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Toxoplasma gondii seropositivity and cognitive functions
in school-aged children
A. MENDY
1
*,E.R.VIEIRA
2
, A. N. ALBATINEH
3
and J. GASANA
4
1
Department of Epidemiology,College of Public Health,University of Iowa,Iowa City,Iowa,USA
2
Department of Physical Therapy,Florida International University,Miami,Florida,USA
3
Department of Biostatistics,Florida International University,Miami,Florida,USA
4
Department of Occupational and Environmental Health,Florida International University,Miami,FL/South Florida
Asthma Consortium,Ft. Lauderdale,Florida,USA
(Received 17 December 2014; revised 3 March 2015; accepted 12 April 2015)
SUMMARY
Toxoplasma gondii (T. gondii) infects one-third of the world population, but its association with cognitive functions in
school-aged children is unclear. We examined the relationship between Toxoplasma seropositivity and neuropsychological
tests scores (including math, reading, visuospatial reasoning and verbal memory) in 1755 school-aged children 12–16 years
old who participated to the Third National Health and Nutrition Examination Survey, using multiple linear regressions
adjusted for covariates. Toxoplasma seroprevalence was 7·7% and seropositivity to the parasite was associated with lower
reading skills (regression coefficient [β]=−5·86, 95% confidence interval [CI]: −11·11, −0·61, P= 0·029) and memory cap-
acities (β=−0·86, 95% CI: −1·58, −0·15, P= 0·017). The interaction between T. gondii seropositivity and vitamin E sign-
ificantly correlated with memory scores. In subgroup analysis, Toxoplasma-associated memory impairment was worse in
children with lower serum vitamin E concentrations (β=−1·61, 95% CI: −2·44, −0·77, P< 0·001) than in those with
higher values (β=−0·12, 95% CI: −1·23, 0·99, P= 0·83). In conclusion, Toxoplasma seropositivity may be associated
with reading and memory impairments in school-aged children. Serum vitamin E seems to modify the relationship
between the parasitic infection and memory deficiency.
Key words: Toxoplasma gondii, infection, parasites, cognition, cognitive function, intelligence, memory, reading, math,
school-aged children, vitamins, Vitamin E.
INTRODUCTION
Toxoplasma gondii (T. gondii) is an intracellular para-
sitic protozoan hosted by cats capable of infecting all
warm blooded animals including humans (Nicolle
and Manceaux, 1908). About 30% of the world
population lives with the parasite and in some coun-
tries, Toxoplasma prevalence is as high as 70% (Jones
et al. 2001; Pappas et al. 2009). T. gondii is transmit-
ted to humans through ingestion of contaminated
undercooked meat, unwashed vegetables, contami-
nated drinking water, contact with infected cat
feces, vertical transmission from mother to child,
and occasionally via transplantation of infected
organs (Jones et al. 2001).
Despite severe Toxoplasma encephalitis described
in immunocompromised patients or ocular and
neuropsychiatric illnesses reported in children with
congenital Toxoplasma infection, latent toxoplasmo-
sis is believed to be mostly asymptomatic (Gilbert
et al. 2006). Yet, it has been suggested that the para-
site could affect behaviour and cognition in im-
munocompetent humans ( Havlíček et al. 2001;
Flegr, 2007; Flegr et al. 2012; Guenter et al. 2012).
It has even been hypothesized that the parasite
could alter the host behaviour with the specific
purpose of increasing transmission to its definitive
cat host (‘manipulation hypothesis’). The infection
seems to make rodents lose their innate aversion
for cat urine, rather developing an attraction to it;
nonetheless, they preserve their aversion to odours
of other predators which are not Toxoplasma defini-
tive hosts (Vyas et al. 2007; Berenreiterová et al.
2011). Following an acute phase of tachyzoites
proliferation in various organs, bradyzoites are
formed in muscular and cerebral tissues during the
latent infection and may persist for as long as a
lifetime in neurons. This potentially affects neu-
ronal function and/or increases neuronal cell death
resulting in probable neurological impairments
(Henriquez et al. 2009; Prandovszky et al. 2011).
Previous studies have proposed the release of cyto-
kines as a possible mediator of cognitive and behav-
ioural changes associated with Toxoplasma infection
(Stock et al. 2014). There is also evidence that the
neurochemical changes induced by the parasite via
its genome coding aromatic amino acid hydroxylases
may account for most of the cognitive and behav-
ioural disturbances (Stock et al. 2014). The neurobe-
havioral effects of T. gondii are apparently dependent
on the gender of the secondary hosts for the parasitic
infection may have an increasing effect on testoster-
one (Flegr et al. 2012). Higher testosterone levels
* Corresponding author. The University of Iowa, College
of Public Health, S161 CPHB 105 River Street, Iowa City,
Iowa 52242, USA. E-mail: angelico-mendy@uiowa.edu
1
Parasitology, Page 1 of 7. ©Cambridge University Press 2015
doi:10.1017/S0031182015000505
have been found associated with greater cognitive
performance in males, while in females a negative
trend was seen (Thilers et al. 2006). Flegr also
observed that T. gondii infected males tend to be ex-
pedient and dogmatic, while infected women tend to
be warm-hearted, persistent and conscientious
(Flegr, 2007). Besides gender, other factors such as
vitamins have been reported to possibly influence
the severity of Toxoplasma infection by enhancing
defence against infections through regulation of
antimicrobial peptide gene expression (e.g. vitamins
A and D) and/or reduction of oxidative stress (e.g.
vitamins E and C) (McCarthy and Davis, 2003;
Rajapakse et al. 2005; Stephensen et al. 2006;
Campbell et al. 2012).
Despite these experimental findings, only a few
human studies have examined the relationship
between T. gondii and cognitive functions, including
older adults, young and middle-aged adults, or con-
genitally infected children (Alford et al. 1974;
Caiaffaet al. 1993; Kusbeci et al. 2011; Flegr et al.
2012; Guenter et al. 2012; Gajewski et al. 2013;
Mendy et al. 2014). No study has ever been done
in school-aged children with latent Toxoplasma
infection. Given the importance of cognitive skills
in school-age, we investigated the association
between T. gondii seropositivity and reading, math-
ematical aptitudes, visuospatial reasoning as well as
verbal memory in children aged 12–16 years. We
hypothesized that sex and serum vitamins may
influence the potential relationships of T. gondii
with cognitive skills and tested them for effect
modification.
MATERIALS AND METHODS
Data source and study design
We used data from the Third National Health and
Nutrition Examination Survey (NHANES III)
conducted from 1988 to 1994 by the National
Centre for Health Statistics (NCHS) of the
Centres for Disease Control and Prevention (CDC)
(CDC, 2006). The NHANES is an ongoing cross-
sectional survey of the US non-institutionalized
civilian population selected using a complex
multistage sampling design to derive a representa-
tive sample of the US population. T. gondii anti-
bodies were measured in participants 12 years and
older and among them, cognitive functions were
tested in those between the ages of 12–16. A total
of 1786 NHANES participants aged 12–16 years
who had data on Toxoplasma seropositivity under-
went cognitive testing. After exclusion of 12 children
with mental retardation reported by parents and 19
participants with missing data, the final sample
included 1755 subjects. NHANES III datasets are
publicly available at http://www.cdc.gov/nchs/nhanes/
nh3data.htm. NHANES protocols were approved by
the institutional review boards of the NCHS and
CDC and informed consent was obtained from all
participants.
T. gondii IgG antibodies
Serum T. gondii IgG antibodies were measured
using the Platelia Toxo-G immunoglobulin G
enzyme immunoassay (SanofiDiagnostics Pasteur,
BioRad, Hercules, California), according to the
manufacturer’s instructions. Before initiation of
the study, the Platelia Toxo-G kit was evaluated
by using a battery of 90 sera (23 negative and 67
positive) in comparison with various titers in
the Centres for Disease Control and Prevention
Toxoplasma immunofluorescence assay-immunoglo-
blin G test and dye test (Dr Jack Remington, Palo
Alto, California); both the specificity and sensitivity
were found to be 100% (Jones et al.2001). Results
were reported in International Units (IU) and, as
per the instructions of the manufacturer, samples
with titer of lower than 6 IU mL
−1
were considered
to be negative, while those with results of 6 IU mL
−1
and higher were considered positive, indicating
infection at some undetermined time.
Cognitive function measures
Cognitive function testing was performed in mobile
exam centres by trained examiners using the reading
and math parts of the Wide Range Achievement
Test-Revised (WRAT-R), as well as the block
design and digit span parts of the Wechsler
Intelligence Scale for Children-Revised (WISC-R).
The WISC-R test was administered first followed
by the WRAT-R. In the WRAT-R reading subset,
children were asked to read aloud each word from
a list of 75 words sequenced by order of increasing
difficulty, until 12 consecutive errors were made.
The reading test assessed the ability to recognize
and name letters, pronounce, spell and write words
(Jastak and Wilkinson, 1984). In the WRAT-R
arithmetic subtest, children were asked to solve as
many problems as possible from a total of 56 in 10
min. If at least six problems were not completed
within the allotted time, the child was asked to
count aloud the 15 dots on the form, read five
numbers, and solve three simple word problems.
The math test assessed the ability to count and
solve mathematical problems in limited amount of
time (Jastak and Wilkinson, 1984). The WISC-R
block design test required children to timely assem-
ble blocks of different colours according to given
patterns; it evaluates perceptional reasoning and ex-
ecutive functions (Wechsler, 1974). In the WISC-R
digit span test children were given sequences of
numbers at a rate of one per second and were asked
to repeat them forward and backward; this test
assessed verbal short-term memory (forward digit
2A. Mendy and others
span) and working memory (backward digit span)
(Wechsler, 1974). Scores were standardized by age
and the tests were administered in the children
primary language (English or Spanish). Raw scores
from all exams were scaled to allow comparisons
between the WISC-R and WRAT-R components.
Continuous scores were utilized, with higher scores
indicating superior performance.
Covariates and serum vitamins
Data on age, gender, race/ethnicity, family income,
level of education, visual and hearing impairments,
and main language spoken in family were collected
during the NHANES using questionnaires. Family
income to poverty ratio was calculated using guide-
lines and adjustment for family size, year and state.
The presence of serum antibody against Hepatitis
B and C, Herpes simplex virus 1 and 2, cytomegalo-
virus (CMV) as well as Helicobacter pylori was deter-
mined using immunodot assay (Hespesviruses) and
enzyme linked immunosorbent assay (ELISA)
(hepatitis, CMV, Helicobacter pylori).
Vitamin B-12 was measured using the Bio-Rad
Laboratories ‘Quantaphase Folate’radioassay kit
which combines serum or a whole blood hemolysate
sample with 125I-folate and 57Co-vitamin B12 in
dithiothreitol and cyanide. Serum vitamin C was mea-
sured using isocratic high performance liquid chroma-
tography with electrochemical detection at 650 mV.
Vitamins A, E, and carotenoids were measured by
isocratic high performance liquid chromatography
with detection at three different wavelengths. The
INCSTAR 25-OH-D assay consists of a two-step
procedure involving a rapid extraction of 25-OH-D
and assayed by equilibrium radioimmunoassay
procedure. Detailed descriptions of the laboratory
procedures are available at: http://www.cdc.gov/nchs/
data/nhanes/nhanes3/cdrom/nchs/manuals/labman.pdf.
Statistical analysis
Descriptive analyses were performed and P-values
for differences in proportions or means by
Toxoplasma seropositivity status were calculated
using chi-square test for categorical variables and
student’st-test for continuous variables. Normal
distribution of the data was tested using the
Kolmogorov–Smirnov test and, given their signifi-
cant skewness, serum vitamins were log-transformed
to improve the Gaussian distribution of the data.
Using linear regression modelling, the coefficients
(β) with corresponding 95% confidence intervals
(CI) were estimated for the association between
Toxoplasma seropositivity and cognitive test scores,
adjusting for age, gender, race/ethnicity, family
income to poverty ratio, years of education, visual
and hearing impairments, main family language
and other infections (Hepatitis B and C, Herpes
simplex virus 1 and 2, CMV, Helicobacter pylori).
Effect modification by gender and log-transformed
serum vitamins A, B 12, C, D and E as well as α
and βcarotenoids was tested by including a
product term in the models and for significant inter-
actions, effect sizes were reported for the associations
between Toxoplasma and the cognitive test scores for
each of the modifier categories. R squared was used
to examine model fitness. Where applicable, a
Bonferroni correction was applied to control for
Type I error given the number of statistical tests
(one for each of the four neuropsychological tests).
Analyses were performed in STATA (Version 11,
STATA Corporation, College Station, TX, USA).
NHANES sampling weights and STATA survey
commands were used in all statistical procedures to
adjust for unequal selection probabilities, non-
responses, over-sampling, post-stratification and
sampling errors, so that estimates were nationally
representative. P-values <0·05 were considered stat-
istically significant.
RESULTS
The study sample consisted of 1755 participants
with a mean age (±standard error (S.E.)) of 13·97
(±0·06) years (range 12–16). In the analysis weighted
for complex survey design, survey non-response
and post stratification, 51·8% of our population con-
sisted of boys and 66·8% were non-Hispanic Whites.
The prevalence of T. gondii seropositivity was 7·7%
(8·5% in boys and 6·9% in girls). The proportion of
children from families whose main language was
not English was significantly higher in the infected
than in the non-infected group. The family income
to poverty ratio was lower in children infected with
Toxoplasma and other infections were more frequent
in this group (Table 1). The concentration of vita-
mins in serum was not different in seropositive and
seronegative children. Overall and especially in
girls, reading, visuospatial reasoning and memory
scores were lower in children with T. gondii infec-
tion. In boys, no significant difference in scores
was seen between Toxoplasma infected and non-
infected groups (Table 1).
In adjusted linear regression, T. gondii seroposi-
tivity was negatively associated with reading skills
(β=−5·86, 95% CI: −11·11, −0·61, P= 0·029) and
memory scores (β=−0·86, 95% CI: −1·58, −0·15,
P= 0·017), but not with math or visuospatial rea-
soning. The interaction between Toxoplasma and
log-transformed serum vitamin E significantly cor-
related with math (P= 0·04) and memory test
scores (P= 0·03). In stratified analysis, T. gondii-
associated memory impairment was significantly
worse in participants with log-transformed
serum vitamin E concentration below the median
(β=−1·61, 95% CI: −2·44, −0·77, P< 0·001)
than in those with values at or above the median
3Toxoplasma and cognition
Table 1. Characteristics of study participants by Toxoplasma gondii (T. gondii) infection status, NHANES III (N = 1755)
Characteristics
Boys (N= 818) Girls (N= 937) All (N= 1755)
T. gondii −T. gondii + Total P T. gondii −T. gondii + Total P T. gondii −T. gondii + Total P
Age, mean (S.E.), years 13·91
(0·09)
13·94
(0·25)
13·91
(0·09)
0·90 14·01
(0·08)
14·40
(0·20)
14·04
(0·07)
0·07 13·96
(0·06)
14·15
(0·17)
13·97
(0·06)
0·29
Race/ethnicity, %
Non-hispanic whites 69·0 65·5 68·7 <0·001 65·0 59·9 64·6 <0·001 67·1 63·0 66·8 <0·001
Non-hispanic blacks 13·6 15·6 13·6 15·3 17·7 15·5 14·4 15·4 14·5
Hispanics 8·1 6·6 7·9 9·0 5·5 8·7 8·5 6·1 8·3
Other 9·3 14·2 9·7 10·7 16·9 11·2 10·0 15·5 10·4
Education, mean (S.E.), years 7·43
(0·10)
7·54
(0·27)
7·44
(0·09)
0·69 7·71
(0·09)
7·88
(0·23)
7·72
(0·08)
0·49 7·56
(0·07)
7·69
(0·18)
7·57
(0·06)
0·50
Had trouble seeing, % 11·6 7·2 11·3 0·41 12·4 23·4 13·2 0·15 12·0 14·5 12·2 0·58
Had hearing trouble, % 6·2 4·4 6·0 0·69 5·9 0·4 5·5 0·01 6·0 2·6 5·8 0·28
Family language not English, % 5·7 9·3 6·0 0·11 6·0 20·7 7·2 0·02 5·8 14·5 6·5 0·01
Other infections, % 55·6 71·7 57·0 0·05 61·4 75·8 62·4 0·17 58·4 73·5 59·6 0·02
Income to poverty ratio, mean (S.E.) 2·30
(0·09)
1·84
(0·19)
2·26
(0·09)
0·04 2·31
(0·08)
1·68
(0·35)
2·26
(0·08)
0·15 2·30
(0·06)
1·77
(0·19)
2·26
(1·0·06)
0·02
Serum vitamins
Vitamin B12, mean (S.E.), pg/ml 505·40
(14·30)
496·37
(40·59)
504·86
(13·94)
0·80 522·22
(18·49)
489·49
(87·49)
520·82
(18·38)
0·63 513·66
(11·46)
492·18
(50·34)
511·86
(11·21)
0·61
Vitamin C, mean (S.E.), mg dl
−1
0·80
(0·04)
0·87
(0·11)
0·81
(0·04)
0·37 0·84
(0·04)
1·00
(0·14)
0·85
(0·04)
0·19 0·82
(0·03)
0·93
(0·11)
0·83
(0·03)
0·13
Vitamin A, mean (S.E.), μgdl
−1
45·27
(0·88)
45·22
(2·72)
45·26
(0·85)
0·96 43·18
(0·76)
41·56
(0·92)
43·06
(0·71)
0·16 44·26
(0·60)
43·51
(1·54)
44·20
(0·57)
0·67
Vitamin E, mean (S.E.), μgdl
−1
715·83
(12·71)
697·65
(26·01)
714·35
(12·06)
0·45 749·55
(16·98)
750·75
(32·20)
749·64
(15·84)
0·95 731·75
(10·55)
721·40
(23·63)
730·94
(9·96)
0·55
α-carotene, mean (S.E.), μgdl
−1
2·45
(0·50)
2·77
(0·57)
2·48
(0·47)
0·38 2·64
(0·26)
3·72
(1·37)
2·71
(0·29)
0·14 2·54
(0·30)
3·18
(0·95)
2·59
(0·29)
0·11
β-carotene, mean (S.E.), μgdl
−1
12·37
(1·04)
12·71
(1·36)
12·40
(0·99)
0·68 12·76
(0·86)
13·71
(3·12)
12·83
(0·85)
0·60 12·55
(0·69)
13·16
(2·09)
12·60
(0·66)
0·52
Vitamin D, mean (S.E.), mg dl
−1
32·97
(1·07)
33·01
(5·54)
32·98
(1·07)
0·89 27·89
(0·92)
26·82
(1·73)
27·81
(0·85)
0·37 30·44
(0·74)
30·03
(3·14)
30·41
(0·72)
0·67
Cognitive test scores
Standardized math score 92·97
(1·19)
92·27
(2·83)
92·91
(1·11)
0·82 93·55
(0·96)
85·01
(3·25)
92·93
(0·93)
0·01 93·25
(0·77)
89·09
(2·19)
92·92
(0·73)
0·07
Standardized reading score 94·49
(1·00)
87·60
(3·97)
93·91
(0·99)
0·09 93·87
(0·89)
82·56
(4·14)
93·05
(0·88)
0·008 94·19
(0·67)
85·39
(2·84)
93·50
(0·67)
0·003
Block design scaled score 9·58
(0·18)
9·28
(0·46)
9·56
(0·17)
0·54 9·05
(0·17)
7·62
(0·50)
8·94
(0·16)
0·007 9·32
(0·12)
8·55
(0·34)
9·26
(0·12)
0·03
Digit span scaled score 8·47
(0·17)
7·66
(0·47)
8·40
(0·17)
0·10 8·84
(0·15)
7·27
(0·61)
8·72
(0·15)
0·01 8·64
(0·12)
7·49
(0·37)
8·56
(0·11)
0·003
NHANES, National Health and Nutrition Examination Survey; S.E., standard error.
Geometric mean reported for serum vitamins and provitamins and calculated from the log-transformed estimates.
Other infections include hepatitis B and C, herpes simplex virus 1 and 2 seropositivity, helicobacter pylori seropositivity, CMV.
P-values indicate statistical significance of characteristics by T. gondii antibody seropositivity.
4A. Mendy and others
(β=−0·12, 95% CI: −1·23, 0·99, P= 0·03). There
was no relationship between Toxoplasma and
math score in general or in subgroup analysis
by serum vitamin E levels (Table 2). R-squared
for the different models ranged between 0·20
and 0·30.
DISCUSSION
In the present study, we used a representative
sample of the US population to examine the rela-
tionship between Toxoplasma seropositivity and
cognitive functions in children aged 12–16. The
results suggest that T. gondii seropositivity is
associated with poor reading performance and
impaired verbal memory. Serum vitamin E seems
to modify the relationship between the parasite and
verbal memory with greater Toxoplasma-associated
memory impairment found in participants with
lower vitamin E level.
To our knowledge, no previous study has ever
investigated latent Toxoplasma infection and cogni-
tive function in school-aged children. However,
findings of Toxoplasma-associated cognitive impair-
ment have been reported in congenitally infected
children and older adults. An association of congeni-
tal toxoplasmosis with reduced intellectual quotient
measured by the Slosson Intelligence Test in tod-
dlers has been described and mental retardation
has been linked to congenital toxoplasmosis in
school-aged children (Alford et al. 1974; Caiaffa
et al. 1993). In older ages, the infection has recently
been postulated to possibly weaken episodic and
working memory functions (Gajewski et al. 2013;
Mendy et al. 2014). Among adults, Guenter et al.
found no relationship between latent toxoplasmosis
and psychomotor speed and working memory, cog-
nitive flexibility, or audio verbal and visuospatial
working memory (Guenter et al. 2012). A secondary
analysis of the data from this study stratified by
gender was performed by Flegr et al. who noted
that latent toxoplasmosis was significantly associated
with worse verbal fluency in women. It found better
working memory and cognitive flexibility in men
with latent toxoplasmosis compared with non-
infected ones (Flegr et al. 2012). These results
were inconsistent with our results showing that
gender did not modify the association between the
parasite and cognitive deficiency. After extensive lit-
erature review, we found no research on the potential
effects of vitamins on Toxoplasma-associated cogni-
tive impairment; however, a few reports have inves-
tigated how vitamins may modify toxoplasmosis
severity, producing contradictory results. In con-
trast with our findings of improved cognitive func-
tions associated with vitamin E, McCarthy and
Davis noted that vitamin E was detrimental to
T. gondii infected mice by increasing tissue cyst
concentrations, histologic damage and severe
Table 2. Linear regression coefficients (β) for the associations of T. gondii seropositivity and interaction between Toxoplasma and gender and vitamins with cognitive
functions in children 12–16 years of age, NHANES III (N = 1755)
T. gondii
Math score Reading score Block design score Digit span score
β(95% CI) Pβ(95% CI) Pβ(95% CI) Pβ(95% CI) P
All participants −0·99 (−5·39, 3·41) 0·66 −5·86 (−11·11, −0·61)* 0·029 −0·41 (−1·18, 0·36) 0·30 −0·86 (−1·58, −0·15)* 0·017
Interaction Toxoplasma*log-vitamin E 18·00 (0·60, 35·40)* 0·04 5·82 (−18·54, 30·17) 0·64 1·56 (−1·97, 5·08) 0·39 3·40 (0·24, 6·56)* 0·03
Participants with serum vitamin E < median −3·87 (−9·97, 2·23) 0·21 −8·92 (−16·65, −1·19)* 0·024 −1·10 (−1·99, −0·21)* 0·016 −1·61 (−2·44, −0·77)**
a
<0·001
Participants with serum vitamin E ≥median 2·60 (−3,28, 8·47) 0·39 −1·96 (−8·09, 4·17) 0·53 0·26 (−1·01, 1·53) 0·69 −0·12 (−1·23, 0·99) 0·83
NHANES, National Health and Nutrition Examination Survey.
*P< 0·05; **P<0·001.
a
Remains significant after Bonferroni correction (critical alpha < .05/4 = 0·0125).
Linear regression models adjusted for age, gender, race/ethnicity, income to poverty ratio, education level, visual and hearing impairment, main language in family other than English,
and other infections. Significant estimates (P-value < 0.05) presented in bold and underlined.
5Toxoplasma and cognition
meningo-encephalitis (McCarthy and Davis, 2003).
Other vitamins such as vitamin D have been
observed to reduce the survival rate of Toxoplasma
infected mice (Rajapakse et al. 2005), while in a
more recent study, vitamin D inhibited intracellular
T. gondii parasite proliferation in vivo and in vitro
(Rajapakse et al. 2007).
The mechanism by which T. gondii may affect
reading abilities and verbal memory in children
could be due to a modifying effect of neurotransmitter
signal transduction by the parasite (Prandovszky
et al. 2011). In neural cells, Toxoplasma has been
suggested to alter the concentration and metabolism
of dopamine, a critical modulator of neuronal
activities in the frontal cortex and the hippocampus
both involved in learning and working memory
(McConkey et al. 2013). T. gondii infection also initi-
ates a Th1 immune response with production of
interferon-γwhich could mediate cognitive impair-
ment by increased neuronal death (Bate et al. 2006;
McConkey et al. 2013). Furthermore, dopamine
influences attentional processes in children leading
to hyperactivity, inattention, and impulsive be-
haviour all resulting in cognitive deficit as a con-
sequence of ‘acting before thinking’(Nieoullon,
2002). Inattentive behaviour is known to be strongly
associated with impairment of reading which is a cog-
nitively complex process involving multiple skills,
such as phoneme awareness, phonological decoding,
orthographic coding and rapid automatized naming
(Luca et al. 2007;Cornishet al. 2011). Previous
studies have noted sex differences in the relationship
between the infection and cognitive functions. Flegr
et al. speculated that the increasing effect of the para-
sitic infection on testosterone among infected males
couldshiftpersonalityprofiles, increasing motivation
in boys and thus performance in several cognitive
tests (Flegr et al. 2012). It has been proposed that
an increase in testosterone level may have sex
specificeffects on cognition, as it could be associated
with better visuospatial abilities, semantic and epi-
sodic memory in males but worst verbal fluency, se-
mantic and episodic memory in females (Thilers
et al. 2006). Gatkowska et al noted that toxoplasmosis
induced a decreased noradrenergic activity in female
mice, but increased activity in some brain areas of
male mice (Gatkowska et al. 2013). Like dopamine,
noradrenaline is a key neuromodulator involved in
many cognitive functions including arousal, atten-
tion, cognitive flexibility, working and emotional
memory (Chamberlain and Robbins, 2013). More-
over, Xiao et al.examinedtheeffects of persistent
T. gondii infection on gene expression in the frontal
cortex of male and female mice. They realized that
in females, the parasite altered the expression of
genes involved in the forebrain development, neuro-
genesis, and sensory and motor coordination, while
in males, it mostly modulated genes associated with
olfaction (Xiao et al. 2012).
Intriguingly, we found no association of
Toxoplasma infection with arithmetic abilities or
visuospatial reasoning and the reason why is
unclear to us. But, there seemed to be a trend
toward a negative relationship for both of these
tests with the parasitic infection. Research with
regards to the effects of vitamins on Toxoplasma-
related decline in cognition is lacking. In general,
vitamin E, which forms the first line of defence
against lipid peroxidation protects cell components
from oxidation by reactive free radicals; it may
have a stimulatory effect on the immune system by
impacting cytokine production (McCarthy and
Davis, 2003). The effect of antioxidants on severity
of Toxoplasma infection is controversial, despite evi-
dence that oxidative stress induced by the parasite
may be a major factor for virulence and deteriorating
cognition (McCarthy and Davis, 2003). Concordant
with a beneficial effect of antioxidants on T. gondii in-
fection, quercetin, a flavanol with antioxidant proper-
ties was found to suppress bradyzoites formation in a
cell culture model, maybe by inhibiting heat shock
protein synthesis (Weiss et al. 1998).
Our study had limitations. Given the cross-sectional
study design, temporality between T. gondii infection
and cognitive functions impairment cannot be assessed
and causal inferences cannot be drawn. Some of our
covariates such as visual and hearing impairments
were self-reported and may have been subject to
misclassification. Nevertheless, this study has major
strengths. The large size representative sample of the
US population makes findings generalizable and the
broad range of covariates adjusted for increases
the power of statistical inferences.
In conclusion, T. gondii may be associated with
impaired reading ability and verbal memory in
school-aged children between 12 and 16 years old
as a result of cumulative effects of a latent infection.
Vitamin E seems to modify the relationship. Future
longitudinal studies are needed to confirm these
findings and research could include trials to
confirm a possible efficacy of vitamin E supplemen-
tation in improving cognitive impairment hypothet-
ically associated with the infection.
CONFLICT OF INTEREST
The authors have no conflict of interest to declare.
FINANCIAL SUPPORT
This research received no specific grant from any
funding agency, commercial or not-for-profit sectors.
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7Toxoplasma and cognition
