Neurofilaments as biomarkers in multiple sclerosis

Teunissen, Charlotte E.; Khalil, Michael

doi:10.1177/1352458512443092

Cited by 209 publications

(194 citation statements)

References 39 publications

(85 reference statements)

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“…NF-L levels have been found to reflect acute axonal damage and NF-H chronic irreversible damage, therefore implying prognostic value for disease progression or disability [23]. In addition, immunosuppression therapies using Natalizumab or Fingolimod have been evaluated using soluble NF-L and NF-H levels in CSF with interesting results [24][25][26].…”

Section: Discussionmentioning

confidence: 99%

Multiple Sclerosis: Neurofilament Pathology in Spinal Motor Neurons

Müller-Wielsch¹,

Cannella²,

Raine³

2017

J Mult Scler

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Objective: While traditionally a disorder of myelin, in multiple sclerosis (MS) neuronal and axonal damage has in recent years become an important topic of clinical relevance. To address this, alterations in neurofilament phosphorylation, known markers of neuronal health, were investigated in anterior horn cells in MS spinal cord tissue for signs of motor neuron damage. Methods:Spinal cord tissue was examined from 13 MS and 6 control patients. Fresh frozen sections were labelled with antibodies against phosphorylated and non-phosphorylated epitopes of neurofilament H (NF-H) and analyzed by light microscopy. Results:In MS, increased expression of phosphorylated NF-H in spinal motor neuron perikarya (abnormal for neurons) occurred in 61.5% of cases, mostly in chronic active lesions, with the strongest immunoreactivity at the lumbar level. Inflammatory activity was common in chronic active but rare in chronic silent lesions. In one case with an acute lesion, we saw swollen axons positive for non-phosphorylated NF-H, a pathologic marker in axons, but no signs of perikaryal damage. Expression of non-phosphorylated NF-H in spinal motor neuron perikarya was similar in both MS and controls. Conclusion:In line with previous studies, our findings implicate anterior horn cell damage as a common feature in MS. We propose that underlying mechanisms may involve reduced synaptic input and/or retrograde degeneration, subjects which remain to be investigated. For the neuron count of a subgroup of MS cases, 5 serial sections of each patient stained with Nissl stain (0.075 % cresyl violet) were examined with stereological methods using StereoInvestigator software (MicroBrightField Inc., Williston, VT, USA). In the anterior horn as the region of interest, all neuronal perikarya were counted, measured and grouped according to their size into motor neurons (diameter ≥ 24 μm) and interneurons (diameter (≥ 10-24 μm) [21]. For evaluation, total numbers of motor neurons per patient were compared. Further details of the procedure can be found in an earlier publication [11].Images were captured with a digital camera (Axiocam and software by Carl Zeiss); GraphPadPrism software was used for graph production. ResultsEstablished, gliotic lesions devoid of myelin and displaying variable degrees of axonal degeneration were common in all cases with chronic lesions but inflammatory changes (reflecting ongoing demyelination), were only seen in chronic active lesions. Such changes comprised perivascular cuffs and scattered lipid-laden macrophages in the white matter (mainly anterior or lateral columns) and occasional collections of small lymphocytes within the meninges.By immunocytochemistry, clear differences were seen between MS and control cases in the expression of phosphorylated NF-H in anterior horn cell perikarya. Specifically, eight of thirteen MS patients showed widespread phosphorylated (abnormal) NF-H positivity compared to none of the controls (3 healthy, 2 OND: olivopontocerebellar degeneration and polyglucosan inclusion disease...

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Section: Discussionmentioning

confidence: 99%

Multiple Sclerosis: Neurofilament Pathology in Spinal Motor Neurons

Müller-Wielsch¹,

Cannella²,

Raine³

2017

J Mult Scler

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“…Neurofilament subunits and fragments that are released during neuronal damages may even be processed in disease specific ways. However, neurofilament detection assays still have to be refined to increase sensitivity and specificity [6,37,50].…”

Section: Biomarker Candidates In the Central Nervous Systemmentioning

confidence: 99%

Molecular Biomarkers in Multiple Sclerosis

Paap

Hecker²,

Koczan³

et al. 2013

J Clin Cell Immunol

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Multiple Sclerosis (MS) is a chronic immune-modulated disorder of the central nervous system (CNS) affecting mainly young adults. Due to the complexity and heterogenic etiology of this disease diagnosis, treatment, and estimations concerning the future course of the disease for the individual patient are challenging. To encounter the variability in phenotype, disease progression and response to treatments, various new drugs are in development to complement existing treatment options. Since years intensive efforts are directed to identify biomarkers that are associated with various aspects of MS on different levels of the organizational hierarchy of the human body (e.g. DNA, RNA, proteins, cells).We researched the last ten years of literature to identify those proposed candidates that had been repeatedly published as being associated with MS etiology, clinical manifestation, disease course, and treatment response.Here, we present a categorized overview over molecular biomarkers in MS.However, despite of the large sum of studies and the long list of candidate markers, today only very few biomarkers are of clinical value. This is mostly due to lack of comparability and statistical power in most studies. However, there are recent advances in the field of applicable molecular biomarkers in MS: For example measurement of anti-AQP4 levels allows differentiation between neuromyelitis optica (NMO) and MS.

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“…[7][8][9] There is evidence showing that both CSF and serum Nfs levels are associated with disease activity, physical disability, and magnetic resonance imaging (MRI) changes in MS; however, clinical follow-up time was relatively short in most of these studies. 1,2,7 In a recent study in 51 MS patients, it has been shown that higher CSF NfH values could prognosticate an unfavourable disease evolution during a follow-up time of 15 years. 3 Another study in 95 MS cases with a median follow-up time of 14 years could demonstrate that elevated CSF NfL levels were predictive of future physical disability.…”

mentioning

confidence: 99%

“…3 Nf belong to intermediate filament proteins and consist of three isotypes, which are a neurofilament light (NfL) chain of 68 kDa, a neurofilament intermediate (NfM) chain of 150 kDa, and a neurofilament heavy (NfH) chain of 190-210 kDa. 1 Evidence for increased Nf levels in MS mainly exists for NfL and NfH, whereas NfM has not been extensively studied so far. 4 Analysis of Nf levels was so far limited to cerebrospinal fluid (CSF), because detection systems were not sensitive enough to measure the generally lower concentration of Nf in blood samples.…”

mentioning

confidence: 99%

Neurofilaments as biomarkers in multiple sclerosis

Cited by 209 publications

References 39 publications

Multiple Sclerosis: Neurofilament Pathology in Spinal Motor Neurons

Multiple Sclerosis: Neurofilament Pathology in Spinal Motor Neurons

Molecular Biomarkers in Multiple Sclerosis

Are neurofilaments valuable biomarkers for long-term disease prognostication in MS?

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