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INNOSC Theranostics and
Pharmacological Sciences BDNF-AS biomarker in multiple sclerosis

and intriguing behavior in the context of MS and other
neurodegenerative diseases. First, it was found that
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immune cells secrete BDNF in MS lesions but only in
those with active myelin degeneration. Second, despite
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this finding, studies have shown that BDNF levels in the
serum/plasma, cerebrospinal fluid (CSF), and peripheral
blood mononuclear cells are lower in MS patients. 25-30
Interestingly, BDNF levels in the SPMS group were found
to be lower than in the RRMS and the PPMS groups.
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A similar pattern of low BDNF levels in the serum has
been observed in other neurological diseases, such as
schizophrenia, 37,38 depression, 39,40 Alzheimer’s disease, 41,42
Figure 1. Average cycle threshold (Ct) values of GAPDH in multiple and Huntington’s disease. 43,44 In contrast, autism has been
sclerosis patients and healthy controls. The normality of the data was associated with higher serum levels of BDNF. 45
assessed using the non-parametric Shapiro–Wilk and Kolmogorov– 46
Smirnov tests, yielding non-significant P = 0.153 and 0.200, respectively. A study by Modarresi et al. demonstrated that
A parametric one-way analysis of the variance test showed no statistically inhibiting BDNF-AS can increase endogenous BDNF
significant differences in the Ct values of GAPDH across all groups protein expression, stimulate neurite formation, and
(P = 0.068). Error bars represent standard errors. promote neuronal differentiation. Therefore, in our
Abbreviations: PPMS: Primary progressive multiple sclerosis; study, we aim to comprehensively examine the levels of
RRMS: Relapsing-remitting multiple sclerosis; SPMS: Secondary
progressive multiple sclerosis. BDNF-AS in the serum of MS patients across all subtypes
of the disease. Interestingly, we found that BDNF-AS
significant differences between the MS groups themselves. levels were significantly lower in the serum of MS patients
These results are depicted in Figure 2. compared to healthy controls. This observation may reflect
a downregulation mechanism that inhibits BDNF-AS
3.4. ROC curve analysis to upregulate BDNF protein expression in MS lesions,
Based on the above findings, a ROC curve was generated, potentially stimulating synaptic plasticity, and myelin
and the area under the curve (AUC) was calculated to regeneration in MS plaques as part of an attempt to recover
evaluate the diagnostic value of BDNF-AS. The calculated from the demyelinating event characteristic in MS.
AUC (mean ± S.E.) was 0.869 ± 0.041, with a 95% One interesting finding that might contradict this
confidence interval of 0.789 – 0.948. The optimal cutoff explanation is the downregulation of BDNF itself in the
point, determined by the highest Youden index value serum of MS patients. 25-29 This observation could challenge
across all possible cutoffs, was 0.31, which corresponds to our hypothesis that the downregulation of BDNF-AS
75.93% sensitivity and 100% specificity. These findings are facilitates overexpression of BDNF in MS. However,
summarized in Figure 3. the reduced levels of BDNF in the serum or CSF of MS
patients. 28,29 may suggest that BDNF is predominantly
3.5. Correlation analysis localized within MS lesions rather than being secreted
Spearman’s non-parametric correlation test was used to into body fluids. Therefore, the overexpression of BDNF
examine the relationship between the relative expression resulting from BDNF-AS downregulation may occur
of the BDNF-AS gene and various factors, including EDSS, only in MS lesions, where this mechanism is activated.
age, MS duration, age at onset, and frequency of relapses Alternatively, this observation may indicate the presence of
in the previous 3 years. The analysis revealed a significant, another compensatory mechanism that mimics the effects
moderately positive correlation with age at onset of MS of BDNF-AS in inhibiting BDNF. Nevertheless, our initial
(r = 0.384, P < 0.01), but no correlation was found with hypothesis remains the most plausible explanation, as any
any of the other factors. These findings, along with the compensatory mechanism would likely influence BDNF
correlation parameters, are presented using the four- levels in MS lesions, which is not observed given the higher
parametric logistic regression model, as shown in Figure 4. expression of BDNF in these lesions.
Our finding of lower expression of the BDNF-AS in
4. Discussion MS, whereas BDNF remains downregulated, is in line
The investigation into the expression of BDNF-AS was with a study by Gharzi et al. on RRMS patients, which
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prompted by its established role in the negative regulation found that the correlation between BDNF and BDNF-AS
of the neurotrophic protein BDNF, which exhibits complex may not always be negative. This finding may extend to

Volume 8 Issue 1 (2025) 95 doi: 10.36922/itps.4407