Vitamin D, Smoking Conversely Predict Cognitive Function in Multiple Sclerosis


Data led the authors to believe that vitamin D might have neuroprotective properties and that levels may be a prognostic marker of long-term cognition and neuroaxonal integrity.

Marianna Cortese, MD, PhD

Marianna Cortese, MD, PhD

Results from the clinical trial BENEFIT (Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment; NCT00185211) and its 11-year assessment (BENEFIT-11; NCT01795872) suggest that low vitamin D levels and smoking after clinical onset can predict worse long-term cognitive function and neuronal integrity in patients with multiple sclerosis (MS).

At Year 11, those with a 50 nmol/L higher mean serum 25-hydroxyvitamin-D (25(OH)D) had 65% lower odds (95% CI, 0.14—0.89) of a poorer Paced Auditory Serial Addition (PASAT) performance. All told, a higher vitamin D predicted better cognitive performance while smoking conversely predicted worse performance.

The research, published in Neurology and conducted by Marianna Cortese, MD, PhD, postdoctoral research fellow, Harvard School of Public Health, and colleagues, showed that PASAT scores were lower in smokers and heavy smokers than nonsmokers (P = .026).

Cortese and colleagues measured anti-Epstein-Barr virus nuclear antigen (EBNA-1) immunoglobin G (IgG) at baseline but did not find that the levels predicted cognitive performance (P = .88), and associations with neurofilament light chain (NfL) concentrations at Year 11 further cemented these findings. Data showed that a 50 nmol/L higher mean 25(OH)D in the first 2 years was associated with 20% lower NfL levels (95 CI, —36 to 0), whereas smokers had 20% higher NfL levels than nonsmokers (95% CI, 2–40).

A trend in the data showed that smokers generally had up to 0.6 standard deviations (SDs) worse long-term cognitive performance, equating to 5.4 points on the PASAT. Patients who had cotinine levels constantly >193 ng/mL, otherwise considered heavy smokers, were among the most pronounced.

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Anti-EBNA-1 IgG antibodies and anti-VCA antibodies were not associated with PASAT scores in any of the analyses.

The data examined included 278 patients with clinically isolated syndrome who participated in the BENEFIT trial and completed the 11-year assessment, BENEFIT-11. The long-term follow-up study measured 25(OH)D; cotinine (as a smoking biomarker), and EBNA-1 IgG at baseline and 6, 12, and 24 months to see whether they contributed to predicting PASAT-3 scores and NfL concentrations at 11 years.

Statistical analysis done examined whether serum concentrations of 25(OH)D, cotinine, and anti-EBNA1 IgGs measured within the first 24 months after CIS contributed to predict cognitive performance and neuroaxonal integrity at year 11. Using linear regression, Cortese and colleagues examined the neuroaxonal integrity by assessing the associations of 25(OH)D, cotinine, and anti-EBNA1 IgG within the first 24 months.

“These results are consistent with the suggestion that vitamin D supplementation and smoking cessation early after MS onset might protect long-term cognitive function and central neuroaxonal integrity, independent of disease-modifying treatment,” Cortese and study authors concluded.


Cortese M, Munger KL, Martinez-Lapiscina EH, et al. Vitamin D, smoking, EBV, and long-term cognitive performance in MS. Neurology. 2020;94(18): e1950-e1960. doi: WNL.0000000000009371.

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