Currently, there is no single test for multiple sclerosis (MS). Diagnosis is confirmed through clinical evaluation, abnormalities revealed by magnetic resonance imaging (MRI), and analysis of cerebrospinal fluid (CSF) chemistry. The early and accurate diagnosis of the disease, monitoring of progression, and gauging of therapeutic intervention are important but elusive elements of patient care. Moreover, a deeper understanding of the disease pathology is needed, including discovery of accurate biomarkers for MS. Herein we review putative biomarkers of MS relating to neurodegeneration and contributions to neuropathology, with particular focus on autoimmunity. In addition, novel assessments of biomarkers not driven by hypotheses are discussed, featuring our application of advanced proteomics and metabolomics for comprehensive phenotyping of CSF and blood. This strategy allows comparison of component expression levels in CSF and serum between MS and control groups. Examination of these preliminary data suggests that several CSF proteins in MS are differentially expressed, and thus, represent putative biomarkers deserving of further evaluation.

Kevin C. O&#x2019;Connor

Sushmita Mimi Roy

Christopher H. Becker

David A. Hafler

Aaron B. Kantor

Comprehensive Phenotyping in Multiple Sclerosis: Discovery Based Proteomics and the Current Understanding of Putative Biomarkers

The gene for ataxia-telangiectasia (A-T:MIM:#208900), ATM, spans about 150&#x7e;kb of genomic DNA and is composed of 62 coding exons. ATM mutations are found along the entire coding sequence of the gene, without evidence of mutational hot spots. Using DNA as the starting material, we used denaturing high performance liquid chromatography (DHPLC) technique to search for ATM gene mutations. Initially, DHPLC was validated in a retrospective study of 16 positive control samples that included 19 known mutations; 100&#x25; of mutations were detected. Subsequently, DHPLC was used to screen for mutations a cohort of 22 patients with the classical form of A-T. A total of 27 different mutations were identified on 38 of the 44 alleles, corresponding to a 86&#x25; detection rate. Fourteen of the mutations were novel. In addition, 15 different variants and polymorphisms of unknown functional significance were found. The high incidence of new and individual A-T mutations in our cohort of patients demonstrates marked mutational heterogeneity of A-T in Italy and corroborate the efficiency of DHPLC as a method for the mutation screening of A-T patients.

Monia Magliozzi

Maria Piane

Isabella Torrente

Lorenzo Sinibaldi

Giovanni Rizzo

Camilla Savio

Patrizia Lulli

Alessandro De Luca

Bruno Dallapiccola

Luciana Chessa

DHPLC Screening of ATM Gene in Italian Patients Affected by Ataxia-Telangiectasia: Fourteen Novel ATM Mutations

Cerebrospinal fluid (CSF) is the body fluid closest to the pathology of multiple sclerosis (MS). For many candidate biomarkers CSF is the only fluid that can be investigated. Several factors need to be standardized when sampling CSF for biomarker research: time/volume of CSF collection, sample processing/storage, and the temporal relationship of sampling to clinical or MRI markers of disease activity. Assays used for biomarker detection must be validated so as to optimize the power of the studies. A formal method for establishing whether or not a particular biomarker can be used as a surrogate end-point needs to be adopted. This process is similar to that used in clinical trials, where the reporting of studies has to be done in a standardized way with sufficient detail to permit a critical review of the study and to enable others to reproduce the study design. A commitment must be made to report negative studies so as to prevent publication bias. Pre-defined consensus criteria need to be developed for MS-related prognostic biomarkers. Currently no candidate biomarker is suitable as a surrogate end-point. Bulk biomarkers of the neurodegenerative process such as glial fibrillary acidic protein (GFAP) and neurofilaments (NF) have advantages over intermittent inflammatory markers.

Gavin Giovannoni

Multiple Sclerosis Cerebrospinal Fluid Biomarkers

The first international workshop on &#x201c;Biomarkers in Multiple Sclerosis&#x201d; was organized by B. Bielekova, R. Hohlfeld, R. Martin and U. Utz from April 14&#x2013;16, 2004, in Washington, DC. The workshop intended to discuss the current status and potential applicability of biological markers for the understanding of the pathogenesis, diagnosis, and therapy of multiple sclerosis. The present review summarizes the presentation on the potential role of antibodies as biomarkers for diagnosis, disease activity, classification and prediction of clinical courses in multiple sclerosis.

Thomas Berger

Markus Reindl

Biomarkers in Multiple Sclerosis: Role of Antibodies

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that principally targets the optic nerves and spinal cord and often leads to severe disability and occasionally life threatening respiratory failure. Although its clinical manifestations overlap with those of multiple sclerosis (MS), in established cases these two conditions can be distinguished on the basis of clinical, radiological, and routine spinal fluid studies. The diagnosis in early cases or limited forms of NMO is difficult. We recently discovered a unique IgG autoantibody (NMO-IgG) that is highly specific to patients with NMO and thus a valuable diagnostic aid. Its antigen, aquaporin-4 (AQP4), is the central nervous system&#x2019;s predominant water channel protein. This antibody has not yet been proven to be pathogenic, but several facts suggest that it might be, including the similarity of the immunohistochemical pattern of NMO-(AQP4) IgG binding to mouse CNS tissues to the pattern of immune complex deposition in autopsied patients&#x2019; spinal cord tissue. The spectrum of diseases identified by NMO-IgG is broader than has previously been recognized clinically and includes incomplete forms of NMO, such as recurrent transverse myelitis without optic neuritis and recurrent optic neuritis without myelitis.

Brian G. Weinshenker

Dean M. Wingerchuk

Sean J. Pittock

Claudia F. Lucchinetti

Vanda A. Lennon

NMO-IgG: A Specific Biomarker for Neuromyelitis Optica

Roland Martin

Bibiana Bielekova

Reinhard Hohlfeld

Ursula Utz

Biomarkers in Multiple Sclerosis

Blood-brain barrier (BBB) disruption is one of the hallmarks of multiple sclerosis (MS). It is incompletely understood whether BBB disruption is the initial MS event leading to MS lesion formation or whether it is merely a consequence of cellular infiltration in the central nervous system (CNS). The presence of gadolinium enhancing (Gd+) lesions on serial brain MRI scans is frequently used to evaluate BBB disruption. The presence of Gd enhancement has therefore been used as a reference for most works evaluating promising biomarkers of BBB disruption that are reviewed here. These promising biomarkers include cytokines and chemokines, and their receptors, cell surface markers, and matrix metalloproteinases and their natural inhibitors. At this time, none of these markers have been shown as sensitive as the presence of Gd enhancement to reflect BBB disruption. However, MRI scanning is not only unpractical and expensive; it may also under represent the overall extent of BBB disruption. Developing new MS biomarkers that are sensitive and specific for BBB disruption could 1) improve the monitoring of disease activity; 2) improve the monitoring of response to MS therapies which target BBB disruption; and 3) advance our understanding of dynamic MS processes participating in BBB disruption.

Emmanuelle Waubant

Biomarkers Indicative of Blood-Brain Barrier Disruption in Multiple Sclerosis

Multiple Myeloma (MM) is a severely debilitating neoplastic disease of B cell origin, with the primary source of morbidity and mortality associated with unrestrained bone destruction. Surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) was used to screen for potential biomarkers indicative of skeletal involvement in patients with MM. Serum samples from 48 MM patients, 24 with more than three bone lesions and 24 with no evidence of bone lesions were fractionated and analyzed in duplicate using copper ion loaded immobilized metal affinity SELDI chip arrays. The spectra obtained were compiled, normalized, and mass peaks with mass-to-charge ratios (m/z) between 2000 and 20,000 Da identified. Peak information from all fractions was combined together and analyzed using univariate statistics, as well as a linear, partial least squares discriminant analysis (PLS-DA), and a non-linear, random forest (RF), classification algorithm. The PLS-DA model resulted in prediction accuracy between 96&#x2013;100&#x25;, while the RF model was able to achieve a specificity and sensitivity of 87.5&#x25; each. Both models as well as multiple comparison adjusted univariate analysis identified a set of four peaks that were the most discriminating between the two groups of patients and hold promise as potential biomarkers for future diagnostic and/or therapeutic purposes.

Sudeepa Bhattacharyya

Joshua Epstein

Larry J. Suva

Biomarkers that Discriminate Multiple Myeloma Patients with or without Skeletal Involvement Detected Using SELDI-TOF Mass Spectrometry and Statistical and Machine Learning Tools

Background: Little information is known about telomerase expression in the chronic benign hyperproliferative skin disease, psoriasis. Further studies are still required to investigate its usefulness as a biomarker of this skin disorder. Aim: To investigate the expression of human telomerase reverse transcriptase (hTERT) in psoriatic lesional skin and its relation to disease severity. Methods: The levels of hTERT-mRNA were quantified using real time RT-PCR in lesional versus nonlesional skin specimens from 24 psoriatic patients. Results: The expression of hTERT was detected in 16 psoriatic lesional specimens (66.7&#x25;), but in none of the normal skin. There was no relation between hTERT expression level and age of the patient or the duration of the disease. Among hTERT-positive patients, a significant positive correlation was observed between hTERT-mRNA levels and both the Psoriasis Area-and-Severity Index (PASI) and scaling scores (p = 0.012 &#x26; p = 0.006, respectively). Conclusion: Telomerase mRNA is detectable in lesional skin of most psoriatic patients and correlates with the severity of the disease and the rate of epidermal proliferation.

Moushira A. Mahmoud

Roshdy W. Mohamed

Fadia M. Attia

Mona A. Atwa

Samir M. Abdel-moneim

Expression of Telomerase Reverse Transcriptase in Psoriatic Lesional Skin

Leukocyte infiltrates characterize tissue inflammation and are thought to be integral in the pathogenesis of multiple sclerosis (MS). This attribute underlines the importance of understanding mechanisms of leukocyte migration. Chemokines are secreted proteins which govern leukocyte trafficking into targeted organs. Chemokine receptors (CKR) are differentially expressed on leukocytes and their modulation is a potential target for MS disease modifying therapies. Chemokines and their receptors are also potential biomarkers of both disease activity and response to treatment. We describe the fluctuations in CKR expression on peripheral leukocytes in a group of MS patients followed longitudinally for up to 36 months. We observed little fluctuation in CKR expression within each patient over time, despite considerable variability in CKR expression between patients. These observations suggest that individual patients have a CKR set point, and this set point varies from one patient to another. Evaluation of chemokines or chemokine receptors as biomarkers in MS will need to account for this individual variability in CKR expression.

Robert J. Fox

Pia Kivis&#xe4;kk

Jar-Chi Lee

Barbara Tucky

Claudia Lucchinetti

Richard A. Rudick

Richard M. Ransohoff

Chemokine Receptors as Biomarkers in Multiple Sclerosis

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Disease Markers publishes papers related to the identification of disease markers, the elucidation of their role and mechanism, as well as their application in the prognosis, diagnosis and treatment of diseases.

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Chief Editor Paola Gazzaniga is an Associate Professor in the Department of Molecular Medicine at Sapienza University of Rome, Italy. Her core research focuses on liquid biopsies in patients with solid tumors.

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Disease Markers

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Disease Markers

Biomarkers in Multiple Sclerosis

Biomarkers in Multiple Sclerosis

Articles

Comprehensive Phenotyping in Multiple Sclerosis: Discovery Based Proteomics and the Current Understanding of Putative Biomarkers

DHPLC Screening of ATM Gene in Italian Patients Affected by Ataxia-Telangiectasia: Fourteen Novel ATM Mutations

Multiple Sclerosis Cerebrospinal Fluid Biomarkers

Biomarkers in Multiple Sclerosis: Role of Antibodies

NMO-IgG: A Specific Biomarker for Neuromyelitis Optica

Biomarkers in Multiple Sclerosis

Biomarkers Indicative of Blood-Brain Barrier Disruption in Multiple Sclerosis

Biomarkers that Discriminate Multiple Myeloma Patients with or without Skeletal Involvement Detected Using SELDI-TOF Mass Spectrometry and Statistical and Machine Learning Tools

Expression of Telomerase Reverse Transcriptase in Psoriatic Lesional Skin

Chemokine Receptors as Biomarkers in Multiple Sclerosis