Low Vitamin B12 Level Is Associated With Worsening in Parkinson’s Disease

People with early, untreated Parkinson’s disease who have low vitamin B₁₂ levels appear to have greater worsening of mobility and cognitive decline over time, according to research published online ahead of print March 6 in Movement Disorders. The results suggest that correcting low levels may slow disease progression.

Chadwick W. Christine, MD

Previous research revealed that low serum vitamin B₁₂ levels are common in patients with moderately advanced Parkinson’s disease and are associated with neuropathy and cognitive impairment. Investigators led by Chadwick W. Christine, MD, a neurologist at the University of California, San Francisco, sought to understand what contributes to variation in the progression of Parkinson’s disease.

An Analysis of the DATATOP Study

Because little is known about B₁₂’s role in early disease, the investigators analyzed data from patients with early, untreated Parkinson’s disease who participated in the DATATOP study, a double-blind, randomized trial designed to test whether treatment with selegiline, the antioxidant alpha-tocopherol, or both slowed disease progression.

They measured serum methylmalonic acid, homocysteine, and holotranscobalamin in addition to B₁₂ because of the limited sensitivity of serum B₁₂ testing alone to detect B₁₂ deficiency. At baseline, 13% of 680 patients had borderline-low B₁₂ levels (ie, less than 184 pmol/L), and 5% had deficient B₁₂ levels (ie, less than 157 pmol/L). Homocysteine was moderately elevated (ie, greater than 15 mmol/L) in 7% of subjects, and 14% of patients with borderline-low B₁₂ also had elevated homocysteine.

Homocysteine Was Associated With Cognitive Outcomes

Low B₁₂ at baseline predicted greater worsening of mobility, in terms of a higher ambulatory capacity score. Investigators calculated this score by adding the falling, freezing when walking, walking, gait, and postural stability scores of the Unified Parkinson’s Disease Rating Scale (UPDRS). Participants in the low-B₁₂ tertile (ie, less than 234 pmol/L) developed greater morbidity, as assessed by greater annualized worsening of the ambulatory capacity score. Participants in the low-B₁₂ tertile had annualized change of 1.53, compared with 0.77 in the upper tertile. The worsening score mostly resulted from poorer gait and postural instability.

“We consider the magnitude of difference to be clinically relevant, particularly given that components of gait dysfunction that develop in Parkinson’s disease may not respond to dopaminergic treatments or [deep brain stimulation],” said Dr. Christine and colleagues.

Elevated homocysteine predicted greater cognitive decline. Baseline elevated homocysteine was associated with lower baseline Mini-Mental State Examination (MMSE) score, as well as greater annualized decline in MMSE (–1.96 vs 0.06).

Of the 456 subjects who continued in the study for nine to 24 months and had a second blood sample available, 226 had an increase of more than 20% in B₁₂ levels, 210 stayed within 20% of the original B₁₂ measurement, and 19 had a decrease greater than 20%.

Overall, mean annualized increase in B₁₂ was 52.6 pmol/L, mean annualized decrease of homocysteine was 0.83 mmol/L, and mean annualized increase of holotranscobalamin was 14.7 pmol/L.

“These findings are consistent with improved nutritional status during the course of the study, likely attributed to subjects starting the optional [multivitamin] after the baseline visit and/or subjects changing their diets,” said the investigators.

While the improvement in B₁₂ status did not lead to statistically significant improvements in UPDRS scores, there was a trend toward improvement, which provides “support for a disease-modifying effect of B₁₂,” they added.

The researchers speculated that a link between low B₁₂ levels and worse outcomes could be attributed to an independent comorbid effect on the CNS and peripheral nervous system or a direct effect on Parkinson’s disease pathogenesis. Alternatively, low B₁₂ may be a marker of an unknown associated factor.

“Given that low B₁₂ status is associated with neurologic and other medical morbidities and is readily treated, great care would be needed to design an ethically acceptable randomized, prospective study to evaluate the effect of B₁₂ supplementation on Parkinson’s disease progression, given that serum measurements collected as part of a prospective study in unsupplemented patients would likely reveal some subjects with B₁₂ deficiency,” said Dr. Christine and colleagues.

Study Raises Questions

“The course of Parkinson’s disease can be quite variable, and it is difficult for clinicians to predict what will happen to an individual person with Parkinson’s disease, but identifying prognostic factors ought to help practitioners answer their patients’ questions and potentially improve the understanding of mechanisms underlying the disease pathogenesis,” said Francisco Cardoso, MD, PhD, Professor of Neurology at the Federal University of Minas Gerais in Belo Horizonte, Brazil, in an accompanying editorial.

If vitamin B₁₂ is related to the progression of Parkinson’s disease, then replacing it may slow patients’ decline. But the findings raise questions that need to be addressed, said Dr. Cardoso.

“First, what constitutes a low vitamin B₁₂ level is not a simple issue. If the evaluation is limited to measurement of vitamin B₁₂ concentration, the diagnosis of genuine deficiency is unreliable. Most experts agree that combined measurement of vitamin B₁₂ with determination of homocysteine levels is necessary, and while Christine et al measured both levels, their statistical analysis and subsequent conclusions are exclusively based on the levels of the vitamin.

“Moreover, 34 patients in the study were classified as having ‘borderline-low’ vitamin B₁₂ levels, and 14 had both borderline-low B₁₂ level and high homocysteine concentration. This brings into question whether the researchers identified Parkinson’s disease patients who actually had low B₁₂ levels.

“The design of the DATATOP trial could also introduce some bias into the findings. At the time of publication, the study was criticized for disregarding the symptomatic effect of selegiline and for a lack of objective definition of criteria for the trial’s primary end point—introduction of levodopa.

“This could have led to the termination of individuals at different stages of the disease, introducing a potential bias in the sample of patients who remained in the study for enough time to undergo subsequent determination of B₁₂ levels.”

Furthermore, the findings of Christine et al contrast with those of previous research. The underlying mechanism of vitamin B₁₂ in Parkinson’s disease is unclear. “Nevertheless, the results of the study by Dr. Christine and his colleagues are intriguing, and further investigations to address this hypothesis are warranted,” Dr. Cardoso concluded.

—Nicola Garrett

Suggested Reading

Cardoso F. Vitamin B₁₂ and Parkinson’s disease: What is the relationship? Mov Disord. 2018 Mar 6 [Epub ahead of print].

Christine CW, Auinger P, Joslin A, et al. Vitamin B₁₂ and homocysteine levels predict different outcomes in early Parkinson’s disease. Mov Disord. 2018 Mar 6 [Epub ahead of print].