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Parkinson's disease stabilized with just 1200 IU of vitamin D – RCT May 2013

Randomized, double-blind, placebo-controlled trial of vitamin D supplement in Parkinson's disease 1,2,3,4

Am J Clin Nutr May 2013 ajcn.051664
Masahiko Suzuki, Masayuki Yoshioka, Masaya Hashimoto, Maiko Murakami, Miki Noya, Daisuke Takahashi, and Mitsuyoshi Urashima; urashima at jikei.ac.jp
1 From the Department of Neurology, Katsushika Medical Center (MS, MY, MH, MM, and MN) and the Division of Molecular Epidemiology (MN, DT, and MU), Jikei University School of Medicine, Tokyo, Japan.
Author Notes
↵2 Funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
↵3 Supported by the Ministry of Education, Culture, Sports, Science and Technology in the Japan-Supported Program for the Strategic Research Foundation at Private Universities and the Jikei University School of Medicine.
↵4 Address correspondence and reprint requests to M Urashima, Division of Molecular Epidemiology, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo 105-8461, Japan.

Background: In our previous study, higher serum 25-hydroxyvitamin D [25(OH)D] concentrations and the vitamin D receptor (VDR) FokI CC genotype were associated with milder Parkinson's disease (PD).

Objective: We evaluated whether vitamin D3 supplementation inhibits the progression of PD on the basis of patient VDR subgroups.

Design: Patients with PD (n = 114) were randomly assigned to receive vitamin D3 supplements (n = 56; 1200 IU/d) or a placebo (n = 58) for 12 mo in a double-blind setting. Outcomes were clinical changes from baseline and the percentage of patients who showed no worsening of the modified Hoehn and Yahr (HY) stage and Unified Parkinson's Disease Rating Scale (UPDRS).

Results: Compared with the placebo, vitamin D3 significantly prevented the deterioration of the HY stage in patients [difference between groups: P = 0.005; mean ± SD change within vitamin D3 group: +0.02 ± 0.62 (P = 0.79); change within placebo group: +0.33 ± 0.70 (P = 0.0006)].
Interaction analyses showed that VDR FokI genotypes modified the effect of vitamin D3 on changes in the HY stage (P-interaction = 0.045), UPDRS total (P-interaction = 0.039), and UPDRS part II (P-interaction = 0.021).
Compared with the placebo, vitamin D3 significantly prevented deterioration of the HY stage in patients with

  • FokI TT [difference between groups: P = 0.009; change within vitamin D3 group: −0.38 ± 0.48 (P = 0.91); change within placebo group, +0.63 ± 0.77 (P = 0.009)] and
  • FokI CT [difference between groups: P = 0.020; change within vitamin D3 group: ±0.00 ± 0.60 (P = 0.78); within placebo group: +0.37 ± 0.74 (P = 0.014)] but not FokI CC.

Similar trends were observed in UPDRS total and part II.

Conclusion: Vitamin D3 supplementation may stabilize PD for a short period in patients with FokI TT or CT genotypes without triggering hypercalcemia, although this effect may be nonspecific for PD. This trial was registered at UMIN Clinical Trials Registry as UMIN000001841.

Received September 22, 2012; Accepted January 23, 2013.

Comment by VitaminDWiki

This is the first RCT of PD and Vitamin D to report results.
Many other RCT are underway using much higher levels of vitamin D
Non-RCT have found excellent results with >10,000 IU of vitamin D daily

See also VitaminDWiki

Another article (editorial?) in the same issue

Low vitamin D concentration exacerbates adult brain dysfunction1,2

Xiaoying Cui, Natalie J Groves, Thomas HJ Burne, Darryl W Eyles, and John J McGrath
1 From the Queensland Brain Institute, University of Queensland, St Lucia, Australia (XC, NJG, THJB, DWE, and JJM), and Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, Australia (THJB, DWE, and JJM).
↵2 Address correspondence to JJ McGrath, Queensland Brain Institute, University of Queensland, St Lucia QLD 4072, Australia. E-mail: j.mcgrath at uq.edu.au.

The links between vitamin D and brain function have strengthened considerably in the past decade (1).
The empirical evidence includes the following:

  • 1) convincing data from in vitro and animal experimental studies,
  • 2) inconsistent findings from observational and analytic epidemiology, and
  • 3) inconsistent findings from the handful of randomized controlled studies done in the field.

Occasionally, the evidence from these different research domains converges. In this issue of the Journal, Suzuki et al (2) report the outcomes of a double-blind, placebo-controlled trial of vitamin D supplementation (1200 IU/d, for 1 y) on various Parkinson disease (PD)–related outcomes. Although the sample size was modest (n = 114), there were clear group differences in several of the outcomes. In addition, there were tantalizing findings showing that vitamin D supplementation interacted with common polymorphisms in the gene coding for the vitamin D receptor (VDR) to prevent decline. The findings are informative: those who received placebo (and thus those who were more likely to have persisting 25-hydroxyvitamin D insufficiency or deficiency) had a steady worsening on PD outcomes. In contrast, those who received vitamin D supplements had no change in PD outcomes over the year. The results strongly suggest that low vitamin D status exacerbates disease progression.

The active form of vitamin D (1,25-dihydroxyvitamin D) operates via the VDR, the smallest member of the family of nuclear receptors (which includes other brain-critical signaling pathways such as retinoic acid, thyroid hormone, sex hormones, etc). The brain distributions of the VDR, and the key enzyme required for the conversion of the prohormone (25-hydroxyvitamin D) to 1,25-dihydroxyvitamin D, have been mapped (3). Of particular relevance to the target article, VDR was most strongly expressed in dopamine-rich areas such as the substantia nigra. We have recently confirmed that all large tyrosine hydroxylase–positive (dopaminergic) neurons in the human substantia nigra also express VDR (4). In addition, there is in vitro evidence that 1,25-dihydroxyvitamin D increases the expression of tyrosine hydroxylase (5).

The timing of vitamin D deficiency produces variable effects on the brain. There is a growing body of convergent evidence linking low prenatal vitamin D to an increased risk of neurodevelopmental disorders such as schizophrenia (6). It is thought that the mechanisms linking developmental vitamin D deficiency with neurodevelopmental disorders probably relates to the well-described pro-differentiation, antiproliferative properties of the active form of vitamin D (and of steroids in general). Thus, the absence of vitamin D deprives the developing brain of an expected signal.

The links between vitamin D deficiency and adult brain function suggest that other mechanisms may be involved. Animal experiments that have examined the impact of transient vitamin D deficiency on adult brain outcomes suggest relatively modest neurochemical and behavioral phenotypes (7). However, there is convergent evidence that vitamin D may have “neuroprotective” properties (8). For example, vitamin D has a direct neuroprotective action against excitotoxic insults by downregulating l-type calcium channels (9), and pretreatment with vitamin D attenuates the effects of various stressors of interest in PD disease, including 6-hydroxydopamine–induced neurotoxicity (10). An experimental study based on a rodent ischemic stroke model reported that animals allocated to a vitamin D–deficient diet (before the stroke lesion) subsequently had significantly greater ischemic brain damage and worse functional impairments (compared with rodents fed vitamin D–replete chow) (11). Overall, these findings suggest that low vitamin D affects adult brain function in subtle ways but may exacerbate “second hit” stressors. This hypothesis is entirely consistent with the findings from Suzuki et al (2). Vitamin D insufficiency or deficiency exacerbated the progression of an underlying brain disorder (the PD-related outcomes worsened in the placebo arm). In contrast, those who received the vitamin D supplement had no disease progression over the year of the study (but still required ongoing l-dopa treatment).

From a neuroscience perspective, there is a growing body of evidence showing that developmental vitamin D deficiency alters brain development—it may be a “sufficient cause” with respect to neurodevelopmental disorders such as schizophrenia. In contrast, adult vitamin D deficiency leaves the brain more vulnerable to second hits and/or exacerbates the progression of concurrent brain disorders—but as a cause, it is neither necessary nor sufficient. Regardless, because vitamin D deficiency is prevalent in the community, and may exacerbate a range of adverse brain outcomes (eg, PD and stroke), optimizing vitamin D status could translate to important gains from a public health perspective. The consequences of persistent vitamin D deficiency on adult brain outcomes may be delayed (ie, have a long latency) and interact with a range of other exposures and risk factors. We speculate that adult vitamin D deficiency could exacerbate the progression of a wide range of other brain disorders such as multiple sclerosis, dementia, and depression.

If the findings of Suzuki et al (2) are replicated, and if future studies confirm that the treatment of vitamin D deficiency is not associated with unintended adverse outcomes, then there is a case to translate this treatment promptly. Even if optimal vitamin D status delays PD progression by a small degree, this treatment is cheap, simple to access (eg, across the counter), relatively safe, and publicly acceptable.

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