Parkinson’s Disease relationship to Vitamin D

Parkinson disease: Low vitamin D and Parkinson disease—a causal conundrum – Jan 2014 Evatt
2 minute video by Evatt 2014? 4 minute audio
Clinical Intervention Trial by Dr. Evatt for the VA
Clinical Intervention Trial at another VA location to be completed 2015
THE KINASE LRRK2, MUTATED IN PARKINSONS DISEASE, IS REQUIRED FOR VITAMIN D3 AND PHOSPHATE METABOLISM - 2013
25-Hydroxyvitamin D depletion does not exacerbate MPTP-induced dopamine neuron damage in mice. – 2012 Evatt
High prevalence of hypovitaminosis D status in patients with early Parkinson disease. – 2011 Evatt
Parkinson Disease and Vitamin D: An Interplay Between Genes and the Environment? – comment Dec 2011
Beyond vitamin status: is there a role for vitamin d in Parkinson disease? – 2010 Evatt
Serum Vitamin D and the Risk of Parkinson Disease – 2010
See also VitaminDWiki

Parkinson disease: Low vitamin D and Parkinson disease—a causal conundrum – Jan 2014 Evatt

Nature Reviews Neurology. 10, 8–9 (2014) doi:10.1038/nrneurol.2013.252
Marian L. Evatt mevatt@emory.edu
Director, Atlanta VA Parkinson's Consortium Center, Neurology/Geriatrics and Extended Care Service,
Department of Veterans Affairs, 1841 Clifton Road NE, Atlanta. CA 30329, USA.

Increasing evidence suggests that Parkinson disease (PD) should be included on the growing list of diseases associated with vitamin D insufficiency. A recent study reconfirms this association and supports the monitoring of vitamin D concentrations in patients with PD. The conundrum of causality regarding this association, however, remains unanswered.

Publisher: Rent for $5 or buy for $18 purchased June 2014
Notes from reading the publication
1997: Japanese noticed low vitamin D in people with PD
2007: First hypothesis that low vitamin D could have a role in PD
2013: Lower levels of vitamin D associated with more severe PD (perhaps due to not being outside as much)
29 year study suggested that low vitamin D preceded PD
The 1200 RCT PD trial found association with 2 of 3 polymorphisms

2 minute video by Evatt 2014? 4 minute audio

Studies shedding light on vitamin D - Parkinson’s link

Marian Evatt, MD:
Doctors have known for decades that vitamin D promotes calcium uptake and bone formation, but evidence is accumulating that it regulates the immune system and the development of the nervous system. In fact, growing evidence suggests a link between low vitamin D levels and Parkinson's disease, but whether this is a cause-and-effect relationship is unknown.

That’s why neurologist Marian Evatt, MD, and her colleagues are conducting a clinical trial exploring the effects of vitamin D supplementation on patients with Parkinson's disease who have low vitamin D levels. The study also includes further epidemiological studies of vitamin D in Parkinson's disease.

Vitamin D is called a vitamin, but that’s a misnomer. It’s actually a steroid hormone, which we make by exposing our skin to sunshine. But no matter what it’s called, vitamin D is fundamental for growth, development, and cell maintenance throughout life, and even before birth.

Parkinson's disease affects nerve cells in several parts of the brain, particularly those that use the chemical messenger dopamine to control movement. The most common symptoms are tremor, stiffness and slowness of movement.

In addition to getting vitamin D from sunshine, fatty fish or fortified foods such as milk and cereals can be a good source of D. “Vitamin D has become associated with many chronic diseases: diabetes, hypertension, cardiovascular disease, and some of the autoimmune diseases, including multiple sclerosis,” says Evatt. “But we haven’t yet determined the specific effect of vitamin D in specific conditions because it has such broad effects.”

Clinical Intervention Trial by Dr. Evatt for the VA

7743 IU vitamin D daily, 6 months, no loading dose
Contacts: Elaine Sperin, LPN esperin@emory.edu; Shirley Triche, RN, FNP striche@emory.edu

Clinical Intervention Trial at another VA location to be completed 2015

10,000 vitamin D daily, 4 months, no loading dose VA Portland Oregon Brenna M Lobb (503) 220-8262 ext 51871 Brenna.Lobb@va.gov

THE KINASE LRRK2, MUTATED IN PARKINSONS DISEASE, IS REQUIRED FOR VITAMIN D3 AND PHOSPHATE METABOLISM - 2013

Acta Physiologica 2013; Volume 207, Supplement 694, 92nd Annual Meeting of the German Physiological Society, 02/03/2013-05/03/2013, Heidelberg, Germany
Mühlemann 1 R. , Minder 1 N., Bettoni 1 C., Ruminska 1 J., Daryadel 1 A., Schnitzbauer 1 U., Kumar 1 M., Mohebbi 1 N., Biber 1 J., Hernando 1 N., Rovelli 2 G., Shimshek 2 D., van der Putten 2 H., Wagner 1 *C.
1 University of Zurich, Institute of Physiology, Zurich, Switzerland
2 Novartis Institutes for Biomedical Research, Basel, Switzerland

Mutations in the Leucine Rich Repeat Kinase (LRRK2, Park8) underlie about 5 % of familial and 1-2 % of sporadic cases of Parkinson disease (PD). LRRK2 is almost ubiquitously expressed with particularly high levels in kidney, lung, and brain. The role of LRRK2, its up- and downstream regulators and targets are unknown. Here we show in mice either lacking Lrrk2 or expressing the G2019S mutant (the most common mutation in PD patients) and in rats deficient for LRRK2 that phosphate metabolism is highly disturbed. The levels of PTH, FGF23, and 1,25OH2-vitamin D3 are altered in all three animal models. Renal phosphate excretion is increased in animals lacking Lrrk2 and decreased in G2019S mutants. Expression of the vitamin D receptor and the vitamin D activating and inactivating enzymes Cyp27b1 and Cyp24a1, as well as of klotho (coligand for FGF23) are altered in most organs expressing LRRK2. Changes in dietary phosphate intake in Lrrk2 WT and KO mice alter phosphate and vitamin D target genes in a LRRK2 dependent manner and application of vitamin D3 to wildtype mice increases LRRK2 expression. In vitro, inhibition of LRRK2 alters expression of Cyp24a1 and the intestinal phosphate transporter NaPiIIb. Our data suggest that LRRK2 plays a central role in regulating phosphate metabolism and hormones involved in its control.!

25-Hydroxyvitamin D depletion does not exacerbate MPTP-induced dopamine neuron damage in mice. – 2012 Evatt

PLoS One. 2012;7(7):e39227. doi: 10.1371/journal.pone.0039227. Epub 2012 Jul 2.
Dean ED, Mexas LM, Cápiro NL, McKeon JE, DeLong MR, Pennell KD, Doorn JA, Tangpricha V, Miller GW, Evatt ML.

Recent clinical evidence supports a link between 25-hydroxyvitamin D insufficiency (serum 25-hydroxyvitamin D [25(OH)D] levels <30 ng/mL) and Parkinson's disease. To investigate the effect of 25(OH)D depletion on neuronal susceptibility to toxic insult, we induced a state of 25(OH)D deficiency in mice and then challenged them with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We found there was no significant difference between control and 25(OH)D-deficient animals in striatal dopamine levels or dopamine transporter and tyrosine hydroxylase expression after lesioning with MPTP. Additionally, we found no difference in tyrosine hydroxylase expression in the substantia nigra pars compacta. Our data suggest that reducing 25(OH)D serum levels in mice has no effect on the vulnerability of nigral dopaminergic neurons in vivo in this model system of parkinsonism.

PMID: 22768297
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High prevalence of hypovitaminosis D status in patients with early Parkinson disease. – 2011 Evatt

Arch Neurol. 2011 Mar;68(3):314-9. doi: 10.1001/archneurol.2011.30.
Evatt ML, DeLong MR, Kumari M, Auinger P, McDermott MP, Tangpricha V; Parkinson Study Group DATATOP Investigators.

BACKGROUND: Vitamin D insufficiency has been reported to be more common in patients with Parkinson disease (PD) than in healthy control subjects, but it is not clear whether having a chronic disease causing reduced mobility contributes to this relatively high prevalence.

OBJECTIVE: To examine the prevalence of vitamin D insufficiency in a cohort of untreated patients with early PD (diagnosed within 5 years of study entry). DESIGN, SETTING, AND

PATIENTS The Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) cohort is a well-characterized cohort of subjects with early, nondisabling PD. The cohort is well suited for examining the prevalence of vitamin D insufficiency early in the course of the disease. We conducted a survey study of vitamin D status in stored blood samples from patients with PD enrolled in the placebo group of the DATATOP trial. Samples from baseline visits and end point/final visits (mean [SD], 18.9 [13.1] months) were analyzed for 25-hydroxyvitamin D (25[OH]D) concentration in blinded fashion.

MAIN OUTCOME MEASURES: The mean vitamin D concentration and the prevalence of vitamin D insufficiency at baseline and end point/final visits.

RESULTS: Among 199 subjects, 170 (85.4%) had samples from the baseline and end point visits available for analysis; 13 were excluded (10 with low probability of having PD and 3 with 25[OH]D concentrations>3 SDs above the mean). In the remaining 157 subjects, the mean (SD) 25(OH)D concentrations at the baseline and end point visits were 26.3 (8.6) ng/mL and 31.3 (9.0) ng/mL, respectively (to convert to nanomoles per liter, multiply by 2.496). The prevalence of vitamin D insufficiency (25[OH]D concentration<30.0 ng/mL) was 69.4% at baseline and 51.6% at the end point.

CONCLUSIONS: The prevalence of vitamin D insufficiency in patients with early PD was similar to or higher than those reported in previous studies. Vitamin D concentrations did not decline during progression of PD. Further studies are needed to elucidate the natural history and significance of vitamin D insufficiency in PD.

Comment in: Parkinson disease and vitamin D: an interplay between genes and the environment? [Arch Neurol. 2011]

PMID: 21403017
Evatt 2011 PDF is attached at the bottom of this page

Parkinson Disease and Vitamin D: An Interplay Between Genes and the Environment? – comment Dec 2011

Gabriele C. DeLuca, MD, DPhil; Grace Li, BA; Sreeram Ramagopalan, DPhil
Arch Neurol. 2011;68(12):1615-1616. doi:10.1001/archneurol.2011.1078.

We read with interest the article by Evatt et al1 on the prevalence of hypovitaminosis D status in patients with early Parkinson disease. Epidemiologically, a season of birth effect and a latitude effect have been observed for this disorder.2,3 Genetic studies have shown polymorphisms in the VDR gene that are associated with the risk of Parkinson disease.4 Genome-wide association studies have identified several candidate genes that are associated with risk of Parkinson disease, several of which have VDR binding associated with them, raising the possibility that vitamin D may influence their expression.5 These potential vitamin D–regulated genes in Parkinson disease have important roles to play in the nervous system, including nigrostriatal dopaminergic neurotransmission, neurogenesis, neurite outgrowth, and neural ectodermal expression (Table).6- 8 The interplay between gene and environment in determining the risk of . . .
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Beyond vitamin status: is there a role for vitamin d in Parkinson disease? – 2010 Evatt

Arch Neurol. 2010 Jul;67(7):795-7. doi: 10.1001/archneurol.2010.123.
Evatt ML.
Editorial Comment on: Serum vitamin D and the risk of Parkinson disease. [Arch Neurol. 2010]
Two years ago, Newmark and Newmark1 hypothesized that insufficient vitamin D could play a role in the pathogenesis of Parkinson disease (PD). The study by Knekt et al2 in this issue of the Archives is the first longitudinal analysis of vitamin D status as a risk of incident PD and examines a cohort of more than 3000 participants from the Mini-Finland Health Survey. As an important logical progression from previous epidemiological and animal studies of vitamin D and PD, Knekt and colleagues' study begins to address some of the questions posed by Newmark and Newmark.1 Furthermore, it provides preliminary data supporting future interventional studies of the role of vitamin D in the pathogenesis of PD. . . . .

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Serum Vitamin D and the Risk of Parkinson Disease – 2010

Arch Neurol. 2010;67(7):808-811. doi:10.1001/archneurol.2010.120.
Paul Knekt, DPH; Annamari Kilkkinen, PhD; Harri Rissanen, MSc; Jukka Marniemi, PhD; Katri Sääksjärvi, MSc; Markku Heliövaara, PhD

Objective To investigate whether serum vitamin D level predicts the risk of Parkinson disease.

Design Cohort study.

Setting The study was based on the Mini-Finland Health Survey, which was conducted from 1978 to 1980, with Parkinson disease occurrence follow-up through the end of 2007. During the 29-year follow-up period, 50 incident Parkinson disease cases occurred. Serum 25-hydroxyvitamin D level was determined from frozen samples stored at baseline. Estimates of the relationship between serum vitamin D concentration and Parkinson disease incidence were calculated using the Cox model.

Participants Three thousand one hundred seventy-three men and women, aged 50 to 79 years and free of Parkinson disease at baseline.

Main Outcome Measure Parkinson disease incidence.

Results Individuals with higher serum vitamin D concentrations showed a reduced risk of Parkinson disease. The relative risk between the highest and lowest quartiles was 0.33 (95% confidence interval, 0.14-0.80) after adjustment for sex, age, marital status, education, alcohol consumption, leisure-time physical activity, smoking, body mass index, and month of blood draw.

Conclusions The results are consistent with the suggestion that high vitamin D status provides protection against Parkinson disease. It cannot, however, be excluded that the finding is due to residual confounding and further studies are thus needed.

Vitamin D plays an important role in the pathogenesis of skeletal disorders and calcium homeostasis.1 Vitamin D inadequacy also predicts increased risk of other chronic conditions, eg, cancer,2 cardiovascular diseases,3 and type 2 diabetes mellitus.4 Recently, chronically inadequate vitamin D intake was proposed to play a significant role in the pathogenesis of Parkinson disease.5 According to the suggested biological mechanism, Parkinson disease may be caused by a continuously inadequate vitamin D status leading to a chronic loss of dopaminergic neurons in the brain. The epidemiological evidence of an association between vitamin D and Parkinson disease is, however, limited to cross-sectional studies6- 8 showing lower vitamin D status in patients with Parkinson disease compared with healthy controls.

Parkinson disease is a major cause of disability in elderly individuals. Its risk factors are relatively unknown. However, both biological plausibility and epidemiological data indicate that vitamin D deficiency may contribute to its development.5 The present cohort study investigated whether serum 25-hydroxyvitamin D level predicts Parkinson disease incidence in a population from northern latitudes where exposure to the sun is limited and therefore vitamin D status is continuously low.
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