Molecular biomarkers in multiple sclerosis

Multiple sclerosis (MS) is an inflammatory-neurodegenerative disease of the central nervous system presenting with significant inter- and intraindividual heterogeneity. However, the application of clinical and imaging biomarkers is currently not able to allow individual characterization and prediction. Complementary, molecular biomarkers which are easily quantifiable come from the areas of immunology and neurobiology due to the causal pathomechanisms and can excellently complement other disease characteristics. Only a few molecular biomarkers have so far been routinely used in clinical practice as their validation and transfer take a long time. This review describes the characteristics that an ideal MS biomarker should have and the challenges of establishing new biomarkers. In addition, clinically relevant and promising biomarkers from the blood and cerebrospinal fluid are presented which are useful for MS diagnosis and prognosis as well as for the assessment of therapy response and side effects.

Multiple sclerosis (MS) is a chronic autoimmune disease characterized by inflammatory demyelination and neurodegeneration in the central nervous system (CNS) [1]. The disease shows a great heterogeneity with regard to radiological and histopathological changes, clinical appearance and progression, as well as therapy response [2,3,4,5,6]. It is therefore very important to define specific features of the disease that facilitate diagnosis and prognosis and allow an assessment of the therapeutic response and risk of side effects [7,8,9]. Currently, the lesion load in the CNS determined by magnetic resonance imaging (MRI) as well as clinical characteristics, e.g., relapse rate and disability progression, play the most important role [10]. However, although it is possible to quantify and standardize these characteristics in larger patient groups, it is not possible until now in individual patients [11, 12].

Molecular biomarkers, on the other hand, are easily quantifiable and can excellently complement MRI and clinical characteristics [13]. Biomarkers for MS come from the areas of immunology and neurobiology due to the causal pathomechanisms [14]. Although the importance of molecular biomarkers has been increasingly recognized in recent years, their validation is a lengthy process, so that only a few biomarkers have so far been routinely used in clinical practice [15]. However, the number of potential biomarkers at different stages of testing is promising. This review describes the characteristics that an ideal MS biomarker should have and the challenges of establishing new biomarkers [16]. In addition, clinically relevant and promising biomarkers from the blood and cerebrospinal fluid (CSF) are presented which are useful for MS diagnosis and prognosis as well as for the assessment of therapy response and side effects.

A biomarker is defined as a characteristic that can be objectively measured and evaluated and serves as an indicator of normal biological processes, pathological processes or pharmacological reactions to therapy [17]. Ideally, this is a binary system, in other words a characteristic that is present in people with a certain disease and is absent in healthy people or people with another disease or vice versa. If the disease worsens or improves, the concentration of the biomarker should increase or decrease accordingly [18]. Another characteristic of an ideal biomarker is that it is safe for the patient and as easy to detect as possible, in the best case it is a non-invasive method. The analytical detection method should be highly accurate and reproducible and at the same time fast, simple, and cost-effective in order to ensure comprehensive implementation [19]. Thereby, the result of the detection method should be insensitive to systematic influencing factors such as sample collection, sample processing, and sample storage [20].

In addition to the typical clinical characteristics of a disease, imaging biomarkers are often used with the aid of imaging methods. In MS, for example, MRI provides information on the size, number, age, and development of lesions in the CNS and plays an important role in diagnosis and therapy monitoring [21,22,23]. In the future, brain atrophy could also gain importance if its measurement becomes possible in individual patients [24,25,26,27,28,29]. Imaging biomarkers are distinguished from molecular biomarkers, which comprise deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and proteins. The advantages of DNA as a molecular marker are a less demanding handling as well as an easier and less expensive detection [30]. In contrast, RNA and proteins are quantitative characteristics that, as opposed to DNA, are suitable for monitoring disease specific processes. In the field of MS, all established molecular biomarkers are currently proteins, most of them antibodies [15, 31, 32].

For the detection of molecular biomarkers, a sample must be taken from the patient. In MS, the body fluids blood and CSF, which offer different advantages and disadvantages, are particularly suitable (Table 1). Since blood collection is the less invasive procedure, the validation of new molecular biomarkers should examine whether serum or plasma detection is as suitable as CSF detection.

In the development and establishment of new biomarkers, the above-mentioned properties of an ideal biomarker have to be taken into account and some additional difficulties have to be overcome, which are described below [35].

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