Unrecognised vitamin D deficiency is common in Parkinson disease: a report from the Harvard Biomarker Study

The headline findings from this study are dramatic: patients with PD are nearly twice as likely as age matched controls to be deficient in vitamin D. Although this study does not reveal much regarding a possible causal role for vitamin D in PD, the results are clinically relevant.

An association between PD and low vitamin D levels has previously been reported in smaller observational studies (Sato et al., 1997; Evatt et al., 2008; Knekt et al., 2010) - although none of these found a correlation between vitamin D levels and disease severity. Further evidence for a causal role of vitamin D in PD come from genetic studies which have shown polymorphisms in the vitamin D receptor to be associated with increased risk of developing PD (Scherzner et al., 2007; Butler et al., 2011; Kim et al., 2005). Furthermore, in animal models of PD, vitamin D appears to have a neuroprotective effect (Wang et al., 2001). Taken together, this evidence points towards a link between vitamin D and Parkinson's disease, but up until now the studies have been small and subject to limitations.

This large case-control study provides new support for the existence of a relationship between PD and low vitamin D3 levels. Patients with PD were found to be nearly twice as likely as age matched controls to be deficient in vitamin D3 (17.6% vs 9.3%, p=0.002) and the degree of deficiency is correlated to the severity and duration of disease. However, after adjusting for age, sex, race and vitamin D3 supplementation the association between PD and vitD3 deficiency was only just statistically significant (p=0.047). As Raja Mahana points out in a response to the article, there was no adjusting for multiple statistical tests, which, if performed, may have tipped this value over the edge of the 95% cutoff for statistical significance (Mahana, 2013).

In addition, importantly, no significant association was found with total vitamin D levels, suggesting that vitamin D2 levels were not changed in patients with PD (they may even have been higher). The authors offer no explanation for these seemingly conflicting results - in fact, they do not mention this in their discussion at all.

This failure to discuss important negative findings, combined with the borderline statistical significance and the lack of correction for multiple comparisons mean this study should be treated with a degree of scepticism.

Further limitations include:

1. Confounding - some additional, unmeasured factors may account for the association
2. Generalisability - patients and controls were drawn entirely from two hospitals in a small area of Massachusetts and are therefore not representative of all patients with Parkinson's disease. Further studies in minority populations that may be at even higher risk of vitamin D deficiency are necessary.
3. Correlation does not imply causation - the association found in this study could be explained if vitamin D deficiency accelerates PD pathology or if PD predisposes to vitamin D deficiency, because of a reduced tendency to go outdoors (sunlight is needed for the body to synthesise vitamin D).

Therefore it is impossible to make any claims about whether vitamin D deficiency causes Parkinson's Disease or whether Parkinson's Disease results in vitamin D deficiency from the results of this study alone.

Nonetheless, this study does show that patients with PD are at a considerably increased risk of vitamin D deficiency, whether as a result of confounding/reverse causality or not. The issues of confounding and reverse causality are only really important for scientists trying to understand whether low vitamin D has a causal role in PD. From a clinical viewpoint, all that really matters is that patients with PD have an increased risk of being vitamin D deficient and this, combined with an increased risk of falls and fractures, makes patients with PD an important population in which to consider testing of vitamin D levels and supplementation (Dobson et al, 2013).

Ding H, Dhima K, Lockheart K et al. (2013). Unrecognized vitamin D3 deficiency is common in Parkinson disease Neurology DOI: 10.1212/WNL.0b013e3182a95818

Abstract: Unrecognized vitamin D3 deficiency is common in Parkinson disease

Objective: To conclusively test for a specific association between the biological marker 25-hydroxy-vitamin D3, a transcriptionally active hormone produced in human skin and liver, and the prevalence and severity of Parkinson disease (PD).

Methods: We used liquid chromatography/tandem mass spectrometry to establish an association specifically between deficiency of 25-hydroxy-vitamin D3 and PD in a cross-sectional and longitudinal case-control study of 388 patients (mean Hoehn and Yahr stage of 2.1 6 0.6) and 283 control subjects free of neurologic disease nested in the Harvard Biomarker Study.

Results: Plasma levels of 25-hydroxy-vitamin D3 were associated with PD in both univariate and multivariate analyses with p values 5 0.0034 and 0.047, respectively. Total 25-hydroxy-vitamin D levels, the traditional composite measure of endogenous and exogenous vitamin D, were deficient in 17.6%of patients with PD compared with 9.3% of controls. Low 25-hydroxy-vitamin D3 as well as total 25-hydroxy-vitamin D levels were correlated with higher total Unified Parkinson’s Disease Rating Scale scores at baseline and during follow-up.

Conclusions: Our study reveals an association between 25-hydroxy-vitamin D3 and PD and suggests that thousands of patients with PD in North America alone may be vitamin D–deficient. This finding has immediate relevance for individual patients at risk of falls as well as public health, and warrants further investigation into the mechanism underlying this association.

Additional references:

  

Butler MW, Burt A, Edwards TL, Zuchner S, Scott WK, Martin ER, Vance JM, Wang L (2011) Vitamin D receptor gene as a candidate gene for Parkinson disease. Ann Hum Genet 75: 201-210

Dobson R, Yarnall A, Noyce AJ, Giovannoni G (2013) Bone health in chronic neurological diseases: a focus on Multiple sclerosis and Parkinsonian syndromes. Pract Neurol 13: 70-79

Evatt ML, Delong MR, Khazai N, Rosen A, Triche S, Tangpricha V (2008) Prevalence of vitamin d insufficiency in patients with Parkinson disease and Alzheimer disease. Arch Neurol 65: 1348-1352

Kim JS, Kim YI, Song C, Yoon I, Park JW, Choi YB, Kim HT, Lee KS (2005) Association of vitamin D receptor gene polymorphism and Parkinson's disease in Koreans. J Korean Med Sci 20: 495-498

Knekt P, Kilkkinen A, Rissanen H, Marniemi J, Sääksjärvi K, Heliövaara M (2010) Serum vitamin D and the risk of Parkinson disease. Arch Neurol 67: 808-811

Mehanna R (2013) Is Parkinson's disease associated with deficit in Vitamin D? Neurology

Sato Y, Iwamoto J, Honda Y (2011) Amelioration of osteoporosis and hypovitaminosis D by sunlight exposure in Parkinson's disease. Parkinsonism Relat Disord 17: 22-26

Scherzer CR, Eklund AC, Morse LJ, Liao Z, Locascio JJ, Fefer D, Schwarzschild MA, Schlossmacher MG, Hauser MA, Vance JM, Sudarsky LR, Standaert DG, Growdon JH, Jensen RV, Gullans SR (2007) Molecular markers of early Parkinson's disease based on gene expression in blood. Proc Natl Acad Sci U S A 104: 955-960

Wang JY, Wu JN, Cherng TL, Hoffer BJ, Chen HH, Borlongan CV, Wang Y (2001) Vitamin D(3) attenuates 6-hydroxydopamine-induced neurotoxicity in rats. Brain Res 904: 67-75