Biomarkers for diagnosis thread

A forum to discuss research on the origins of MS and its development.

Biomarkers for diagnosis thread

Postby frodo » Sun Jul 09, 2017 5:55 am

Hi all,

Biomarkers can be used not only as a diagnosis, but also as a window to the underlying pathology. Therefore I start this thread about biomarkers, in which I will put the information that I can find.

Let's start with this one: "Molecular-Based Diagnosis of Multiple Sclerosis and Its Progressive Stages". They identify a set of 17 biomarkers

http://www.neurology.org/content/88/16_ ... .395.short

Results: A molecular diagnostic test of MS uses 17 variables to differentiate MS from all other conditions with the validated area under the receiver operating characteristic curve (AUC) of 0.95. This test is dominated by immunological biomarkers. Primary- and secondary-progressive MS are biologically indistinguishable, with quantitatively comparable intrathecal inflammation to RRMS. A molecular test that differentiates RRMS from progressive MS with a validated AUC=0.90 is based on 27 variables related to oligodendroglial and neuronal damage.

Conclusions: The identified molecular taxonomy maybe helpful in diagnostically challenging cases and provides opportunities for biomarker-supported drug development in MS. Our data are applicable to other CNS diseases.
Last edited by frodo on Wed Aug 16, 2017 1:10 am, edited 1 time in total.
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Re: Biomarkers research thread

Postby frodo » Mon Jul 17, 2017 3:02 pm

Other biomarker under research, maybe pathogenic. The auto-antibody Kir4.1. Under study since 2012, it seems that one of its forms, (LG, lower glycosilated) is finally related to MS. This could amount up to an 28% of MS patients.

Detection of potassium channel KIR4.1 antibodies in Multiple Sclerosis patients

http://www.sciencedirect.com/science/ar ... 5916303957

Abstract

The presence of KIR4.1 antibodies has been proposed to be a characteristic of Multiple Sclerosis (MS). This could have a significant impact on disease management. However, the validation of the initial findings has failed till date. Conflicting results have been attributed to difficulties in isolating the lower-glycosylated (LG) KIR4.1 expressed in oligodendrocytes, the putative target antigen of autoantibodies.

The aim of this study is to verify the presence of KIR4.1 antibodies in MS patients, by independently replicating the originally-described procedure.

Assay procedure consisted of KIR4.1 expression in HEK293 cells, 3-step elution to isolate LG-KIR4.1 in elution fraction 3, and ELISA. Sera of 48 MS patients and 46 HCs were studied in 21 working sessions.

In a preliminary analysis, we observed different KIR4.1 antibody levels between MS patients and Healthy Controls (HCs). However, a high variability across working sessions was observed and the sensitivity of the assay was very low. Thus, stringent criteria were established in order to identify working sessions in which the pure LG-KIR4.1 was isolated. As per these criteria, we detected LG-KIR4.1 antibodies in 28% of MS patients and 5% of HCs.
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Re: Biomarkers research thread

Postby frodo » Wed Jul 26, 2017 12:26 am

An interesting biomarker: The eye's retina. Two procedures are available: Confocal corneal microscopy (CCM) and OCT (optic confocal tomography). The first one is new, and is now on the news. They both meassure the retinal fiber layer (RFL) and are able to diagnose MS. Is important to notice that to date there is no single test available that can diagnose MS.

http://iovs.arvojournals.org/article.as ... id=2645785

Image

Images D, E, F belong to a control, a recent MS patient and an old MS patient.
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Re: Biomarkers research thread

Postby frodo » Mon Jul 31, 2017 3:33 am

Peripheral blood lymphocytes immunophenotyping predicts disease activity in clinically isolated syndrome patients.

https://www.ncbi.nlm.nih.gov/pubmed/28754092

Abstract
BACKGROUND:

Clinically isolated syndrome (CIS) represents first neurological symptoms suggestive of demyelinating lesion in the central nervous system (CNS). Currently, there are no sufficient immunological or genetic markers predicting relapse and disability progression, nor there is evidence of the efficacy of registered disease modifying treatments (DMTs), such as intramuscular interferon beta1a. The aim of the study is to evaluate immunological predictors of a relapse or disability progression.
METHODS:

One hundred and eighty one patients with CIS were treated with interferon beta1a and followed over the period of 4 years. Lymphocyte subsets were analyzed by flow cytometry. A Kaplan-Meier estimator of survival probability was used to analyze prognosis. For statistical assessment only individual differences between baseline values and values at the time of relapse or confirmed disability progression were analysed.
RESULTS:

Higher levels of B lymphocytes predicted relapse-free status. On the other hand, a decrease of the naïve subset of cells (CD45RA+ in CD4+) after 12, 24, and 36 months of follow-up were associated with an increased risk of confirmed disability progression.
CONCLUSION:

Our data suggest that the quantification of lymphocyte subsets in patients after the first demyelinating event suggestive of MS may be an important biomarker.
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B cell biomarkers

Postby frodo » Wed Aug 02, 2017 2:30 am

A paper that says more about how B cells contribute to MS. 48 kDa Myo1c mean a 48 kilo-dalton (size meassure) protein named miosin.

Modern aspects of B lymphocytes in the pathogenesis of multiple sclerosis: the use of B-cell biomarkers in clinical practice

Abstract

Background.

The purpose was to investigate the correlation between the level of 48 kDa form of unconventional myosin 1c (48 kDa Myo1c) (marker of apoptosis in cells) in the blood serum of patients with multiple sclerosis (MS), and features of the disease debut in the context of the modern understanding of the key role of B lymphocytes even at the early stage of pathological process in MS. Materials and methods. 61 patients with multiple sclerosis and 20 healthy donors aged 19–57 years participated in the research.

Methods of investigation:

clinical (complaints, life and disease history, general and neurological examination), laboratory (identification of 48 kDa Myo1c in the blood serum by consequent serum protein sedimentation, electrophoresis and digital analysis of electrophoregrams; presence of Myo1c was confirmed by Western blot with anti-Myo1c antibodies).

Results.

In the group of MS patients with high level of 48 kDa Myo1c, the average age of the patients at the time of disease onset was the lowest, but significant statistical relationships between concentrations of 48 kDa Myo1c in the serum of patients and age of MS debut were not found.

At the onset of MS as a reduction of visual acuity, the average level of 48 kDa Myo1c in the blood serum of patients was revealed significantly more often, and at the onset of oculomotor disorders — a low level, indicating a less favorable course of the disease due to the low apoptosis of autoreactive lymphocytes. Levels of serum 48 kDa Myo1c were not significantly dependent on the disease activity in MS patients at the time of examination and blood sampling, and therefore the use of this biomarker is possible not only during the exacerbation of the disease, but also during remission.

Conclusions. Modern researches show that in MS B lymphocytes are involved not only in the synthesis of oligoclonal autoantibodies, but also in the antibody-independent mechanisms, especially in the presentation of antigens to T cells, synthesis of pro-inflammatory cytokines, the formation of ectopic lymphoid follicle-like clusters in the central nervous system.

Therefore, it is a reasonable to use B cell markers, including 48 kDa Myo1c, in clinical practice, particularly, to predict the course of MS aggressiveness and effectiveness of disease-modifying therapies.
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Re: B cell biomarkers

Postby frodo » Wed Aug 02, 2017 2:57 am

Circulating microRNA are remainings of DNA of dead cells that appear circulating in the blood stream. Some of them can be used as biomarkers for MS. This article speaks about "circular RNA" but probably they mean "circulating"

Circular RNA profiling reveals that circular RNAs from ANXA2 can be used as new biomarkers for multiple sclerosis

Abstract

Multiple sclerosis is an autoimmune disease, with higher prevalence in women, in whom the immune system is dysregulated. This dysregulation has been shown to correlate with changes in transcriptome expression as well as in gene-expression regulators, such as non-coding RNAs (e.g. microRNAs).

Indeed, some of these have been suggested as biomarkers for multiple sclerosis even though few biomarkers have reached the clinical practice. Recently, a novel family of non-coding RNAs, circular RNAs, has emerged as a new player in the complex network of gene-expression regulation. MicroRNA regulation function through a ‘sponge system’ and a RNA splicing regulation function have been proposed for the circular RNAs. This regulating role together with their high stability in biofluids makes them seemingly good candidates as biomarkers.

Given the dysregulation of both protein-coding and non-coding transcriptome that have been reported in multiple sclerosis patients, we hypothesised that circular RNA expression may also be altered. Therefore, we carried out expression profiling of 13.617 circular RNAs in peripheral blood leucocytes from multiple sclerosis patients and healthy controls finding 406 differentially expressed (P-value < 0.05, Fold change > 1.5) and demonstrate after validation that, circ_0005402 and circ_0035560 are underexpressed in multiple sclerosis patients and could be used as biomarkers of the disease.
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Re: Biomarkers research thread

Postby centenarian100 » Wed Aug 02, 2017 4:13 pm

Hey Frodo. Thank you for your posts in this section. You are single-handedly keeping this section alive. I heard that the Kir4.1 data could not be replicated and that the original results were actually from pooled sera. Is this correct?

-Cent

frodo wrote:Other biomarker under research, maybe pathogenic. The auto-antibody Kir4.1. Under study since 2012, it seems that one of its forms, (LG, lower glycosilated) is finally related to MS. This could amount up to an 28% of MS patients.

Detection of potassium channel KIR4.1 antibodies in Multiple Sclerosis patients

http://www.sciencedirect.com/science/ar ... 5916303957

Abstract

The presence of KIR4.1 antibodies has been proposed to be a characteristic of Multiple Sclerosis (MS). This could have a significant impact on disease management. However, the validation of the initial findings has failed till date. Conflicting results have been attributed to difficulties in isolating the lower-glycosylated (LG) KIR4.1 expressed in oligodendrocytes, the putative target antigen of autoantibodies.

The aim of this study is to verify the presence of KIR4.1 antibodies in MS patients, by independently replicating the originally-described procedure.

Assay procedure consisted of KIR4.1 expression in HEK293 cells, 3-step elution to isolate LG-KIR4.1 in elution fraction 3, and ELISA. Sera of 48 MS patients and 46 HCs were studied in 21 working sessions.

In a preliminary analysis, we observed different KIR4.1 antibody levels between MS patients and Healthy Controls (HCs). However, a high variability across working sessions was observed and the sensitivity of the assay was very low. Thus, stringent criteria were established in order to identify working sessions in which the pure LG-KIR4.1 was isolated. As per these criteria, we detected LG-KIR4.1 antibodies in 28% of MS patients and 5% of HCs.
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Re: Biomarkers research thread

Postby frodo » Thu Aug 03, 2017 12:33 am

centenarian100 wrote:Hey Frodo. Thank you for your posts in this section. You are single-handedly keeping this section alive. I heard that the Kir4.1 data could not be replicated and that the original results were actually from pooled sera. Is this correct?


As far as I know, the available information is contradictory by now. Some groups claim to have it replicated, and some other groups claim to have tried with no success. We will have to wait to have an answer.

From my point of view, I think is really possible that a subset of MS cases are kir4.1 related, but I wouldn't expect this to be the general case.

Thanks for your thanks. :-)
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Re: Biomarkers research thread

Postby frodo » Thu Aug 03, 2017 2:35 am

This would be even better than a blood test !!!!

Exhaled Breath Markers for Non-Imaging and Non-Invasive Measures for Detection of Multiple Sclerosis.
https://www.ncbi.nlm.nih.gov/pubmed/28768105

Multiple sclerosis (MS) is the most common chronic neurological disease affecting young adults. MS diagnosis is based on clinical characteristics and confirmed by examination of the cerebrospinal fluids or by magnetic resonance imaging of the brain and/or spinal cord.

However, neither of the current diagnostic procedures are adequate as a routine tool to determine disease progression. Thus, diagnostic biomarkers are needed. In the current study, a novel approach that could meet these expectations is presented.

The approach is based on non-invasive analysis of volatile organic compounds (VOCs) in breath. Exhaled breath was collected from 204 volunteers, 164 MS and 58 control individuals.

Analysis was performed by: gas-chromatography mass-spectrometry (GC-MS) and nanomaterial-based sensors array. Predictive models were derived from the sensors, using Artificial Neural Networks. GC-MS analysis revealed significant differences in VOCs abundance between MS patients and Controls. Sensor data analysis on training sets were able to binary discriminate between MS patients and Controls with accuracies up-to 90%.

Blinded sets showed 95% positive predictive value between MS-remission and control and 100% sensitivity with 100% negative predictive value between MS not-treated (NT) and control, and 86% NPV between relapse and control.

Possible links between VOC biomarkers and the MS pathogenesis were established. Preliminary results suggest the applicability of a new nanotechnology-based method for MS diagnostics.
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Re: Biomarkers research thread

Postby frodo » Fri Aug 04, 2017 11:36 pm

Sensing of Alzheimer’s Disease and Multiple Sclerosis Using Nano-Bio Interfaces

http://content.iospress.com/articles/jo ... /jad160206

Abstract: It is well understood that patients with different diseases may have a variety of specific proteins (e.g., type, amount, and configuration) in their plasmas. When nanoparticles (NPs) are exposed to these plasmas, the resulting coronas may incorporate some of the disease-specific proteins. Using gold (Au) NPs with different surface properties and corona composition, we have developed a colorimetric sensor array for the discrimination and detection of two neurodegenerative diseases, Alzheimer’s disease (AD) and multiple sclerosis (MS).

Applying a variety of techniques, including UV-visible spectra, array response analyses and liquid chromatography-tandem mass spectrometry, we found the corona-NP complexes, obtained from different human serums, had distinct protein composition, including some specific proteins that are known as AD and MS biomarkers.

The array responses, analyzed by chemometrics and statistical methods, demonstrate promising capabilities of the sensor to unambiguously identify and discriminate AD and MS. The developed sensor array might enable a simple, inexpensive and rapid detection/discrimination of neurodegenerative diseases.
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Re: Biomarkers research thread

Postby frodo » Mon Aug 07, 2017 2:17 am

More about biomarkers. In this article they use 12-biomarkers to classify CIS patients.

They are first classified by serum IL-7 levels (Interleukin) and the rest of the biomarkers complement the study. They say that both PP-MS and RR-MS share decreased biomarkers of inflammation and tissue regeneration in CSF.

Source:

http://www.sciencedirect.com/science/ar ... 1616307008

Highlights

• A decision-tree model is proposed for better define early Multiple Sclerosis diagnosis.
• DPP4-substrate-chemokines CXCL9 and CXCL10 are strong prognostic biomarkers.
• Decreased inflammatory markers in CSF suggest a defective intrinsic immune response.

Abstract

Delay in the diagnosis of multiple sclerosis (MS) stems from the lack of specific clinical and analytical markers to assist in the early diagnosis and prediction of progressive course. We propose a decision-tree model that better defines early at onset MS patients and those with the progressive form by analysing a 12-biomarkers panel in serum and CSF samples of patients with MS, other neurological diseases (OND) and healthy contols. Thus, patients at onset of neurological disease were first classified by serum IL-7 levels < 141 pg/ml (OR = 6.51, p < 0.001). Combination of IL-7 and CXCL10 indicated risk for a specific MS clinical form, where IL-7 < 141 and CXCL10 < 570 pg/ml were associated with the highest risk for PP-MS (OR = 22, p = 0.01). Unexpectedly, both PP-MS and RR-MS patients shared significantly decreased prototypical biomarkers of inflammation and tissue regeneration in CSF than OND suggesting a defective intrinsic immune response playing a role at the beginning of the disease.
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The retina as biomarker

Postby frodo » Sun Aug 13, 2017 2:09 pm

This is not a body fluid biomarker, but probably is good enough for taking care of it. OCT is an optic system that measures the retina health, and it is reported to predict diagnosis of MS.

The most remarkable is the conclusion: Retrograde transneuronal degeneration caused by optic radiation lesions might play a role in progressive RNFL loss. In addition, the result of the study also indicates that the disease-related neurodegenerative changes in the retina start much earlier than the clinical diagnosis of MS


Progression retinal ganglion cell loss in multiple sclerosis is associated with new lesions in the optic radiations.
https://www.ncbi.nlm.nih.gov/pubmed/28799222

BACKGROUND:

The mechanism of retinal ganglion cell (RGC) and retinal nerve fibre layer (RNFL) loss in multiple sclerosis (MS) remains unknown. This study aims to investigate the association between temporal RNFL (tRNFL) thinning and disease activity in the brain determined by T2 lesions on MRI.
METHODS:

55 consecutive relapsing-remitting MS (RRMS) patients and 25 controls were enrolled. All patients underwent annual optical coherence tomography (OCT) and high-resolution MRI scans for tRNFL thickness and brain lesion volume analysis, respectively.
RESULTS:

Significant tRNFL thickness reduction was observed over the 3-year follow-up period at a relatively constant rate (1.02 μm per year). Thinning of tRNFL fibers was more prominent in younger patients (p = 0.01). The tRNFL loss was associated with new MRI lesions in the optic radiations (OR). There was significantly greater tRNFL thinning in patients with new lesional activity in OR compared to patients with new lesions outside of OR (p = 0.009).
CONCLUSIONS:

This study supports the notion that retrograde transneuronal degeneration caused by optic radiation lesions might play a role in progressive RNFL loss. In addition, the result of the study also indicates that the disease-related neurodegenerative changes in the retina start much earlier than the clinical diagnosis of MS
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Re: Biomarkers research thread

Postby frodo » Thu Aug 24, 2017 12:25 am

Closer to a blood test. Two more micro-RNAs disregulated. Micro-RNA are small fragments of RNA that are normally located inside a cell, but in some cases they can leave and enter blood stream.

Identification of miR-24 and miR-137 as novel candidate multiple sclerosis miRNA biomarkers using multi-staged data analysis protocol

Abstract

Many studies have investigated misregulation of miRNAs relevant to multiple sclerosis (MS) pathogenesis. Abnormal miRNAs can be used both as candidate biomarker for MS diagnosis and understanding the disease miRNA-mRNA regulatory network. In this comprehensive study, misregulated miRNAs related to MS were collected from existing literature, databases and via in silico prediction.

A multi-staged data integration strategy (including the construction of miRNA-mRNA regulatory network and systematic data analysis) was conducted in order to investigate MS related miRNAs and their regulatory networks. The final outcome was a bi-layer MS related regulatory network constructed with 27 miRNAs (seven of them were novel) and 59 mRNA targets. To verify the accuracy of the bioinformatics strategy three novel and five previously reported miRNAs from the network model were selected for experimental validation using the real-time PCR assay.

The obtained results proved the accuracy of the network. The expression of themiR-24 and miR-137(as novel MS candidate biomarker) and miR-16, and miR-181 (as previously reported MS candidate biomarker) showed significant deregulation in 33 MS patients compared to the control. The optimized data integration strategy conducted in this study found two miRNAs (miR-24and miR-16)that can be considered as candidate biomarkers for MS and also has the potential to generate a regulatory network to aid in further understanding the mechanisms underlying this disease.
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Re: Biomarkers research thread

Postby NHE » Thu Aug 24, 2017 2:57 am

frodo wrote:Closer to a blood test. Two more micro-RNAs disregulated. Micro-RNA are small fragments of RNA that are normally located inside a cell, but in some cases they can leave and enter blood stream.

Identification of miR-24 and miR-137 as novel candidate multiple sclerosis miRNA biomarkers using multi-staged data analysis protocol


Free full text.

http://mbrc.shirazu.ac.ir/article_4153_ ... 39fc57.pdf
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Optical tomography recommended as biomarker

Postby frodo » Tue Sep 19, 2017 2:31 am

Optical tomography recommended as biomarker

Retinal layer segmentation in multiple sclerosis: a systematic review and meta-analysis.
Source: https://www.ncbi.nlm.nih.gov/pubmed/28920886

Conclusion: The largest and most robust differences between the eyes of people with multiple sclerosis and control eyes were found in the peripapillary RNFL and macular GCIPL. Inflammatory disease activity might be captured by the INL. Because of the consistency, robustness, and large effect size, we recommend inclusion of the peripapillary RNFL and macular GCIPL for diagnosis, monitoring, and research.
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