., Berglund, A., Hillert, J., Nilsson, P., . . . Olsson, T. (2018). A Swedish nationwide pharmaco-epidemiological and genetic study of the long-term safety and effectiveness of natalizumab (IMSE 1). Paper presented at 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), OCT 10-12, 2018, Berlin, GERMANY. Multiple Sclerosis, 24, 699-700
Open this publication in new window or tab >>A Swedish nationwide pharmaco-epidemiological and genetic study of the long-term safety and effectiveness of natalizumab (IMSE 1)
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2018 (English)In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 24, p. 699-700Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Sage Publications, 2018
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-369956 (URN)000446861401578 ()
Conference
34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), OCT 10-12, 2018, Berlin, GERMANY
Funder
Swedish Research CouncilThe Swedish Brain Foundation
Available from: 2018-12-18 Created: 2018-12-18 Last updated: 2018-12-18Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-7045-1806

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