Nutrients 2015, 7, 7197-7208; doi:10.3390/nu7095333
OPEN ACCESS
nutrients ISSN 2072-6643 www.mdpi.com/journal/nutrients Article
Associations between B Vitamins and Parkinson’s Disease Liang Shen Shandong Provincial Research Center for Bioinformatic Engineering and Technique, School of Life Sciences, Shandong University of Technology, Zibo 255049, China; E-Mail: [email protected]; Tel./Fax: +86-533-278-2220 Received: 3 July 2015 / Accepted: 20 August 2015 / Published: 27 August 2015
Abstract: B vitamins may correlate with Parkinson’s disease (PD) through regulating homocysteine level. However, there is no comprehensive assessment on the associations between PD and B vitamins. The present study was designed to perform a meta-analytic assessment of the associations between folate, vitamin B6, and vitamin B12 and PD, including the status of B vitamins in PD patients compared with controls, and associations of dietary intakes of B vitamins and risk of PD. A literature search using Medline database obtained 10 eligible studies included in the meta-analyses. Stata 12.0 statistical software was used to perform the meta-analysis. Pooled data revealed that there was no obvious difference in folate level between PD patients and healthy controls, and PD patients had lower level of vitamin B12 than controls. Available data suggested that higher dietary intake of vitamin B6 was associated with a decreased risk of PD (odds ratio (OR) = 0.65, 95% confidence intervals (CI) = (0.30, 1.01)), while no significant association was observed for dietary intake of folate and vitamin B12 and risk of PD. PD patients had lower level of vitamin B12 and similar level of folate compared with controls. Dietary intake of vitamin B6 exhibited preventive effect of developing PD based on the available data. As the number of included studies is limited, more studies are needed to confirm the findings and elucidate the underpinning underlying these associations. Keywords: Parkinson’s disease; B vitamins; dietary intake; meta-analysis
1. Introduction Parkinson’s disease (PD) is a geriatric neurodegenerative disorder with increasing global prevalence resulting in tremors, rigidity, and bradykinesia [1–3]. Although the mechanisms underlying the dopaminergic neurons degeneration in PD remain obscure, oxidative stress has been widely accepted
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to play a prominent role [4,5]. Homocysteine (Hcy) is a sulfur-containing metabolite generated in the essential amino acid methionine cycle. Hcy exhibits multiple neurotoxic effects involved in the pathogenesis of several neurodegenerative disorders, including dementia, Alzheimer’s disease and PD [6–8]. In recent years, many studies have investigated the associations between Hcy and PD and supported that patients with PD have increased levels of Hcy in comparison with age-matched healthy controls [9–13]. Increased levels of Hcy may lead to dopaminergic cell death in PD patients through neurotoxic effect [14–16] and thus, regulation of Hcy metabolism might decrease the risk of PD through decreasing plasma Hcy. As methionine synthesis from Hcy requires B vitamins as cofactors, high B vitamins intake will decrease plasma Hcy level and may exert preventive effects of developing PD. However, to the best of our knowledge, there is no comprehensive assessment on the associations between PD and B vitamins. Thus, the present study was designed to comprehensively assess: (i) the B vitamins status in PD patients and controls; and (ii) efficacy of dietary intakes of B vitamins in lowering risk of PD, through meta-analyzing the available literatures. Levodopa is the most effective drug in the symptomatic management of PD and it was found that plasma Hcy levels are elevated in patients treated with levodopa. Thus, the meta-analyses of levodopa treated or untreated PD patients and controls were performed separately. 2. Methods 2.1. Literature Search With the following search terms “Parkinson’s disease” and “B vitamins” or “folate” or “folic acid” or “vitamin B6” or “vitamin B12” or “cobalamin”, a literature search was performed in Medline database from inception until February 2015. To avoid missing potentially relevant studies by the search strategy, the reference lists of retrieved articles were also manually screened. A restriction to human studies and references published in English is imposed in the references selection. The review, opinion and editorial references as well as mechanistic studies were not considered. By reviewing titles, abstracts, and a full text of all citations identified with database searches, the potentially relevant references were identified on the basis of the following inclusion criteria. 2.2. Inclusion Criteria Studies were included if they met the following criteria. The individual studies were examined and determined to be of sound science. For the meta-analysis of the B vitamins levels in PD patients, it was required that the included studies clearly provided the mean and standard deviation (SD) values of B vitamins levels for PD patients and matched controls. For the meta-analysis of the dietary intake of B vitamins and risk of PD, the odds ratios (ORs) or relative risks (RRs) or hazard ratios (HRs) with 95% confidence intervals (CI) of PD risk should be clearly provided.
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vitamins and risk 95% Nutrients 2015, 7 of PD, the odds ratios (ORs) or relative risks (RRs) or hazard ratios (HRs) with 7199 confidence intervals (CI) of PD risk should be clearly provided. 2.3. Statistical Analysis Analysis 2.3. Statistical With With prespecified prespecified data data extraction extraction tables, tables, data data was was extracted extracted from from the the included included studies studies about about the the characteristics of study populations, B vitamin levels or PD risk and adjusting factors. The extracted data characteristics of study populations, B vitamin levels or PD risk and adjusting factors. The extracted data was was used used to to obtain obtain the the corresponding corresponding standardized standardized mean mean difference difference (SMD) (SMD) and and 95% 95% CI CI of of B B vitamins vitamins levels Possible statistical statistical heterogeneity levels in in PD PD patients patients and and controls, controls, or or OR OR and and 95% 95% CI CI of of PD PD risk. risk. Possible heterogeneity 2 between The random-effect random-effect model model was was used between the the eligible eligible studies studies was was assessed assessed using using the the II² statistic. statistic. The used to to pool the SMD of B vitamins levels and OR of PD risk. All calculations were done with the Stata 12.0 pool the SMD of B vitamins levels and OR of PD risk. All calculations were done with the Stata 12.0 statistical statistical software software (STATA (STATACorp., Corp.,College CollegeStation, Station,TX, TX,USA). USA). 3. Results 3. Results Figure showed the identification flow Figure 11 showed the literature literature selection selection and and identification flow diagram. diagram. Our Our literature literature search search resulted resulted in 552 initial hits and 10 eligible studies finally included in the meta-analysis [17–26]. Seven studies finally included in the meta-analysis [17–26]. including 10 study populations [17–23] provided data on folate and vitamin B12 levels in PD patients and controls, among which, 8 study populations were levodopa treated and 2 were levodopa untreated. 3 studies provided data on dietary intakes of B vitamins vitamins and and PD PD risk risk [24–26]. [24–26].
Potentially relevant studies from initial search (n = 552) Level I screening abstracts: 478 excluded Full-text articles assessed for eligibility (n = 74) Level II screening full papers: not having enough data to analyze 64 excluded Studies included in meta-analyses (n = 10) Figure 1. Search strategy for meta-analysis. Figure 1. Search strategy for meta-analysis. Table Table 1 listed the study and population characteristics of folate levels in PD patients and controls. According to to the the pooled pooleddata dataasasshown shown in Figure 2, obvious no obvious difference in folate levelfound was in Figure 2, no difference in folate level was found between levodopa treated or untreated patients and Similar controls. Similar theextracted basis of between levodopa treated or untreated patients and controls. analysis on analysis the basis on of the the in Table that 2 indicated B12lower level in wasboth lower in bothtreated levodopa treated dataextracted in Tabledata 2 indicated vitamin that B12vitamin level was levodopa (summary (summary SMD = ´0.35, 95% CI = (´0.50, ´0.21)) and untreated (summary SMD = ´0.53, 95% CI = (´0.86, ´0.19), Figure 3) PD patients than matched controls with low statistical heterogeneity. At present, there is not enough data of vitamin B6 levels to perform meta-analysis study.
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There were three studies included in the meta-analysis of the association between dietary intakes of folate, vitamin B6 and vitamin B12 and risk of PD (Table 3). According to the pooled OR, dietary intakes of folate and vitamin B12 were not associated with lower PD risks (OR = 1.01, 95% CI = (0.68, 1.34), Figure 4; and OR = 1.05, 95% CI = (0.76, 1.35), Figure 5). In comparison, dietary intake of vitamin B6 was related to decreased risk of developing PD (OR = 0.65, 95% CI = (0.30, 1.01), Figure 6) with moderate statistical heterogeneity. Table 1. Characteristics of studies of folate levels (nmol/L) in levodopa treated and untreated Parkinson’s disease (PD) patients and controls.
References
Miller et al. 2003 [17] Religa et al. 2006 [18] Triantafyllou et al. 2008 [19] Shin et al. 2009 [20] Yuan et al. 2009 [21] Białecka et al. 2012 [22] Song et al. 2013 [23] Song et al. 2013 [23] Religa et al. 2006 [18] Yuan et al. 2009 [21]
Subgroup
Mean age (years)
n
Folate levels (nmol/L) (Mean ˘ SD) PD Control
PD
Control
PD Control
Treated
64 ˘ 9
60 ˘ 10
20
20
12.8 ˘ 11.6
12.6 ˘ 10.8
Treated
70.5 ˘ 7.57
71.2 ˘ 6.0
99
100
20.87 ˘ 9.58
17.13 ˘ 12.21
Treated
70.1 ˘ 8.0
69.6 ˘ 8.1
111
93
9.92 ˘ 5.17
12.35 ˘ 6.57
Treated
63.5 ˘ 7.8
65.4 ˘ 7.8
33
41
19.26 ˘ 9.06
23.11 ˘ 10.87
Treated
71.83 ˘ 10.34
69.95 ˘ 8.46
48
110
18.28 ˘ 10.8
20.37 ˘ 10.33
Treated
64.4 ˘ 10.1
64.8 ˘ 9.6
320
254
20.16 ˘ 9.52
21.52 ˘ 9.28
Treated
66.45 ˘ 6.60
66.23 ˘ 11.83
33
48
34.46 ˘ 25.69
38.54 ˘ 33.57
Treated
70.50 ˘ 6.75
66.23 ˘ 11.83
28
48
29.47 ˘ 27.21
38.54 ˘ 33.57
Untreated
66.0 ˘ 7.11
71.2 ˘ 6.0
15
100
16.88 ˘ 6.39
17.13 ˘ 12.21
69.95 ˘ 8.46
28
110
20.87 ˘ 8.11
20.37 ˘ 10.33
Untreated 70.57 ˘ 9.09
SD: standard deviation.
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72015
Study
%
ID
SMD (95% CI)
Weight
Miller et al. 2003 [17]
0.02 (-0.60, 0.64)
5.11
Religa et al. 2006 [18]
0.34 (0.06, 0.62)
13.33
Triantafyllou et al. 2008 [19]
-0.42 (-0.69, -0.14)
13.38
Shin et al. 2009 [20]
-0.38 (-0.84, 0.08)
7.78
Yuan et al. 2009 [21]
-0.20 (-0.54, 0.14)
11.15
Bialecka et al. 2012 [22]
-0.14 (-0.31, 0.02)
18.23
Song et al. 2013 [23]
-0.13 (-0.58, 0.31)
8.21
Song et al. 2013 [23]
-0.29 (-0.76, 0.18)
7.65
Subtotal (I-squared = 58.5%, p = 0.018)
-0.14 (-0.33, 0.04)
84.84
Treated
.
Untreated Religa et al. 2006 [18]
-0.02 (-0.56, 0.52)
6.24
Yuan et al. 2009 [21]
0.05 (-0.36, 0.47)
8.92
Subtotal (I-squared = 0.0%, p = 0.837)
0.02 (-0.31, 0.35)
15.16
-0.12 (-0.28, 0.04)
100.00
.
Overall (I-squared = 49.2%, p = 0.039)
-2
0
2
Figure 2. Pooled estimate of standardized mean difference (SMD) and 95% confidence Figure 2. Pooled estimate of standardized mean difference (SMD) and 95% confidence interval (CI) of Parkinson’s disease (PD) and folate level in plasma. interval (CI) of Parkinson’s disease (PD) and folate level in plasma. Table 2. Summary of studies regarding plasma vitamin B12 level (pmol/L) in in levodopa Table 2. Summary of studies regarding plasma vitamin B12 level (pmol/L) in in levodopa treated and untreated PD patients and controls. treated and untreated PD patients and controls. References References Milleretetal. al. Miller 2003 2003[17] [17] Religa et Religa etal. al. 2006 [18] 2006 [18] Triantafyllou etetal. Triantafyllou 2008 [19] al. 2008 [19] Shin et al. Shin et al. 2009 2009 [20] [20] Yuan et al. 2009 Yuan et al. [21] 2009 [21] Białecka et al. Białecka et al. 2012 [22] 2012 [22] Song et al. 2013 Song et al. 2013 [23] [23]
PD PD
Control Control
PD PDControl Control
Vitamin levels(pmol/L) (pmol/L) VitaminB12 B12 levels (Mean ˘ SD) (Mean ± SD) PD Control PD Control
Treated Treated
6464˘±99
60 ˘6010 ± 10
20 20 20 20
375 167 375˘ ± 167
Treated Treated
70.5 ˘±7.57 70.5 7.57
71.271.2 ˘ 6.0 ± 6.0
99 99 100100
Treated
Treated
70.1 ˘±8.0 70.1 8.0
69.669.6 ˘ 8.1 ± 8.1
111 111 93 93
Treated
63.5 ˘ 7.8 63.5 ± 7.8
65.465.4 ˘ 7.8 ± 7.8
33 33 41 41
528.71 ˘ 299.70 651.93 651.93 ˘ 236.25 528.71 ± 299.70 ± 236.25
Treated
71.83 ˘ 10.34
69.95 ˘ 8.46
48
110
354.76 ˘ 191.32
Treated
64.4 ˘ 10.1
64.8 ˘ 9.6
320
254
244.95 ˘ 104.77
Subgroup
Mean ageage (years) Mean (years)
n n
Subgroup
Treated
Treated
Treated
Treated Treated
71.83 ± 10.34
64.4 ± 10.1
66.45 ˘ 6.60 66.45 ± 6.60
69.95 ± 8.46
64.8 ± 9.6
66.23 ˘ 11.83 66.23 ± 11.83
48
110
320
33
254
48 33
249
241.04 129.04 17.13 17.13 ˘ 12.21 241.04˘ ± 129.04 ± 12.21 216.03 90.5 216.03 ˘ ± 90.5
354.76 ± 191.32
244.95 ± 104.77
473.61 ˘ 220.53 48
464 464 ± 249˘
473.61 ± 220.53
283.54 ˘ 114.43 283.54 ± 114.43
362.46 ˘ 135.82
362.46 ± 135.82
295.12 ˘ 150.51 295.12 ± 150.51
480.53 ˘ 239.45 480.53 ± 239.45
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Mean age (years) Table
Subgroup
References
PD age (years) Mean References
2. Cont.
Control
PD n
6 Vitamin B12 levels (pmol/L) (Mean ˘ SD) ControlVitamin B12 PD Control levels (pmol/L) (Mean ± SD)
n
Subgroup
PD Control PD Song et al. 2013 Treated 70.50 ˘ 6.75 66.23 ˘ 11.83 Song et[23] al. 2013 Treated 70.50 ± 6.75 66.23 ± 11.83 28 [23] et al. Religa Untreated 66.0 ˘ 7.11 71.2 ˘ 6.0 2006et[18] Religa al. Untreated 66.0 ± 7.11 71.2 ± 6.0 15 Yuan[18] et al. 2006 Untreated 70.57 ˘ 9.09 69.95 ˘ 8.46 2009 Yuan et [21] al. Untreated
70.57 ± 9.09
2009 [21]
69.95 ± 8.46
28
Control
28 48
15
100
470.61 ˘ 239.45 470.61 ± 239.45
201.42 ˘ 63.82 201.42 ± 63.82
110 110
Control
428.84 ˘ 265.56 428.84 ± 265.56
100
28
PD
48
305.08 ˘ 178.03 305.08 ± 178.03
299.95 ˘ 112.20 299.95 ± 112.20
362.46 ˘ 135.82 362.46 ± 135.82
PD: Parkinson’s disease; SD: standard deviation. PD: Parkinson’s disease; SD: standard deviation. Study
%
ID
SMD (95% CI)
Weight
Miller et al. 2003 [17]
-0.42 (-1.05, 0.21)
3.76
Religa et al. 2006 [18]
-0.41 (-0.69, -0.13)
14.07
Triantafyllou et al. 2008 [19]
-0.66 (-0.94, -0.38)
13.92
Shin et al. 2009 [20]
-0.46 (-0.93, 0.00)
6.41
Yuan et al. 2009 [21]
-0.05 (-0.39, 0.29)
10.69
Bialecka et al. 2012 [22]
-0.39 (-0.56, -0.23)
25.44
Song et al. 2013 [23]
-0.03 (-0.47, 0.41)
6.94
Song et al. 2013 [23]
-0.17 (-0.63, 0.30)
6.35
Subtotal (I-squared = 35.3%, p = 0.146)
-0.35 (-0.50, -0.21)
87.58
Religa et al. 2006 [18]
-0.62 (-1.17, -0.07)
4.79
Yuan et al. 2009 [21]
-0.48 (-0.89, -0.06)
7.64
Subtotal (I-squared = 0.0%, p = 0.689)
-0.53 (-0.86, -0.19)
12.42
-0.38 (-0.51, -0.25)
100.00
Treated
.
Untreated
.
Overall (I-squared = 23.4%, p = 0.228)
-2
0
2
Figure 3. Pooled estimate of standardized mean difference (SMD) and 95% confidence Figure 3. Pooled estimate of standardized mean difference (SMD) and 95% confidence interval (CI) of Parkinson’s disease (PD) and vitamin B12 level in plasma. interval (CI) of Parkinson’s disease (PD) and vitamin B12 level in plasma.
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Table 3. Summary of studies regarding dietary intakes of folate, vitamin B6 and vitamin B12 and risk of PD.
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Relative risk Relative risk Relative risk References (95% CI) for (95% CI) for (95% CI) for Adjustment Table 3. Summary offolate studies regarding dietary intakes of folate, vitamin B6 and vitamin vitamin B6 vitamin B12
B12 and risk of PD. Chen et al. 2004 [22] References
Relative risk 1.2 (0.8, 1.7) (95% CI) for folate
De Lau et al. 2006 [23] 0.75 (0.37, 1.49)
Relative 1.0 (0.7,risk 1.4)
Relative risk 1.4) 1.0 (0.7,
(95% CI) for
(95% CI) for
vitamin B6
vitamin B12
age, smoking, total energy intake, alcohol consumption, caffeine Adjustment intake, and lactose intake
0.46 (0.22, 0.96) 1.11 (0.61, 2.01)
age, sex, and total energy intake age, sex, region, smoking, 1.0 (0.7, 1.4) 1.0 (0.7, 1.4) alcohol consumption, caffeine intake, education, BMI, and dietary and lactose intake factors, including cholesterol, 0.46 (0.22, 0.96) 1.11 (0.61, 2.01) age, sex, and total energy intake dietary glycaemic index, age, sex, region, smoking, education, 0.48 (0.23, 0.99) 1.29 (0.69, 2.44) vitamin E , vitamin C, BMI, and dietary factors, including β-carotene, alcohol, caffeine cholesterol, dietary glycaemic index, 0.48 (0.23, 0.99) 1.29 (0.69, 2.44) Fe, and intake of other vitamin and E , vitamin C, β-carotene, vitamins alcohol, caffeine andBFe, and intake of age, smoking, total energy intake,
Chen et al. 2004 [22]
1.2 (0.8, 1.7)
De Lau et al. 2006 [23]
0.75 (0.37, 1.49)
Murakami et al. 2010 0.93 (0.38, 2.31) [24] Murakami et al. 2010 [24]
0.93 (0.38, 2.31)
7
other B vitamins
PD: Parkinson’s disease; CI: confidence interval. PD: Parkinson’s disease; CI: confidence interval. Study
%
ID
OR (95% CI)
Weight
Chen et al. 2004 [22]
1.20 (0.80, 1.70)
53.67
de Lau et al. 2006 [23]
0.75 (0.37, 1.49)
34.66
Murakami et al. 2010 [24]
0.93 (0.38, 2.31)
11.67
Overall (I-squared = 0.0%, p = 0.463)
1.01 (0.68, 1.34)
100.00
0
1
3
Figure 4. Forest plots of dietary intakes of folate and risk of Parkinson’s disease (PD). Figure 4. Forest plots of dietary intakes of folate and risk of Parkinson’s disease (PD).
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Study
%
Study
%
ID
OR (95% CI)
Weight
ID
OR (95% CI)
Weight
Chen et al. 2004 [22]
1.00 (0.70, 1.40)
70.92
Chen et al. 2004 [22]
1.00 (0.70, 1.40)
70.92
de Lau et al. 2006 [23]
1.11 (0.61, 2.01)
17.73
de Lau et al. 2006 [23]
1.11 (0.61, 2.01)
17.73
Murakami et al. 2010 [24]
1.29 (0.69, 2.44)
11.35
Murakami et al. 2010 [24]
1.29 (0.69, 2.44)
11.35
Overall (I-squared = 0.0%, p = 0.821)
1.05 (0.76, 1.35)
100.00
Overall (I-squared = 0.0%, p = 0.821)
1.05 (0.76, 1.35)
100.00
0
1
3
0
1
3
Figure 5. Forest plots of dietary intakes of vitamin B12 and risk of PD. Figure 5. Forest plots of dietary intakes of vitamin B12 and risk of PD. Study
%
Study
%
ID
OR (95% CI)
Weight
ID
OR (95% CI)
Weight
Chen et al. 2004 [22]
1.00 (0.70, 1.40)
34.42
Chen et al. 2004 [22]
1.00 (0.70, 1.40)
34.42
de Lau et al. 2006 [23]
0.46 (0.22, 0.96)
33.11
de Lau et al. 2006 [23]
0.46 (0.22, 0.96)
33.11
Murakami et al. 2010 [24]
0.48 (0.23, 0.99)
32.47
Murakami et al. 2010 [24]
0.48 (0.23, 0.99)
32.47
Overall (I-squared = 64.3%, p = 0.061)
0.65 (0.30, 1.01)
100.00
Overall (I-squared = 64.3%, p = 0.061)
0.65 (0.30, 1.01)
100.00
0
1
3
0
1
3
Figure 6. Forest plots of dietary intakes of vitamin B6 and risk of PD. Figure 6. Forest plots of dietary intakes of vitamin B6 and risk of PD. Figure 6. Forest plots of dietary intakes of vitamin B6 and risk of PD. 4. Discussion Discussion 4. 4. Discussion In the present meta-analysis, the available data indicated no obvious difference in folate level between In the present meta-analysis, the available data indicated no obvious difference in folate level between PDInpatients and meta-analysis, controls, whilethevitamin B12 level was lower in PDdifference patients than matched the present available data indicated no obvious in folate level controls. between PD patients and controls, while vitamin B12 level was lower in PD patients than matched controls. Higher dietary of vitamin B6 may B12 be associated a decreased risk ofthan PD,matched while there is no PD patients andintake controls, while vitamin level waswith lower in PD patients controls. Higher dietary intake of vitamin B6 may be associated with a decreased risk of PD, while there is no Higher intake vitamin may associated evidencedietary to support theofeffects of B6 folate andbevitamin B12.with a decreased risk of PD, while there is no evidence to support the effects of folate and vitamin B12. evidence to support thebeen effects of folate and vitamin Homocysteine has found to exhibit multipleB12. neurotoxic effects and it is rational to infer that Homocysteine has been found to exhibit multiple neurotoxic effects and it is rational to infer that high Homocysteine hasofbeen found tomay exhibit multiple and itplasma is rational to infer that high high dietary intakes B vitamins lower the riskneurotoxic of PD by effects decreasing homocysteine levels. dietary intakes of B vitamins may lower the risk of PD by decreasing plasma homocysteine levels. The dietary intakes of B vitamins the studies risk of PD by decreasing plasma homocysteine levels. The The present meta-analysis onmay the lower available suggested that there was no significant association present meta-analysis on the available studies suggested that there was no significant association present the available studies significant betweenmeta-analysis dietary intake on of folate and vitamin B12 suggested and risk ofthat PD, there whilewas highno dietary intakesassociation of vitamin between dietary intake of folate and vitamin B12 and risk of PD, while high dietary intakes of vitamin between dietary intake folate andrisk vitamin anditrisk of PD, while intakes vitamin B6 was associated withofdecreased of PD.B12 Thus, is speculated thathigh theredietary may exist an of alternative
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mechanism underlying the protective effects of vitamin B6 for PD. Oxidative stress has been widely accepted to play an important role in the pathogenesis of PD [4,5]. Besides its function as a cofactor, vitamin B6 is reported to possess antioxidant activity [27,28]. Pyridoxine is found to exhibit singlet oxygen quench capacity comparable with those of highly efficient antioxidants vitamins C and E [27]. It was demonstrated that vitamin B6 deficiency can lead to oxidative stress in rat liver and heart, while vitamin B6 supplementation can alleviate oxidative stress [29,30]. For instance, antioxidant activity of vitamin B6 can delay homocysteine-induced atherosclerosis in rats [31]. Moreover, it was reported that in stroke disease B vitamins supplementation may possess antioxidant and anti-inflammatory activities independent of the hypothesized homocysteine-lowering activity [32]. Thus, based on these evidences, it is proposed that besides regulating homocysteine levels the antioxidant potential of vitamin B6 may lower the risk of PD through inhibiting oxidative stress. Several limitations of the present study warrant mention. First, the number of eligible studies is limited, especially for the analysis in the B vitamins levels in levodopa untreated PD patients. Second, the B vitamins dietary intakes are based on self-administered diet questionnaire, and the dosages varied in the included studies, which may potentially affect the results, and studies with control of people’s diet are recommended. Third, only studies published in English were included in the analysis. To summarize, available data indicated that that PD patients had lower level of vitamin B12 and similar level of folate compared with controls. High dietary intake of vitamin B6 may be associated with a decreased risk of PD, while no obvious association was observed for dietary intake of folate and vitamin B12 and risk of PD. As the number of included studies is limited, more studies are warranted to confirm the findings and elucidate the mechanisms underlying these associations. Acknowledgments This work was supported by the National Natural Science Foundation of China (Grant No. 30800184), Shandong Provincial Natural Science Foundation for Excellent Young Scholars (Grant No. ZR2015JL010) and Shandong Provincial Natural Science Foundation (Grant No. ZR2014CL008). Conflicts of Interest The author declare no conflict of interest. References 1. Lees, A.J.; Hardy, J.; Revesz, T. Parkinson’s disease. Lancet 2009, 373, 2055–2066. [CrossRef] 2. Connolly, B.S.; Lang, A.E. Pharmacological treatment of Parkinson disease: A review. JAMA 2014, 311, 1670–1683. [CrossRef] [PubMed] 3. De Lau, L.M.; Breteler, M.M. Epidemiology of Parkinson’s disease. Lancet Neurol. 2006, 5, 525–535. [CrossRef] 4. Jenner, P. Oxidative stress in Parkinson’s disease. Ann. Neurol. 2003, 53, S26–S36. [CrossRef] [PubMed] 5. Dias, V.; Junn, E.; Mouradian, M.M. The role of oxidative stress in Parkinson’s disease. J. Parkinsons. Dis. 2013, 3, 461–491. [PubMed]
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OPEN ACCESS
nutrients ISSN 2072-6643 www.mdpi.com/journal/nutrients Article
Associations between B Vitamins and Parkinson’s Disease Liang Shen Shandong Provincial Research Center for Bioinformatic Engineering and Technique, School of Life Sciences, Shandong University of Technology, Zibo 255049, China; E-Mail: [email protected]; Tel./Fax: +86-533-278-2220 Received: 3 July 2015 / Accepted: 20 August 2015 / Published: 27 August 2015
Abstract: B vitamins may correlate with Parkinson’s disease (PD) through regulating homocysteine level. However, there is no comprehensive assessment on the associations between PD and B vitamins. The present study was designed to perform a meta-analytic assessment of the associations between folate, vitamin B6, and vitamin B12 and PD, including the status of B vitamins in PD patients compared with controls, and associations of dietary intakes of B vitamins and risk of PD. A literature search using Medline database obtained 10 eligible studies included in the meta-analyses. Stata 12.0 statistical software was used to perform the meta-analysis. Pooled data revealed that there was no obvious difference in folate level between PD patients and healthy controls, and PD patients had lower level of vitamin B12 than controls. Available data suggested that higher dietary intake of vitamin B6 was associated with a decreased risk of PD (odds ratio (OR) = 0.65, 95% confidence intervals (CI) = (0.30, 1.01)), while no significant association was observed for dietary intake of folate and vitamin B12 and risk of PD. PD patients had lower level of vitamin B12 and similar level of folate compared with controls. Dietary intake of vitamin B6 exhibited preventive effect of developing PD based on the available data. As the number of included studies is limited, more studies are needed to confirm the findings and elucidate the underpinning underlying these associations. Keywords: Parkinson’s disease; B vitamins; dietary intake; meta-analysis
1. Introduction Parkinson’s disease (PD) is a geriatric neurodegenerative disorder with increasing global prevalence resulting in tremors, rigidity, and bradykinesia [1–3]. Although the mechanisms underlying the dopaminergic neurons degeneration in PD remain obscure, oxidative stress has been widely accepted
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to play a prominent role [4,5]. Homocysteine (Hcy) is a sulfur-containing metabolite generated in the essential amino acid methionine cycle. Hcy exhibits multiple neurotoxic effects involved in the pathogenesis of several neurodegenerative disorders, including dementia, Alzheimer’s disease and PD [6–8]. In recent years, many studies have investigated the associations between Hcy and PD and supported that patients with PD have increased levels of Hcy in comparison with age-matched healthy controls [9–13]. Increased levels of Hcy may lead to dopaminergic cell death in PD patients through neurotoxic effect [14–16] and thus, regulation of Hcy metabolism might decrease the risk of PD through decreasing plasma Hcy. As methionine synthesis from Hcy requires B vitamins as cofactors, high B vitamins intake will decrease plasma Hcy level and may exert preventive effects of developing PD. However, to the best of our knowledge, there is no comprehensive assessment on the associations between PD and B vitamins. Thus, the present study was designed to comprehensively assess: (i) the B vitamins status in PD patients and controls; and (ii) efficacy of dietary intakes of B vitamins in lowering risk of PD, through meta-analyzing the available literatures. Levodopa is the most effective drug in the symptomatic management of PD and it was found that plasma Hcy levels are elevated in patients treated with levodopa. Thus, the meta-analyses of levodopa treated or untreated PD patients and controls were performed separately. 2. Methods 2.1. Literature Search With the following search terms “Parkinson’s disease” and “B vitamins” or “folate” or “folic acid” or “vitamin B6” or “vitamin B12” or “cobalamin”, a literature search was performed in Medline database from inception until February 2015. To avoid missing potentially relevant studies by the search strategy, the reference lists of retrieved articles were also manually screened. A restriction to human studies and references published in English is imposed in the references selection. The review, opinion and editorial references as well as mechanistic studies were not considered. By reviewing titles, abstracts, and a full text of all citations identified with database searches, the potentially relevant references were identified on the basis of the following inclusion criteria. 2.2. Inclusion Criteria Studies were included if they met the following criteria. The individual studies were examined and determined to be of sound science. For the meta-analysis of the B vitamins levels in PD patients, it was required that the included studies clearly provided the mean and standard deviation (SD) values of B vitamins levels for PD patients and matched controls. For the meta-analysis of the dietary intake of B vitamins and risk of PD, the odds ratios (ORs) or relative risks (RRs) or hazard ratios (HRs) with 95% confidence intervals (CI) of PD risk should be clearly provided.
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vitamins and risk 95% Nutrients 2015, 7 of PD, the odds ratios (ORs) or relative risks (RRs) or hazard ratios (HRs) with 7199 confidence intervals (CI) of PD risk should be clearly provided. 2.3. Statistical Analysis Analysis 2.3. Statistical With With prespecified prespecified data data extraction extraction tables, tables, data data was was extracted extracted from from the the included included studies studies about about the the characteristics of study populations, B vitamin levels or PD risk and adjusting factors. The extracted data characteristics of study populations, B vitamin levels or PD risk and adjusting factors. The extracted data was was used used to to obtain obtain the the corresponding corresponding standardized standardized mean mean difference difference (SMD) (SMD) and and 95% 95% CI CI of of B B vitamins vitamins levels Possible statistical statistical heterogeneity levels in in PD PD patients patients and and controls, controls, or or OR OR and and 95% 95% CI CI of of PD PD risk. risk. Possible heterogeneity 2 between The random-effect random-effect model model was was used between the the eligible eligible studies studies was was assessed assessed using using the the II² statistic. statistic. The used to to pool the SMD of B vitamins levels and OR of PD risk. All calculations were done with the Stata 12.0 pool the SMD of B vitamins levels and OR of PD risk. All calculations were done with the Stata 12.0 statistical statistical software software (STATA (STATACorp., Corp.,College CollegeStation, Station,TX, TX,USA). USA). 3. Results 3. Results Figure showed the identification flow Figure 11 showed the literature literature selection selection and and identification flow diagram. diagram. Our Our literature literature search search resulted resulted in 552 initial hits and 10 eligible studies finally included in the meta-analysis [17–26]. Seven studies finally included in the meta-analysis [17–26]. including 10 study populations [17–23] provided data on folate and vitamin B12 levels in PD patients and controls, among which, 8 study populations were levodopa treated and 2 were levodopa untreated. 3 studies provided data on dietary intakes of B vitamins vitamins and and PD PD risk risk [24–26]. [24–26].
Potentially relevant studies from initial search (n = 552) Level I screening abstracts: 478 excluded Full-text articles assessed for eligibility (n = 74) Level II screening full papers: not having enough data to analyze 64 excluded Studies included in meta-analyses (n = 10) Figure 1. Search strategy for meta-analysis. Figure 1. Search strategy for meta-analysis. Table Table 1 listed the study and population characteristics of folate levels in PD patients and controls. According to to the the pooled pooleddata dataasasshown shown in Figure 2, obvious no obvious difference in folate levelfound was in Figure 2, no difference in folate level was found between levodopa treated or untreated patients and Similar controls. Similar theextracted basis of between levodopa treated or untreated patients and controls. analysis on analysis the basis on of the the in Table that 2 indicated B12lower level in wasboth lower in bothtreated levodopa treated dataextracted in Tabledata 2 indicated vitamin that B12vitamin level was levodopa (summary (summary SMD = ´0.35, 95% CI = (´0.50, ´0.21)) and untreated (summary SMD = ´0.53, 95% CI = (´0.86, ´0.19), Figure 3) PD patients than matched controls with low statistical heterogeneity. At present, there is not enough data of vitamin B6 levels to perform meta-analysis study.
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There were three studies included in the meta-analysis of the association between dietary intakes of folate, vitamin B6 and vitamin B12 and risk of PD (Table 3). According to the pooled OR, dietary intakes of folate and vitamin B12 were not associated with lower PD risks (OR = 1.01, 95% CI = (0.68, 1.34), Figure 4; and OR = 1.05, 95% CI = (0.76, 1.35), Figure 5). In comparison, dietary intake of vitamin B6 was related to decreased risk of developing PD (OR = 0.65, 95% CI = (0.30, 1.01), Figure 6) with moderate statistical heterogeneity. Table 1. Characteristics of studies of folate levels (nmol/L) in levodopa treated and untreated Parkinson’s disease (PD) patients and controls.
References
Miller et al. 2003 [17] Religa et al. 2006 [18] Triantafyllou et al. 2008 [19] Shin et al. 2009 [20] Yuan et al. 2009 [21] Białecka et al. 2012 [22] Song et al. 2013 [23] Song et al. 2013 [23] Religa et al. 2006 [18] Yuan et al. 2009 [21]
Subgroup
Mean age (years)
n
Folate levels (nmol/L) (Mean ˘ SD) PD Control
PD
Control
PD Control
Treated
64 ˘ 9
60 ˘ 10
20
20
12.8 ˘ 11.6
12.6 ˘ 10.8
Treated
70.5 ˘ 7.57
71.2 ˘ 6.0
99
100
20.87 ˘ 9.58
17.13 ˘ 12.21
Treated
70.1 ˘ 8.0
69.6 ˘ 8.1
111
93
9.92 ˘ 5.17
12.35 ˘ 6.57
Treated
63.5 ˘ 7.8
65.4 ˘ 7.8
33
41
19.26 ˘ 9.06
23.11 ˘ 10.87
Treated
71.83 ˘ 10.34
69.95 ˘ 8.46
48
110
18.28 ˘ 10.8
20.37 ˘ 10.33
Treated
64.4 ˘ 10.1
64.8 ˘ 9.6
320
254
20.16 ˘ 9.52
21.52 ˘ 9.28
Treated
66.45 ˘ 6.60
66.23 ˘ 11.83
33
48
34.46 ˘ 25.69
38.54 ˘ 33.57
Treated
70.50 ˘ 6.75
66.23 ˘ 11.83
28
48
29.47 ˘ 27.21
38.54 ˘ 33.57
Untreated
66.0 ˘ 7.11
71.2 ˘ 6.0
15
100
16.88 ˘ 6.39
17.13 ˘ 12.21
69.95 ˘ 8.46
28
110
20.87 ˘ 8.11
20.37 ˘ 10.33
Untreated 70.57 ˘ 9.09
SD: standard deviation.
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72015
Study
%
ID
SMD (95% CI)
Weight
Miller et al. 2003 [17]
0.02 (-0.60, 0.64)
5.11
Religa et al. 2006 [18]
0.34 (0.06, 0.62)
13.33
Triantafyllou et al. 2008 [19]
-0.42 (-0.69, -0.14)
13.38
Shin et al. 2009 [20]
-0.38 (-0.84, 0.08)
7.78
Yuan et al. 2009 [21]
-0.20 (-0.54, 0.14)
11.15
Bialecka et al. 2012 [22]
-0.14 (-0.31, 0.02)
18.23
Song et al. 2013 [23]
-0.13 (-0.58, 0.31)
8.21
Song et al. 2013 [23]
-0.29 (-0.76, 0.18)
7.65
Subtotal (I-squared = 58.5%, p = 0.018)
-0.14 (-0.33, 0.04)
84.84
Treated
.
Untreated Religa et al. 2006 [18]
-0.02 (-0.56, 0.52)
6.24
Yuan et al. 2009 [21]
0.05 (-0.36, 0.47)
8.92
Subtotal (I-squared = 0.0%, p = 0.837)
0.02 (-0.31, 0.35)
15.16
-0.12 (-0.28, 0.04)
100.00
.
Overall (I-squared = 49.2%, p = 0.039)
-2
0
2
Figure 2. Pooled estimate of standardized mean difference (SMD) and 95% confidence Figure 2. Pooled estimate of standardized mean difference (SMD) and 95% confidence interval (CI) of Parkinson’s disease (PD) and folate level in plasma. interval (CI) of Parkinson’s disease (PD) and folate level in plasma. Table 2. Summary of studies regarding plasma vitamin B12 level (pmol/L) in in levodopa Table 2. Summary of studies regarding plasma vitamin B12 level (pmol/L) in in levodopa treated and untreated PD patients and controls. treated and untreated PD patients and controls. References References Milleretetal. al. Miller 2003 2003[17] [17] Religa et Religa etal. al. 2006 [18] 2006 [18] Triantafyllou etetal. Triantafyllou 2008 [19] al. 2008 [19] Shin et al. Shin et al. 2009 2009 [20] [20] Yuan et al. 2009 Yuan et al. [21] 2009 [21] Białecka et al. Białecka et al. 2012 [22] 2012 [22] Song et al. 2013 Song et al. 2013 [23] [23]
PD PD
Control Control
PD PDControl Control
Vitamin levels(pmol/L) (pmol/L) VitaminB12 B12 levels (Mean ˘ SD) (Mean ± SD) PD Control PD Control
Treated Treated
6464˘±99
60 ˘6010 ± 10
20 20 20 20
375 167 375˘ ± 167
Treated Treated
70.5 ˘±7.57 70.5 7.57
71.271.2 ˘ 6.0 ± 6.0
99 99 100100
Treated
Treated
70.1 ˘±8.0 70.1 8.0
69.669.6 ˘ 8.1 ± 8.1
111 111 93 93
Treated
63.5 ˘ 7.8 63.5 ± 7.8
65.465.4 ˘ 7.8 ± 7.8
33 33 41 41
528.71 ˘ 299.70 651.93 651.93 ˘ 236.25 528.71 ± 299.70 ± 236.25
Treated
71.83 ˘ 10.34
69.95 ˘ 8.46
48
110
354.76 ˘ 191.32
Treated
64.4 ˘ 10.1
64.8 ˘ 9.6
320
254
244.95 ˘ 104.77
Subgroup
Mean ageage (years) Mean (years)
n n
Subgroup
Treated
Treated
Treated
Treated Treated
71.83 ± 10.34
64.4 ± 10.1
66.45 ˘ 6.60 66.45 ± 6.60
69.95 ± 8.46
64.8 ± 9.6
66.23 ˘ 11.83 66.23 ± 11.83
48
110
320
33
254
48 33
249
241.04 129.04 17.13 17.13 ˘ 12.21 241.04˘ ± 129.04 ± 12.21 216.03 90.5 216.03 ˘ ± 90.5
354.76 ± 191.32
244.95 ± 104.77
473.61 ˘ 220.53 48
464 464 ± 249˘
473.61 ± 220.53
283.54 ˘ 114.43 283.54 ± 114.43
362.46 ˘ 135.82
362.46 ± 135.82
295.12 ˘ 150.51 295.12 ± 150.51
480.53 ˘ 239.45 480.53 ± 239.45
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Mean age (years) Table
Subgroup
References
PD age (years) Mean References
2. Cont.
Control
PD n
6 Vitamin B12 levels (pmol/L) (Mean ˘ SD) ControlVitamin B12 PD Control levels (pmol/L) (Mean ± SD)
n
Subgroup
PD Control PD Song et al. 2013 Treated 70.50 ˘ 6.75 66.23 ˘ 11.83 Song et[23] al. 2013 Treated 70.50 ± 6.75 66.23 ± 11.83 28 [23] et al. Religa Untreated 66.0 ˘ 7.11 71.2 ˘ 6.0 2006et[18] Religa al. Untreated 66.0 ± 7.11 71.2 ± 6.0 15 Yuan[18] et al. 2006 Untreated 70.57 ˘ 9.09 69.95 ˘ 8.46 2009 Yuan et [21] al. Untreated
70.57 ± 9.09
2009 [21]
69.95 ± 8.46
28
Control
28 48
15
100
470.61 ˘ 239.45 470.61 ± 239.45
201.42 ˘ 63.82 201.42 ± 63.82
110 110
Control
428.84 ˘ 265.56 428.84 ± 265.56
100
28
PD
48
305.08 ˘ 178.03 305.08 ± 178.03
299.95 ˘ 112.20 299.95 ± 112.20
362.46 ˘ 135.82 362.46 ± 135.82
PD: Parkinson’s disease; SD: standard deviation. PD: Parkinson’s disease; SD: standard deviation. Study
%
ID
SMD (95% CI)
Weight
Miller et al. 2003 [17]
-0.42 (-1.05, 0.21)
3.76
Religa et al. 2006 [18]
-0.41 (-0.69, -0.13)
14.07
Triantafyllou et al. 2008 [19]
-0.66 (-0.94, -0.38)
13.92
Shin et al. 2009 [20]
-0.46 (-0.93, 0.00)
6.41
Yuan et al. 2009 [21]
-0.05 (-0.39, 0.29)
10.69
Bialecka et al. 2012 [22]
-0.39 (-0.56, -0.23)
25.44
Song et al. 2013 [23]
-0.03 (-0.47, 0.41)
6.94
Song et al. 2013 [23]
-0.17 (-0.63, 0.30)
6.35
Subtotal (I-squared = 35.3%, p = 0.146)
-0.35 (-0.50, -0.21)
87.58
Religa et al. 2006 [18]
-0.62 (-1.17, -0.07)
4.79
Yuan et al. 2009 [21]
-0.48 (-0.89, -0.06)
7.64
Subtotal (I-squared = 0.0%, p = 0.689)
-0.53 (-0.86, -0.19)
12.42
-0.38 (-0.51, -0.25)
100.00
Treated
.
Untreated
.
Overall (I-squared = 23.4%, p = 0.228)
-2
0
2
Figure 3. Pooled estimate of standardized mean difference (SMD) and 95% confidence Figure 3. Pooled estimate of standardized mean difference (SMD) and 95% confidence interval (CI) of Parkinson’s disease (PD) and vitamin B12 level in plasma. interval (CI) of Parkinson’s disease (PD) and vitamin B12 level in plasma.
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Table 3. Summary of studies regarding dietary intakes of folate, vitamin B6 and vitamin B12 and risk of PD.
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Relative risk Relative risk Relative risk References (95% CI) for (95% CI) for (95% CI) for Adjustment Table 3. Summary offolate studies regarding dietary intakes of folate, vitamin B6 and vitamin vitamin B6 vitamin B12
B12 and risk of PD. Chen et al. 2004 [22] References
Relative risk 1.2 (0.8, 1.7) (95% CI) for folate
De Lau et al. 2006 [23] 0.75 (0.37, 1.49)
Relative 1.0 (0.7,risk 1.4)
Relative risk 1.4) 1.0 (0.7,
(95% CI) for
(95% CI) for
vitamin B6
vitamin B12
age, smoking, total energy intake, alcohol consumption, caffeine Adjustment intake, and lactose intake
0.46 (0.22, 0.96) 1.11 (0.61, 2.01)
age, sex, and total energy intake age, sex, region, smoking, 1.0 (0.7, 1.4) 1.0 (0.7, 1.4) alcohol consumption, caffeine intake, education, BMI, and dietary and lactose intake factors, including cholesterol, 0.46 (0.22, 0.96) 1.11 (0.61, 2.01) age, sex, and total energy intake dietary glycaemic index, age, sex, region, smoking, education, 0.48 (0.23, 0.99) 1.29 (0.69, 2.44) vitamin E , vitamin C, BMI, and dietary factors, including β-carotene, alcohol, caffeine cholesterol, dietary glycaemic index, 0.48 (0.23, 0.99) 1.29 (0.69, 2.44) Fe, and intake of other vitamin and E , vitamin C, β-carotene, vitamins alcohol, caffeine andBFe, and intake of age, smoking, total energy intake,
Chen et al. 2004 [22]
1.2 (0.8, 1.7)
De Lau et al. 2006 [23]
0.75 (0.37, 1.49)
Murakami et al. 2010 0.93 (0.38, 2.31) [24] Murakami et al. 2010 [24]
0.93 (0.38, 2.31)
7
other B vitamins
PD: Parkinson’s disease; CI: confidence interval. PD: Parkinson’s disease; CI: confidence interval. Study
%
ID
OR (95% CI)
Weight
Chen et al. 2004 [22]
1.20 (0.80, 1.70)
53.67
de Lau et al. 2006 [23]
0.75 (0.37, 1.49)
34.66
Murakami et al. 2010 [24]
0.93 (0.38, 2.31)
11.67
Overall (I-squared = 0.0%, p = 0.463)
1.01 (0.68, 1.34)
100.00
0
1
3
Figure 4. Forest plots of dietary intakes of folate and risk of Parkinson’s disease (PD). Figure 4. Forest plots of dietary intakes of folate and risk of Parkinson’s disease (PD).
Nutrients 2015, 7 Nutrients 2015, 77 Nutrients
8 7204 8
Study
%
Study
%
ID
OR (95% CI)
Weight
ID
OR (95% CI)
Weight
Chen et al. 2004 [22]
1.00 (0.70, 1.40)
70.92
Chen et al. 2004 [22]
1.00 (0.70, 1.40)
70.92
de Lau et al. 2006 [23]
1.11 (0.61, 2.01)
17.73
de Lau et al. 2006 [23]
1.11 (0.61, 2.01)
17.73
Murakami et al. 2010 [24]
1.29 (0.69, 2.44)
11.35
Murakami et al. 2010 [24]
1.29 (0.69, 2.44)
11.35
Overall (I-squared = 0.0%, p = 0.821)
1.05 (0.76, 1.35)
100.00
Overall (I-squared = 0.0%, p = 0.821)
1.05 (0.76, 1.35)
100.00
0
1
3
0
1
3
Figure 5. Forest plots of dietary intakes of vitamin B12 and risk of PD. Figure 5. Forest plots of dietary intakes of vitamin B12 and risk of PD. Study
%
Study
%
ID
OR (95% CI)
Weight
ID
OR (95% CI)
Weight
Chen et al. 2004 [22]
1.00 (0.70, 1.40)
34.42
Chen et al. 2004 [22]
1.00 (0.70, 1.40)
34.42
de Lau et al. 2006 [23]
0.46 (0.22, 0.96)
33.11
de Lau et al. 2006 [23]
0.46 (0.22, 0.96)
33.11
Murakami et al. 2010 [24]
0.48 (0.23, 0.99)
32.47
Murakami et al. 2010 [24]
0.48 (0.23, 0.99)
32.47
Overall (I-squared = 64.3%, p = 0.061)
0.65 (0.30, 1.01)
100.00
Overall (I-squared = 64.3%, p = 0.061)
0.65 (0.30, 1.01)
100.00
0
1
3
0
1
3
Figure 6. Forest plots of dietary intakes of vitamin B6 and risk of PD. Figure 6. Forest plots of dietary intakes of vitamin B6 and risk of PD. Figure 6. Forest plots of dietary intakes of vitamin B6 and risk of PD. 4. Discussion Discussion 4. 4. Discussion In the present meta-analysis, the available data indicated no obvious difference in folate level between In the present meta-analysis, the available data indicated no obvious difference in folate level between PDInpatients and meta-analysis, controls, whilethevitamin B12 level was lower in PDdifference patients than matched the present available data indicated no obvious in folate level controls. between PD patients and controls, while vitamin B12 level was lower in PD patients than matched controls. Higher dietary of vitamin B6 may B12 be associated a decreased risk ofthan PD,matched while there is no PD patients andintake controls, while vitamin level waswith lower in PD patients controls. Higher dietary intake of vitamin B6 may be associated with a decreased risk of PD, while there is no Higher intake vitamin may associated evidencedietary to support theofeffects of B6 folate andbevitamin B12.with a decreased risk of PD, while there is no evidence to support the effects of folate and vitamin B12. evidence to support thebeen effects of folate and vitamin Homocysteine has found to exhibit multipleB12. neurotoxic effects and it is rational to infer that Homocysteine has been found to exhibit multiple neurotoxic effects and it is rational to infer that high Homocysteine hasofbeen found tomay exhibit multiple and itplasma is rational to infer that high high dietary intakes B vitamins lower the riskneurotoxic of PD by effects decreasing homocysteine levels. dietary intakes of B vitamins may lower the risk of PD by decreasing plasma homocysteine levels. The dietary intakes of B vitamins the studies risk of PD by decreasing plasma homocysteine levels. The The present meta-analysis onmay the lower available suggested that there was no significant association present meta-analysis on the available studies suggested that there was no significant association present the available studies significant betweenmeta-analysis dietary intake on of folate and vitamin B12 suggested and risk ofthat PD, there whilewas highno dietary intakesassociation of vitamin between dietary intake of folate and vitamin B12 and risk of PD, while high dietary intakes of vitamin between dietary intake folate andrisk vitamin anditrisk of PD, while intakes vitamin B6 was associated withofdecreased of PD.B12 Thus, is speculated thathigh theredietary may exist an of alternative
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mechanism underlying the protective effects of vitamin B6 for PD. Oxidative stress has been widely accepted to play an important role in the pathogenesis of PD [4,5]. Besides its function as a cofactor, vitamin B6 is reported to possess antioxidant activity [27,28]. Pyridoxine is found to exhibit singlet oxygen quench capacity comparable with those of highly efficient antioxidants vitamins C and E [27]. It was demonstrated that vitamin B6 deficiency can lead to oxidative stress in rat liver and heart, while vitamin B6 supplementation can alleviate oxidative stress [29,30]. For instance, antioxidant activity of vitamin B6 can delay homocysteine-induced atherosclerosis in rats [31]. Moreover, it was reported that in stroke disease B vitamins supplementation may possess antioxidant and anti-inflammatory activities independent of the hypothesized homocysteine-lowering activity [32]. Thus, based on these evidences, it is proposed that besides regulating homocysteine levels the antioxidant potential of vitamin B6 may lower the risk of PD through inhibiting oxidative stress. Several limitations of the present study warrant mention. First, the number of eligible studies is limited, especially for the analysis in the B vitamins levels in levodopa untreated PD patients. Second, the B vitamins dietary intakes are based on self-administered diet questionnaire, and the dosages varied in the included studies, which may potentially affect the results, and studies with control of people’s diet are recommended. Third, only studies published in English were included in the analysis. To summarize, available data indicated that that PD patients had lower level of vitamin B12 and similar level of folate compared with controls. High dietary intake of vitamin B6 may be associated with a decreased risk of PD, while no obvious association was observed for dietary intake of folate and vitamin B12 and risk of PD. As the number of included studies is limited, more studies are warranted to confirm the findings and elucidate the mechanisms underlying these associations. Acknowledgments This work was supported by the National Natural Science Foundation of China (Grant No. 30800184), Shandong Provincial Natural Science Foundation for Excellent Young Scholars (Grant No. ZR2015JL010) and Shandong Provincial Natural Science Foundation (Grant No. ZR2014CL008). Conflicts of Interest The author declare no conflict of interest. References 1. Lees, A.J.; Hardy, J.; Revesz, T. Parkinson’s disease. Lancet 2009, 373, 2055–2066. [CrossRef] 2. Connolly, B.S.; Lang, A.E. Pharmacological treatment of Parkinson disease: A review. JAMA 2014, 311, 1670–1683. [CrossRef] [PubMed] 3. De Lau, L.M.; Breteler, M.M. Epidemiology of Parkinson’s disease. Lancet Neurol. 2006, 5, 525–535. [CrossRef] 4. Jenner, P. Oxidative stress in Parkinson’s disease. Ann. Neurol. 2003, 53, S26–S36. [CrossRef] [PubMed] 5. Dias, V.; Junn, E.; Mouradian, M.M. The role of oxidative stress in Parkinson’s disease. J. Parkinsons. Dis. 2013, 3, 461–491. [PubMed]
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