Markers In Multiple Sclerosis Research Articles

Magnetization transfer ratio as a marker for myelin in multiple sclerosis

I read the recent report on magnetization transfer ratio as a marker for myelin in multiple sclerosis with a great interest (1). Vavasour et al concluded that “MTR was correlated with WC in MS tissue, indicating that inflammation and edema influence MTR (1).” This finding is very interesting. However, due to the few subjects, the usefulness of the work might be limited. Indeed, the magnetization transfer ratio is widely mentioned for its usefulness as marker in multiple sclerosis. With the detected limitation, it is interesting to add other parameters from the imaging study to increase the diagnostic property. Further studies on the analysis of other MT parameters, such as magnetization transfer rate (k(for)) and relative measure of water content (T1(free)), will be useful. Ropele et al reported that “Estimates of k(for) and T1(free) appear to complement MTR measurements for the understanding of MT changes that occur with different types of MS abnormalities in the brain (2).” Viroj Wiwanitkit MD*, * Wiwanitkit House Bangkhae, Bangkok, Thailand.

No influence of KIF1B on neurodegenerative markers in multiple sclerosis

In search of genetic causes of multiple sclerosis (MS), a number of genes have consistently shown association with MS susceptibility in the past couple of years.1 All of these identified genes are directly or indirectly involved with the inflammatory process. However, it has become increasingly clear that MS consists of both an inflammatory and a progressive neurodegenerative process,2 which is illustrated by the fact that new and potent anti-inflammatory drugs have been unable to halt neurodegeneration. The relation between episodes of inflammation and the neurodegenerative component characterized by irreversible axonal loss are far from clear at this point. Some authors have argued that neurodegeneration is independent of inflammation, while others argue that the 2 components are closely associated and are actually interdependent.2,3 The neurodegenerative component is clinically highly relevant since it is held predominantly responsible for disability accumulation, although several questions regarding this issue remain.2 Until recently, no genetic marker for neurodegeneration in MS was identified. However, in 2008, it was reported for the first time that a “neurodegenerative gene,” i.e., the KIF1B rs10492972 [C] variant, was associated with MS susceptibility.4 KIF1B is involved in axonal transport of mitochondria and synaptic vesicle precursors. Dysregulation of axonal transport plays a role in several neurodegenerative diseases.4 The authors suggested that KIF1B could be the first gene involved in MS susceptibility with a possible neurodegenerative effect.4 Unfortunately, this finding could later not be confirmed in other …

High Resolution Spectral Domain Optical Coherence Tomography (SD-OCT) in Multiple Sclerosis: The First Follow Up Study over Two Years

Background“Non-invasive, faster and less expensive than MRI” and “the eye is a window to the brain” are recent slogans promoting optical coherence tomography (OCT) as a new surrogate marker in multiple sclerosis (MS). Indeed, OCT allows for the first time a non-invasive visualization of axons of the central nervous system (CNS). Reduction of retina nerve fibre layer (RNFL) thickness was suggested to correlate with disease activity and duration. However, several issues are unclear: Do a few million axons, which build up both optic nerves, really resemble billions of CNS neurons? Does global CNS damage really result in global RNFL reduction? And if so, does global RNFL reduction really exist in all MS patients, and follow a slowly but steadily ongoing pattern? How can these (hypothesized) subtle global RNFL changes be reliably measured and separated from the rather gross RNFL changes caused by optic neuritis? Before generally being accepted, this interpretation needs further critical and objective validation.MethodologyWe prospectively studied 37 MS patients with relapsing remitting (n = 27) and secondary progressive (n = 10) course on two occasions with a median interval of 22.4±0.5 months [range 19–27]. We used the high resolution spectral domain (SD-)OCT with the Spectralis 3.5 mm circle scan protocol with locked reference images and eye tracking mode. Patients with an attack of optic neuritis within 12 months prior to the onset of the study were excluded.Principal FindingsAlthough the disease was highly active over the observation period in more than half of the included relapsing remitting MS patients (19 patients/32 relapses) and the initial RNFL pattern showed a broad range, from normal to markedly reduced thickness, no significant changes between baseline and follow-up examinations could be detected.ConclusionsThese results show that caution is required when using OCT for monitoring disease activity and global axonal injury in MS.

Determinants of interferon β efficacy in patients with multiple sclerosis

Many patients with multiple sclerosis (MS) experience clinical relapses or progression of disability, or exhibit evidence of disease activity on MRI, despite the use of disease-modifying therapy. Although evidence clearly supports the efficacy of interferon β (IFN-β) in treating MS, the factors that determine the response to this drug in individual patients have not been fully elucidated. As more treatment options become available, the early identification of factors that can affect or predict the efficacy of agents in individual patients is important, because such knowledge facilitates early switching of treatment. Despite years of research and numerous reports of promising therapy markers for MS, few markers have emerged as clinically useful. Several studies suggest, however, that development of MRI lesions within 6-24 months after the initiation of IFN-β treatment predicts an unfavorable response. In addition, persistently high titers of neutralizing antibodies diminish or abrogate the therapeutic effects of IFN-β, and help to identify patients who do not respond. This Review highlights advances in research on the response to IFN-β in patients with MS and aims to provide a practical approach for incorporating clinical data, biological markers and MRI measures of disease activity into their therapeutic management.

CSF and serum total-tau and phospho-tau(181P) in MS patients

AbstractIn search of biological marker in multiple sclerosis (MS), total-tau and phospho-tau (Thr181) concentrations were established in CSF and serum of 78 patients with MS, using commercially available kits. Serum and CSF concentrations of IgG, IgM, and albumin were assayed simultaneously to calculate quotients and indices of intrathecal synthesis. Serum t-tau detection was strikingly low (23.1%); therefore, this factor was excluded from further analysis. Serum p-tau levels did not correlate with any of indices or quotients. Unexpectedly, CSF t-tau and p-tau showed an inverse relation with MSSS and EDSS, which has not been published elsewhere. Our results do not support utility of serum t-tau and p-tau as surrogate markers for MS.

Identification of antibodies as biological markers in serum from multiple sclerosis patients by immunoproteomic approach

We identified the antibody against mitochondrial heat shock protein 70 (mtHSP70) in serum from multiple sclerosis (MS) patients by proteomics-based analysis. The prevalence of the anti-mtHSP70 antibody is significantly higher in serum from MS patients than in serum from Parkinson disease patients, multiple cerebral infarction patients, infectious meningoencephalitis patients, and healthy controls (HCs) (68% sensitivity; 74% specificity). We studied the clinical features and magnetic resonance imaging findings of MS patients with the anti-mtHSP70 antibody. As a result, there were no significant differences between the anti-mtHSP70-antibody-positive and -negative MS patients. Additionally, in our comprehensive analysis of the prevalence of both the anti-mtHSP70 antibody and the anti-phosphoglycerate mutase 1 (PGAM1) antibody, which was previously reported by us to also show a higher prevalence in serum from MS patients, the positivity rates of both these antibodies were significantly higher in serum from MS patients than in serum from patients with other neurological diseases and from HCs; moreover, the specificity of this combination assay was higher than that of the assay of only one antibody (57% sensitivity; 93% specificity). Results of our study suggest that not only the anti-PGAM1 antibody but also the anti-mtHSP70 antibody is good diagnostic markers of MS and the combination of both these antibodies is useful for a more specific diagnosis of MS.

POI18 Increased urinary free immunoglobulin light chain excretion in patients with multiple sclerosis

BackgroundPlasma and B cells have been implicated in multiple sclerosis (MS). The presence of intrathecal oligoclonal IgG and free light chains (FLCs) is a feature of MS and rituximab has...

Properdin factor B allotype F and HLA-Dwl as protective markers in multiple sclerosis

Properdin factor B allotype F and HLA-Dwl as protective markers in multiple sclerosis

Matrix metalloproteinase-9 and matrix metalloproteinase-2 as biomarkers of various courses in multiple sclerosis

Background Matrix metalloproteinases are notable contributors to neuroinflammation and blood-brain barrier disruption in multiple sclerosis (MS). Objective The goal of this study was to determine the serum levels of matrix metalloproteinase-9 (MMP-9), matrix metalloproteinase-2 (MMP-2), and their tissue inhibitors (TIMP-1) and (TIMP-2), and to investigate their possible relations to type, disability, and severity of MS. Materials and methods Eighty-seven patients with definite MS according to the McDonald criteria and 50 healthy controls were enrolled in the study. Their clinical status was evaluated with the Expanded Disability Status Scale. Serum levels were analyzed by enzyme-linked immunoassay. Results A significant elevation in MMP-9 serum levels and in the MMP-9/TIMP-1 ratio was found in the whole MS group (P < 0.001), in the relapsing–remitting MS (RRMS) (P < 0.001), and secondary-progressive MS (SPMS) (P < 0.001) groups when compared with the controls. A significant elevation in MMP-2 serum levels and in the MMP-2/TIMP-2 ratio was observed in the primary progressive (P < 0.001) and the SPMS (P < 0.002) groups when compared with the RRMS group, and this increase was also associated with the disability (P < 0.001) and severity (P < 0.05) of the disease. Conclusion We confirmed that metalloproteinases are useful biological markers in MS, providing information about the clinical type, disability, and severity of the disease.

Kallikreins are associated with secondary progressive multiple sclerosis and promote neurodegeneration

Tissue kallikrein KLK1 and the kallikrein-related peptidases KLK2-15 are a subfamily of serine proteases that have defined or proposed roles in a range of central nervous system (CNS) and non-CNS pathologies. To further understand their potential activity in multiple sclerosis (MS), serum levels of KLK1, 6, 7, 8 and 10 were determined in 35 MS patients and 62 controls by quantitative fluorometric ELISA. Serum levels were then correlated with Expanded Disability Status Scale (EDSS) scores determined at the time of serological sampling or at last clinical follow-up. Serum levels of KLK1 and KLK6 were elevated in MS patients (p<or=0.027), with highest levels associated with secondary progressive disease. Elevated KLK1 correlated with higher EDSS scores at the time of serum draw and KLK6 with future EDSS worsening in relapsing remitting patients (p<or=0.007). Supporting the concept that KLK1 and KLK6 promote degenerative events associated with progressive MS, exposure of murine cortical neurons to either kallikrein promoted rapid neurite retraction and neuron loss. These novel findings suggest that KLK1 and KLK6 may serve as serological markers of progressive MS and contribute directly to the development of neurological disability by promoting axonal injury and neuron cell death.

Nontraditional approaches to biomedical screening: Communication II

On the basis of theoretical studies and literature data, biochemical markers of multifactorial diseases (such as presenile dementia (PD) or Alzheimer’s disease (AD), multiple sclerosis (MS), and rheumatoid arthritis (RA), reflecting the pathogenetic features of these diseases have been systematized. Amyloid β is regarded as a common marker for PD (AD) and RA (along with the BB isozyme of creatine kinase, transaminase, α and -β secretases, acetylcholine, choline acetyltransferase, and acetylcholine esterase); myelin basic protein, tumor necrosis factor α, cephalin, and linoleic acid, as markers of MS; and circulating immune complexes, rheumatoid factor (RF IgG), granzyme A, perforin, acid phosphatase, and cathepsins, as markers of RA. Their contents in biological material obtained from patients were significantly higher or lower than in similar material from healthy subjects. Changes in the levels of some markers in patients were correlated with the severity of the corresponding diseases. Arguments are presented for the possibility of nontraditional biomedical screening of potential means of “molecular biochemical treatment” of these diseases by testing biologically active compounds for these markers.

Coagulation status and biochemical and inflammatory markers in multiple sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system and is the most common cause of neurologic disability in young adults. In this study, the coagulation status and biochemical and non-specific inflammatory markers in patients with MS were investigated. Plasma prothrombin time, activated partial thrombin time, fibrinogen, D-dimer, serum high sensitive C-reactive protein, homocysteine, blood urea nitrogen, creatinine, calcium, total protein, albumin, total cholesterol, vitamin B12, folate levels and erythrocyte sedimentation rate were measured in 42 patients with MS and 31 healthy subjects as a control group. There was a positive correlation between homocysteine and D-dimer levels ( r = 0.84, p < 0.01). However, there was no significant correlation between homocysteine, vitamin B12 ( r = 0.18) and folate ( r = 0.23) levels. Serum total protein, albumin and calcium levels of MS patients were lower than the control group. There are some alterations in the coagulation and biochemical status in MS patients. These findings may contribute to better understanding of the etiopathogenesis and clinical characteristics of this disease.

Specificity and Correlation With Disease Activity of Cerebrospinal Fluid Osteopontin Levels in Patients With Multiple Sclerosis

Despite recent advances in therapy that have improved the overall disease course in multiple sclerosis (MS), the prognosis at the outset remains unpredictable. To investigate whether cerebrospinal fluid (CSF) osteopontin levels correlate with disability or active disease in MS and to determine whether elevated CSF osteopontin levels are only seen in MS. Cerebrospinal fluid osteopontin was assayed using enzyme-linked immunosorbent assay in duplicate by an observer blinded to the clinical status of the sample. Cerebrospinal fluid samples were not obtained from any patient who had received high-dose corticosteroid therapy in the month before analysis. Medical research institute. Thirty patients (18 women and 12 men; age range, 24-71 years) with clinically definite MS and 36 patients (22 women and 14 men; age range, 20-71 years) with other neurological diseases (ONDs) or nonneurological illnesses were included in the study. Disease activity for patients with MS was based on observations in the year preceding the study, including the number of relapses, the change in disability according to the Expanded Disability Status Scale, and increased T2-weighted or gadolinium-enhancing lesions on brain magnetic resonance imaging. Higher CSF osteopontin levels were seen in patients with MS having active disease and in patients with ONDs that are actively deteriorating or inflammatory. However, CSF osteopontin levels in patients with MS did not correlate with disability status. Cerebrospinal fluid osteopontin levels do not correlate with disability in MS but tend to be higher in patients with active disease. Elevated CSF osteopontin levels are not a specific marker for MS, as they are found in patients with ONDs and nonneurological illnesses. In ONDs, the highest CSF osteopontin levels are seen in patients with rapidly progressive neurological dysfunction or widespread inflammation of the central nervous system.

Validation of linear cerebral atrophy markers in multiple sclerosis

Linear measures of cerebral ventricular enlargement may act as surrogate measures of cerebral atrophy in multiple sclerosis (MS). Linear atrophy markers were measured from routine MRI scans during a population survey of 171 Tasmanian MS patients and 91 healthy controls. Thirty-five Victorian MS clinic patients were recruited as a validation cohort with 14 of these re-assessed 4 years later. In the population survey, we measured three linear brain atrophy markers: inter-caudate distance (ICD), third ventricle width (TVW) and frontal horn width (FHW). TVW (OR 2.0, p = 0.001) and ICD (OR 16.1, p < 0.001) differentiated between MS cases and controls. In the validation study, we correlated the intercaudate ratio (ICR = ICD/brain width) and third ventricular ratio (TVR = TVW/brain width) with brain parenchymal volume. Cross-sectionally, ICR ( R = −0.453, p < 0.01) and TVR ( R = −0.653, p < 0.01) were correlated with brain parenchymal volume. Longitudinally, brain parenchymal volume loss was inversely correlated with increased ICD ( R = −0.77, p < 0.01) and TVW ( R = −0.71, p < 0.01). This study shows that ICD measurements obtained from clinical MRI scans are valid brain atrophy measures for use in monitoring MS progression.

Cleavage of cystatin C is not associated with multiple sclerosis

Recently, Irani and colleagues proposed a C-terminal cleaved isoform cystatin C (12.5 kDa) in cerebrospinal fluid as a marker of multiple sclerosis. In this study, we demonstrate that the 12.5 kDa product of cystatin C is formed by degradation of the first eight N-terminal residues. Moreover, such a degradation is not specific in the cerebrospinal fluid of multiple sclerosis, but rather is given by an inappropriate sample storage at -20 degrees C. We conclude that the use of the 12.5 kDa product of cystatin C in cerebrospinal fluid might lead to a fallacious diagnosis of multiple sclerosis. Preanalytical validation procedure is mandatory for proteomics investigations.

Statistical Issues Related to the Use of MRI Data in Multiple Sclerosis

Since magnetic resonance imaging (MRI) of the brain has proved to be the most important paraclinical tool for diagnosing multiple sclerosis (MS) and monitoring its evolution, methodological and statistical issues related to the use of MRI markers in MS have been the focus of several studies in the past 10 years. While many of these methodological issues have been addressed using standard procedures available from other areas of application of medical statistics, in some cases statistical procedures that are not standard have been developed specifically for MRI variables in MS. Two of the major achievements in the statistical methods applied to the use of MRI variables in MS in the past 10 years were the identification of a parametric model to describe the distribution of MRI lesion counts across patients and the study of the relationships between MRI markers and clinical variables, with the aim to validate MRI parameters as surrogates for clinical progression.

Multiple sclerosis: Disease biomarkers as indicated by pathophysiology

Multiple sclerosis (MS), the most important human inflammatory demyelinating disease of the central nervous system, is characterized by heterogenous genetic backgrounds and immunopathogenetic subtypes, various clinical disease courses, and inhomogeneous and unpredictable therapeutic effects. Because of this heterogeneity, subtyping of our MS patients by genetical, clinical, neuroradiological, and neuroimmunological parameters will be an urgent need in the near future. Therefore the importance of identifying biological markers for MS has evolved over the past years. Evidence for a possible role of antibodies as biological markers for MS comes from several studies indicating that intrathecal antibody production and the dominance of B-cells are associated with a more progressive disease course. This review summarizes the current status and potential applicability of antibodies as biological markers for the diagnosis, classification, disease activity and prediction of clinical courses in MS. Antibodies (and other molecules) serving as biomarkers will help to establish a differential therapeutic concept in MS, which should allow to treat individuals selectively according to their pathogenetic subtype and disease status.

Assessment of motor phenotype in Multiple Sclerosis using a force plate – a new biomarker for clinical studies?

Background: Assessment of severity of symptoms in patients with Multiple Sclerosis (MS) in the setting of clinical studies is usually performed using categorical clinical scales such as the EDSS. Objective measures of disease phenotype are desirable to quantitatively and sensitively assess the progression of MS. Assessment of motor phenotype dysfunction may serve as a useful surrogate marker in MS that is easy to assess even in out-patient settings.

Mitochondrial DNA variants in Bulgarian patients affected by multiple sclerosis

The occurrence of multiple sclerosis (MS) in subjects clustering to a particular mitochondrial DNA (mtDNA) haplogroup/haplotype or carrying mtDNA mutations associated with Leber's hereditary optic neuropathy (LHON) has suggested that mitochondrial genome may contribute to susceptibility to MS. In the present study, 58 unrelated Bulgarian patients with relapsing remitting form of MS and 104 randomly selected healthy individuals were analysed for the presence of 14 mtDNA polymorphisms determining major European haplogroups as well as three (4216, 14 798, 13 708) secondary LHON mutations. Restriction enzyme analysis used to screen patients and controls for the common haplogroup-associated polymorphisms showed that each of these changes was present in MS patients at a similar frequency to control subjects. However, 21 of the 58 patients (36.2%) were positive for T4 216C mutation, while only 11.3% of the controls carried this secondary LHON base change (P < 0.01; OR = 4.38). Our finding indicated that 4216C base substitution could be considered as a predisposing marker for MS and supported the hypothesis that particular mtDNA variants could contribute to genetic susceptibility of MS, and merits further investigation.

How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis

In their Point of View entitled "Experimental Allergic Encephalomyelitis: A Misleading Model of Multiple Sclerosis," Sriram and Steiner(1) wrote, "The most disappointing aspect of EAE [experimental allergic encephalomyelitis] as a potential model for MS is its almost total inability to point toward a meaningful therapy or therapeutic approach for MS." Actually, EAE has led directly to the development of three therapies approved for use in multiple sclerosis (MS): glatiramer acetate, mitoxantrone, and natalizumab. Several new approaches to MS are in clinical trials based on positive indications in preclinical work relying on EAE. New clues to the pathogenesis of MS and new potential surrogate markers for MS are shown from research involving EAE when it is critically coupled with actual findings in MS. There are pitfalls in overreliance on the EAE model, or on any animal model for any human disease. Nevertheless, over the past 73 years, the EAE model has proved itself remarkably useful for aiding research on MS.