Vitamin D Deficiency Linked to Early Cognitive Impairment in MS

Nancy A. Melville

March 01, 2021

Vitamin D deficiency detected at the time of diagnosis of multiple sclerosis (MS) is associated with cognitive impairment and may also affect disability, according to new research that adds to the known adverse relationship between low vitamin D and MS.

"We confirmed that low vitamin D may affect not only early disability but also cognition in newly MS diagnosed patients," first author Eleonora Virgilio, MD, of the MS Center, Neurology Unit, University of Eastern Piedmont, Novara, Italy, told Medscape Medical News.

"The possible effects of Vitamin D on both cognition (in particular, information processing speed) and early disability in newly diagnosed MS patients needs to be further investigated because this association might represent a marker of future disability, supporting the need for prompt supplementation," she said.

The findings were presented February 25 at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2021.

Low Vitamin D and MS

Previous studies have linked insufficient serum vitamin D with everything from the development of MS to activity and disease progression, but less has been reported on a specific link to the impairment of cognitive function, an important complication of MS.

"Cognitive impairment, and, in particular, slowed information processing speed, is very frequent in the MS population from the early stages of disease, and frequently underestimated," Virgilio noted.

"It has yet to be completely elucidated what the exact underlying mechanisms are," she said.

To evaluate the relationship, Virgilio and her colleagues enrolled 60 patients in Italy with MS who were newly diagnosed and had serum vitamin D levels collected upon diagnosis.

The participants were also tested at diagnosis with the Symbol Digit Modalities Test (SDMT) for information processing speed, which is a hallmark of the cognitive impairment that can occur in MS and is typically the first cognitive domain to show effects of the disease.

Among the patients, 40 were female and the mean age at diagnosis was 39.5 years; 90% had relapsing-remitting MS at baseline and 10% had progressive MS.

Their median Expanded Disability Status Scale (EDSS) score at diagnosis was 1.5 (0 - 4).

At baseline, as many as 85% of the participants (51) had low serum vitamin D levels, defined as below 30 ng/ml, which Virgilio noted is consistent with other rates reported among people with MS in the Lombardy region of Italy, where the study was conducted.

The patients had a mean vitamin D level of 21.17 ng/ml (± 10.02), with 51.7% considered to have a deficiency (less than 20 ng/ml) and 33.3% with an insufficiency (20 - 30 ng/ml).

Of the patients, 16 (27%) had cognitive impairment, defined as a z-score of 1.5 or less. Their mean raw SDMT score was 46.50 (± 14.73) and mean z-score was –0.62 (± 1.29).

Importantly, those with cognitive impairment were significantly more likely to have severe hypovitaminosis D compared with those with sufficient vitamin D levels, none of whom showed cognitive impairment (P = .02).

Furthermore, vitamin D levels positively correlated with SDMT raw values (P = .001) and z-score (P = .008).

Over a mean follow-up of 2 years, a significant correlation was observed between serum vitamin D levels at diagnosis and early disability on the MS severity score (MSSS; P = .02) and a weak correlation with age-related MSSS (ARMSS; P = .08) at the last clinical follow-up.

Virgilio noted that factors including disease treatment effects or other factors could have played a role in the weaker results.

"It is possible that the linear correlation we found was not as strong as expected (due to) an effect of treatment with disease-modifying therapies or vitamin D supplementation, or because of the short follow-up available at the moment for our population — only for a mean period of 2 years after MS diagnosis."

The mechanisms for vitamin D deficiency in the MS population are likely multifactorial, with genetic as well as environmental links, she noted.

"The immunomodulatory effects of vitamin D are well known," Virgilio said.

"Vitamin D was already linked to cognitive function in other neurodegenerative diseases, [including] Alzheimer's disease, but more importantly, also in other autoimmune diseases, such as systemic lupus erythematosus," she explained.

Vitamin D Also Linked to Long-Term Cognitive Function

The study adds to recent research showing longer-term effects of vitamin D deficiency and cognitive impairment in MS: In the longitudinal BENEFIT trial published in 2020, researchers following 278 patients with MS over the course of 11 years found that a 50 nm/l higher mean vitamin D level in the first 2 years of the study was associated with a 65% lower odds of a poor performance on Paced Auditory Serial Addition Test (PASAT) scores at the 11-year follow-up.

That study also looked at neurofilament light chain concentrations, which are associated with MS disease activity, and found they were 20% lower among those with higher vitamin D at baseline. Smokers also had lower cognitive scores.

"Lower vitamin D and smoking after clinical onset predicted worse long-term cognitive function and neuronal integrity in patients with MS," the authors concluded.

Marianna Cortese, MD, PhD, who was first author on the BENEFIT trial, said the new research adds to the understanding of the issue.

"It is great that further studies are being conducted on the relationship between vitamin D levels and cognitive function in MS, and it is relevant to look at processing speed in particular, since there is no established treatment for this symptom that can severely affect patients' quality of life," Cortese, of Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, told Medscape Medical News.

In terms of the key question of a role of the effects of vitamin D supplementation on cognitive function, she noted that more needs to be understood.

"Collectively, both studies point toward a potential beneficial effect of vitamin D on cognitive function, but in both studies we are dealing with observational findings," Cortese said.

"Association is not causation, and it would be interesting to assess whether vitamin D supplementation could make a real difference. [However], such a clinical trial would be challenging to conduct," she noted.

Among the factors that are especially important to rule out in future trials, Cortese noted, is the issue of reverse causation, or the idea that greater disability can result in more time indoors and less sun exposure, hence lower vitamin D.

Until more is known, vitamin D supplementation is typically recommended in MS, but Cortese cautioned not to overdo it.

"I think many neurologists do recommend vitamin D supplementation to patients, but very high doses should definitely be avoided," she said. "Normal or optimal vitamin D levels can be achieved for most people with doses of 1000-4000 IU per day."

The authors and Cortese have disclosed no relevant financial relationships.

ACTRIMS Forum 2021: Poster #P158. Presented February 25, 2021.

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