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  • 1.
    Bergman, J.
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Dring, Ann
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wuolikainen, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Bergenheim, Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
    Cytokine levels in interstitial brain fluid in progressive multiple sclerosis measured via intracerebral microdialysis2016In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 22, p. 511-511Article in journal (Refereed)
  • 2.
    Ingre, Caroline
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Press, Rayomand
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    A 50bp deletion in the SOD1 promoter lowers enzyme expression but is not associated with ALS in Sweden2016In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, E-ISSN 2167-9223, Vol. 17, no 5-6, p. 452-457Article in journal (Refereed)
    Abstract [en]

    Mutations in the superoxide dismutase (SOD1) gene have been linked to amyotrophic lateral sclerosis (ALS). A 50 base pair (bp) deletion of SOD1 has been suggested to reduce transcription and to be associated with later disease onset in ALS. This study was aimed to reveal if the 50bp deletion influenced SOD1 enzymatic activity, occurrence and phenotype of the disease in a Swedish ALS/control cohort. Blood samples from 512 Swedish ALS patients and 354 Swedish controls without coding SOD1 mutations were analysed for the 50bp deletion allele. The enzymatic activity of SOD1 in erythrocytes was analysed and genotype-phenotype correlations were assessed. Results demonstrated that the genotype frequencies of the 50bp deletion were all found to be in Hardy-Weinberg equilibrium. No significant differences were found for age of onset, disease duration or site of onset. SOD1 enzymatic activity showed a statistically significant decreasing trend in the control group, in which the allele was associated with a 5% reduction in SOD1 activity. The results suggest that the 50bp deletion has a moderate reducing effect on SOD1 synthesis. No modulating effects, however, were found on ALS onset, phenotype and survival in the Swedish population.

  • 3.
    Jonsson, Pär
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sjövik-Johansson, Elin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lindberg, Johan
    Schuppe-Koistinen, Ina
    Kusano, Miyako
    Sjöström, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Moritz, Thomas
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Predictive metabolite profiling applying hierarchical multivariate curve resolution to GC-MS data: a potential tool for multi-parametric diagnosis2006In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 5, no 6, p. 1407-1414Article in journal (Refereed)
    Abstract [en]

    A method for predictive metabolite profiling based on resolution of GC-MS data followed by multivariate data analysis is presented and applied to three different biofluid data sets (rat urine, aspen leaf extracts, and human blood plasma). Hierarchical multivariate curve resolution (H-MCR) was used to simultaneously resolve the GC-MS data into pure profiles, describing the relative metabolite concentrations between samples, for multivariate analysis. Here, we present an extension of the H-MCR method allowing treatment of independent samples according to processing parameters estimated from a set of training samples. Predictions or inclusion of the new samples, based on their metabolite profiles, into an existing model could then be carried out, which is a requirement for a working application within, e.g., clinical diagnosis. Apart from allowing treatment and prediction of independent samples the proposed method also reduces the time for the curve resolution process since only a subset of representative samples have to be processed while the remaining samples can be treated according to the obtained processing parameters. The time required for resolving the 30 training samples in the rat urine example was approximately 13 h, while the treatment of the 30 test samples according to the training parameters required only approximately 30 s per sample (approximately 15 min in total). In addition, the presented results show that the suggested approach works for describing metabolic changes in different biofluids, indicating that this is a general approach for high-throughput predictive metabolite profiling, which could have important applications in areas such as plant functional genomics, drug toxicity, treatment efficacy and early disease diagnosis.

  • 4.
    Jonsson, Pär
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Chorell, Elin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Constrained randomization and multivariate effect projections improve information extraction and biomarker pattern discovery in metabolomics studies involving dependent samples2015In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 11, no 6, p. 1667-1678Article in journal (Refereed)
    Abstract [en]

    Analytical drift is a major source of bias in mass spectrometry based metabolomics confounding interpretation and biomarker detection. So far, standard protocols for sample and data analysis have not been able to fully resolve this. We present a combined approach for minimizing the influence of analytical drift on multivariate comparisons of matched or dependent samples in mass spectrometry based metabolomics studies. The approach is building on a randomization procedure for sample run order, constrained to independent randomizations between and within dependent sample pairs (e.g. pre/post intervention). This is followed by a novel multivariate statistical analysis strategy allowing paired or dependent analyses of individual effects named OPLS-effect projections (OPLS-EP). We show, using simulated data that OPLS-EP gives improved interpretation over existing methods and that constrained randomization of sample run order in combination with an appropriate dependent statistical test increase the accuracy and sensitivity and decrease the false omission rate in biomarker detection. We verify these findings and prove the strength of the suggested approach in a clinical data set consisting of LC/MS data of blood plasma samples from patients before and after radical prostatectomy. Here OPLS-EP compared to traditional (independent) OPLS-discriminant analysis (OPLS-DA) on constrained randomized data gives a less complex model (3 versus 5 components) as well a higher predictive ability (Q2 = 0.80 versus Q2 = 0.55). We explain this by showing that paired statistical analysis detects 37 unique significant metabolites that were masked for the independent test due to bias, including analytical drift and inter-individual variation.

  • 5. Khademi, Mohsen
    et al.
    Dring, Ann
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Al Nimer, Faiez
    Harris, Robert
    Andersson, Magnus
    Brundin, Lou
    Piehl, Fredrik
    Olsson, Tomas
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Multivariate analysis of inflammatory and neuronal injury markers in cerebrospinal fluid of multiple sclerosis: higher levels are associated with younger age2012In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 253, no 1-2, p. 100-100Article in journal (Other academic)
  • 6. Khademi, Mohsen
    et al.
    Dring, Ann M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Al Nimer, Faiez
    Harris, Robert A.
    Andersson, Magnus
    Brundin, Lou
    Piehl, Fredrik
    Olsson, Tomas
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Intense Inflammation and Nerve Damage in Early Multiple Sclerosis Subsides at Older Age: A Reflection by Cerebrospinal Fluid Biomarkers2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 5, p. e63172-Article in journal (Refereed)
    Abstract [en]

    Inflammatory mediators have crucial roles in leukocyte recruitment and subsequent central nervous system (CNS) neuroinflammation. The extent of neuronal injury and axonal loss are associated with the degree of CNS inflammation and determine physical disability in multiple sclerosis (MS). The aim of this study was to explore possible associations between a panel of selected cerebrospinal fluid biomarkers and robust clinical and demographic parameters in a large cohort of patients with MS and controls (n = 1066) using data-driven multivariate analysis. Levels of matrix metalloproteinase 9 (MMP9), chemokine (C-X-C motif) ligand 13 (CXCL13), osteopontin (OPN) and neurofilament-light chain (NFL) were measured by ELISA in 548 subjects comprising different MS subtypes (relapsing-remitting, secondary progressive and primary progressive), clinically isolated syndrome and persons with other neurological diseases with or without signs of inflammation/infection. Principal component analyses and orthogonal partial least squares methods were used for unsupervised and supervised interrogation of the data. Models were validated using data from a further 518 subjects in which one or more of the four selected markers were measured. There was a significant association between increased patient age and lower levels of CXCL13, MMP9 and NFL. CXCL13 levels correlated well with MMP9 in the younger age groups, but less so in older patients, and after approximately 54 years of age the levels of CXCL13 and MMP9 were consistently low. CXCL13 and MMP9 levels also correlated well with both NFL and OPN in younger patients. We demonstrate a strong effect of age on both inflammatory and neurodegenerative biomarkers in a large cohort of MS patients. The findings support an early use of adequate immunomodulatory disease modifying drugs, especially in younger patients, and may provide a biological explanation for the relative inefficacy of such treatments in older patients at later disease stages.

  • 7.
    Nordin, Angelica
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Akimoto, Chizuru
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Alstermark, Helena
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Forsberg, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Baumann, Peter
    Pinto, Susana
    de Carvalho, Mamede
    Hübers, Annemarie
    Nordin, Frida
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Ludolph, Albert C.
    Weishaupt, Jochen H.
    Meyer, Thomas
    Grehl, Torsten
    Schweikert, Kathi
    Weber, Markus
    Burkhardt, Christian
    Neuwirth, Christoph
    Holmøy, Trygve
    Morita, Mitsuya
    Tysnes, Ole-Bjørn
    Benatar, Michael
    Wuu, Joanne
    Lange, Dale J.
    Bisgård, Carsten
    Asgari, Nasrin
    Tarvainen, Ilkka
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Neurology, Ulm University, Ulm, Germany.
    Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation: a large multinational screening study2017In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, E-ISSN 2167-9223, Vol. 18, no 3-4, p. 256-264Article in journal (Refereed)
    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.

  • 8.
    Nordin, Angelica
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Akimoto, Chizuru
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Division of Neurology, Department of Internal Medicine, Jichi Medical University, 3311-1 Yakushiji Shimotsukeshi, Tochigi 329-0498, Japan.
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Alstermark, Helena
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Graffmo, Karin S
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Forsberg, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Extensive size variability of the GGGGCC expansion in C9orf72 in both neuronal and non-neuronal tissues in 18 patients with ALS or FTD2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 11, p. 3133-3142Article in journal (Refereed)
    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.

  • 9. Otto, Markus
    et al.
    Bowser, Robert
    Turner, Martin
    Berry, James
    Brettschneider, Johannes
    Connor, James
    Costa, Julia
    Cudkowicz, Merit
    Glass, Jonathan
    Jahn, Olaf
    Lehnert, Stefan
    Malaspina, Andrea
    Parnetti, Lucilla
    Petzold, Axel
    Shaw, Pamela
    Sherman, Alexander
    Steinacker, Petra
    Suessmuth, Sigurd
    Teunissen, Charlotte
    Tumani, Hayrettin
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ludolph, Albert
    Roadmap and standard operating procedures for biobanking and discovery of neurochemical markers in ALS2012In: Amyotrophic Lateral Sclerosis and other Motor Neuron Disorders, ISSN 1466-0822, E-ISSN 1743-4483, Vol. 13, no 1, p. 1-10Article, review/survey (Refereed)
    Abstract [en]

    Despite major advances in deciphering the neuropathological hallmarks of amyotrophic lateral sclerosis (ALS), validated neurochemical biomarkers for monitoring disease activity, earlier diagnosis, defining prognosis and unlocking key pathophysiological pathways are lacking. Although several candidate biomarkers exist, translation into clinical application is hindered by small sample numbers, especially longitudinal, for independent verification. This review considers the potential routes to the discovery of neurochemical markers in ALS, and provides a consensus statement on standard operating procedures that will facilitate multicenter collaboration, validation and ultimately clinical translation.

  • 10.
    Trupp, Miles
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Öhrfelt, Annika
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Mölndal, Sweden.
    Zetterberg, Henrik
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Molndal, Sweden; UCL Inst Neurol, London, England.
    Obudulu, Ogonna
    Swedish Agr Univ, Dept Plant Physiol & Forest Genet, Swedish Metabol Ctr, Umea, Sweden.
    Malm, Linus
    Swedish Agr Univ, Dept Plant Physiol & Forest Genet, Swedish Metabol Ctr, Umea, Sweden.
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Moritz, Thomas
    Swedish Agr Univ, Dept Plant Physiol & Forest Genet, Swedish Metabol Ctr, Umea, Sweden.
    Blennow, Kaj
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Molndal, Sweden.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Metabolite and peptide levels in plasma and CSF differentiating healthy controls from patients with newly diagnosed Parkinson's disease2014In: Journal of Parkinson's Disease, ISSN 1877-7171, E-ISSN 1877-718X, Vol. 4, no 3, p. 549-560Article in journal (Refereed)
    Abstract [en]

    Background: Parkinson's disease (PD) is a progressive, multi-focal neurodegenerative disease for which there is no effective disease modifying treatment. A critical requirement for designing successful clinical trials is the development of robust and reproducible biomarkers identifying PD in preclinical stages. Objective: To investigate the potential for a cluster of biomarkers visualized with multiple analytical platforms to provide a clinically useful tool. Methods: Gas Chromatography-Mass Spectrometry (GC-TOFMS) based metabolomics and immunoassay-based protein/peptide analyses on samples from patients with PD diagnosed in Northern Sweden. Low molecular weight compounds from both plasma and cerebrospinal fluid (CSF) from 20 healthy subjects (controls) and 20 PD patients at the time of diagnosis (baseline) were analyzed. Results: In plasma, we found a significant increase in several amino acids and a decrease in C16-C18 saturated and unsaturated fatty acids in patients as compared to control subjects. We also observed an increase in plasma levels of pyroglutamate and 2-oxoisocaproate (ketoleucine) that may be indicative of increased metabolic stress in patients. In CSF, there was a generally lower level of metabolites in PD as compared to controls, with a specific decrease in 3-hydroxyisovaleric acid, tryptophan and creatinine. Multivariate analysis and modeling of metabolites indicates that while the PD samples can be separated from control samples, the list of detected compounds will need to be expanded in order to define a robust predictive model. CSF biomarker immunoassays of candidate peptide/protein biomarkers revealed a significant decrease in the levels of A beta-38 and A beta-42, and an increase in soluble APP alpha in CSF of patients. Furthermore, these peptides showed significant correlations to each other, and positive correlations to the CSF levels of several 5- and 6-carbon sugars. However, combining these metabolites and proteins/peptides into a single model did not significantly improve the statistical analysis. Conclusions: Together, this metabolomics study has detected significant alterations in plasma and CSF levels of a cluster of amino acids, fatty acids and sugars based on clinical diagnosis and levels of known protein and peptide biomarkers.

  • 11.
    Wu, Junfang
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Trupp, Miles
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Öhman, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    NMR analysis of the CSF and plasma metabolome of rigorously matched amyotrophic lateral sclerosis, Parkinson's disease and control subjects2016In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 12, no 6, article id 101Article in journal (Refereed)
    Abstract [en]

    Introduction: Amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD) are two severe neurodegenerative disorders for which the disease mechanisms are poorly understood and reliable biomarkers are absent.

    Objectives: To identify metabolite biomarkers for ALS and PD, and to gain insights into which metabolic pathways are involved in disease.

    Methods: Nuclear magnetic resonance (NMR) metabolomics was utilized to characterize the metabolite profiles of cerebrospinal fluid (CSF) and plasma from individuals in three age, gender, and sampling-date matched groups, comprising 22 ALS, 22 PD and 28 control subjects.

    Results: Multivariate analysis of NMR data generated robust discriminatory models for separation of ALS from control subjects. ALS patients showed increased concentrations of several metabolites in both CSF and plasma, these are alanine (CSF fold change = 1.22, p = 0.005), creatine (CSF-fc = 1.17, p = 0.001), glucose (CSF-fc = 1.11, p = 0.036), isoleucine (CSF-fc = 1.24, p = 0.002), and valine (CSF-fc = 1.17, p = 0.014). Additional metabolites in CSF (creatinine, dimethylamine and lactic acid) and plasma (acetic acid, glutamic acid, histidine, leucine, pyruvate and tyrosine) were also important for this discrimination. Similarly, panels of CSF-metabolites that discriminate PD from ALS and control subjects were identified.

    Conclusions: The results for the ALS patients suggest an affected creatine/creatinine pathway and an altered branched chain amino acid (BCAA) metabolism, and suggest links to glucose and energy metabolism. Putative metabolic markers specific for ALS (e.g. creatinine and lactic acid) and PD (e.g. 3-hydroxyisovaleric acid and mannose) were identified, while several (e.g. creatine and BCAAs) were shared between ALS and PD, suggesting some overlap in metabolic alterations in these disorders.

  • 12.
    Wuolikainen, Anna
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Acimovic, Jure
    Loevgren-Sandblom, Anita
    Parini, Paolo
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Bjoerkhem, Ingemar
    Cholesterol, Oxysterol, Triglyceride, and Coenzyme Q Homeostasis in ALS. Evidence against the Hypothesis That Elevated 27-Hydroxycholesterol Is a Pathogenic Factor2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, p. e113619-Article in journal (Refereed)
    Abstract [en]

    High plasma levels of cholesterol have been suggested to be neuroprotective for the degenerative disease amyotrophic lateral sclerosis (ALS) and to be associated with increased survival time. The gene encoding cholesterol 27-hydroxylase, CYP27A1, was recently identified as a susceptibility gene for sporadic ALS. A product of this enzyme is 27-hydroxycholesterol. We investigated plasma samples from 52 ALS patients and 40 control subjects (spouses) regarding cholesterol homeostasis, lipid profiles, and coenzyme Q. Eleven of the patients carried mutations in C9orf72 and seven in SOD1. Plasma levels of 27-hydroxycholesterol were significantly lower in male patients with ALS than in controls. It was not possible to link the reduced levels to any specific mutation, and there was no significant correlation between 27-hydroxycholesterol and survival. With normalization for diet using the spouses, a correlation was found between survival and total cholesterol, very low density lipoprotein cholesterol, low density lipoprotein cholesterol, and coenzyme Q. We conclude that cholesterol, 24S-hydroxycholesterol, 25-hydroxycholesterol, 27-hydroxycholesterol and lipid profiles in plasma are of limited prognostic value in individual ALS patients.

  • 13.
    Wuolikainen, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology. Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hedenström, Mattias
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Moritz, Thomas
    Marklund, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersen, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Optimization of procedures for collecting and storing of CSF for studying the metabolome in ALS2009In: Amyotrophic Lateral Sclerosis, ISSN 1748-2968, Vol. 10, no 4, p. 229-236Article in journal (Refereed)
    Abstract [en]

    There is a need for biomarkers for early diagnosis, development and evaluation of treatment efficacy in amyotrophic lateral sclerosis (ALS). We aimed to investigate if pre-analytical factors induce artefacts in metabolomic data of cerebrospinal fluid (CSF) from patients with ALS. CSF from 16 patients was studied using a statistical experimental design protocol with the following parameters: storage temperature (-80 degrees C/ - 20 degrees C), type of collection tube (polypropylene/polystyrene), and time delay from collecting to freezing (0, 10, 30, 90, 150 min). Gas chromatography-mass spectrometry was used to analyse CSF from 12 of the patients while CSF from one patient was analysed with nuclear magnetic resonance spectroscopy. The extent of CO(2) evaporization from CSF collected in tubes of different sizes at different temperatures and with/without lid were studied in three addtional patients. We found that alterations in storage temperature affect the metabolite composition of CSF more than any other studied pre-analytical parameter. CO(2) evaporization may induce artefacts in the metabolome by increasing the pH. In conclusion, minimization of evaluated artefacts can be obtained by collecting the CSF directly into tubes with tightly sealed lids in N(2)(l) and after freezing transfer of the tubes to -80 degrees C to minimize evaporation of CO(2).

  • 14.
    Wuolikainen, Anna
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ahnlund, Maria
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Moritz, Thomas
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Trupp, Miles
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Multi-platform mass spectrometry analysis of the CSF and plasma metabolomes of rigorously matched amyotrophic lateral sclerosis, Parkinson's disease and control subjects2016In: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 12, no 4, p. 1287-1298Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) are protein-aggregation diseases that lack clear molecular etiologies. Biomarkers could aid in diagnosis, prognosis, planning of care, drug target identification and stratification of patients into clinical trials. We sought to characterize shared and unique metabolite perturbations between ALS and PD and matched controls selected from patients with other diagnoses, including differential diagnoses to ALS or PD that visited our clinic for a lumbar puncture. Cerebrospinal fluid (CSF) and plasma from rigorously age-, sex- and sampling-date matched patients were analyzed on multiple platforms using gas chromatography (GC) and liquid chromatography (LC)-mass spectrometry (MS). We applied constrained randomization of run orders and orthogonal partial least squares projection to latent structure-effect projections (OPLS-EP) to capitalize upon the study design. The combined platforms identified 144 CSF and 196 plasma metabolites with diverse molecular properties. Creatine was found to be increased and creatinine decreased in CSF of ALS patients compared to matched controls. Glucose was increased in CSF of ALS patients and alpha-hydroxybutyrate was increased in CSF and plasma of ALS patients compared to matched controls. Leucine, isoleucine and ketoleucine were increased in CSF of both ALS and PD. Together, these studies, in conjunction with earlier studies, suggest alterations in energy utilization pathways and have identified and further validated perturbed metabolites to be used in panels of biomarkers for the diagnosis of ALS and PD.

  • 15.
    Wuolikainen, Anna
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Moritz, Thomas
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    ALS patients with mutations in the SOD1 gene have an unique metabolomic profile in the cerebrospinal fluid compared with ALS patients without mutations2012In: Molecular Genetics and Metabolism, ISSN 1096-7192, E-ISSN 1096-7206, Vol. 105, no 3, p. 472-478Article in journal (Refereed)
    Abstract [en]

    A specific biochemical marker for early diagnosing and for monitoring disease progression in amyotrophic lateral sclerosis (ALS) will have important clinical applications. ALS is a heterogeneous syndrome with multiple subtypes with ill-defined borders. A minority of patients carries mutations in the Cu/Zn-superoxide dismutase (SOD1) gene but the disease mechanism remains unknown for all types of ALS. Using a GC-TOFMS platform we studied the cerebrospinal fluid (CSF) metabolome in 16 ALS patients with six different mutations in the SOD1 gene and compared with ALS-patients without such mutations. OPLS-DA was used for classification modeling. We find that patients with a SOD1 mutation have a distinct metabolic profile in the CSF. In particular, the eight patients homozygous for the D90A SOD1 mutation showed a distinctively different signature when modeled against ALS patients with other SOD1 mutations and sporadic and familial ALS patients without a SOD1 gene mutation. This was found irrespective of medication with riluzole and survival time. Among the metabolites that contributed most to the CSF signature were arginine, lysine, ornithine, serine, threonine and pyroglutamic acid, all found to be reduced in patients carrying a D90A SOD1 mutation. ALS-patients with a SOD1 gene mutation appear as a distinct metabolic entity in the CSF, in particular in patients with the D90A mutation, the most frequently identified cause of ALS. The findings suggest that metabolomic profiling using GC-TOFMS and multivariate data analysis may be a future tool for diagnosing and monitoring disease progression, and may cast light on the disease mechanisms in ALS.

  • 16.
    Wuolikainen, Anna
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Moritz, Thomas
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersen, Peter Munch
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Disease-related changes in the cerebrospinal fluid metabolome in amyotrophic lateral sclerosis detected by GC/TOFMS2011In: PloS one, ISSN 1932-6203, Vol. 6, no 4, p. e17947-Article in journal (Refereed)
    Abstract [en]

    Background/Aim: The changes in the cerebrospinal fluid (CSF) metabolome associated with the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) are poorly understood and earlier smaller studies have shown conflicting results.The metabolomic methodology is suitable for screening large cohorts of samples. Global metabolomics can be used for detecting changes of metabolite concentrations in samples of fluids such as CSF.

    Methodology: Using gas chromatography coupled to mass spectrometry (GC/TOFMS) and multivariate statistical modeling, we simultaneously studied the metabolome signature of, 120 small metabolites in the CSF of patients with ALS, stratified according to hereditary disposition and clinical subtypes of ALS in relation to controls.

    Principal Findings: The study is the first to report data validated over two sub-sets of ALS vs. control patients for a large set of metabolites analyzed by GC/TOFMS. We find that patients with sporadic amyotrophic lateral sclerosis (SALS) have a heterogeneous metabolite signature in the cerebrospinal fluid, in some patients being almost identical to controls. However, familial amyotrophic lateral sclerosis (FALS) without superoxide dismutase-1 gene (SOD1) mutation is less heterogeneous than SALS. The metabolome of the cerebrospinal fluid of 17 ALS patients with a SOD1 gene mutation was found to form a separate homogeneous group. Analysis of metabolites revealed that glutamate and glutamine were reduced, in particular in patients with a familial predisposition. There are significant differences in the metabolite profile and composition among patients with FALS, SALS and patients carrying a mutation in the SOD1 gene suggesting that the neurodegenerative process in different subtypes of ALS may be partially dissimilar.

    Conclusions/Significance: patients with a genetic predisposition to amyotrophic lateral sclerosis have a more distinct and homogeneous signature than patients with a sporadic disease.

1 - 16 of 16
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