Background and Objectives: Gastrointestinal dysfunction is a common non motor symptom in Parkinson's disease (PD). However, the potential association between vitamin D and gastroparesis in PD has not been previously investigated. The aim of this study was to compare vitamin D levels between drug-naive de novo PD patients with normal gastric emptying and those with delayed gastric emptying. Methods: Fifty-one patients with drug-naive de novo PD and 20 age-matched healthy controls were enrolled in this study. Gastric emptying time (GET) was assessed by scintigraphy, and gastric emptying half-time (T1/2) was determined. The PD patients were divided into a delayed-GET group and a normal-GET group. Results: The serum 25-hydroxyvitamin D3 levels were decreased in the delayed-GET group compared with the normal-GET and control groups (11.59 ± 4.90 vs. 19.43 ± 6.91 and 32.69 ± 4.93, respectively, p < 0.01). In the multivariate model, the serum 25-hydroxyvitamin D3 level was independently associated with delayed gastric emptying in PD patients. Conclusions: Vitamin D status may be an independent factor for gastric dysmotility in PD. Although the underlying mechanism remains to be characterized, vitamin D status may play a role in the pathogenesis of delayed gastric emptying in drug-naive PD.

Nonmotor symptoms (NMS) are now considered an important aspect of Parkinson's disease (PD) [1]. NMS are commonly observed and negatively affect the quality of life in PD patients [2,3]. Among these symptoms, gastrointestinal (GI) dysfunction has been reported in all stages of PD, and GI symptoms are common and cause considerable morbidity [4,5]. Most GI dysfunction is associated with impaired motility; at the stomach level, which is one of the earliest sites of α-synuclein accumulation in PD, GI dysfunction presents as delayed gastric emptying [6].

Delayed gastric emptying can cause upper GI symptoms, including nausea, vomiting, early satiety, retching and abdominal discomfort [7,8]. These symptoms may negatively affect the daily life of PD patients. Additionally, delayed gastric emptying can affect the absorption and action of L-dopa and contribute to response fluctuation, which is responsible for low L-dopa levels [9,10].

The pathophysiology of delayed gastric emptying in PD is poorly understood. The stomach is one of the first areas affected by α-synuclein in PD, and neural control of gastric motility is affected by the vagal pathway and the enteric nervous system [11]. Therefore, PD processes, including the accumulation of α-synuclein in the dorsal motor nucleus of the vagus nerve and the enteric nervous system, may affect gastric motor control. Hormonal systems involving the brain-gut axis may also modulate GI motility [12]. One likely candidate for this regulation is ghrelin, which exhibits prokinetic effects and centrally enhances the appetite [13]. Recently, Wang et al. [14] reported that ghrelin prevented L-dopa-induced delayed gastric emptying in a rodent model.

Vitamin D is a hormone with autocrine and paracrine functions that affects bone and calcium metabolism [15]. However, several studies have demonstrated an additional role for vitamin D in neuroprotection through various mechanisms, including antioxidation, neuronal calcium regulation, immunomodulation, enhanced nerve conduction, detoxification and autophagy [16,17,18,19,20,21]. Furthermore, vitamin D has recently been suggested to be involved in the pathogenesis and progression of PD [22], and recently, we reported that vitamin D levels were associated with orthostatic hypotension in PD patients [23]. Therefore, also considering that degenerative processes of the enteric nervous system and the dorsal vagal nucleus correlate with delayed gastric emptying, it is postulated that the vitamin D status may also be associated with gastric dysmotility.

The aim of this study was to compare vitamin D levels between drug-naive, de novo PD patients with normal gastric emptying and those with delayed gastric emptying and to investigate the correlation between serum vitamin D levels and gastric emptying time (GET). We also assessed the associations among serum ghrelin levels, vitamin D levels, and GET.

Patients

This study was designed as a cross-sectional, monocenter, observational study of 51 drug-naive de novo PD patients and 20 age-matched healthy controls. We prospectively recruited 23 PD patients with delayed GET. Next, we enrolled age-matched 28 patients who showed delayed GET and 20 age-matched healthy control subjects. After completing enrolment, we retrospectively analyzed the data.

All subjects visited the Neurology Clinic of Gangneung Asan Hospital from July 2013 to September 2014. All PD patients were newly diagnosed on the basis of criteria issued by the UK Parkinson's Disease Society Brain Bank, and all patients were free of any Parkinsonian medication. The exclusion criteria were a history of medical disorders affecting GET and serum 25-hydroxyvitamin D3 levels, including diabetes, liver disease, renal failure, cardiopulmonary disease, GI disease and a history of GI surgery. Patients with vitamin D supplementation or a medication history that could alter gastric emptying, including anticholinergic drugs or tricyclic antidepressants, were also excluded. All PD patients were categorized into 2 groups by gastric emptying scintigraphy: normal gastric emptying and delayed gastric emptying. Basic demographic data, including gender, age and body mass index (BMI), were recorded for all PD patients and control subjects. The Unified Parkinson's Disease Rating Scale-III (UPDRS-III), the Hoehn and Yahr stage, and the mini-mental state examination for Koreans (MMSE-K) were applied to assess disease severity and cognitive function. The type of PD was also assessed [24]. The GI domain of the NMS scale (NMSS) was evaluated to assess the severity of GI symptoms in PD patients. Laboratory analyses were performed to estimate parathyroid hormone, BUN, creatinine levels, serum calcium, liver enzymes and lipid profiles. The glomerular filtration rate (GFR) was calculated using the Modification of Diet in Renal Disease (MDRD) formula.

Statement of Ethics

The study protocol was approved by the ethics committee of Gangneung Asan Hospital. Detailed information regarding the present study was provided to all participants, and written informed consent was obtained from all participants.

Gastric Emptying Study

All patients were required to fast for at least 6 h prior to the gastric emptying scintigraphy. Patients were provided with the gastric-emptying scintigraphy meal consisting of a fried egg prepared with technetium-99m DTPA 1 mCi, 2 slices of bread and 100 ml of water. The patients were required to eat the meal within 10 min. After the meal was given, the patients were placed upright, and anterior and posterior images of the stomach and bowel were simultaneously obtained at 0, 30, 60, 90 and 120 min with a dual-headed gamma camera (ECAM; Siemens Medical Solutions) using a low-energy high-resolution collimator. Manual regions of interest (ROI) were drawn on the anterior and posterior images for all acquisition times using an irregular ROI tool to outline the stomach. The total gastric ROI included the fundus and antrum; particular efforts were made to avoid any loops of the small bowel in close proximity to the stomach.

The geometric mean of the anterior and posterior gastric counts for each time point was calculated and corrected for technetium-99m decay (6.02-hour half-life); geometric mean count = (anterior counts × posterior counts)1/2. The counts per region of interest on each image were corrected for radioactive decay. The data points were connected by straight lines. A simple half-time of gastric emptying (T1/2) was calculated. Based on the normal range of gastric emptying scintigraphy in our laboratory, a T1/2 value of 60 min was used as the cutoff point to discriminate between normal and delayed gastric emptying.

Serum Vitamin D and Ghrelin Measurements

Blood samples collected into EDTA-treated tubes from each subject after a 12-hour overnight fast to minimize interference from sunlight exposure and dietary intake were used to evaluate serum 25-hydroxyvitamin D3 levels and ghrelin levels [25]. Plasma and serum blood samples were stored at -70°C until analysis. High-performance liquid chromatography/tandem mass spectrometry (Agilent 1260; Agilent Technologies, Santa Clara, Calif., USA and USA/API 400; Applied Biosystems, Foster City, Calif., USA) was used to estimate 25-hydroxyvitamin D3 levels [26]. The coefficient of variation for 25-hydroxyvitamin D3 for the laboratory is 4.0% within assays and 5.1% between assays. Fasting ghrelin levels in serum from all PD patients were measured with a commercial ELISA kit (Millipore, Saint Charles, Mo., USA) according to the manufacturer's guidelines.

Statistical Analyses

All data are expressed as the mean and standard deviation and were analyzed with a commercial statistical software program (SPSS 12.0, Chicago, Ill., USA). Categorical variables were compared using the χ2 test, and continuous variables were compared using one-way ANOVA followed by the Tukey test and a standard t test. A binary logistic regression test by enter method was applied to estimate the odds ratio (OR) of each variable. The dependent variable was the presence of delayed gastric emptying in PD patients, and independent variables included age, sex, serum fasting ghrelin, BMI, PD subtype, UPDRS-III, MMSE-K and 25-hydroxyvitamin D3 levels. In a multivariate logistic model, the dependent variable was also the presence of delayed GET in PD patients, and the independent variable was the 25-hydroxyvitamin D3 level. Other variables were considered covariates. Hosmer-Lemeshow goodness-of-fit statistics were used to assess the model fit. p <0.01 was regarded as significant. The relationships between the 25-hydroxyvitamin D3 levels and other variables, including the GET and serum ghrelin levels in the PD and control groups, were explored using correlation analyses.

Table 1 presents the basic demographic, clinical and laboratory data for the participants. The comparison of variables, including age, gender and BMI, showed no significant differences among the three groups. However, in the post hoc analysis, the BMI of PD patients with delayed GET was significantly higher than that in the control group (25.46 ± 4.45 vs. 22.68 ± 2.64, p < 0.05). There were also no significant differences in the laboratory parameters, including BUN, creatinine, calcium, MDRD-GFR, parathyroid hormone and liver enzymes. 25-Hydroxyvitamin D3 levels were significantly different among the delayed-GET group, the normal-GET group and the control group (11.59 ± 4.90 in the delayed-GET group vs. 19.43 ± 6.91 in the normal-GET group, 11.59 ± 4.90 vs. 32.69 ± 4.93 in the control group and 19.43 ± 6.91 vs. 32.69 ± 4.93 in the post hoc analysis, all p < 0.01). In the PD patients, serum fasting ghrelin levels were lower in the delayed-GET group than in the normal-GET group (131.16 ± 151.66 vs. 243.51 ± 191.36, p < 0.05) and the NMSS score of the GI domain was higher in the delayed-GET group than in the normal-GET group (5.91 ± 7.53 vs. 2.61 ± 3.63, p < 0.05). There was also a significant difference in the types of parkinsonism between the two groups (p < 0.05), but the disease severity and MMSE-K showed no significant differences between the two groups. The 25-hydroxyvitamin D3 levels showed significant negative correlations with T1/2 values, reflecting GET in PD patients (r = -0.34, p < 0.05; fig. 1). However, there was no significant correlation between 25-hydroxyvitamin D3 levels and T1/2 in the control group. Correlation between 25-hydroxyvitamin D3 levels and other variables, including UPDRS-III, MMSE-K and serum fasting ghrelin levels, showed no significances. There was also no significant correlation between serum fasting ghrelin levels and the T1/2 of the gastric emptying scan (r = -0.22, p = 0.11). In the univariate logistic regression, akinetic rigid PD type and the 25-hydroxyvitamin D3 level had a significant influence on the presence of delayed gastric emptying in PD patients (OR = 3.00, 95% confidence interval (CI): 1.11-14.43, p < 0.05; OR = 0.80, CI: 0.70-0.91, p < 0.01). After adjusting for the other variables, the 25-hydroxyvitamin D3 level was an independent significant variable presence of delayed GET in PD patients (OR = 0.83, CI: 0.72-0.98, p < 0.05; table 2).

Table 1

The baseline demographic and laboratory parameters of the enrolled subjects

The baseline demographic and laboratory parameters of the enrolled subjects
The baseline demographic and laboratory parameters of the enrolled subjects
Table 2

Univariate and multivariate logistic regression analysis for the presence of delayed GET in PD patients, with the OR, 95% CI and p values displayed for various variables including 25-hydroxyvitamin D3 level (adjusted for all variables)

Univariate and multivariate logistic regression analysis for the presence of delayed GET in PD patients, with the OR, 95% CI and p values displayed for various variables including 25-hydroxyvitamin D3 level (adjusted for all variables)
Univariate and multivariate logistic regression analysis for the presence of delayed GET in PD patients, with the OR, 95% CI and p values displayed for various variables including 25-hydroxyvitamin D3 level (adjusted for all variables)
Fig. 1

Scatter plot of the 25-hydroxyvitamin D3 levels and T1/2 in PD patients with normal GET, PD patients with delayed GET and controls. The 25-hydroxyvitamin D3 levels showed a significant negative correlation with the T1/2 values, reflecting GET in PD patients.

Fig. 1

Scatter plot of the 25-hydroxyvitamin D3 levels and T1/2 in PD patients with normal GET, PD patients with delayed GET and controls. The 25-hydroxyvitamin D3 levels showed a significant negative correlation with the T1/2 values, reflecting GET in PD patients.

Close modal

It is well known that numerous PD patients have GI symptoms and impaired gastric motility. Kedar et al. [27] suggested that low vitamin D status could contribute to impaired gastric motility from a study of 59 gastroparesis patients (42 idiopathic, 17 with diabetes mellitus). However, no previous study has investigated the association between vitamin D status and gastroparesis in PD patients.

To our knowledge, we have demonstrated for the first time that vitamin D deficiency may be associated with delayed GET in drug-naive, de novo PD. Vitamin D status was negatively correlated with GET in the PD group, whereas there was no correlation between vitamin D status and GET in the control group. The strength of the present study is that our study population only consisted of de novo PD patients. Therefore, we could exclude the effect of dopaminergic medications, including L-dopa, which can influence GET.

Although the mechanism by which vitamin D levels affect GET in PD remains unknown, there are several possible explanations for the association between vitamin D and GET in PD. We suggest that vitamin D may affect GET in PD via the following mechanisms.

First, it is well established that neuronal degeneration with α-synuclein accumulation occurs in the dorsal motor nucleus of the vagus nerve, which is responsible for controlling gastric emptying in PD [28]. Lewy bodies have also been observed in the myenteric plexus of the lower esophagus and stomach [29].

Recently, many studies of PD models have demonstrated roles for vitamin D in neuronal cell differentiation and neuroprotection via various mechanisms [17,18,19,20,21]. Therefore, vitamin D may be neuroprotective against PD-related degenerative processes in the dorsal motor vagal system and enteric nervous system, indicating that vitamin D plays an important role in gastric dysmotility in PD. However, according to our data, the UPDRS-III score reflecting disease severity was not significantly different between the delayed-GET and normal-GET groups even though the UPDRS-III score showed a higher trend in the delayed-GET group compared with the normal-GET group. Previously, Peterson et al. [30] reported that the UPDRS-III score correlates with vitamin D levels, which indicates that vitamin D deficiency in PD patients might reflect disease severity. Therefore, this explanation was still speculative and even contradictory to previous studies. One possible explanation might be the recruitment of relatively early-stage, de novo PD patients in our study. In addition, in the pathological presymptomatic stage of PD, Lewy bodies are confined to the olfactory system, the dorsal motor nucleus of the vagus nerve, the locus ceruleus and reticular formation. Braak et al. [6] also suggested that one of the first areas of α-synuclein deposition is the stomach. Therefore, the neuroprotective effect of vitamin D on degenerative sites affecting gastric empting could be acting separately from the nigrostriatal system, which correlated with motor symptoms in PD patients.

Second, the inhibition of Helicobacter pylori colonization in gastric mucosa may be a possible explanation for the association between vitamin D status and delayed gastric emptying. Vitamin D is known to be an important regulator of the immune response and may enhance the intracellular elimination of the replicating bacteria. Guo et al. [31] reported that the vitamin D receptor significantly affected gastric mucosa homeostasis and protected the host from H. pylori infection. H. pylori infection causes gastric mucosal atrophy, which lowers serum ghrelin levels and causes motility dysfunction in the stomach [32]. Recently, Saito et al. [33] reported that gastric motility dysfunction was significantly associated with chronic H. pylori infection in mice. Therefore, vitamin D status can affect gastric emptying via modulation of the gastric microenvironment related to H. pylori infection.

However, many studies have shown that H. pylori infection is not associated with GET in non-Parkinsonian individuals [34,35]. Therefore, this hypothesis is only one potential, tentative explanation because there have been few studies of the relationship between H. pylori infection and GET in PD patients. Further studies are necessary to investigate this hypothesis.

Finally, vitamin D status can affect the hormonal control of gastric emptying. Several GI-related peptides, including ghrelin, CCK, motilin, GLP-1, and peptide YY, regulate GET. Among these peptides, ghrelin is the best-characterized peptide that is associated with PD. In this study, we found that serum fasting ghrelin levels showed significant differences between the delayed-GET and normal-GET groups. It is well known that serum ghrelin levels correlate with appetite and GET [13]. Wang et al. [14] suggested that ghrelin prevents L-dopa-induced delayed gastric emptying in a rat model. To our knowledge, our results are the first to demonstrate a difference in serum ghrelin levels between normal-GET and delayed-GET groups of PD patients. However, there was no correlation between the T1/2 value of the gastric emptying scan and serum ghrelin. Furthermore, after adjusting for other variables, the serum ghrelin level was not significantly associated with delayed GET. Therefore, the importance of serum ghrelin levels in relation to gastric emptying in PD should be further investigated.

We observed that serum vitamin D levels were significantly different between the delayed-GET and normal-GET groups. However, vitamin D levels between the normal-GET group and control also revealed significance differences. This result indicates that the delayed-GET group might have other factors that could influence gastric motility. Evans et al. [36] reported that GET was prolonged in the elderly non-PD group, and Goetze et al. [37] suggested that the type of meal and disease severity affect gastric emptying. In PD patients, L-dopa itself also could cause delayed GET, and hormonal control, including ghrelin and motilin, could also contribute to gastric emptying [38]. In this study, the serum ghrelin level and akinetic rigid type showed significant differences between the delayed-GET and normal-GET groups. After adjusting for these variables, 25-hydroxyvitamin D3 independently contributed to delayed GET. Furthermore, in the control group, there was no correlation between serum vitamin D levels and GET, while the PD group revealed a significant correlation. Therefore, the effect of vitamin D on gastric emptying might be specific to PD patients.

The current study has several limitations. First, the small sample size is a major limitation, and further studies enrolling large numbers of de novo PD patients are necessary to elucidate a clear association between 25-hydroxyvitamin D3 levels and GET in PD. Second, a 60-min cutoff value for T1/2 was used to define delayed gastric emptying. Although this cutoff point was derived from normal validated data in our laboratory, and although Hardoff et al. [39] also used a single cutoff point for T1/2 to define delayed GET, stricter criteria for gastroparesis may be more suitable for evaluating the exact association between GI dysautonomia and 25-hydroxyvitamin D3 levels. Third, this study cannot suggest an exact mechanism by which 25-hydroxyvitamin D3 influences GET in PD patients with delayed GET. Fourth, we cannot determine whether a low level of vitamin D was the cause or consequence of delayed GET in PD due to the cross-sectional study design, and this limitation requires further studies for vitamin D intervention. Finally, serum 25-hydroxyvitamin D3 levels are strongly dependent on the level of outdoor activity of the patients for sun exposure. Although the enrolled patients in our study were in a relatively early stage of PD, the absence of an index or proxy for the physical activity of PD patients could be a potential confounder. Therefore, further studies adjusting the duration of daily sun exposure time are necessary to elucidate the association between 25-hydroxyvitamin D3 levels and GET.

The current study is the first to reveal the association between 25-hydroxyvitamin D3 levels and GET in PD patients, and our results suggest that 25-hydroxyvitamin D3 deficiency may be an independent factor for gastric dysmotility in PD. Although the underlying mechanism remains unclear, we postulate that vitamin D status potentially plays a role in the pathogenesis of delayed gastric emptying in PD patients. Further prospective studies enrolling large numbers of drug-naive, de novo PD patients and an investigation of the mechanism relating 25-hydroxyvitamin D3 and gastric emptying should be explored. Furthermore, studies on 25-hydroxyvitamin D3 as a therapeutic candidate for delayed GET in PD are strongly encouraged.

This work was funded by the Gangneung Asan Hospital Biomedical Research Centre Promotion Fund.

The authors of the manuscript have no conflicts of interest to declare.

1.
Chaudhuri KR, Healy DG, Schapira AHV: Non-motor symptoms of Parkinson's disease: diagnosis and management. Lancet Neurol 2006;5:235-245.
2.
Chaudhuri KR, Schapira AH: Non-motor symptoms of Parkinson's disease: dopaminergic pathophysiology and treatment. Lancet Neurol 2009;8:464-474.
3.
Jang W, Park J, Shin KJ, Kim J-S, Kim JS, Youn J, Cho JW, Oh E, Ahn JY, Oh K-W et al: Safety and efficacy of recombinant human erythropoietin treatment of non-motor symptoms in Parkinson's disease. J Neurol Sci 2014;337:47-54.
4.
Cersosimo MG, Benarroch EE: Autonomic involvement in Parkinson's disease: pathology, pathophysiology, clinical features and possible peripheral biomarkers. J Neurol Sci 2012;313:57-63.
5.
Pfeiffer RF: Gastrointestinal dysfunction in Parkinson's disease. Lancet Neurol 2003;2:107-116.
6.
Braak H, de Vos RAI, Bohl J, Del Tredici K: Gastric α-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology. Neurosci Lett 2006;396:67-72.
7.
Edwards LL, Pfeiffer RF, Quigley EMM, Hofman R, Balluff M: Gastrointestinal symptoms in Parkinson's disease. Mov Disord 1991;6:151-156.
8.
Jost WH: Gastrointestinal dysfunction in Parkinson's disease. J Neurol Sci 2010;289:69-73.
9.
Deleu D, Ebinger G, Michotte Y: Clinical and pharmacokinetic comparison of oral and duodenal delivery of levodopa/carbidopa in patients with Parkinson's disease with a fluctuating response to levodopa. Eur J Clin Pharmacol 1991;41:453-458.
10.
Djaldetti R, Baron J, Ziv I, Melamed E: Gastric emptying in Parkinson's disease: patients with and without response fluctuations. Neurology 1996;46:1051-1054.
11.
Cersosimo MG, Benarroch EE: Pathological correlates of gastrointestinal dysfunction in Parkinson's disease. Neurobiol Dis 2012;46:559-564.
12.
Sanger GJ, Lee K: Hormones of the gut-brain axis as targets for the treatment of upper gastrointestinal disorders. Nat Rev Drug Discov 2008;7:241-254.
13.
Ejskjaer N, Vestergaard ET, HellstrÖM PM, Gormsen LC, Madsbad S, Madsen JL, Jensen TA, Pezzullo JC, Christiansen JS, Shaughnessy L, et al: Ghrelin receptor agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis. Aliment Pharmacol Ther 2009;29:1179-1187.
14.
Wang L, Murphy NP, Stengel A, Goebel-Stengel M, Pierre DHS, Maidment NT, Taché Y: Ghrelin prevents levodopa-induced inhibition of gastric emptying and increases circulating levodopa in fasted rats. Neurogastroenterol Motil 2012;24:e235-e245.
15.
Grant WB: Epidemiology of disease risks in relation to vitamin D insufficiency. Prog Biophys Mol Biol 2006;92:65-79.
16.
Annweiler C, Beauchet O: Possibility of a new anti-Alzheimer's disease pharmaceutical composition combining memantine and vitamin D. Drugs Aging 2012;29:81-91.
17.
Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ: Distribution of the vitamin D receptor and 1α-hydroxylase in human brain. J Chem Neuroanat 2005;29:21-30.
18.
Jang W, Kim HJ, Li H, Jo KD, Lee MK, Song SH, Yang HO: 1,25-Dihydroxyvitamin D3 attenuates rotenone-induced neurotoxicity in SH-SY5Y cells through induction of autophagy. Biochem Biophys Res Commun 2014;451:142-147.
19.
Jang W, Park H-H, Lee K-Y, Lee Y, Kim H-T, Koh S-H: 1,25-Dihydroxyvitamin D3 attenuates L-dopa-induced neurotoxicity in neural stem cells. Mol Neurobiol 2015;51:558-570.
20.
Sanchez B, Relova JL, Gallego R, Ben-Batalla I, Perez-Fernandez R: 1,25-Dihydroxyvitamin D3 administration to 6-hydroxydopamine-lesioned rats increases glial cell line-derived neurotrophic factor and partially restores tyrosine hydroxylase expression in substantia nigra and striatum. J Neurosci Res 2009;87:723-732.
21.
Smith M, Fletcher-Turner A, Yurek D, Cass W: Calcitriol protection against dopamine loss induced by intracerebroventricular administration of 6-hydroxydopamine. Neurochem Res 2006;31:533-539.
22.
Newmark HL, Newmark J: Vitamin D and Parkinson's disease - a hypothesis. Mov Disord 2007;22:461-468.
23.
Jang W, Park J, Kim J, Youn J, Oh E, Kwon K, Jo K, Lee M, Kim HT: Vitamin D deficiency in Parkinson's disease patients with orthostatic hypotension. Acta Neurol Scand 2015;132:242-250.
24.
Jankovic J, McDermott M, Carter J, Gauthier S, Goetz C, Golbe L, Huber S, Koller W, Olanow C, Shoulson I: Variable expression of Parkinson's disease: a base-line analysis of the DAT ATOP cohort. Neurology 1990;40:1529-1529.
25.
Holick MF: Vitamin D status: measurement, interpretation, and clinical application. Ann Epidemiol 2009;19:73-78.
26.
van den Ouweland JW, Vogeser M, Bächer S: Vitamin D and metabolites measurement by tandem mass spectrometry. Rev Endocr Metab Disord 2013;14:159-184.
27.
Kedar A, Nikitina Y, Henry OR, Abell KB, Vedanarayanan V, Griswold ME, Subramony C, Abell TL: Gastric dysmotility and low serum vitamin D levels in patients with gastroparesis. Horm Metab Res 2013;45:47-53.
28.
Tanaka Y, Kato T, Nishida H, Yamada M, Koumura A, Sakurai T, Hayashi Y, Kimura A, Hozumi I, Araki H, et al: Is there a delayed gastric emptying of patients with early-stage, untreated Parkinson's disease? An analysis using the 13C-acetate breath test. J Neurol 2011;258:421-426.
29.
Wakabayashi K, Takahashi H, Takeda S, Ohama E, Ikuta F: Parkinson's disease: the presence of Lewy bodies in Auerbach's and Meissner's plexuses. Acta Neuropathol 1988;76:217-221.
30.
Peterson AL, Mancini M, Horak FB: The relationship between balance control and vitamin D in Parkinson's disease - a pilot study. Mov Disord 2013;28:1133-1137.
31.
Guo L, Chen W, Zhu H, Chen Y, Wan X, Yang N, Xu S, Yu C, Chen L: Helicobacter pylori induces increased expression of the vitamin D receptor in immune responses. Helicobacter 2014;19:37-47.
32.
Suzuki H, Moayyedi P: Helicobacter pylori infection in functional dyspepsia. Nat Rev Gastroenterol Hepatol 2013;10:168-174.
33.
Saito Y, Suzuki H, Tsugawa H, Suzuki S, Matsuzaki J, Hirata K, Hibi T: Dysfunctional gastric emptying with down-regulation of muscle-specific microRNAs in Helicobacter pylori-infected mice. Gastroenterology 2011;140:189-198.
34.
Chang CS, Chen GH, Kao CH, Wang SJ: Delayed gastric emptying does not predispose to Helicobacter pylori infection in non-ulcer dyspepsia patients. Nucl Med Commun 1995;16:1063-1067.
35.
Miyaji, Azuma, Ito, Abe, Ono, Suto, Yamazaki, Kohli, Kuriyama: The effect of Helicobacter pylori eradication therapy on gastric antral myoelectrical activity and gastric emptying in patients with non-ulcer dyspepsia. Aliment Pharmacol Therapeut 1999;13:1473-1480.
36.
Evans M, Triggs E, Cheung M, Broe G, Creasey H: Gastric emptying rate in the elderly: implications for drug therapy. J Am Geriatr Soc 1981;29:201-205.
37.
Goetze O, Nikodem A, Wiezcorek J, Banasch M, Przuntek H, Mueller T, Schmidt W, Woitalla D: Predictors of gastric emptying in Parkinson's disease. Neurogastroenterol Motil 2006;18:369-375.
38.
Robertson GS, Jagger C, Johnson PR, Rathbone BJ, Wicks AC, Lloyd DM, Veitch PS: Selection criteria for preoperative endoscopic retrograde cholangiopancreatography in the laparoscopic era. Arch Surg 1996;131:89-94.
39.
Hardoff R, Sula M, Tamir A, Soil A, Front A, Badarna S, Honigman S, Giladi N: Gastric emptying time and gastric motility in patients with Parkinson's disease. Mov Disord 2001;16:1041-1047.

All authors contributed equally to this study.

Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.