Abstract

Background: Multiple sclerosis (MS) is a complex, chronic neuroinflammatory disease influenced by both genetic and environmental factors. While global research has identified potential environmental influences, most evidence comes from Western populations, creating a significant knowledge gap for regions like Egypt, which has witnessed a dramatic rise in MS prevalence over recent decades. This study hypothesized that Egyptian MS patients exhibit a distinct biological signature in their blood, characterized by an imbalance in essential and toxic trace elements (the metallome) and alterations in stress-response biomarkers associated with neuroaxonal injury and cellular stress. Objective: This study aimed to comprehensively profile and compare serum levels of selected trace elements and protein biomarkers between Egyptian patients with MS and matched healthy controls. The primary goal was to identify a disease-associated biological signature and evaluate its diagnostic and clinical relevance. Subjects and Methods: A case-control study was conducted with 100 confirmed MS patients recruited from Mansoura International Hospital and 100 age- and sex-matched healthy controls. Diagnosis was confirmed using the 2017 McDonald criteria. Serum samples were analyzed for nine trace metals (Aluminum (Al), Barium (Ba), Cadmium (Cd), Chromium (Cr), Copper (Cu), Lead (Pb), Manganese (Mn), Molybdenum (Mo), Nickel (Ni)) via inductively coupled plasma atomic emission spectrometry (ICP-AES), and three protein biomarkers (Neurofilament Light Chain (NfL), Heat Shock Protein 70 (HSP70), and Heat Shock Protein 90 (HSP90) via ELISA. Statistical analysis included univariate comparisons, age-adjusted logistic regression, and advanced machine learning algorithms (LASSO, Random Forest, XGBoost) for classification and 6 feature importance. Mixture modeling and network analyses were employed to explore combined exposure effects and inter-analyte relationships. Results: MS patients demonstrated a profoundly altered metallomic and proteomic profile. Serum levels of Ni and Cr were markedly elevated, with median concentrations approximately 90-fold higher in patients (Ni: 25.36 vs. 0.28 ng/mL; Cr: 53.52 vs. 0.57 ng/mL; p< 0.001). Mn was 17.7- fold higher (2.51 vs. 0.14 ng/mL; p< 0.001). Conversely, Cu was significantly lower (48.11 vs. 62.48 ng/mL; p=0.003). Among protein biomarkers, NfL (5.66 vs. 4.26 pg/mL; p< 0.001) and HSP90 (14.75 vs. 8.79 pg/mL; p=0.002) were elevated, while HSP70 was reduced (2.83 vs. 3.91 pg/mL; p< 0.001). Age-adjusted models identified Ni (OR=3.75, 95% CI: 2.56–5.50) and Cr (OR=3.61, 95% CI: 2.51–5.18) as the strongest risk factors, whereas Cu (OR=0.64) and HSP70 (OR=0.40) were protective. Machine learning models achieved outstanding classification performance, with Random Forest achieving an AUC of 0.975. Feature importance and mixture analyses consistently identified Ni and Cr as the primary drivers of risk within the exposure mixture. No significant correlations were found between analyte levels and expanded disability status scale or disease duration. Conclusion: This study reveals a unique and significant dysregulation of trace elements and stressresponse proteins in Egyptian MS patients, characterized by a synergistic elevation of toxic metals (notably Ni and Cr) coupled with a deficiency in protective elements (Cu) and chaperone proteins (HSP70). This signature provides the first concrete, population-specific biochemical evidence linking environmental exposures to MS risk in Egypt. The findings underscore the importance of region-specific environmental research and open new avenues for public health strategies focused on exposure mitigation and the development of targeted diagnostic and therapeutic approaches. 7 Keywords: Multiple Sclerosis; trace elements; inflammatory markers; machine learning; Nickel; Chromium; HSP70.

School

School of Sciences and Engineering

Department

Biotechnology Program

Degree Name

MA in Global Public Health

Graduation Date

Spring 5-31-2026

Submission Date

2-12-2026

First Advisor

Anwar Abdelnaser

Committee Member 1

Dr. Mohamed Salama

Committee Member 2

Dr. Ahmed Basiouny

Extent

107 p.

Document Type

Master's Thesis

Institutional Review Board (IRB) Approval

Approval has been obtained for this item

Disclosure of AI Use

Thesis editing and/or reviewing

Other use of AI

N/A

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Available for download on Friday, August 14, 2026

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