Multiple Sclerosis: MicroRNA Expression Profiles Accurately Differentiate Patients with Relapsing-Remitting Disease from Healthy Controls
TL;DR: The miRNA expression profiles in blood cells may serve as a biomarker for MS, and deregulation of mi RNA expression may play a role in the pathogenesis of MS.
Abstract: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, which is heterogenous with respect to clinical manifestations and response to therapy. Identification of biomarkers appears desirable for an improved diagnosis of MS as well as for monitoring of disease activity and treatment response. MicroRNAs (miRNAs) are short non-coding RNAs, which have been shown to have the potential to serve as biomarkers for different human diseases, most notably cancer. Here, we analyzed the expression profiles of 866 human miRNAs. In detail, we investigated the miRNA expression in blood cells of 20 patients with relapsing-remitting MS (RRMS) and 19 healthy controls using a human miRNA microarray and the Geniom Real Time Analyzer (GRTA) platform. We identified 165 miRNAs that were significantly up- or downregulated in patients with RRMS as compared to healthy controls. The best single miRNA marker, hsa-miR-145, allowed discriminating MS from controls with a specificity of 89.5%, a sensitivity of 90.0%, and an accuracy of 89.7%. A set of 48 miRNAs that was evaluated by radial basis function kernel support vector machines and 10-fold cross validation yielded a specificity of 95%, a sensitivity of 97.6%, and an accuracy of 96.3%. While 43 of the 165 miRNAs deregulated in patients with MS have previously been related to other human diseases, the remaining 122 miRNAs are so far exclusively associated with MS. The implications of our study are twofold. The miRNA expression profiles in blood cells may serve as a biomarker for MS, and deregulation of miRNA expression may play a role in the pathogenesis of MS.
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University of Amsterdam1, University of Toronto2, Centre Hospitalier Universitaire de Toulouse3, Cleveland Clinic4, Tohoku University5, Charles University in Prague6, University College Dublin7, University of Basel8, Icahn School of Medicine at Mount Sinai9, Lund University10, University College London11, University of California, San Francisco12, Mayo Clinic13, University of Texas Health Science Center at Houston14
TL;DR: These revisions simplify the McDonald Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use.
Abstract: New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use.
8,883 citations
TL;DR: The disease-specific profiles of circulating microRNAs, and the methodologies used for their detection and quantification are reviewed, and possible functions of circulatingmicroRNAs and their potential as non-invasive biomarkers are discussed.
Abstract: The control of gene expression by microRNAs influences many cellular processes and has been implicated in the control of many (patho)physiological states. Recently, microRNAs have been detected in serum and plasma, and circulating microRNA profiles have now been associated with a range of different tumour types, diseases such as stroke and heart disease, as well as altered physiological states such as pregnancy. Here we review the disease-specific profiles of circulating microRNAs, and the methodologies used for their detection and quantification. We also discuss possible functions of circulating microRNAs and their potential as non-invasive biomarkers.
463 citations
TL;DR: The data indicate that deregulated miRNAs in blood might be used as biomarkers in the diagnosis of AD or other neurological diseases.
Abstract: Alzheimer disease (AD) is the most common form of dementia but the identification of reliable, early and non-invasive biomarkers remains a major challenge. We present a novel miRNA-based signature for detecting AD from blood samples. We apply next-generation sequencing to miRNAs from blood samples of 48 AD patients and 22 unaffected controls, yielding a total of 140 unique mature miRNAs with significantly changed expression levels. Of these, 82 have higher and 58 have lower abundance in AD patient samples. We selected a panel of 12 miRNAs for an RT-qPCR analysis on a larger cohort of 202 samples, comprising not only AD patients and healthy controls but also patients with other CNS illnesses. These included mild cognitive impairment, which is assumed to represent a transitional period before the development of AD, as well as multiple sclerosis, Parkinson disease, major depression, bipolar disorder and schizophrenia. miRNA target enrichment analysis of the selected 12 miRNAs indicates an involvement of miRNAs in nervous system development, neuron projection, neuron projection development and neuron projection morphogenesis. Using this 12-miRNA signature, we differentiate between AD and controls with an accuracy of 93%, a specificity of 95% and a sensitivity of 92%. The differentiation of AD from other neurological diseases is possible with accuracies between 74% and 78%. The differentiation of the other CNS disorders from controls yields even higher accuracies. The data indicate that deregulated miRNAs in blood might be used as biomarkers in the diagnosis of AD or other neurological diseases.
430 citations
Cites background from "Multiple Sclerosis: MicroRNA Expres..."
...In previous studies [51] we already investigated the influence of age and gender on the miRNA expression profile of whole blood....
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TL;DR: The identification of specific miRNA expression patterns in autoimmune diseases as well as a comprehensive understanding of the role of miRNA in disease pathogenesis offers promise of not only novel molecular diagnostic markers but also new gene therapy strategies for treating SLE and other inflammatory autoimmune diseases.
399 citations
TL;DR: The progress of miRNA research related to human diseases, as well as the potential for miRNA to becoming the next generation of diagnostics and therapeutics are overviewed.
325 citations
Cites background from "Multiple Sclerosis: MicroRNA Expres..."
...Immune-related diseases Multiple sclerosis miR-145, miR-34a, miR-155, miR-326 [80,81] Systemic lupus erythematosus miR-146a [82,83] Type II diabetes miR-144, miR-146a, miR-150, miR-182, miR-103, miR-107 [84] Nonalcoholic fatty liver disease miR-200a, miR-200b, miR-429, miR-122, miR-451, miR-27 [86] Non-alcoholic steatohepatitis miR-29c, miR-34a, miR-155, miR-200b [87]...
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...Dozens of miRNA signatures were identified by comparing the miRNA expression profiles of relapsingremitting MS and healthy controls [80]....
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References
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TL;DR: It is shown here that miRNAs are present in human plasma in a remarkably stable form that is protected from endogenous RNase activity and established the measurement of tumor-derived mi RNAs in serum or plasma as an important approach for the blood-based detection of human cancer.
Abstract: Improved approaches for the detection of common epithelial malignancies are urgently needed to reduce the worldwide morbidity and mortality caused by cancer. MicroRNAs (miRNAs) are small (≈22 nt) regulatory RNAs that are frequently dysregulated in cancer and have shown promise as tissue-based markers for cancer classification and prognostication. We show here that miRNAs are present in human plasma in a remarkably stable form that is protected from endogenous RNase activity. miRNAs originating from human prostate cancer xenografts enter the circulation, are readily measured in plasma, and can robustly distinguish xenografted mice from controls. This concept extends to cancer in humans, where serum levels of miR-141 (a miRNA expressed in prostate cancer) can distinguish patients with prostate cancer from healthy controls. Our results establish the measurement of tumor-derived miRNAs in serum or plasma as an important approach for the blood-based detection of human cancer.
7,296 citations
"Multiple Sclerosis: MicroRNA Expres..." refers background in this paper
...Recent proof-of-principle studies demonstrated that the analysis of miRNA expression in sera or blood cells may be a promising approach for blood-based diagnosis of a number of human cancers and also autoimmune diseases [8–10]....
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Journal Article•
TL;DR: I MicroRNAs (miRNAs) are an abundant class of small non-protein-coding RNAs that function as negative gene regulators as discussed by the authors, and have been shown to repress the expression of important cancer-related genes and might prove useful in the diagnosis and treatment of cancer.
Abstract: I MicroRNAs (miRNAs) are an abundant class of small non-protein-coding RNAs that function as negative gene regulators. They regulate diverse biological processes, and bioinformatic data indicates that each miRNA can control hundreds of gene targets, underscoring the potential influence of miRNAs on almost every genetic pathway. Recent evidence has shown that miRNA mutations or mis-expression correlate with various human cancers and indicates that miRNAs can function as tumour suppressors and oncogenes. miRNAs have been shown to repress the expression of important cancer-related genes and might prove useful in the diagnosis and treatment of cancer.
6,064 citations
VU University Amsterdam1, University of Rennes2, Vita-Salute San Raffaele University3, University of Düsseldorf4, University of Basel5, Icahn School of Medicine at Mount Sinai6, Foothills Medical Centre7, National Institutes of Health8, University of Toronto9, Lund University10, Mayo Clinic11, University of Texas Health Science Center at Houston12
TL;DR: New evidence and consensus now strengthen the role of these criteria in the multiple sclerosis diagnostic workup to demonstrate dissemination of lesions in time, to clarify the use of spinal cord lesions, and to simplify diagnosis of primary progressive disease.
Abstract: New diagnostic criteria for multiple sclerosis integrating magnetic resonance image assessment with clinical and other paraclinical methods were introduced in 2001. The "McDonald Criteria" have been extensively assessed and used since 2001. New evidence and consensus now strengthen the role of these criteria in the multiple sclerosis diagnostic workup to demonstrate dissemination of lesions in time, to clarify the use of spinal cord lesions, and to simplify diagnosis of primary progressive disease. The 2005 Revisions to the McDonald Diagnostic Criteria for MS should simplify and speed diagnosis, whereas maintaining adequate sensitivity and specificity.
4,862 citations
"Multiple Sclerosis: MicroRNA Expres..." refers methods in this paper
...Patients with MS and healthy controls We included 20 patients with a diagnosis of RRMS according to McDonald criteria [18] as well as 19 healthy controls in our study (see supplemental Table S1)....
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TL;DR: It is demonstrated that miRNAs are present in the serum and plasma of humans and other animals such as mice, rats, bovine fetuses, calves, and horses, and can serve as potential biomarkers for the detection of various cancers and other diseases.
Abstract: Dysregulated expression of microRNAs (miRNAs) in various tissues has been associated with a variety of diseases, including cancers. Here we demonstrate that miRNAs are present in the serum and plasma of humans and other animals such as mice, rats, bovine fetuses, calves, and horses. The levels of miRNAs in serum are stable, reproducible, and consistent among individuals of the same species. Employing Solexa, we sequenced all serum miRNAs of healthy Chinese subjects and found over 100 and 91 serum miRNAs in male and female subjects, respectively. We also identified specific expression patterns of serum miRNAs for lung cancer, colorectal cancer, and diabetes, providing evidence that serum miRNAs contain fingerprints for various diseases. Two non-small cell lung cancer-specific serum miRNAs obtained by Solexa were further validated in an independent trial of 75 healthy donors and 152 cancer patients, using quantitative reverse transcription polymerase chain reaction assays. Through these analyses, we conclude that serum miRNAs can serve as potential biomarkers for the detection of various cancers and other diseases.
4,184 citations
"Multiple Sclerosis: MicroRNA Expres..." refers background in this paper
...Evidence suggests that miRNAs are present in a remarkably stable form in human blood, where they occur as free circulating nucleic acids, in microvesicles, and in mononuclear blood cells [7,8]....
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TL;DR: The history of clinical diagnostic criteria demonstrates the evolution from rather tentative classifications of restricted value to the more elaborate 1983 scheme which incorporates some laboratory procedures under the rubric paraclinical tests as well as a new category based on the presence of specific abnormalities of the cerebrospinal fluid (CSF).
1,902 citations