BERLIN—Higher vitamin D levels at multiple sclerosis (MS) onset predict higher cognitive function 11 years later, according to research presented at ECTRIMS 2018. People who are heavy smokers at MS onset have a clinically significant decline in cognitive function at 11 years, according to the researchers.
“Higher vitamin D in the first years after clinically isolated syndrome (CIS) was associated with better cognitive function and lower neuronal injury at Year 11,” said Marianna Cortese, MD, a research fellow at the Harvard T.H. Chan School of Public Health in Boston. “Vitamin D supplementation during the early years with the disease might be neuroprotective.”
The BENEFIT-11 Trial
According to Dr. Cortese, 40% to 70% of patients with MS experience cognitive decline during their disease course. There is no specific treatment for cognitive decline.
Smoking, low levels of vitamin D, and Epstein-Barr virus (EBV) seropositivity are known risk factors for MS and have been associated with more active MS and progressive disease. Whether these factors predict cognitive status had not been known, said Dr. Cortese.
Investigators in the BENEFIT-11 trial sought to determine whether low vitamin D levels, smoking status, and EBV seropositivity detected early after the first disease manifestation in MS would affect later cognitive function.
The observational study followed 278 participants with CIS in the original BENEFIT trial, which was a randomized, double-blind, placebo-controlled study of interferon beta-1b for the early treatment of CIS. The primary goal of BENEFIT-11, said Dr. Cortese, was to assess the effects of early treatment on long-term outcomes.
“To minimize reverse causation, we used exposure status in the first two years after CIS to predict progression outcomes at Year 11,” explained Dr. Cortese. The investigators obtained biomarkers at baseline and at study Months 6, 12, and 24. Cotinine was used as a biomarker for current or recent nicotine exposure. Serum 25(OH)D levels were used to determine vitamin D levels, and immunoglobulin G levels for EBV antigen-1 were used to indicate EBV seropositivity.
The cognitive performance measure used in the study was the Paced Auditory Serial Addition Test (PASAT), a validated test of processing speed, attention, and working memory, said Dr. Cortese. This test was performed at enrollment, and at study Years 1, 2, 5, and 11. At study Year 11, neuroaxonal injury was measured using serum neurofilament light chain levels.
In multivariable analysis, the researchers adjusted for baseline age and sex, treatment allocation at baseline, unifocal versus multifocal disease on baseline MRI, BMI, and whether the patient was treated with steroids during CIS.
Vitamin D Protected Against Neuroaxonal Injury
“Higher quintiles of mean vitamin D levels during the first two years were associated with lower odds of scoring worse on the PASAT at Year 11,” said Dr. Cortese. The significant trend across the quintiles suggests a dose–response relationship, she said. Dr. Cortese explained that “scoring worse” meant scoring below the median.
A 50-nmol/L increase in mean 25(OH)D in study Months 6 through 24 predicted 65% lower odds of having a PASAT score below the median at Year 11. “Within-person increases in vitamin D during the study were also significantly associated with a better PASAT score when we used the repeated measurement in a linear mixed model,” said Dr. Cortese.
Cotinine levels obtained during the first two years were used to determine smoking status. If all levels were below 10 ng/mL, the participant was designated a nonsmoker. If any levels were above 25 ng/mL, that patient was classified as a smoker. The investigators also looked at the nine patients who were heavy smokers, as indicated by cotinine levels over 189 ng/mL.
“Smokers, compared to nonsmokers, had a significantly lower standardized PASAT score at Year 11,” said Dr. Cortese. “Heavy smokers had an up to 0.6-standard deviation-lower PASAT score at Year 11.... This difference corresponds to about 5 points of the PASAT, so I would say [the score is] clinically meaningful.” Early smoking had a dose–response relationship with later cognitive status. “It continues to be important to encourage smoking cessation for patients,” said Dr. Cortese.
Epstein-Barr antibodies were not associated with cognitive function at Year 11.
“The findings of neuroaxonal injury at Year 11 using serum neurofilament light chain measures corroborated the main findings on cognitive function at Year 11,” said Dr. Cortese. A 50-nmol increase in vitamin D level within the first five years was associated with 20% lower neurofilament light chain levels at Year 11, said Dr. Cortese. Conversely, patients who had cotinine levels higher than 25 ng/mL during the first five years had neurofilament light chain levels that were 20% higher than those of other participants. “They had more neuroaxonal loss,” said Dr. Cortese. Neurofilament light chain levels at Year 11 were not associated with early EBV status, she said.
Radiologic and other clinical data from BENEFIT-11 are also being studied and will be reported in the future, said Dr. Cortese.
Dr. Cortese reported no conflicts of interest. Several coauthors reported financial relationships with pharmaceutical companies. The study was supported by the NIH and the National MS Society, with clinical support from Bayer HealthCare.