Role of BDNF-mediated neuroplasticity in patients affected by Fibromyalgia versus other chronic rheumatic diseases.

Background Fibromyalgia (FM) is still often viewed as a psychosomatic disorder. However, the increased pain sensitivity to stimuli in FM patients is not a phenomena of imagination, but the result of specific abnormalities in the central nervous system (CNS) pain matrix. Brain-derived neurotrophic factor (BDNF) is an endogenous protein involved in neuronal survival and synaptic plasticity of the central and peripheral nervous systems. Several lines of evidence converge to indicate that BDNF also participates in structural and functional plasticity of nociceptive pathways in the CNS and within the dorsal root ganglia and spinal cord. At these levels, release of BDNF appears to modulate or even mediate nociceptive sensory inputs and pain hypersensitivity. In the literature few studies evaluated BDNF levels in serum, plasma and cerebrospinal fluid samples of FM patients, finding increased levels of this neurotrophin compared to healthy controls. A number of studies also investigated BDNF levels in synovial fluid and plasma samples from patients affected by rheumatoid arthritis (RA), who are chronically subjected to pain, even though of inflammatory and autoimmune origin. No studies instead have been performed on patients affected by chronic fatigue syndrome (CFS), a condition that frequently overlaps with FM and whose etiopathogenesis, still unclear, is probably different from that of FM. Objectives The primary objective of the present PhD thesis project was therefore to investigate BDNF-mediated neuroplasticity, by detecting BDNF levels in FM patients, and therefore by comparing these levels to the ones found in CFS, RA and healthy volunteers. Secondary objectives were: (i) the relation between BDNF levels and clinical variables, including neurocognitive disorders, which were assessed in FM and CFS patients by means of a computerized system; (ii) the relation between BDNF levels and psychiatric comorbidity in FM and CFS patients; (iii) the relation between BDNF levels and inflammatory status in RA patients; (iv) serum and plasmatic BDNF levels in a subgroup of FM patients before, immediately after, and 3-months after thermal treatments. Materials and methods Among the patients recruited in the study, there were 68 FM, 45 CFS, and 46 RA together with 40 healthy controls. BDNF serum levels were determined by enzyme-linked immune-sorbent assay (Promega), and the differences among the various groups were observed. Demographic and clinical parameters were investigated in relation to BDNF levels. Moreover, a subgroup of FM patients (n=28) also participated to a clinical trial held at the Montecatini Thermal Baths, and another subgroup of FM patients (n=40), together with CFS patients, also completed a computerized test battery for the assessment of neurocognitive disorders. Results The main findings of the work can be summarized as follows: (i) the increased BDNF levels in sera of patients affected by FM, CFS and RA (but only those who were positive to rheumatoid factor of all isotypes), compared to healthy volunteers; (ii) the positive correlation between BDNF and rheumatoid factor (IgG and IgM isotypes), and the negative one with C-reactive protein; (iii) the lack of correlation between BDNF and neurocognitive disorders, assessed by the software CNS Vital Signs©; (iv) the higher prevalence of neurocognitive disorders in FM than in CFS patients, despite the more frequent complaint of CFS patients; (v) the tight relationship between neurocognitive impairments and chronic pain, which is independent of psychiatric comorbidity. Conclusions The conclusion reached by this study is that BDNF-mediated neuroplasticity in FM, CFS and RA could be interpreted as a protective mechanism against injuries, chronic pain and, more generally, against chronic stress conditions. This hypothesis could explain the elevated BDNF levels found in sera -but not in plasma- samples, and their decrease after thermal treatment. Although BDNF is not specific for FM or chronic pain -the difference here reported between BDNF levels of FM, CFS, RA patients compared to healthy controls are not strong enough to allow the use of BDNF in the diagnostic field- this work on one hand opens the way to new investigations on FM, CFS and RA etiopathogenesis, and on the other could suggest BDNF as a useful biomarker for FM/chronic pain therapy monitoring.