nutrients

Systematic Review
Effects of Selenium Supplementation in Patients with Mild
Cognitive Impairment or Alzheimer’s Disease: A Systematic
Review and Meta-Analysis
Meire Ellen Pereira 1,2 , Júlia Vicentin Souza 2 , Maria Eduarda Andrade Galiciolli 1,2 , Fernanda Sare 2 ,
Giovanna Scorsin Vieira 2 , Isabeli Lopes Kruk 2 and Cláudia Sirlene Oliveira 1,2, *

1 Instituto de Pesquisa Pelé Pequeno Príncipe, Rua Silva Jardim 1632, Curitiba 80250-060, Brazil
2 Faculdades Pequeno Príncipe, Avenida Iguaçu 333, Curitiba 80230-020, Brazil
* Correspondence: [email protected]

Abstract: Elevated levels of oxidative stress could cause and aggravate Alzheimer’s disease (AD).
Selenium (Se) is a trace element with antioxidant and anti-inflammatory activity with neuroprotective
effects. To evaluate the effects of Se supplementation in patients with AD or mild cognitive impair-
ment (MCI) through a systematic review and meta-analysis, data were searched and collected from
four electronic databases, including clinical trial studies published until December 2020, following the
PRISMA guidelines. Statistical analysis was performed by RevMan, and the risk of bias was assessed
using the Rob 2 tool. A total of 1350 scientific papers were collected, and following evaluation
11 papers were included in the systematic review and 6 of these were used in the meta-analysis.
Studies that evaluated only Se supplementation observed an improvement in Se levels, glutathione
peroxidase (GPX) activity, and in some cognitive tests in MCI patients; similarly, improvement in
Citation: Pereira, M.E.; Souza, J.V.;
Se levels and mini-mental score was also observed in AD patients. Regarding supplementation of
Galiciolli, M.E.A.; Sare, F.;
Se plus other nutrients, improvement in cognitive tests was observed in both AD and MCI patients.
Vieira, G.S.; Kruk, I.L.; Oliveira, C.S.
Effects of Selenium Supplementation
Therefore, Se supplementation is a good alternative for patients with AD and MCI for improving Se
in Patients with Mild Cognitive levels and GPX activity. More detailed studies are required to further evaluate the effects of Se on the
Impairment or Alzheimer’s Disease: cognitive deficit and oxidative stress associated with AD and MCI.
A Systematic Review and
Meta-Analysis. Nutrients 2022, 14, Keywords: selenium; neurodegenerative disease; Brazil nut; oxidative stress
3205. https://doi.org/10.3390/
nu14153205
Academic Editors: Anthony Perkins
and James Cuffe 1. Introduction
Received: 1 July 2022 Selenium (Se) is a trace element that can be found naturally in inorganic (e.g., selenite
Accepted: 4 August 2022 and selenate) or organic (e.g., selenocysteine and selenomethionine) chemical forms [1–5].
Published: 5 August 2022 Se is essential for human health because it is part of selenoproteins, which participate in
antioxidant and anti-inflammatory pathways [1,6,7]. Se is pivotal for human development
Publisher’s Note: MDPI stays neutral
and plays a significant role in the central nervous system [1,6]. Several studies in rodents
with regard to jurisdictional claims in
have demonstrated that the depletion of some selenoproteins, such as selenoprotein P
published maps and institutional affil-
(SELP), causes irreversible brain damage, predisposition to seizures, impaired motor co-
iations.
ordination, and cognitive decline [7–9]. Interestingly, Rueli et al. [10] demonstrated that
SELP is significantly increased in the choroid plexus and cerebrospinal fluid of patients
with Alzheimer’s disease (AD); on the other hand, Garlet et al. [11] observed a decrease in
Copyright: © 2022 by the authors. blood glutathione peroxidase (GPX) activity in AD patients. However, the precise roles of
Licensee MDPI, Basel, Switzerland. Se and selenoproteins in AD are still not well established.
This article is an open access article Described in 1907 by the German neuropathologist Alois Alzheimer, AD is a progres-
distributed under the terms and sive neurodegenerative disease that manifests itself with reduced cognitive ability and
conditions of the Creative Commons memory loss, being one of the most common forms of dementia. It is characterized by
Attribution (CC BY) license (https:// the existence of neurofibrillary tangles containing β-amyloid peptide and tau protein in
creativecommons.org/licenses/by/ the pathological brain tissue, leading to neuronal degeneration [7,12,13]. Moreover, its
4.0/).

Nutrients 2022, 14, 3205. https://doi.org/10.3390/nu14153205 https://www.mdpi.com/journal/nutrients

Nutrients 2022, 14, 3205 2 of 15

pathophysiology is related to the large production of reactive oxygen species, inflammatory

markers, decreased antioxidant agents, and brain metabolic changes [7,12–14].
Mild cognitive impairment (MCI) can be defined as a decline in cognition beyond what
is expected in normal aging. This impairment cannot yet be characterized as dementia, but it
is associated with lower quality of life, decreased independence, relationship problems, and
greater medical needs [15,16]. Therefore, depending on the underlying cause, the clinical
condition of patients with MCI may improve, stabilize, or progress to dementia [17,18].
Dietary supplementation composed of adequate nutrients may be associated with
a decreased risk, not only for developing AD but also other dementias [19,20]. Several
nutrients, such as vitamins C, D, and E, vitamins of the B-complex, and omega-3, are
associated with improvements in the symptoms of AD and MCI [21–23]. Similarly, Se has
been studied as a trace element with possible benefits in neurodegenerative diseases and
has been analyzed as a potential agent for preventing the development and progression of
AD and MCI [24,25].
Studying the relationship between Se intake and the maintenance of brain function
can help to understand the benefits of Se in AD and MCI. Therefore, the objective of this
systematic review and meta-analysis was to evaluate the effects of Se supplementation on
Se levels and oxidative stress, as well as to verify whether Se supplementation improves
patient performance in cognitive tests.

2. Materials and Methods

2.1. Protocol and Registration
The protocol for this systematic review was registered in the International Prospective
Register of Systematic Reviews (PROSPERO; CRD42021240649) and was carried out based
on the Pattern of Reporting Systematic Review and Meta-Analysis (PRISMA) guideline [26].
The acronym PICO, which corresponds to P = patient or population, I = intervention or
indicator, C = comparison or control, and O = outcome, was used to define the guiding
question [27,28]. Therefore, in relation to the guiding question of this systematic review
and meta-analysis, the acronym PICO corresponds to: P = patients with AD or MCI;
I = supplementation with organic or inorganic Se, isolated or in combination with other
compounds; C = patients without Se supplementation or who received placebo; and
O = improvement in cognitive performance and/or Se availability.

2.2. Search Strategy

The Cochrane Library, SciELO, Scopus, and PubMed databases were used in this
systematic review. The databases were searched through titles and abstracts, using the
keywords “selenium supplementation”, “selenium”, “neuroinflammation”, “Alzheimer’s
disease”, and “mild cognitive impairment”, and the Boolean operators “OR” and “AND”
(Supplementary Table S1). It is noteworthy that all searches for this study began on
December 2020 and finished on March 2021.

2.3. Eligibility Criteria

This systematic review included studies that met the following criteria: patients
with AD or MCI supplemented with Se (organic or inorganic) or Se plus other nutrients.
The exclusion criteria included book chapters, absence of Se supplementation, systematic
reviews, other neurodegenerative diseases, and in vitro or animal studies.

2.4. Data Extraction

The articles selected for this systematic review were analyzed and classified using the
Mendeley Library (Elsevier BV, Amsterdam, The Netherlands). The paper selection process
was performed by six reviewers divided into pairs (MEP and FS; JVS and MEAG; and GSV
and ILK), who, in the first stage, independently read the titles and abstracts of the papers
in relation to the eligibility criteria; any discrepancies were solved by a seventh reviewer
(CSO). In the second stage of the selection process, the full text of the potentially eligible
Nutrients 2022, 14, 3205 3 of 15

records was read. The data extraction included publication year, pathology type (AD or
MCI), the country where the study was conducted, design of the study, total number of
participants, and the variables that were extracted and selected according to the tests of
interest to the topic and the criteria of the systematic review. In addition, the data extracted
from the total number of participants in the selected articles included interventions, which
divided the participants into two experimental groups (intervention and control). It is
worth mentioning that when there was more than groups intervention and control group,
this was also presented. Data were extracted from the groups regarding intervention
parameters, intervention exposure time, number of participants in the groups, age, number
of female and male participants, tests performed, analyzed variables, and results. The data
were organized in an Excel 2016 spreadsheet (Microsoft Corp, Washington, WA, USA).

2.5. Quality Assessment

Quality assessment was performed using the Cochrane Risk of Bias for Randomized
Trials (RoB 2) tool, which is recommended for assessing the risk of bias in randomized
trials included in Cochrane reviews. The RoB 2 tool is structured around a fixed set of
five domains: domain 1 assesses the randomization process; domain 2 assesses deviations
from intended interventions; domain 3 assesses missing results data; domain 4 assesses
outcome measurements; and domain 5 assesses the selection of the reported results. Within
each domain, there are several questions that aim to obtain information about the study
characteristics that are relevant to the risk of bias. A proposal for judging the risk of bias
arising from each domain was generated by an algorithm, based on the answers to the
questions. As such, the judgment may be “Low” or “High” risk of bias, or it may express
“Some concerns” [29].

2.6. Statistical Analysis

The meta-analysis was performed using the Review Manager (RevMan) software
version 5.3, and the obtained results were considered significant when p < 0.05. Random
model effects were analyzed, and heterogeneity was evaluated using Higgins inconsistency
analyses (I2 ), Cochrane’s Q test, and Tau2 .

3. Results
3.1. Selection of Papers
In this study, 1350 scientific papers were collected from four electronic databases. Of
these, 226 were duplicates, in 65 documents the abstract was unavailable, and 1049 documents
were excluded because they did not meet the eligibility criteria; hence, 65 documents were
assessed for eligibility. Of these, 31 did not test Se supplementation, 3 were in vitro
studies, 3 were reviews, 9 correlated Se supplementation with other diseases, 2 were
conference posters, 1 was a book chapter, 1 had a deficiency of data, 1 was duplicated,
3 reported Se supplementation for AD prevention, and 1 evaluated the adverse effects of
Se supplementation; in addition, 1 paper was manually included because it fulfilled the
inclusion criteria but it had not been collected through the database searches described
above. This resulted in a total of 11 papers that were included in this systematic review:
4 of these papers explored only Se supplementation, and 7 explored Se plus other nutrients
supplementation; of those 11 papers, 6 were used in the meta-analysis (Figure 1).

3.2. Characteristics of the Systematically Selected Papers

The 11 papers systematically selected for this study comprised research conducted on
five continents: South America (Brazil), North America (USA), Europe (The Netherlands,
Germany, Belgium, Spain, Italy, France, and United Kingdom), Asia (Iran), and Oceania
(Australia). Most of the papers were from Europe (27.3%), followed by papers from South
America (18.2%), Europe and North America (18.2%), North America (18.2%), Asia (9.1%),
and Oceania (9.1%) (Figure 2A). Regarding the studies of only Se supplementation, 50%
of them were carried out in Oceania and the other 50% in South America (Figure 2B). In
 Nutrients 2022, 14, x FOR PEER REVIEW
Nutrients 2022, 14, 3205 4 of 15

plus other
contrast, nutrients
in studies of Sesupplementation; of those 11 papers,
plus other nutrients supplementation, 42.8%6 were
werecarried
used out
in the
in meta-
Europe and
(Figure 1). North America, and the remainder were carried out in North America (28.6%),
Europe (14.3%), and Asia (14.3%) (Figure 2C).

trients 2022, 14, x FOR PEER REVIEW 5 o

(16.6%); randomized, controlled, double-blind, and parallel-group trials (16.6%); and r

domized, double-blind, and controlled clinical trials (16.6%) (Table 2).
Figure1.1.PRISMA
Figure PRISMAflowflow diagram.
diagram.

3.2. Characteristics of the Systematically Selected Papers

The 11 papers systematically selected for this study comprised research con
on five continents: South America (Brazil), North America (USA), Europe (The
lands, Germany, Belgium, Spain, Italy, France, and United Kingdom), Asia (Ira
Oceania (Australia). Most of the papers were from Europe (27.3%), followed by
from South America (18.2%), Europe and North America (18.2%), North America
Asia (9.1%), and Oceania (9.1%) (Figure 2A). Regarding the studies of only Se supp
Figure 2. (A)
Figure
tation, Continents
(A)
2. 50% Continents
of them where
where
were the
the studies
studies
carried were
were
out incarried
carried out inout
Oceania in all
alland
papers papers
the otherincluded
included in in in this system
this systematic
50% South Amer
review;
review; (B) (B) continentswhere
continents where the
the studies
studies were carried
were out in
carried papers
out in that performed
papers that only Se supple-
performed only Se 42.8
sup
ure 2B). In contrast, in studies of Se plus other nutrients supplementation,
mentation; and (C) continents where the studies were carried out in papers that performed
mentation; and (C) continents where the studies were carried out in papers that performed Se p Se plus
carried out supplementation.
in Europe and North America, and the remainder were carried out i
otherother nutrients
nutrients supplementation.
America (28.6%), Europe (14.3%), and Asia (14.3%) (Figure 2C).
The
Thepapers
papersincluded in this
included insystematic review were
this systematic review outlined
wereas: randomized
outlined clini-
as: randomized
cal trials (18.2%); phase IIa randomized control trials (9.1%); randomized, double-blind,
trials (18.2%); phase IIa randomized control trials (9.1%); randomized, double-bli
placebo-controlled trials (27.3%); randomized double-blind clinical trials (18.2%
domized, double-blind, controlled, and multicenter trials (9.1%); randomized, con
double-blind, and parallel-group trials (9.1%); and randomized, double-blind, a
garding sex, the prevalence of female patients was evident: 77 females versus 40 males;
there were 49 females with MCI and 28 females with AD. The age range of the patients
with MCI was 77.3–79.1 years old, whereas that of patients with AD 68.7–78.8 years old
(Table 1). 14, 3205
Nutrients 2022, 5 of 15

Among the studies of Se plus other nutrients supplementation included in this sys-
tematic review, 87.5% of the participants had AD, and 12.5% had MCI. In terms of sex, the
and placebo-controlled trials (27.3%); randomized double-blind clinical trials (18.2%); ran-
prevalence of females was also
domized, evident, controlled,
double-blind, with a total of 393 female
and multicenter patients
trials (9.1%); versus
randomized, 382 male
controlled,
patients. The age range of the patients
double-blind, with MCI
and parallel-group was
trials 70.5–88.8
(9.1%); years old,
and randomized, whereas
double-blind, and that
con- of
trolled clinical trials (9.1%) (Tables 1 and 2). The only Se supplementation studies were
patients with AD was outlined
69.1–86.5 years oldclinical
as: randomized (Table 2).double-blind, and placebo-controlled pilot stud-
trial,
ies (40.0%); randomized clinical trials (40.0%); and phase IIa randomized control trials
(20.0%) (Table 1). The Se plus other nutrients supplementation studies were outlined as:
3.4. Selenium Supplementation
randomized, double-blind, and placebo-controlled trials (16.6%); randomized double-blind
In the systematically selected
clinical papers
trials (33.3%); that evaluated
randomized, double-blind,the effects
controlled, andof only Setrials
multicenter supplemen-
(16.6%);
randomized, controlled, double-blind, and parallel-group trials (16.6%); and randomized,
tation, some studies performed
double-blind,supplementation with
and controlled clinical trials the inorganic
(16.6%) (Table 2). form of Se (40%), oth-
ers with its organic form (40%), and others did not specify the form of Se used (20%) (Fig-
3.3. Patient Characteristics
ure 3A). Among the studies exploring supplementation only with Se that were included in this
In studies where systematic
Se was administered
review, 60% included along with
patients other
with AD nutrients,
and 40% Se MCI.
patients with wasRegarding
combined
with a multivitamin sex, the prevalence
called Souvenaid of female patients was evident:
(containing 77 females versus 40
eicosapentaenoic males;docosahex-
acid, there were
49 females with MCI and 28 females with AD. The age range of the patients with MCI was
aenoic acid, choline, uridine
77.3–79.1 monophosphate,
years old, whereas that of vitamin E, vitamin
patients with AD 68.7–78.8C,years
vitamin B12,
old (Table 1). vitamin
B6, and folic acid), with probiotics (containing
Among the studies L. acidophilus,
of Se plus other B. bifidum,
nutrients supplementation and B.
included longum),
in this sys-
tematic review, 87.5% of the participants had AD, and 12.5% had MCI. In terms of sex, the
with a multivitamin called Formula
prevalence F was
of females (containing
also evident,carnosine,
with a total of thiamine, riboflavin,
393 female patients versus 382nicotin-
male
amide, vitamin B6, folic acid,The
patients. cyanocobalamin, vitamin
age range of the patients with MCI C,was
vitamin
70.5–88.8E, coenzyme
years Q10,
old, whereas beta
that of
patients with AD was 69.1–86.5 years old (Table 2).
carotene, L-cysteine, and G. biloba), and with zinc sulfate and primula oil (Figure 3B).
The time of supplementation in the studies that evaluated only Se supplementation
3.4. Selenium Supplementation
In the systematically
was 24 (80.0%) and 12 (20.0%) weeks. In the selected papersother
Se plus that evaluated
nutrients the effects of only
studies, theSeperiod
supple- of
mentation, some studies performed supplementation with the inorganic form of Se (40%),
supplementation was others
24 (81.8%), 20 (9.1%),
with its organic and and
form (40%), 12 others
(9.1%) didweeks (Tables
not specify the form1 of
and 2). (20%)
Se used
(Figure 3A).

Figure 3. (A) Forms of Se supplementation in the paper that evaluated only the Se supplementation;
Figure 3. (A) Forms of Se(B)
supplementation in the paper that evaluated only the Se supplementation;
Other compounds that are tested in supplementation (Se plus other nutrients).
(B) Other compounds that are tested in supplementation (Se plus other nutrients).
In studies where Se was administered along with other nutrients, Se was combined
with a multivitamin called Souvenaid (containing eicosapentaenoic acid, docosahexaenoic
3.5. Improvement of Se Levels
acid, choline, uridine monophosphate, vitamin E, vitamin C, vitamin B12, vitamin B6, and
folic acid), with probiotics (containing L. acidophilus, B. bifidum, and B. longum), with a
In the systematically selected papers, Se levels were measured in different tissues,
multivitamin called Formula F (containing carnosine, thiamine, riboflavin, nicotinamide,
such as in plasma andvitamin
erythrocytes incyanocobalamin,
B6, folic acid, patients with MCI,
vitamin C, and inE,serum
vitamin coenzymeand
Q10,cerebrospinal
beta carotene,
L-cysteine, and G. biloba), and with zinc sulfate and primula oil (Figure 3B).
fluid (CSF) in patients with AD (Tables 1 and 2). In the only Se supplementation studies,
The time of supplementation in the studies that evaluated only Se supplementation
40.0% of the selected papers analyzed
was 24 (80.0%) and 12Se in plasma,
(20.0%) weeks. In 20.0% inother
the Se plus serum, 20.0%
nutrients in erythrocytes,
studies, the period of
supplementation was 24 (81.8%), 20 (9.1%), and 12 (9.1%)
and 20.0% in CSF. The range of Se in plasma before supplementation was 49.9–62.3 weeks (Tables 1 and 2). μg/L
and increased to 246.2–315.9 μg/L after Se supplementation; the range of Se in serum was
122.2–145.4 μg/L and increased to 176.7–858.3 μg/L after Se supplementation; the range of
Se in erythrocytes was 59.5–65.1 μg/L and increased to 517.0–640.9 μg/L after Se supple-
mentation; finally, the range of Se in the CSF was 1.4–1.6 μg/L and increased to 2.5–20.2
μg/L after Se supplementation. In addition, it was possible to observe in Table 1 that the
Nutrients 2022, 14, 3205 6 of 15

Table 1. Summary of systematically selected papers (only Se supplementation).

Se Levels Cognitive Tests

Reference Country Pathology Groups Study Type Characteristics of the Participants
(µg/L) (Score)

Plasma COWAT
Sex Control Control
Control Pre: 50.0 ± 15.5 Pre: 16.3 ± 3.7
Female = 6 Post: 47.8 ± 11.7 Post: 14.1 ± 3.9
Male = 3
Se supplementation Se supplementation
Se supplementation Pre: 56.2 ± 18.3 Pre: 12.8 ± 3.3
Se supplementation
Cardoso Female = 8 Post: 290.6 ± 74.6 Post: 14.1 ± 3.9
group consumed one Randomized clinical
et al. Brazil MCI Male = 3
Brazil nut daily for trial
[30] Erythrocyte Constructional praxis
24 weeks.
Age Control Control
Control Pre: 50.8 ± 21.0 Pre: 8.7 ± 2.6
77.6 ± 6.6 Post: 33.5 ± 16.1 Post: 8.3 ± 2.4

Se supplementation Se supplementation Se supplementation

77.7 ± 4.3 Pre: 59.5 ± 20.6 Pre: 7.7 ± 2.3
Post: 574.6 ± 181.4 Post: 9.2 ± 2.2

Plasma
GPX1-rs1050450
CC
Sex Pre: 49.9 ± 10.3
GPX1-rs1050450 Post: 246.2 ± 54.0
CC CT + CT
Female = 7 Pre: 59.9 ± 21.6
Male = 1 Post: 315.9 ± 75.8
CT + CT
Female = 7 SEPP-rs7579
Male = 5 GG
Pre: 59.6 ± 21.3
SEPP-rs7579 Post: 277.8 ± 62.1
GG GA + AA
Female = 6 Pre: 50.3 ± 11.7
Male = 5 Post: 312.9 ± 98.9
GA + AA
Female = 7 SEPP-rs3877899
Male = 1 GG
Pre: 52.8 ± 12.0
SEPP-rs3877899 Post: 299.9 ± 68.7
GG GA
Female = 8 Pre: 62.3 ± 27.5
Se supplementation
Cardoso Male = 4 Post: 274.2 ± 92.4
group consumed one Randomized clinical
et al. Brazil MCI GA -
Brazil nut daily for trial
[15] Female = 6 Erythrocyte
24 weeks.
Male = 2 GPX1-rs1050450
CC
Age Pre: 65.1 ± 13.6
GPX1rs1050450 Post: 519.2 ± 239.8
CC CT + TT
77.3 ± 7.1 Pre: 56.4 ± 24.2
CT + TT Post: 606.2 ± 151.2
77.83 ± 4.1
SEPP-rs7579
SEPPrs7579 GG
GG Pre: 58.2 ± 22.5
77.4 ± 4.4 Post: 536.6 ± 116.9
GA + AA GA + AA
78.0 ± 6.5 Pre: 61.9 ± 19.8
Post: 640.9 ± 270.4
S3877899
GG SEPP-rs3877899
76.7 ± 3.6 GG
GA Pre: 57.1 ± 16.9
79.1 ± 7.2 Post: 607.4 ± 177.6
GA
Pre: 63.7 ± 28.4
Post: 517.0 ± 199.1

MMSE
Control
Pre: 20
Post: 19

Supranutritional
Sex
Pre: 20
Control
Post: 19
Female = 8
Se nutritional dose Male = 12
ADAS-Cog
(control): 320 µg
Control
sodium selenate 3 times Supranutritional
Pre: 22.1
Malpas a day for 24 weeks. Female = 9
Phase IIa randomized Post: 22.2
et al. Australia AD Male = 11 -
control trial
[25] Se supranutritional
Supranutritional
dose: 10 mg sodium Age
Pre:19.7
selenate 3 times a day Control
Post: 22.3
for 24 weeks. 71
COWAT
Supranutritional
Control
70
Pre: 29
Post: 28

Supranutritional
Pre: 25
Post: 20
Nutrients 2022, 14, 3205 7 of 15

Table 1. Cont.

Characteristics of the Se Levels Cognitive Tests

Reference Country Pathology Groups Study Type
Participants (µg/L) (Score)

Serum
Nutritional
Sex
Pre: 122.2 ± 26.3
Nutritional
Post: 176.7 ± 46.2
Female = 4
Se nutritional dose
Male = 4
(control): 320 µg Supranutritional
sodium selenate 3 times Pre: 145.4 ± 28.8
Randomized, Supranutritional
a day for 24 weeks. Post: 858.3 ± 447.1
Cardoso et al. double-blind, Female = 15
Australia AD -
[31] placebo-controlled pilot Male = 4
Se supranutritional Cerebrospinal fluid
study
dose: 10 mg sodium Nutritional
Age
selenate 3 times a day Pre: 1.6± 0.6
Nutritional
for 24 weeks. Post: 2.5± 0.7
73.4 ± 5.5
Supranutritional
Supranutritional
69.5 ± 8.3
Pre: 1.4 ± 0.5
Post: 20.2 ± 9.1

Sex
MMSE
Uninformed
Placebo: placebo Placebo
(starch) for 12 weeks. Pre:9.3 ± 4.1
Randomized, Age
Tamtaji et al. [12] Post: 9.1 ± 4.4
Iran AD double-blind, controlled Placebo -
Selenium: received
clinical trial 78.5 ± 8.0
selenium 200mg/day Selenium
for 12 weeks. Pre:9.9 ± 4.0
Selenium
Post:10.4 ± 4.2
78.8 ± 10.2

MMSE: Mini Mental State Examination; COWAT: Controlled Oral Word Association Test—Verbal fluency; and
ADAS-Cog: Alzheimer’s Disease Assessment Scale-cognitive subscale.

3.5. Improvement of Se Levels

In the systematically selected papers, Se levels were measured in different tissues,
such as in plasma and erythrocytes in patients with MCI, and in serum and cerebrospinal
fluid (CSF) in patients with AD (Tables 1 and 2). In the only Se supplementation studies,
40.0% of the selected papers analyzed Se in plasma, 20.0% in serum, 20.0% in erythrocytes,
and 20.0% in CSF. The range of Se in plasma before supplementation was 49.9–62.3 µg/L
and increased to 246.2–315.9 µg/L after Se supplementation; the range of Se in serum
was 122.2–145.4 µg/L and increased to 176.7–858.3 µg/L after Se supplementation; the
range of Se in erythrocytes was 59.5–65.1 µg/L and increased to 517.0–640.9 µg/L after
Se supplementation; finally, the range of Se in the CSF was 1.4–1.6 µg/L and increased to
2.5–20.2 µg/L after Se supplementation. In addition, it was possible to observe in Table 1
that the control group (not supplemented) showed no variation, or even a decrease in Se
levels. In fact, the meta-analysis (Figure 4) revealed that Se supplementation significantly
increased Se levels by an average of 4.09 (3.45, 4.72) times in plasma (p < 0.00001), 1.88 (1.08,
2.67) in serum (p < 0.00001), 3.73 (2.96, 4.50) in erythrocytes (p < 0.00001), and 2.18 (0.51,
3.85) in CSF (p = 0.01).
For the Se plus other nutrients studies, 42.9% of the systematically selected papers
analyzed Se levels in plasma, while the other studies (57.1%) did not analyze Se levels.
The Se plasma concentration before supplementation was 86.8 µg/L and increased to
102.6–110.5 µg/L after Se supplementation (Table 2). These results were presented as
medians, and it was not possible to perform the meta-analysis for this parameter.

3.6. Oxidative Stress

Regarding the oxidative stress analysis, 40% of the studies that evaluated only Se
supplementation measured the malondialdehyde (MDA) levels in plasma. It was observed
that the range of plasma MDA levels before Se supplementation was 0.4–0.5 µmol/L,
whereas after supplementation it was 0.5–0.6 µmol/L (Supplementary Table S2). The
meta-analysis (Figure 5) revealed that after Se supplementation MDA levels increased
significantly by an average of 0.95 (0.44, 1.45) times (p = 0.0002). Regarding the papers
included in the Se plus other nutrients supplementation, 28.6% analyzed MDA levels in
plasma; before supplementation, the range of plasma MDA levels was 1.2–2.6 µmol/L
whereas after supplementation it was 1.5–2.7 µmol/L (Supplementary Table S2). It was
not possible to perform the meta-analysis of this parameter because some results were
presented as medians.
Nutrients 2022, 14, 3205 8 of 15

Table 2. Summary of systematically selected papers (Se plus other nutrients supplementation).

Characteristics of the Se Levels Cognitive Test

Reference Country Pathology Groups Study Type
Participants (µg/L) (Score)

ASTR
Olive Oil
Pre: 100.4 ± 17.1
Post: 106.9 ± 19.0

EPO/Zn/Se
Pre: 72.6 ± 28.8
Post: 87.5 ± 36.7

CPM
Olive Oil
Pre: 17.2 ± 6.2
Post: 18.4 ± 9.0

EPO/Zn/Se
Sex
Pre: 12.2 ± 6.7
Olive Oil
Post: 15.8 ± 8.6
Olive Oil (control): six Female = 11
capsules of olive oil and Male = 4
GNT
one placebo tablet for
Olive Oil
20 weeks. EPO/Zn/Se
Pre: 9.4 ± 7.8
Randomized, Female = 12
Post: 10.6 ± 8.5
Van Rhijn et al. [32] United Kingdom MCI EPO/Zn/Se: six double-blind, Male = 3 -
primrose oil capsule placebo-controlled trial
EPO/Zn/Se
(500 mg) and one tablet Age
Pre: 7.2 ± 5.2
(200 mg zinc sulphate Olive Oil
Post: 9.8 ± 5.4
and 1 mg sodium 83.4 ± 5.4
selenite) for 20 weeks.
DCT
EPO/Zn/Se
Olive Oil
78.7 ± 8.2
Pre: 63.8 ± 14.9
Post: 69.8 ± 18.8

EPO/Zn/Se
Pre: 61.2 ± 20.0
Post: 69.7 ± 22.2

CAMCOG
Olive Oil
Pre: 65.1 ± 17.3
Post: 67.8 ± 17.7

EPO/Zn/Se
Pre: 62.50 ± 16.60
Post: 68.30 ± 17.70

Sex
Placebo
Female = 15
Placebo: 500 mg of Male = 10
MMSE
fructose and flavoring
Placebo
one ampoule/day for Formula F
Pre: 23.9 ± 1.0
24 weeks. Randomized Female = 14
Post: 24.2 ± 1.3
Cornelli [33] United States AD double-blind clinical Male = 9 -
Formula F: Formula F * trial
Formula F
containing 27.5 µg of Age
Pre: 23.2 ± 1.1
Se one ampoule/day Placebo
Post: 24.3 ± 1.4
for 24 weeks. 74 ± 4.9

Formula F
75 ± 4.2

MMSE
Sex Control
Control Pre: 24.0 ± 2.5
Female = 54 Post: 24.0 ± 3.4
Control: 125 mL
Male = 52
tetrapackages without
Active
actives once a day for
Active Pre: 23.8 ± 2.7
The Netherlands, 24 weeks. Randomized,
Female = 52 Post: 24.1 ± 3.5
Germany, Belgium, double-blind,
Scheltens et al. [34] AD Male = 54 -
United Kingdom and Active: 125 mL controlled, multicenter
ADAS-Cog
United States tetrapackages with trial
Age Control
Souvenaid ** containing
Control Pre: 25.5 ± 8.8
60 µg of Se once a day
73.3 ± 7.8 Post: 25.8 ± 7.8
for 24 weeks.
Active Active
74.1 ± 7.2 Pre: 25.9 ± 7.6
Post: 25.9 ± 7.7

NTB
Sex
Control
Control
Pre: 0.1 ± 0.1
Control: 125 mL Female = 65
Post: 0.1 ± 0.5
tetrapackages without Male = 64
Active
actives once a day for
Pre: 0.1 ± 0.8
24 weeks. Randomized, Active
The Netherlands, Post: 0.2 ± 0.4
controlled, Female = 62
Scheltens et al. [35] Germany, Belgium, AD -
Active: 125 mL double-blind, Male = 68
Spain, Italy, and France ADAS-Cog
tetrapackages with parallel-group trial
Control
Souvenaid ** containing Age
Pre: 1.2 ± 1.5
60 µg of Se once a day Control
Post: 1.4 ± 1.4
for 24 weeks. 73.2 ± 8.4
Active
Active
Pre: 1.6 ± 1.7
74.4 ± 6.9
Post: 1.7 ± 1.6

Sex
Control
Control: 125 mL Female = 135
tetrapackages without Male = 127 ADAS-Cog
actives once a day for Control
24 weeks. Active Pre: 23.4 ± 9.3
Randomized,
Female = 139 Post: 24.4 ± 10.9
Shah et al. [36] United States AD double-blind clinical -
Active: 125 mL Male = 126
trial
tetrapackages with Active
Souvenaid ** containing Age Pre: 23.9 ± 9.6
60 µg of Se once a day Control Post: 25.4 ± 11.6
for 24 weeks. 76.9 ± 8.2
Active
76.6 ± 8.2
Nutrients 2022, 14, 3205 9 of 15

Table 2. Cont.

Characteristics of the Se Levels Cognitive Test

Reference Country Pathology Groups Study Type
Participants (µg/L) (Score)

Sex
Control
Control: 125 mL Female = 54
tetrapackages without Male = 52 Plasma
actives once a day for Control
The Netherlands, 24 weeks. Randomized Active Pre: 86.8
Germany, Belgium, double-blind, Female = 52 Post: 78.9
Rijpma et al. [37] AD -
United Kingdom and Active: 125 mL multicenter, controlled Male = 54
United States tetrapackages with trial Active
Souvenaid ** containing Age Pre: 86.8
60 µg of Se once a day Control Post: 102.6
for 24 weeks. 73.3 ± 7.8
Active
74.1 ± 7.2

Sex
Control
Control: 125 mL Female = 65
tetrapackages without Male = 64 Plasma
actives once a day for Control
24 weeks. Randomized Active Pre: 86.8
The Netherlands,
double-blind, Female = 62 Post: 86.8
Rijpma et al. [37] Germany, Belgium, AD -
Active: 125 mL multicenter, controlled Male = 68
Spain, Italy, and France
tetrapackages with trial Active
Souvenaid ** containing Age Pre: 86.8
60 µg of Se once a day Control Post: 110.5
for 24 weeks. 73.2 ± 8.4
Active
74.4 ± 6.9

Sex MMSE
Placebo: placebo Uninformed Placebo
(starch) for 12 weeks. Pre: 9.3 ± 4.1
Randomized,
Age Post: 9.1 ± 4.4
Tamtaji et al. [12] Iran AD double-blind, controlled -
Selenium: 200 mg of Se Placebo
clinical trial
plus probiotic *** every 78.5 ± 8.0 Selenium plus probiotic
day for 12 weeks. Probiotic plus selenium Pre: 9.4 ± 3.5
76.2 ± 8.1 Post:10.9 ± 3.8

EPO/Zn/Se: primrose oil, zinc sulphate and sodium selenite; ASTR: Anomalous Sentences Repetition Test; CPM:
Colored Progressive Matrices; DCT: Digit Copying Test; GNT: Graded Naming Test; CAMCOG: Cambridge
Cognitive Examination; MMSE: Mini-Mental State Examination; ADAS-Cog: Alzheimer’s Disease Assessment
Scale-cognitive subscale; and NTB: Neuropsychological Test Battery. * Formula F contain: 100 mg Carnosine,
1.4 mg Thiamine (B1), 1.6 mg Riboflavin (B2), 18 mg Nicotinamide (B3), 2 mg Pyridoxine (B6), 200 µg Folic acid
(B9),
Nutrients 2022, 1 µgPEER
14, x FOR Cyanocobalamin
REVIEW (B12), 30 mg Vitamin C, 20 mg Vitamin E, 10 mg Coenzyme 15 Q10,
of 21 800 RE β -Carotene,
27.5 µg Selenium, 10 mg L-cysteine, and 25 mg Ginkgo biloba. ** Souvenaid contains: 300 mg Eicosapentaenoic
acid, 1200 mg Docosahexaenoic acid, 106 mg Phospholipids, 400 mg Choline, 625 mg Uridine monophosphate,
40 mg Vitamin E, 80 mg
serum (p <Vitamin
0.00001), C,
3.7360 µg Selenium,
(2.96, 3 mg Vitamin
4.50) in erythrocytes B12, and
(p < 0.00001), 1 mg Vitamin
2.18 B6,inand 400 µg Folic acid.
(0.51, 3.85)
*** Probiotic contains: × 109 CFU of L. acidophilus, B. bifidum, and B. longum.
CSF (p =20.01).

Figure 4. Meta-analysis of Se levels in plasma, serum, erythrocyte, and CSF observed in only sele-
Figure 4. Meta-analysis of Se
nium supplementation levels
studies inpost
pre and plasma, serum, AD:
Se supplementation. erythrocyte, and CSF
Cardoso et al. [31]/MCI: Car- observed in only
doso et al. [30]; Cardoso et al. [15].
selenium supplementation studies pre and post Se supplementation. AD: Cardoso et al. [31]/MCI:
Cardoso et al. [30];For
Cardoso
the Se plusetother
al. [15].
nutrients studies, 42.9% of the systematically selected papers
analyzed Se levels in plasma, while the other studies (57.1%) did not analyze Se levels.
The Se plasma concentration before supplementation was 86.8 μg/L and increased to
102.6–110.5 μg/L after Se supplementation (Table 2). These results were presented as me-
dians, and it was not possible to perform the meta-analysis for this parameter.

3.6. Oxidative Stress

Nutrients 2022,
Nutrients 2022, 14,
14, xx FOR
FOR PEER
PEER REVIEW
REVIEW 16 of
16 of 21
21

whereas after supplementation it was 1.5–2.7 μmol/L (Supplementary Table S2). It was
Nutrients 2022, 14, 3205 10 of 15
not possible to perform the meta-analysis of this parameter because some results were
presented as medians.

Figure 5.
5. Meta-analysis
Meta-analysisofofMDA
MDA levels
levelsin in
plasma
plasmain only selenium
in only supplementation
selenium supplementation studies pre and
studies pre
post Se supplementation. Tamtaji et al. [12] is the only study that underwent treatment
and post Se supplementation. Tamtaji et al. [12] is the only study that underwent treatment for 12 weeks
for
in
12 the other
weeks in studies thestudies
the other Se supplementation underwentunderwent
the Se supplementation 24 weeks. AD: Tamtaji
24 weeks. et al.
AD: [12]; MCI:
Tamtaji et al. Car-
[12];
doso et al. [30]; Cardoso et al. [15].
MCI: Cardoso et al. [30]; Cardoso et al. [15].

GPX
GPX activity
activity in
in erythrocytes
erythrocytes waswas analyzed
analyzed inin 40.0%
40.0% of
of the
the papers
papers from
from the
the only
only Se
Se
supplementation
supplementation studies. The GPX activity mean before supplementation ranged from
studies. The GPX activity mean before supplementation ranged from
33.2–54.0
33.2–54.0 U/gHb,
U/gHb,and and this
this range
range increased
increased to 50.2–67.7 U/gHb
to 50.2–67.7 U/gHb after
after Se
Se supplementation
supplementation
(Supplementary Table S2). In fact, the meta-analysis (Figure 6) showed that
(Supplementary Table S2). In fact, the meta-analysis (Figure 6) showed that GPX
GPX activity
activity
increased significantly by an average of 0.95 (0.59, 1.31) times (p = 0.00001).
increased significantly by an average of 0.95 (0.59, 1.31) times (p = 0.00001).

6. Meta-analysis
Figure 6. Meta-analysisof
ofGPX
GPXactivity
activityinin
erythrocyte observed
erythrocyte in Se
observed in supplementation group
Se supplementation in MCI
group in
MCI patients
patients comparing
comparing prepost
pre and and Se
post Se supplementation
supplementation [15,30].
[15,30].

3.7. Cognitive
3.7. Cognitive Performance
Performance
In the
In theincluded
includedpapers
papersthat
that realized
realized only
only Se supplementation,
Se supplementation, the cognitive
the cognitive tests tests
per-
performed were Controlled Oral Word Association Test—Verbal fluency
formed were Controlled Oral Word Association Test—Verbal fluency (COWAT), con- (COWAT), con-
structional praxis, Mini-Mental State Examination (MMSE), and Alzheimer’s
structional praxis, Mini-Mental State Examination (MMSE), and Alzheimer’s Disease As- Disease
Assessment Scale-Cognitive
sessment Scale-Cognitive subscale
subscale (ADAS-Cog).InInthe
(ADAS-Cog). theSeSesupplemented
supplementedgroup,
group,ititisispos-
pos-
sible to observe that the MMSE score increased from 10.4–19.7 (before Se supplementation)
sible to observe that the MMSE score increased from 10.4–19.7 (before Se supplementa-
to 19.5–20.0 (after Se supplementation); in COWAT before supplementation, the ranges
tion) to 19.5–20.0 (after Se supplementation); in COWAT before supplementation, the
were
ranges12.8–25.0 and after
were 12.8–25.0 and14.1–20.0; in ADAS-Cog
after 14.1–20.0; the score
in ADAS-Cog before
the score supplementation
before supplementation was
19.0 and after the supplementation increased to 22.3; and in constructional praxis
was 19.0 and after the supplementation increased to 22.3; and in constructional praxis test, test, the
score before supplementation was 7.7 and after supplementation increased to 9.2. It was
the score before supplementation was 7.7 and after supplementation increased to 9.2. It
not possible to perform the meta-analysis because in some papers the standard deviation
was not possible to perform the meta-analysis because in some papers the standard devi-
was not presented.
ation was not presented.
In Se plus other nutrients, the cognitive tests performed were the Anomalous Sentences
In Se plus other nutrients, the cognitive tests performed were the Anomalous Sen-
Repetition Test (ASTR), Colored Progressive Matrices (CPM), Digit Copying Test (DCT),
tences Repetition Test (ASTR), Colored Progressive Matrices (CPM), Digit Copying Test
Graded Naming Test (GNT), Cambridge Cognitive Examination (CAMCOG), MMSE,
(DCT),
ADAS-Cog, GradedandNaming Test (GNT), Test
Neuropsychological Cambridge Cognitive
Battery (NTB). Examination
In the (CAMCOG),
Se plus other nutrients
MMSE,
supplemented group, it is possible to observe that the MMSE score increased fromother
ADAS-Cog, and Neuropsychological Test Battery (NTB). In the Se plus nu-
9.4–23.8
trients supplemented group, it is possible to observe that the MMSE score
(before supplementation) to 10.4–24.3 (after supplementation); in ADAS-Cog the scores increased from
9.4–23.8 (before supplementation) to 10.4–24.3 (after supplementation); in ADAS-Cog the
before supplementation were 1.6–25.9 and after supplementation were 1.7–25.9 (Table 2).
The meta-analysis showed no statistical difference in the MMSE and ADAS-Cog tests
(Supplementary Figure S1).
Nutrients 2022, 14, 3205 11 of 15

3.8. Risk of Bias

Using the Rob 2 tool, it was possible to determine the risk of bias for the systematically
selected papers. Thus, among the studies selected for this systematic review, approximately
36.3% had a high risk of bias, 36.3% had some concerns about the risk of bias, and 27.2%
demonstrated a low risk of bias. Regarding the high risk of bias, this was mainly due to
domain 2, which deals with deviations from the intended interventions, probably because,
in some of the selected studies, there was a lack of information about interventions and
how they were applied to the participants. Regarding the bias with some concerns, this
was mainly due to domain 4 which is related to the measurement of the outcome, probably
due to the influence on the results due to possible knowledge of the interventions received
by the participants in some of the studies, or because of the lack of sufficient analyses or
inappropriate measurement of these in other studies (Supplementary Figure S2).

4. Discussion
Se is an essential element for the maintenance of mammalian life and a component
of selenoproteins, which are part of the endogenous antioxidant system. The brain is
particularly dependent on Se supply, and is spared from Se deficiency [1,7]. Moreover,
Se is important for the protection against oxidative stress [37] and inflammatory pro-
cesses [38]. Neurodegenerative diseases, such as AD, are characterized by increased
oxidative stress and neuroinflammation, which may be due to the accumulation of β-
amyloid peptides [7,39,40]. Interestingly, Cardoso et al. [41] demonstrated that patients
with AD had significantly lower Se levels in plasma, erythrocytes, and serum, compared to
age-matched healthy controls. Similarly, through a systematic review and meta-analysis,
Reddy et al. [42] showed a decrease in circulatory, erythrocyte, and CSF Se levels in patients
with AD. For the first time, our study demonstrated, through a systematic review and
meta-analysis, the possible benefits of Se supplementation on Se levels in patients with
MCI or AD, as well as on markers of oxidative stress and on cognitive test performance.

4.1. Improvement of Se Levels

According to the Food and Nutrition Board at the Institute of Medicine of the National
Academies, USA, it is recommended that people aged >14 years ingest 55 µg Se/day [43].
Importantly, the normal blood Se range for adults is 70–130 µg/L [7], and the daily Se
ingestion threshold should not exceed 400 µg because high doses of Se can be toxic to the
body [7,30]. Se is already found in the human diet; therefore, supplementation should be
performed at appropriate doses, as needed [7,44]. The ideal levels of Se were based on Se
levels in the blood, which are associated with maximal GPX activity in adult humans [45,46].
In our study, we observed that in many of the studies that evaluated Se levels before
Se supplementation, AD and MCI individuals had Se levels below the ideal blood Se
levels [15,30,31]. After supplementation, Se levels increased in various tissues. In fact,
the meta-analysis revealed an increase in plasma, serum, erythrocytes, and CSF Se levels.
Cardoso et al. [30] pointed out that there is a correlation between Se levels and GPX activity.
However, the use of supranutritional Se supplementation must be taken with caution,
given Cardoso et al. [31] demonstrated that Se supplementation was associated with some
slight side effects. Thus, further studies are needed to determine if the benefits of Se
supplementation outweigh any potential side effects.

4.2. Oxidative Stress

MDA is one of the products of lipid peroxidation and can be used as a marker of
this process [47]. Patients with AD have increased levels of MDA in the plasma [48]. In
the systematically selected papers reported in our study we observed that MDA levels
did not decrease post-Se-supplementation [12,15,30,37]; in fact, in some cases there was
even a slight increase [15,30,37]. Cardoso et al. [30] pointed out that this increase in MDA
levels after several weeks of Se supplementation may be an adaptive response of the body.
Along these lines, Haddad et al. [49] observed that healthy individuals supplemented with
Nutrients 2022, 14, 3205 12 of 15

walnuts had their serum MDA levels decreased by 7% five hours after supplementation,
but no difference in their serum MDA levels was observed 24 h after supplementation.
Although no decrease in plasma MDA levels was observed after Se supplementation,
GPX activity, an important antioxidant enzyme [6], increased after Se supplementation,
corroborating the increase in Se levels [15,30]. Garlet et al. [11] observed that GPX activity
was positively correlated with Se levels in the blood of individuals with AD. Given that
human AD-affected brain tissue has low levels of Se [41], and that Se supplementation has
been shown to directly interfere with amyloid and iron neurotoxicity through modulation
of GPX activity in primary rat hippocampal neurons [50], supplementation with Se and the
consequent increase in GPX activity seem to be a sound approach for the maintenance of
brain function of individuals affected by AD and MCI.

4.3. Cognitive Performance

MMSE is used as a screening test, and also as a tool to evaluate AD progression
by assessing spatial and temporal orientation, immediate and recall memory, calcula-
tion, comprehension, writing, and drawing; the MMSE test score increases with better
patient performance [51]. In the systematically selected papers, we observed that often
MMSE was performed only as a baseline test, which, in many cases, prevented us from
evaluating whether there was an improvement in MMSE after Se supplementation. Per-
haps performing the test more than once would lead to a better analysis of the patient’s
cognitive improvement.
Cardoso et al. [31] demonstrated that individuals with AD who received a supranutri-
tional amount of Se demonstrated a subtle but significant improvement in MMSE, which
was associated with an increase in CSF Se levels. Moreover, Cardoso et al. [30] observed that
individuals with MCI daily supplemented with Se through Brazil nut intake demonstrated
positive responses to certain cognitive functions, such as verbal fluency (storage capacity of
the semantic memory system, the ability to retrieve information stored in memory, and the
processing of executive functions [52]), and constructive praxis (to assess an individual’s
motor, visuospatial, and visuoconstructive skills [53]). When Se supplementation was
associated with other nutrients, patients with AD also demonstrated a small improvement
in memory performance [35,36].
Oxidative stress is involved in cognitive decline, and studies have shown that patients
with MCI and AD present higher levels of reactive species, which culminate in the oxidative
stress process [41,54]. Se intake can improve normal cellular function by reducing pro-
oxidants molecules and by increasing antioxidant levels in the brain [12], thus reducing
neurofibrillary aggregations and achieving better cognitive performance.

5. Conclusions
Se supplementation is a good alternative for alleviating some of the symptoms of AD
and MCI, such as decreased Se levels and GPX activity, and cognitive deficits. In summary,
the systematically selected studies demonstrated improvements in these parameters as
a result of Se supplementation (Supplementary Table S3). Additional studies should be
performed to analyze the long-term effects of Se supplementation, and how the improved
parameters behave after Se supplementation is terminated.

6. Limitations
The lack of data and disparity in the parameters used made it difficult to carry out
this meta-analysis.

Supplementary Materials: The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/nu14153205/s1, Table S1: Search strategy for each electronic
database; Table S2: MDA levels and GPX activity; Table S3: Main findings in papers included in
this systematic review; Figure S1: Cognitive Performance (MMSE and ADAS-cog) meta-analysis in
selenium plus other compounds group in patients with AD; Figure S2: Risk of bias.
Nutrients 2022, 14, 3205 13 of 15

Author Contributions: Study design, C.S.O. and M.E.P. Data extraction, all authors. Risk of bias,
M.E.P., J.V.S. and F.S. Statistical analyses C.S.O. and M.E.P. Writing of the manuscript, all authors. Final
approval, all authors. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: This study was financed in part by the Coordenação de Aperfeiçoamento de
Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001 and the Instituto de Pesquisa Pelé
Pequeno Príncipe (IPPPP).
Conflicts of Interest: The authors have no financial involvement with any entity or organization
with an interest or financial conflict with the matters discussed in the manuscript.

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