The etiology of MS is still not well known, and the interaction between environmental, genetic, and other factors that trigger an abnormal autoimmune cascade leads to demyelination and axonal injury .
BDNF is secreted by immune cells in response to inflammatory and neuroimmune cascades as a trial to guard against neuronal and axonal damage after various pathological insults . BDNF regulates the relation between the immune and the nervous systems and plays a crucial role in brain-related disorders .
The aim of the present study was to assess the association between serum BDNF level and disease activity and severity in patients of relapsing–remitting MS.
This study was conducted on 60 MS patients: thirty patients in relapse, thirty patients in remission, and 30 control subjects. Assessment of the serum BDNF level was done for both MS patients and control groups. The serum level of BDNF was significantly higher in MS patients in relapse than those in remission. Using the ROC curve, the optimal cutoff value of BDNF that predicted disease activity was ≥ 265 pg/ml, with a sensitivity of 80% and a specificity of 66.7%.
Similar to our findings, Sarchielli and colleagues  assessed the BDNF level in their RRMS patients during attacks and 3 months after relapse and found significantly higher BDNF levels during relapse compared to levels detected in the remission state of the disease. Additionally, Frota and colleagues  found that levels of BDNF in MS patients increased significantly after MS relapse. Bruck and Stadelmann  studied the pathology of multiple sclerosis and reported that BDNF may promote remyelination, and this can support its increase during relapse.
In our study, there was no statistically significant difference between patients in relapse and control or between patients in remission and control. Similar to our findings, Sarchielli and colleagues  found that levels of BDNF in the RRMS patients in a remission phase did not differ from those of control subjects.
In contrast to our results, many studies found that BDNF levels in MS patients were significantly lower than those in the healthy control group [16,17,18]. The low BDNF secretion from immune cells of MS patients may be related to reduced neuroprotection . As a result, low BDNF levels are expected to diminish the potentials for remission in MS patients and induce the progressive phase of the disease .
Also, Al-Temaimi and colleagues  found that BDNF levels were significantly lower in MS patients compared to healthy controls. They concluded that repeated relapses in MS patients lead to exhaustion of BDNF growth promotion, sensitivity, and efficacy and at the end resulting in the decrease in its levels.
On the other hand, Petereit and colleagues  and Liguori and colleagues  studied the role of BDNF in RRMS during remission and without the influence of immunosuppressive or immunomodulatory medications. They found higher blood levels of BDNF in MS patients in remission compared to healthy controls.
The difference between results can be explained by the following: some studies included MS patients of different subtypes including relapsing–remitting, secondary progressive, and primary progressive, whereas our study included only RRMS patients, there is a difference in the numbers of patients included and a difference in disease severity; also, the effect of immunosuppressive or immunomodulatory medications could not be totally eliminated in all studies and this may influence BDNF level.
In our study, there was no significant correlation between different MS patients’ characteristics including the age of patients, age of onset, disease duration, number of relapses in the last 2 years, and total number of relapses with BDNF level.
Similar to our findings, Liguori and colleagues  and Comini-Frota and colleagues  found no correlation between age of patients or disease duration with BDNF level. Also, Pan and colleagues , Caggiula and colleagues , and Sarchielli and colleagues  reported that neither gender nor age correlations were found with BDNF level in RRMS patients.
The cumulative disability in MS has a major negative impact on the quality of life of the patients . In our study, there was no statistically significant correlation between the neurological disability measured by EDSS and BDNF level.
In accordance with our findings, Liguori and colleagues  and Comini-Frota and colleagues  revealed that there was no correlation between EDSS and BDNF level during the observational period of their RRMS patients. On the other hand, Yoshimura and colleagues  found that higher BDNF levels were associated with reduced disability in their MS cohort. The difference between results may be attributed to the selection of patients in a stable clinical phase of the disease (during remission) while our patients included relapse and remission groups.
MRI is a mandatory marker for the diagnosis and assessment of disease activity and progression in patients with MS . Compared to other MRI findings, the load of T2 lesions is considered to be the best marker of MS activity and in long-term follow-up; it has a good correlation with disease severity and disability . Mechanisms of neuronal repair act up to a threshold above which the repair cannot continue and this threshold correlates with the lesions load on T2 .
In our study, there was a positive linear correlation between the number of T2 infratentorial lesions in MS patients in relapse with BDNF level. In accordance with our findings, Sarchielli and colleagues found a positive correlation between the levels of BDNF and disease activity, confirmed by the presence of gadolinium-enhancing lesions in their MS patients .
The number of lesions in the infratentorial region is an important factor to predict the disease severity and the long-term disability in MS patients. The specific structure of the infratentorial area regarding high density of neural fibers can explain the finding that the correlation between clinical outcomes and MRI findings in the infratentorial region is more strong than other areas of the brain .
While Liguori and colleagues  found no significant correlation between the baseline BDNF values and the volume of white or gray matter in RRMS patients, on the other hand, Comini-Frota and colleagues  reported a negative correlation between serum levels of BDNF and the number of T2/FLAIR hyperintense lesions in MS patients.
The difference between results may be attributed to the fact that it was not possible to stratify the sample and to control the effect of immunomodulatory or immunosuppressive medications on BDNF levels. The number of MS patients enrolled in each study was different. Also, manual counting of MRI lesions is not the most accurate form to measure the burden of demyelinating lesions, but it is the most feasible one in clinical practice.
The aim of the current MS treatment is to target the inflammatory cascade, decrease the number of relapses and inflammatory lesions on MRI, and suppress the proinflammatory cytokines in the blood .
Our study found no correlation between patients administered different immunomodulatory therapy for MS either in the relapse or in the remission group and the serum level of BDNF. Immunomodulatory therapy in our patients included monthly IV methylprednisolone, IM interferon beta-1a, SC interferon beta-1b, and SC interferon beta-1a.
In accordance with our findings, Petereit and colleagues  revealed that interferon-beta had no effect on in vitro BDNF secretion in MS. Also, Hamamcioglu and Reder  and Liguori and colleagues  found that IFN-b, in vitro or in vivo, had no additional effect on BDNF production in MS patients.
On the other hand, other studies revealed increased serum BDNF levels in multiple sclerosis patients during interferon beta therapy [25, 28, 34, 35]. The difference between results may be attributed to the different sample sizes, noncompliance of patients, half of our patients were in relapse, and some of them received monthly methylprednisolone.
The limitation of this study is the relatively small number of patients due to financial issues. A separate study should be done to evaluate the serum level of BDNF in a primary progressive type of multiple sclerosis.