Abstract The diagnosis of multiple sclerosis is based on dissemination in time and space. Before 2010 lack of evidence for dissemination in space could be substituted by a paraclinical test, ...cerebrospinal fluid (CSF) oligoclonal bands (OCBs). The present meta-analysis (13,467 patients) shows that the diagnostic specificity of OCB drops from 94% to 61% if inflammatory etiologies are considered. Importantly, this was not caused by poor laboratory practice. This review on CSF OCB further illustrates the conceptional problem of substituting dissemination in space with a biomarker. The potential prognostic value of intrathecal OCB will need to be tested prospectively.
Abstract This review on the role of glial fibrillary acidic protein (GFAP) as a biomarker for astroglial pathology in neurological diseases provides background to protein synthesis, assembly, ...function and degeneration. Qualitative and quantitative analytical techniques for the investigation of human tissue and biological fluid samples are discussed including partial lack of parallelism and multiplexing capabilities. Pathological implications are reviewed in view of immunocytochemical, cell-culture and genetic findings. Particular emphasis is given to neurodegeneration related to autoimmune astrocytopathies and to genetic gain of function mutations. The current literature on body fluid levels of GFAP in human disease is summarised and illustrated by disease specific meta-analyses. In addition to the role of GFAP as a diagnostic biomarker for chronic disease, there are important data on the prognostic value for acute conditions. The published evidence permits to classify the dominant GFAP signatures in biological fluids. This classification may serve as a template for supporting diagnostic criteria of autoimmune astrocytopathies, monitoring disease progression in toxic gain of function mutations, clinical treatment trials (secondary outcome and toxicity biomarker) and provide prognostic information in neurocritical care if used within well defined time-frames.
Demonstrating parallelism in quantitative laboratory tests is crucial to ensure accurate reporting of data and minimise risks to patients. Regulatory authorities make the demonstration of parallelism ...before clinical use approval mandate. However, achieving statistical parallelism can be arduous, especially when parallelism is limited to a subrange of the data. To address potential biases and confounds, I propose a simple graphical method, the Partial Parallelism Plot, to demonstrate partial parallelism. The proposed method offers ease of understanding, intuitiveness, and graphical simplicity. It enables the graphical assessment of quantitative data risk when parallelism is lacking within a defined range. As parallelism may not be consistent across the entire analytical range, the plots focus on partial parallelism. The method can readily be programmed into graphical applications for enhanced interactivity. By providing a clear graphical representation, the method allows researchers to ascertain the presence of parallelism in laboratory tests, thus aiding in the validation process for trials and clinical applications.
This review on the role of neurofilaments as surrogate markers for axonal degeneration in neurological diseases provides a brief background to protein synthesis, assembly, function and degeneration. ...Methodological techniques for quantification are described and a protein nomenclature is proposed. The relevance for recognising antineurofilament autoantibodies is noted. Pathological implications are discussed in view of immunocytochemical, cell-culture and genetic findings. With reference to the present symposium on multiple sclerosis, the current literature on body fluid levels of neurofilaments in demyelinating disease is summarised.
Summary Optical coherence tomography (OCT) is a new method that could aid analysis of neurodegeneration in multiple sclerosis (MS) by capturing thinning of the retinal nerve fibre layer (RNFL). ...Meta-analyses of data for time domain OCT show RNFL thinning of 20·38 μm (95% CI 17·91–22·86, n=2063, p<0·0001) after optic neuritis in MS, and of 7·08 μm (5·52–8·65, n=3154, p<0·0001) in MS without optic neuritis. The estimated RNFL thinning in patients with MS is greater than the extent expected in normal ageing, probably because of retrograde trans-synaptic degeneration and progressive loss of retinal ganglion cells, in addition to the more pronounced thinning caused by optic neuritis if present. RNFL thickness correlates with visual and neurological functioning as well as with paraclinical data. Developments that could improve understanding of the relation between structure and function in MS pathophysiology include spectral or Fourier domain OCT technology, polarisation-sensitive OCT, fluorescence labelling, structural assessment of action-potential propagation, and segmentation algorithms allowing quantitative assessment of retinal layers.
Retinal optical coherence tomography (OCT) is an imaging biomarker for neurodegeneration in multiple sclerosis (MS). In order to become validated as an outcome measure in multicenter studies, ...reliable quality control (QC) criteria with high inter-rater agreement are required.
A prospective multicentre study on developing consensus QC criteria for retinal OCT in MS: (1) a literature review on OCT QC criteria; (2) application of these QC criteria to a training set of 101 retinal OCT scans from patients with MS; (3) kappa statistics for inter-rater agreement; (4) identification reasons for inter-rater disagreement; (5) development of new consensus QC criteria; (6) testing of the new QC criteria on the training set and (7) prospective validation on a new set of 159 OCT scans from patients with MS. The inter-rater agreement for acceptable scans among OCT readers (n = 3) was moderate (kappa 0·45) based on the non-validated QC criteria which were entirely based on the ophthalmological literature. A new set of QC criteria was developed based on recognition of: (O) obvious problems, (S) poor signal strength, (C) centration of scan, (A) algorithm failure, (R) retinal pathology other than MS related, (I) illumination and (B) beam placement. Adhering to these OSCAR-IB QC criteria increased the inter-rater agreement to kappa from moderate to substantial (0.61 training set and 0.61 prospective validation).
This study presents the first validated consensus QC criteria for retinal OCT reading in MS. The high inter-rater agreement suggests the OSCAR-IB QC criteria to be considered in the context of multicentre studies and trials in MS.
Neurofilament light chain (NfL) has emerged as a biomarker of neuroaxonal damage in several neurologic conditions. With increasing availability of fourth-generation immunoassays detecting NfL in ...blood, aspects of pre-analytical stability of this biomarker remain unanswered. This study investigated NfL concentrations in serum and plasma samples of 32 patients with neurological diagnoses using state of the art Simoa technology. We tested the effect of delayed freezing of up to 7 days and statistically determined stability and validity of measured concentrations. We found concentrations of NfL in serum and plasma to remain stable at room temperature when processing of samples is delayed up to 7 days (serum: mean absolute difference 0.9 pg/mL, intraindividual variation 1.2%; plasma: mean absolute difference 0.5 pg/mL, intraindividual variation 1.3%). Consistency of these results was nearly perfect for serum and excellent for plasma (intraclass correlation coefficients 0.99 and 0.94, respectively). In conclusion, the soluble serum and plasma NfL concentration remains stable when unprocessed blood samples are stored up to 7 days at room temperature. This information is essential for ensuring reliable study protocols, for example, when shipment of fresh samples is needed.
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