Gao et al.

BMC Psychiatry 2012, 12:72

http://www.biomedcentral.com/1471-244X/12/72

RESEARCH ARTICLE

Open Access

Selenium level and depressive symptoms in a

rural elderly Chinese cohort
Sujuan Gao1,9*, Yinlong Jin2, Frederick W Unverzagt3, Chaoke Liang2, Kathleen S Hall3, Jingxiang Cao2, Feng Ma2,
Jill R Murrell4, Yibin Cheng2, Ping Li5, Jianchao Bian6 and Hugh C Hendrie3,7,8

Abstract
Background: Selenium is considered a protective agent against free radicals through the maintenance of better
enzyme activity. The few studies examining the relationship between selenium and depression have yielded
inconsistent results and none of these studies considered the role of cognitive function in this context.
Methods: A cross-sectional evaluation of 1737 rural Chinese age 65 and over from two provinces in China was
conducted. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS). Cognitive function was
assessed using various cognitive instruments. Selenium measures were obtained from nail samples. Other
information collected included demographic characteristics and medical history. Analysis of covariance models
were used to identify factors associated with GDS score.
Results: Higher selenium levels were associated with lower GDS scores adjusting for demographic and medical
conditions (p = 0.0321). However, the association between selenium and depressive symptoms was no longer
significant when cognitive function score was adjusted in the model (p = 0.2143).
Conclusions: Higher selenium level was associated with lower depressive symptoms without adjusting for
cognition in this cohort. However, after cognition was adjusted in the model the association between selenium and
depressive symptoms was no longer significant, suggesting that seleniums association with depressive symptoms
may be primarily through its association with cognitive function.

Background
Selenium is a trace element associated with the antioxidant enzyme glutathione peroxidase (GP-x) and is considered a protective agent against free radicals through
the maintenance of better enzyme activity. Several studies examining the relationship between selenium and depression have provided inconsistent results, with some
showing lower selenium levels associated with greater
risk of depression [1-4] while others showing no association [5]. It is interesting to observe that a beneficial effect of selenium supplementation was mostly seen when
a substantial number of participants had low dietary selenium levels and selenium supplementation in subjects
with already adequate selenium levels does not seem to
* Correspondence: [email protected]
1
Department of Biostatistics, Indiana University School of Medicine,
Indianapolis, IN, USA
9
Department of Biostatistics, Indiana University School of Medicine, 410 West
10th Street, Suite 3000, Indianapolis, IN 46202-2872, USA
Full list of author information is available at the end of the article

confer benefit on mood or depressive symptoms [1-3]. It

is also worth noting that none of these studies considered cognitive function of the study participants.
Research has shown that the brain has a unique feature in selenium metabolism by storing selenium so that
GP-x activity in the brain does not decrease as fast as in
the liver after a low selenium diet [6,7]. Based on this
observation, it has been hypothesized that long-term exposure to low selenium may be needed to impact brain
function such as mood or cognitive function [8]. Given
that selenium content in food, especially grain, is highly
variable depending on selenium content of the soils in
which they are grown [9], studying the relationship between long-term selenium exposure and brain functions
may be difficult in populations that are mobile and consume foods produced in different areas of the world.
Moreover, supplements containing selenium are often
ingested particularly by health conscious individuals thus
confounding study results.

2012 Gao et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.

Gao et al. BMC Psychiatry 2012, 12:72

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The rural elderly Chinese population represents an opportunity for examining the relationship between longterm selenium exposure and depressive symptoms. The
rural Chinese are stable with most living in the same village throughout their entire life and consuming locally
grown food. In addition, it is rare for them to take dietary supplements. Our group has previously reported on
the association between selenium and cognitive function
in this cohort. In this article, we investigate the association between selenium levels and depressive symptoms
and examine the role of cognitive function on the association between selenium and depression in the same
cohort.

Methods
Study population

A total of 2000 older adults were recruited for the Selenium and Cognitive Decline study, a longitudinal epidemiologic project funded by the National Institute of
Health examining the long-term impact of selenium on
cognitive function in rural elderly Chinese [8]. Two
counties from Sichuan Province in southwestern China
and two counties from Shandong Province in eastern
China were selected based on: rural areas with historically low in- and out-migration, wide range of selenium
levels but comparable trace elements otherwise, comparable age and gender proportions, and sufficient population to provide 500 elderly subjects per county. Sites
with known endemic diseases (including Keshan disease,
Kaschin-Beck disease, goiter and Cretinism, and fluorosis) were excluded from consideration.
For each village included in the study, a team of interviewers who were employees from provincial or county
offices of Chinese Center for Disease Control traveled to
the area, established a temporary headquarter and conducted a complete census of residents over age 65 in the
area. They enrolled eligible residents by going door-todoor, obtaining informed consent before conducting the
interview and collecting biological samples. There were
no refusals. However, a few subjects with hearing problems were not enrolled. The study was approved by Indiana University Institutional Review Board and the
Institute for Environmental Health and Related Safety,
Chinese Center for Disease Control and Prevention.
A second evaluation of this cohort was conducted approximately two and half years after the initial evaluation. In addition to cognitive assessment, the Geriatric
Depression Scale (GDS) was administered to all participants during the second evaluation.
Measure of depressive symptoms

The GDS is a 30-item scale developed specifically for

use in elderly populations [10]. GDS scores between 11
and 20 are generally considered to represent significant

Page 2 of 8

mild depression and scores of 21 or higher are considered severe depression [11]. The GDS was validated with
a psychiatric outpatient sample in a previous study in
Chinese age 60 or older [12]. Internal consistency was
high (alpha = 0.89), and the test-retest reliability was
0.85. The GDS also showed excellent criterion-related
validity (0.95) when compared to psychiatrist diagnosis,
and substantial concurrent validity (0.96) when compared with the Center for Epidemiologic Studies Depression Scale (CES-D) [13]. Although the GDS is generally
self administered, because of low literacy rates in our cohort, the GDS was administered by trained interviewers
in face-to-face interviews.
Selenium measures

Nail samples from all study subjects were collected during the initial interview and stored in clean plastic bags
labeled with participant identification numbers. The
method of fluorometric determination of trace amount
of selenium with 2,3-diaminonaphthalene, described in
details elsewhere [14], was used to determine trace
amounts of selenium in nail samples. Quality control in
the laboratory was maintained by using certified reference materials and by inter-laboratory comparisons.
Quality control measures used for the laboratory analyses were described in details previously [8].
Cognitive assessment

Cognitive assessment was conducted in face-to-face

interviews using the Community Screening Instrument
for Dementia (CSID), Consortium to Establish a Registry
for Alzheimers Disease (CERAD) 10-word list learning
and recall,[15] Indiana University (IU) Story Recall, Animal Fluency test [16], and IU Token test at baseline and
at the 2.5 year follow-up. The CSID was developed as a
screening tool for dementia in populations with various
cultural backgrounds and literacy levels. The CSID has
demonstrated good two week test retest reliability and
inter-rater reliability as well as good validity in detecting
dementia in various populations [17,18]. CSID scores
range from 0 to 30. The CERAD Word List Learning
test is one of the measures from the CERAD neuropsychological assessment battery which was designed to
assess cognitive skills in the elderly. The IU Story Recall
task was created by the research team to be suitable to
the Chinese culture and the rural population. The Animal Fluency test is a measure of executive function in
which a subject names as many animals as possible in 60
seconds. The IU Token Test is a brief measure of language comprehension and working memory [19]. The
validity of the CSID, CERAD word list learning and recall, and the Animal Fluency test have been previously
established in Chinese population and elsewhere [20].

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Other information

Other information collected during the second evaluation

included age, gender, whether the participant attended
school and years of schooling, marital status, household
composition, alcohol consumption and smoking history,
history of cancer, Parkinsons disease, diabetes, hypertension, stroke, heart attack, head injury and bone fracture
by self-report. Participants height and weight were also
measured during the interview. BMI was derived from
height and weight measurements. Blood spots on filter
paper were collected from all study participants during
the baseline evaluation. APOE genotype was determined
by eluting DNA from a dried blood spot [21] followed by
HhaI digestion of amplified products [22].

Page 3 of 8

Table 1 Mean GDS scores by participants characteristics

N

Mean

SD

p-value
<0.0001

Age group
65-74

1002

7.68

5.83

75-84

652

9.02

5.86

85+

83

9.38

5.55

Male

815

7.52

5.77

Female

922

8.92

5.87

Yes

676

7.05

5.73

No

1061

9.04

5.82

Gender
<0.0001

Ever attended school

<0.0001

Marital status

Statistical analysis

Married

1016

7.65

5.71

We conduct cross-sectional analysis using GDS scores

and cognitive scores collected at the second evaluation
of this cohort. Mean GDS scores were compared by participants characteristics using analysis of variance
(ANOVA) or t-tests. Significant factors in univariate association with GDS scores were included in Analyses of
Covariance (ANCOVA) models. Two sets of ANCOVA
models were used to examine seleniums relationship
with GDS scores. The first model included all significant
covariates in addition to selenium levels as independent
variables. The second ANCOVA model included a composite cognitive z-score obtained from the time of the
GDS administration as well as all variables in the first
model. To ensure robust estimation results, we also conducted nonparametric ANCOVA by using normal scores
derived from the ranks of the GDS scores [23]. The
composite cognitive z-score was created by using the
average of standardized scores of the six cognitive tests
[24,25]. To detect potential non-linear relationship between BMI, selenium levels and GDS scores, we also
conducted models using tertile groups. Logistic regression models were used to investigate whether selenium
levels were associated with mild or severe depression
defined as GDS scores 11 or higher.

Widowed

704

9.08

5.91

Other

17

11.47

8.18

With spouse

828

7.39

5.69

With children

585

8.85

5.58

Living alone

311

9.60

6.51

< 20.45

578

8.80

5.94

[20.45, 23.24)

577

8.38

6.02

23.24

582

7.62

5.57

Yes

697

7.59

5.73

No

1040

8.72

5.91

553

7.72

5.89

Results
The GDS was administered to 1737 participants. Mean
age in the cohort is 74.3 years (SD = 5.2), with 53.1 %
being women and 61.1 % never attended school. Mean
BMI was 22.3 (SD = 3.8). In Table 1, we present mean
GDS scores by participants characteristics. Age, gender,
schooling, marital status, living arrangement, BMI, alcohol, smoking, histories of stroke, heart attack, head injury, fractures and selenium levels were significantly
associated with GDS scores in each separate univariate
analysis. In Table 2, we present results of ANCOVA
models including significant factors associated with GDS
scores. Older age, living alone, lower BMI, history of

<0.0001*

Living arrangement#
<0.0001

Body Mass Index tertiles

0.0025

Ever drink alcohol

<0.0001

Smoking
Current smoker
Former smoker

148

7.39

5.57

Non-smoker

1036

8.68

5.85

Yes

33

8.85

6.51

No

1704

8.25

5.85

0.0013

History of Cancer
0.5634

History of Parkinsons
Yes

36

8.67

6.04

No

1701

8.26

5.86

Yes

75

8.25

5.83

No

1662

8.67

6.64

0.6774

History of diabetes
0.5435

History of hypertension^
Yes

1029

8.36

5.83

No

708

8.13

5.91

45

10.20

6.97

0.4141

History of stroke#
Yes

0.0245

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Table 1 Mean GDS scores by participants characteristics

(Continued)
No

1690

8.21

5.83

Yes

52

12.00

6.42

No

1685

8.15

5.81

Yes

66

11.42

6.44

No

1671

8.14

5.81

Yes

30

12.47

6.00

No

1707

8.19

5.83

Yes

291

8.51

5.69

No

1446

8.22

5.90

Low (<0.32)

561

8.83

5.64

Medium [0.32, 0.47)

582

8.16

5.79

High ( 0.47)

594

7.83

6.10

History of heart attack

>0.0001

History of head injury

<0.0001

History of fracture
<0.0001

APOE e4 carriers

Selenium tertiles, g/g

0.4360

0.0132

<0.0001

Quartile groups defined by

composite cognitive score
Q4 (75 % to 100 %)

434

5.5

4.8

Q3 (50 % to 75 %)

434

7.7

5.7

Q2 (25 % to 50 %)

435

9.1

5.7

Q1 (0 to 25 %)

434

10.7

5.9

* Comparing those married to widowed, excluding those in the other group.

^ Blood pressure measure 140/90 or self-reported history of hypertension.
#: 13 subjects had missing information on living arrangement and 2 subjects
had missing information on the history of stroke.

stroke, heart attack, head injury and fracture were associated with higher GDS scores, while having attended
school and ever drinking alcohol were associated with

lower GDS scores. In this model, higher selenium level

was associated with lower GDS scores while adjusting
for all other significant factors in the model. In a subsequent model using selenium tertile group instead of continuous selenium levels, we also found the lowest
selenium group had significant higher GDS score than
those in the highest selenium group (p = 0.0063) while
the medium selenium group is not significantly different
from the high selenium group (p = 0.2143) (Table 3).
In a second ANCOVA model in Table 2, we included
the composite cognitive z-score in the model to determine whether seleniums association with GDS score is
independent of cognitive function. In this model, higher
cognitive scores were significantly associated with lower
GDS scores. However, selenium level was no longer significantly associated with GDS scores indicating that
there is little direct effect from selenium on GDS scores.
In addition, selenium was significantly associated with
the composite cognitive z-score (p = 0.0011) in a separate ANCOVA model with the composite cognitive zscore as dependent variable adjusting for the same
variables as in model 2.
In Figure 1, mean GDS scores in each selenium tertile
group were presented by quartile cognitive group. Lower
GDS scores were seen in the higher cognitive group while
mean GDS scores no longer show differences across selenium tertile groups. Results obtained using nonparametric ANCOVA models yielded similar results with
significant selenium and GDS association in the model
without cognitive score ( = 0.36, p = 0.0059) and nonsignificance selenium and GDS association in the model
adjusting for cognitive score ( = 0.23, p = 0.0674).
Out of the 1737 individuals with GDS scores, 535
(30.8 %) met the criteria for depression (GDS 11).
Mean selenium levels were 0.39 g/g (SD = 0.18) in the

Table 2 Results of analysis of covariance (ANCOVA) models between selenium levels and depressive symptoms
measured by GDS score adjusting for other factors (n = 1735)a
Without Cognitive Score
Variable

Estimate

Std Err

Age, years

0.10

0.03

1.40
1.37

Attended school vs no school

Live alone

With Cognitive Score

p-value

Estimate

Std Err

0.0002

0.00

0.03

p-value

0.29

<0.0001

0.41

0.29

0.1681

0.35

0.0001

1.53

0.34

<0.0001

0.8688

Ever drink alcohol

0.97

0.29

0.0009

0.74

0.28

0.0093

Body mass index

0.12

0.04

0.0012

0.05

0.04

0.1470

History of stroke

1.96

0.86

0.0223

1.62

0.83

0.0500

History of heart attack

3.31

0.80

<0.0001

3.55

0.77

<0.0001

History of head injury

2.74

0.72

0.0001

2.49

0.69

0.0003

History of fracture

3.00

1.05

0.0042

2.36

1.01

0.0190

1.66

0.77

0.0321

Selenium, g/g
Composite cognitive z-score
a

Two subjects had missing information on history of stroke.

0.93

0.75

0.2143

0.38

0.20

<0.0001

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Table 3 Results of analysis of covariance (ANCOVA) models between selenium tertile groups and depressive symptoms
measured by GDS score adjusting for other factors (n = 1735)a
Without Cognitive Score
Variable

Estimate

Std Err

Age, years

0.10

0.03

1.39
1.35

Attended school vs no school

Live alone

With Cognitive Score

p-value

Estimate

Std Err

0.0002

0.01

0.03

p-value

0.29

<0.0001

0.49

0.29

0.0932

0.36

0.0002

1.47

0.34

<0.0001

0.6132

Ever drink alcohol

1.03

0.29

0.0005

0.74

0.29

0.0095

Body mass index

0.12

0.04

0.0016

0.05

0.04

0.1311

History of stroke

1.98

0.86

0.0209

1.73

0.83

0.0364

History of heart attack

3.34

0.80

<0.0001

3.59

0.78

<0.0001

History of head injury

2.67

0.72

0.0002

2.43

0.69

0.0005

History of fracture

2.92

1.05

0.0054

2.64

1.01

0.0091

0.96

0.35

0.0063

0.58

0.34

0.0876

0.42

0.34

0.2143

0.3712

reference

Selenium tertile group, g/g

<0.32
[0.32, 0.47)
0.47

0.29

0.32

reference

4.61

0.42

<0.0001

Cognitive score quartile groups

Q4 (75 % to 100 %)
Q3 (50 % to 75 %)

2.64

0.39

<0.0001

Q2 (25 % to 50 %)

1.43

0.38

0.0001

reference

Q1 (0 to 25 %)
a

Two subjects had missing information on history of stroke.

depressed subjects and 0.43 g/g (SD = 0.18) in the nondepressed subjects (p = 0.0006). Higher levels of selenium were significantly associated with lower probability
of depression (OR = 0.40, p = 0.0047) in the logistic model

Figure 1 Mean GDS scores by selenium tertiles and cognitive

quartile groups.

without adjusting for cognitive function. The association

between selenium levels and the probability of depression
remained significant (OR = 0.50, p = 0.0331) after adjusting for cognitive function.

Discussions
In this rural elderly Chinese cohort with an extensive
range of selenium distribution, we found that lower selenium levels were significantly associated with higher depressive symptoms adjusting for demographic and
medical conditions. However, when cognitive function
was included as an independent variable in the model,
the relationship between selenium and depressive symptoms was no longer significant, suggesting that seleniums
association with depressive symptoms is explained in part
by its association with cognitive function.
Several previous publications including observational
studies as well as clinical trials had examined the association between selenium levels and depression in various
populations. Two studies observed that low selenium diet
was associated with worsening mood [2,3]. In addition,
there were studies showing that selenium supplementation or high dietary selenium was associated with
improved mood with the most significant effect seen in
participants with low dietary selenium [1,3,26]. However,
a recent randomized trial of selenium supplementation
found that a 6-month selenium supplementation had no

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significant effect on mood or quality of life in 501 participants age 60 to 74 from the United Kingdom [5]. The differences in study findings between the recent trial and
previous results may be explained by differences in dietary selenium levels of study participants. The UK trial
consisted of participants whose baseline selenium status
was higher than the UK national average [5]. It is known
that the brain has a unique feature in storing selenium
and it also receives priority supply of selenium in times
of deprivation [27]. Animal studies have shown that after
generations of selenium deficiency when selenium concentrations in liver, skeletal muscle and blood dropped to
below 1 % of normal level, the brain still retained 60 % of
selenium as in normal controls.[7] In addition, studies
have shown that plasma GP-x activity plateaus after sufficient selenium supply indicating that selenium supplementation in high selenium individuals may not provide
additional benefit [28]. It is perhaps not surprising that
the UK trial found no selenium effect as most of the participants would already have adequate selenium supply
at baseline and additional supplementation was not able
to increase mood measures. However, results of the UK
trial still left open the question of whether low selenium
is associated with depression in those with low dietary
selenium levels at baseline.
The review of current literature suggests that longterm exposure to low selenium may be needed to impact
brain function. The brains unique selenium metabolism
may also make it more difficult to show the effect of
short-term selenium exposure on brain function than on
other organs.
The rural Chinese population offers an opportunity to
investigate the association of long-term selenium exposure and depression by identifying populations where substantial numbers are exposed to low selenium diet for an
extended length of time and comparing their depressive
symptoms to those with normal selenium levels. The
overwhelming majority of our study participants were
life-long residents of the same towns where they were
interviewed and very few take dietary supplements.
Hence the ascertained selenium levels can be inferred as
life-long exposure to selenium without the influence of
supplements. In this stable cohort, we found a significant
association between lower selenium levels and increased
depressive symptoms which is consistent with previous
reports in participants with low dietary selenium intake.
The mechanism underlying an association between selenium and depression is not yet clear, although published
results point to the fact that selenium is important to
brain functions. In animal models, selenium deficiency
was shown to alter neurotransmitter turnover rate [29]
and sodium selenite protected against dopamine loss
[30]. In addition, the enzyme closely related to selenium
activity (GP-x) protected against neuron loss [31], cell

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death [32], and decreased free radical generation or amyloid beta peptide [33]. In human studies, selenium supplementation was shown to reduce intractable epileptic
seizures [34,35]. A recent cross-sectional study reported
that whole blood GPX activity was significantly lower in
depressed patients than in normal controls [36]. More research is needed to elucidate the biological mechanism
for seleniums function in the brain.
To our knowledge, no previous studies on selenium
and depression have examined the role of cognitive function. Numerous studies have reported the co-existence of
cognitive impairment and depression [37], although the
underlying mechanism for such an association is not yet
established. Some suggest that depressive symptoms are
early manifestation of the dementia disorder [38], while
others believe that depression represents an independent
risk factor for cognitive decline [25]. We have previously
reported a significant relationship between selenium level
and cognitive function in the same cohort using data collected from baseline [8]. The non-significant association
between selenium and depressive symptoms after adjusting for cognitive function suggests that cognitive function plays an important role in the relationship between
selenium and depression.
Our study has a number of strengths. Selenium levels
were measured in nail samples reflecting stable longterm exposure. The study included participants from
sites with extensive range of selenium exposure. In
addition, the majority of our study participants were lifelong residents of the same towns where they were interviewed and the participants were known to have not
taken dietary supplements. Hence the ascertained selenium levels can be inferred as life-long exposure to selenium without the influence of supplements. A number of
cognitive instruments were used so that a reliable composite measure of cognitive function can be derived.
There are also important limitations in this study. Our
results were based on cross-sectional analyses in the
sense that cognitive function and depressive symptoms
were measured at the same time. Longitudinal follow-up
of this cohort would be necessary to examine the casual
direction of the association between cognitive function
and depressive symptoms. A second limitation is that we
relied on the GDS to assess depressive symptoms rather
than clinical diagnosis of specific depressive disorders,
an approach adopted by many large epidemiological
studies [25,38]. Further limitations include the exclusion
of potentially important risk factors for depression such
as disability or social support.

Conclusions
In summary, we found that selenium level was inversely
related to depressive symptoms in models without adjusting for cognition in this rural elderly Chinese cohort.

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However, this association appears to be accounted for by

the association between selenium and cognitive function.
Longitudinal follow-up of this cohort will be able to further examine the complex relationship between selenium,
cognitive function and depressive symptoms.
Competing interests
The authors report no conflicts of interest.
Authors contributions
Conception and design: Drs. Gao, Jin, Hall, Liang, Unverzagt, Murrell, and
Hendrie. Acquisition of data: SG, YJ, KSH, CL, JC, FWU, JRM, FM, YC, JB, PL,
and HCH. Analysis and interpretation of data: SG and HCH. Drafting of the
manuscript: SG, YJ, CL, and HCH. Critical revision of the manuscript for
important intellectual content: SG, YJ, KSH, CL, FWU, JRM, JC, FM, YC, JB, PL,
and HCH. Statistical expertise: SG. Obtaining funding: SG, YJ, KSH, CL, FWU,
JRM, and HCH. Administrative, technical or material support: YJ, CL, FM, YC,
PL, JB, and Matesan. Supervision: SG, YJ, CL, and HCH. All authors read and
approved the final manuscript.
Acknowledgments
The research is supported by NIH grant R01 AG019181 and P30 AG10133.
Author details
1
Department of Biostatistics, Indiana University School of Medicine,
Indianapolis, IN, USA. 2Institute for Environmental Health and Related Product
Safety, Chinese Center for Disease Control and Prevention, Beijing, China.
3
Department of Psychiatry, Indiana University School of Medicine,
Indianapolis, IN, USA. 4Department of Pathology and Laboratory Medicine,
Indiana University School of Medicine, Indianapolis, IN, USA. 5Sichuan
Provincial Center for Disease Control and Prevention in China, Chengdu,
China. 6Shandong Institute for Prevention and Treatment of Endemic Disease
in China, Jinan, China. 7Indiana University Center for Aging Research,
Indianapolis, IN, USA. 8Regenstrief Institute, Inc., Indianapolis, IN, USA.
9
Department of Biostatistics, Indiana University School of Medicine, 410 West
10th Street, Suite 3000, Indianapolis, IN 46202-2872, USA.
Received: 13 March 2012 Accepted: 20 June 2012
Published: 3 July 2012
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doi:10.1186/1471-244X-12-72
Cite this article as: Gao et al.: Selenium level and depressive symptoms
in a rural elderly Chinese cohort. BMC Psychiatry 2012 12:72.

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