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  • 1.
    Norgren, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Neurofilament light as a marker for neurodegenerative diseases2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Neurofilaments are the main cytoskeletal constituents in neuronal cells. They are belived to be important for maintaining the structural integrity and calibre of axons and dendrites thereby influencing the conduction velocity of nerve impulses.The neurofilament chains are divided into three groups according to their molecular size, neurofilament light (NF-L), neurofilament medium (NF-M) and neurofilament heavy (NF-H). The neurofilaments are obligate heteropolymers in vivo in which NF-L forms the backbone to which the heavier chains copolymerize to form the 10 nm neurofilament fibre.

    Different degenerative processes in the brain raise significant interest owing to the increasing mean age in the western world. Such diseases include amyotrophic lateral sclerosis, vascular dementia, frontal lobe dementia, progressive supra-nuclear paralysis, multiple system atrophy, low pressure hydrocephalus, and multiple sclerosis (MS).

    We have been able to generate six highly specific monoclonal antibodies for NF-L, and four independent epitopes were elucidated using Biacore and V8 protease degradation. Antibody 2:1 and 47:3 were selected components in a two-site ELISA assay for detection of NF-L in body fluids owing to their outstanding abililty to bind the antigen. The assay has a least detectable dose of 60 ng/l and a standard range of 60 to 64 000 ng/l. The assay was validated on its ability to detect changes of NF-L levels in CSF in patients with different neurological diseases. These were cerebral infarction, amyotrophic lateral sclerosis, relapsing remitting MS, extrapyramidal symptoms, and late onset Alzheimer’s disease. All the patient groups displayed significantly elevated NF-L levels as compared to the controls. We also tested the assay’s ability to monitor the amount of axonal breakdown in an animal model of MS. The NF-L levels were found to be elevated in rodents with chronic experimental autoimmune encephalomyelitis, giving a possible tool for monitoring new treatment strategies for axonal protection in MS. When studying a large population based MS material, we found axonal breakdown to be present early in the disease course and the breakdown was observed both in active relapse and clinically stable disease, indicative of ongoing neurodegeneration. NF-L levels were correlated to progression index, that is, high NF-L levels detected early in disease predict a fast progression of the disease. The amount of glial fibrillary acidic protein, a cytoskeletal protein found in astrocytes, was also quantified and was shown to be a good marker for the more progressive MS subtypes, that is, primary progressive and secondary progressive disease, indicating formation of astrocytic scars and activation of astrocytes.

    The test dealt with in this thesis has the potential to identify the slow chronic degenerative diseases with progressive disappearance of nerve cells and their large myelinated axons. There is a significant need clinically to be able to quantify such types of cell degeneration in relation to the progressive disappearance of nerve functions and to relate these different conditions to treatment regimens, disease progress, and prognosis.

  • 2.
    Norgren, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Karlsson, Jan Erik
    Rosengren, Lars
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Monoclonal antibodies selective for low molecular weight neurofilaments2002In: Hybridoma and Hybridomics, ISSN 1536-8599, Vol. 21, no 1, p. 53-59Article in journal (Refereed)
    Abstract [en]

    Neurofilaments are necessary for the maintenance of axonal caliber and structural organization of nerve cells. The low molecular weight form of neurofilament, the neurofilament light protein, which serves as the core of the filament, was used as immunogen for generation of hybridomas with selective reactivity with this form of the filament. Six hybridomas, out of approximately 100 tested clones, were highly discriminatory. All involved epitopes were localized to the rod region of the antigen, as determined by alpha-chymotrypsin digestion of the purified filament and enzymatic peptide mapping. Synthetic peptides (20 mers) covering the entire rod region did not react with the antibodies. A phage display peptide library was used to identify four consensus sequences for the antibodies. The results indicate that all epitopes were of conformational type. Pair-wise BIAcore data furthermore indicated that the epitopes were independent. The access to such specific reagents is a prerequisite for further elucidation of the biology of the low molecular weight form of neurofilaments proteins.

  • 3.
    Norgren, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Rosengren, Lars
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Elevated neurofilament levels in neurological diseases2003In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 987, no 1, p. 25-31Article in journal (Refereed)
    Abstract [en]

    Neurofilaments, a major cytoskeletal constituent of neuronal cells, can be released into the cerebrospinal fluid during several neurodegenerative diseases. By means of a new sensitive ELISA capable of measuring 60 ng/l of neurofilament light, significant elevations were observed for different neurological disorders. Cerebral infarction presented levels of 19800+/-9100 ng/l, amyothropic lateral sclerosis 3600+/-1200 ng/l, 'relapsing-remitting' MS 2500+/-1500 ng/l, extrapyramidal symptoms 1100+/-300 ng/l, late onset AD 300+/-100 ng/l and vascular dementia 1400+/-800 ng/l. In patients with no signs of neurological diseases the upper normal level and cut-off values was determined to be below 100 ng/l. NF-L determinations will be a valuable complement in identifying neuronal degradation and can be used clinically for diagnostic and monitoring purposes.

  • 4.
    Norgren, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Cerebrospinal fluid levels of neurofilament light in chronic experimental autoimmune encephalomyelitis2005In: Brain Research Bulletin, ISSN 0361-9230, E-ISSN 1873-2747, Vol. 67, no 4, p. 264-268Article in journal (Refereed)
    Abstract [en]

    Experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) is a chronic relapsing-remitting animal model of multiple sclerosis (MS). Neurofilament light (NF-L), a structural protein expressed in neuronal cells can be used to quantify the amount of neuronal damage in MS patients. An immunoassay was used to measure levels of neurofilament light in cerebrospinal fluid (CSF) in rats with myelin oligodendrocyte glycoprotein-induced EAE. Significantly increased levels of neurofilament were found in the immunized animals compared to the controls, strengthening the similarities in the diseases and the progression pattern between the animal model and MS. The turnover of NF-L during this disease is increased since significantly elevated levels also were identified in the spinal cord of the diseased animals and immunohistochemistry gave support for this observation. Monitoring neurofilament levels in EAE can be used to follow disease progression and effects of therapy.

  • 5.
    Norgren, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Rosengren, Lars
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Gunnarsson, Martin
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Neurofilament light and glial fibrillary acidic protein in multiple sclerosis2004In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 63, no 9, p. 1586-1590Article in journal (Refereed)
    Abstract [en]

    Objective: To evaluate levels of neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) in CSF from patients with multiple sclerosis (MS) in relation to clinical progress of the disease.

    Methods: CSF levels of NFL and GFAP were determined by sensitive ELISAs in 99 patients with different subtypes of MS, classified in terms of “ongoing relapse” or “clinically stable disease,” and 25 control subjects. Levels were compared with paraclinical data such as immunoglobulin G index and inflammatory cell count in the CSF, and the levels were related to Expanded Disability Status Scale score and progression index at clinical follow-up evaluations later in the disease course.

    Results: NFL and GFAP levels were elevated in MS patients as compared with control subjects (p < 0.001). The NFL levels were higher at relapses, whereas GFAP levels were unaffected. High NFL levels correlated with progression in patients with an active relapse (r = 0.49; p < 0.01) and in clinically stable patients (r = 0.29; p < 0.05). GFAP correlated to progression in the total patient cohort (r = 0.24; p < 0.05). Moreover, a strong correlation between NFL levels and inflammatory cell counts was evident in the group of patients with an ongoing relapse (r = 0.52; p = 0.001).

    Conclusions: CSF levels of neurofilament light and glial fibrillary acidic protein may have prognostic value in multiple sclerosis.

  • 6. Petzold, Axel
    et al.
    Altintas, Ayse
    Andreoni, Laura
    Bartos, Ales
    Berthele, Achim
    Blankenstein, Marinus A
    Buee, Luc
    Castellazzi, Massimiliano
    Cepok, Sabine
    Comabella, Manuel
    Constantinescu, Cris S
    Deisenhammer, Florian
    Deniz, Gunnur
    Erten, Gaye
    Espiño, Mercedes
    Fainardi, Enrico
    Franciotta, Diego
    Freedman, Mark S
    Giedraitis, Vilmantas
    Gilhus, Nils Erik
    Giovannoni, Gavin
    Glabinski, Andrzej
    Grieb, Pawel
    Hartung, Hans-Peter
    Hemmer, Bernhard
    Herukka, Sanna-Kaisa
    Hintzen, Rogier
    Ingelsson, Martin
    Jackson, Samuel
    Jacobsen, Steve
    Jafari, Naghmeh
    Jalosinski, Marcin
    Jarius, Sven
    Kapaki, Elisabeth
    Kieseier, Bernd C
    Koel-Simmelink, Marleen J A
    Kornhuber, Johannes
    Kuhle, Jens
    Kurzepa, Jacek
    Lalive, Patrice H
    Lannfelt, Lars
    Lehmensiek, Vera
    Lewczuk, Piotr
    Livrea, Paolo
    Marnetto, Fabiana
    Martino, Davide
    Menge, Til
    Norgren, Niklas
    UmanDiagnostics, Umea Biotech Incubator, Tvistevägen 48, SE-90736 Umea, Sweden.
    Papuć, Eva
    Paraskevas, George P
    Pirttilä, Tuula
    Rajda, Cecília
    Rejdak, Konrad
    Ricny, Jan
    Ripova, Daniela
    Rosengren, Lars
    Ruggieri, Maddalena
    Schraen, Susanna
    Shaw, Gerry
    Sindic, Christian
    Siva, Aksel
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Stonebridge, Iva
    Topcular, Baris
    Trojano, Maria
    Tumani, Hayrettin
    Twaalfhoven, Harry A M
    Vécsei, László
    Van Pesch, Vincent
    Vanderstichele, Hugo
    Vedeler, Christian
    Verbeek, Marcel M
    Villar, Luisa Maria
    Weissert, Robert
    Wildemann, Brigitte
    Yang, Cui
    Yao, Karen
    Teunissen, Charlotte E
    Neurofilament ELISA validation2010In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 352, no 1-2, p. 23-31Article in journal (Refereed)
    Abstract [en]

    This multi-center validation study identified the lack of preparation of accurate and consistent protein standards as the main reason for a poor inter-laboratory CV. This issue is also relevant to other protein biomarkers based on this type of assay and will need to be solved in order to achieve an acceptable level of analytical accuracy. The raw data of this study is available online.

  • 7.
    Vågberg, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Norgren, Niklas
    UmanDiagnostics AB, Umeå, Sweden.
    Dring, Ann
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Lindqvist, Thomas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Birgander, Richard
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Zetterberg, Henrik
    Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology, Queen Square, London, United Kingdom.
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Levels and Age Dependency of Neurofilament Light and Glial Fibrillary Acidic Protein in Healthy Individuals and Their Relation to the Brain Parenchymal Fraction2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 8, article id e0135886Article in journal (Refereed)
    Abstract [en]

    Background Neurofilament light (NFL) and Glial Fibrillary Acidic Protein (GFAP) are integral parts of the axonal and astrocytal cytoskeletons respectively and are released into the cerebrospinal fluid (CSF) in cases of cellular damage. In order to interpret the levels of these biomarkers in disease states, knowledge on normal levels in the healthy is required. Another biomarker for neurodegeneration is brain atrophy, commonly measured as brain parenchymal fraction (BPF) using magnetic resonance imaging (MRI). Potential correlations between levels of NFL, GFAP and BPF in healthy individuals have not been investigated. Objectives To present levels of NFL and GFAP in healthy individuals stratified for age, and investigate the correlation between them as well as their correlation with BPF. Methods The CSF was analysed in 53 healthy volunteers aged 21 to 70 (1 sample missing for GFAP analysis) and 48 of the volunteers underwent determination of BPF using MRI. Results Mean (+/- SD) NFL was 355 ng/L (+/- 214), mean GFAP was 421 ng/L (+/- 129) and mean BPF was 0.867 (+/- 0.035). All three biomarkers correlated with age. NFL also correlated with both GFAP and BPF. When controlled for age, only the correlation between NFL and GFAP retained statistical significance. Conclusions This study presents data on age-stratified levels of NFL and GFAP in the CSF of healthy individuals. There is a correlation between levels of NFL and GFAP and both increase with age. A correlation between NFL and BPF was also found, but did not retain statistical significance if controlled for age.

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