Fatigue in Multiple Sclerosis and Its Relationship to Inflammatory and Neurodegenerative Markers of the Disease

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the CNS, leading to non-traumatic neurological impairment in young people. Disability progression in MS is commonly recognized as the disability worsening occurring in patients with progressive MS or in the absence of relapse activity in relapsing progressing MS. This process can begin early in the disease and is not always halted by current therapeutics. The ability to accurately select between active, active progressive and nonactive progressive patients is crucial.

The aim of the proposed study is to use a multimodal approach to achieve better diagnosis and more accurate prediction of disease progression in an individual patient. The diagnostic modalities will include the evaluation of fatigue questionnaires (FIS, ESS, HADS, RAND-36), biomarkers examination: serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP), and mitochondrial respiratory capacity.

The fatigue questionnaire battery is considered an advanced examination that is not commonly performed in MS patients. The Fatigue Impact Scale (FIS) is a tool used to assess the impact of fatigue on various aspects of a patient's life. This questionnaire measures the extent to which fatigue affects physical, cognitive, and psychosocial functioning and helps quantify the severity of fatigue. The Epworth Sleepiness Scale (ESS) is a simple questionnaire used to measure daytime sleepiness, helping to differentiate increased fatigue in patients from potential sleep disorders. Additionally, HADS and RAND-36 is included in the study to rule out potential associations of fatigue with other external influences.

NfL is known to be an excellent biomarker of focal inflammatory activity but lacks the ability to reflect the pathology that drives disease progression. Neurodegeneration and astrocytic activation can be quantified by glial fibrillary acidic protein (sGFAP). Previous research revealed, that higher levels of sGFAP correlated with subsequent progression, particularly in nonactive patients, whereas sNfL reflected acute disease activity in patients with MS at high risk of underlying progressive pathology.

Mitochondria, traditionally recognized as cellular 'powerhouses' due to their pivotal role in energy production, have emerged as multifunctional organelles at the intersection of bioenergetics, metabolic signalling, and immunity. Investigators propose mitochondria as the leading immune organelles, drawing parallels with the broader immune system in their functions of antigen presentation, immune regulation, and immune response. Investigators also consider mitochondria's ability to detect and release danger signals, regulate immune functions, and engage in intercellular crosstalk. Investigators plan to analyse mitochondrial function by means of high-resolution respirometry with the Oroboros O2k in all study participants.

The human leukocyte antigen (HLA) DRB1*1501, which has been consistently associated with MS nearly in all populations will be evaluated in all participants of the study. The HLA-DRB1*15:01 haplotype is of importance in the interaction between B and T cells in MS patients, while two autosomal genome-wide significant MS risk alleles significantly alter the distribution B-cell subsets. Investigators are planning to test an intergenic variant near BCL6 (rs969625), associated with high MS risk and decreased naive/memory ratios, and an intronic variant in OS9 (rs701006) corresponded to low MS risk.

The study is focused on several independent quantifiable parameters to obtain more detailed information about MS and its progression. Based on the results, investigators will further attempt to predict the course of the disease and manage the therapy more effectively to prevent worsening of the patient's condition.