) is an apicomplexan parasite that infects approximately 12% of the U.S. population as of 2010 [1
]. Although the parasite’s definitive host is any member of the cat family, humans can become infected with T. gondii
as an intermediate host via ingestion of contaminated foods or by exposure to cat feces [2
]. Upon successful invasion, T. gondii
infects muscle and neural tissue and encapsulates itself in a cyst that protects it against the host immune system [3
]. T. gondii
biology has unique features that set it apart from other intracellular parasites. For example, using precursors from the infected cell, T. gondii
can synthesize dopamine [4
], although the physiological effects of this dopamine production remain unknown.
Beyond dopamine production, T. gondii
may influence other aspects of host biology. In regards to folate synthesis, T. gondii
may salvage or harvest folate directly from the infected host cell [6
]. It is unknown, however, whether this might affect host health. Further, it is unclear whether T. gondii
depends on the folate acquired from the host or if the system is only supplementary.
In humans, folate is essential for DNA synthesis and repair and is a key factor in cell division and growth [7
]. The brain requires a constant supply of dietary folate for early embryonic neurodevelopment, adult neurogenesis, and the production of neurotransmitters [8
]. Therefore, reduced availability of folate is associated with neurodevelopmental disorders [10
] and may be associated with reduced cognitive function [11
In individuals who do not obtain sufficient dietary folate or who cannot metabolize folate efficiently, neural cells might be generally and persistently deprived of this essential nutrient [15
]. If T. gondii
is indeed capable of harvesting folate from host neural cells, then infected cells may be further starved of this important nutrient and thereby magnify potential impairments in cognitive functioning. Based on these factors, we hypothesized that cognitive function may be associated with an interaction between T. gondii
infection and concentrations of folate and other factors related to folate metabolism such as vitamin B-12 and homocysteine. To test this, we used the National Health and Nutrition Examination Survey III (NHANES III) dataset from the United States’ Centers for Disease Control and Prevention (CDC).
Of the 2037 subjects included in this study, approximately 20% were seropositive for T. gondii
, 50% were female, and approximately 75% were non-Hispanic white. Table 1
presents these and other demographic and study-sample characteristics.
We found no significant interactions between T. gondii
seropositivity and any of the folate-cycle factors in predicting performance on the SDS. In predicting performance on the SDL, T. gondii
seropositivity interacted with folate (β = −1.02, (95% CI: −1.88, –0.16), p
= 0.021; Table 2
), vitamin B-12 (β = −1.60, (95% CI: −2.98, −0.23), p
= 0.023; Table 3
), and homocysteine concentrations (β = 2.40, (95% CI: 0.94, 3.85), p
= 0.002; Table 4
) (Figure 2
). In subjects seronegative for T. gondii
, SDL performance was relatively constant as folate, vitamin B-12 or homocysteine levels varied. However, in subjects seropositive for T. gondii
, performance on the SDL worsened as folate and vitamin B-12 levels decreased and as homocysteine levels increased (Figure 2
). An interaction between T. gondii
seropositivity and folate concentration predicted RT (β = 14.88, (95% CI: 5.99, 23.76), p
= 0.001; Table 2
). In contrast to the SDL, subjects seropositive for T. gondii
performed better on the RT assessment as folate concentration decreased.
4. Discussion and Conclusions
Using a large, nationally representative sample of U.S. adults, this study provides evidence of an interaction between T. gondii
seropositivity and concentrations of several folate-cycle factors in the prediction of general cognitive functioning. In this sample of over 2000 participants, approximately 20% were seropositive for IgG antibodies specific for T. gondii
. While this prevalence of seropositivity is higher than more recent estimates [1
], it is within the expected range for the years in which the NHANES III was conducted (1988–1994) [25
In this study, interactions between T. gondii
seropositivity and folate, vitamin B-12, and homocysteine concentrations particularly affected performance on the SDL, an assessment of ability in learning and recall [23
] that requires attention and intact short-term memory to perform well on the task. Concentrations of folate-cycle factors (including folate, vitamin B-12, and homocysteine) have been found to be associated with memory loss and other cognitive impairments in neurological disorders such as dementia [12
], although these studies did not take into account T. gondii
seropositivity. Further, deficiency in dietary folate has been linked to reduced genesis of neuroprogenitor cells of the adult hippocampus [8
], a brain region that influences both short-term memory and attention [28
]. Low concentrations of folate and/or vitamin B-12 usually result in an elevation of homocysteine, which can damage neural cells and impair cognitive functioning. Indeed, elevated homocysteine also might increase risk for neurodegenerative disorders in the hippocampus and prefrontal cortex [12
]. Therefore, reductions in cellular folate concentrations, such as in the case of folate harvesting by T. gondii
, could limit the bioavailability of this important nutrient and cause elevations in homocysteine in multiple brain regions including the prefrontal cortex or hippocampus [31
] and thus disrupt learning, attention, or other related cognitive functions. Further, this effect may be magnified in individuals who do not regularly obtain sufficient amounts of dietary folate or who cannot metabolize folate efficiently.
Another potential mechanism by which reduced folate availability might impact cognitive functioning lies in the indirect role of folate metabolism in the generation of serotonin and dopamine. Purines synthesized during folate metabolism contribute to the biosynthesis of guanosine triphosphate (GTP), a precursor of tetrahydrobiopterin (BH4
). Tyrosine hydroxylase and tryptophan hydroxylase each utilize BH4
as a co-factor in the production of dopamine and serotonin, respectively. Therefore, reduced availability of dietary folate may indirectly lead to an overall decrease of dopamine and serotonin production [9
]. In the case of T. gondii
seropositivity, the combined effects of low concentrations of folate and simultaneous folate harvesting from T. gondii
might particularly affect infected neural cells. Since dopamine and serotonin both influence various cognitive functions such as memory, attention, and executive function [34
], this link could potentially offer an alternate explanation of the effects observed in this study.
Beyond performance on the SDL, there was a significant interaction between T. gondii
and folate concentration in the prediction of RT. However, the direction of the observed relationship suggested that T. gondii
seropositivity might actually be favorable in regards to RT in cases of low folate concentration and detrimental in cases of high folate concentration. Though not statistically significant, we found a similar relationship in a previous study [37
] exploring interactions between the bacterium Helicobacter pylori
and folate concentration in the prediction of RT. Similar to T. gondii
, Helicobacter pylori
might also reduce folate availability [38
], though by a different mechanism. Despite these differing mechanisms of folate reduction, in both cases, RT improved, suggesting that folate deficiency associated with T. gondii
might enable some advantage in RT. We are unaware of a mechanism that might explain how reductions in folate availability by infectious diseases such as T. gondii
or Helicobacter pylori
could be favorable towards RT performance. The data available in the NHANES III do not allow for an in-depth exploration of this association. Future research into this finding would likely require animal models or neuroimaging combined with biochemical testing to determine how regions of the brain active during RT tasks might be affected by reductions in folate availability.
Some limitations require consideration when interpreting the results of this study. The NHANES data sets are cross-sectional in design and thus preclude the ability to make casual inferences. Further, as the degree to which T. gondii
harvests folate from infected host cells is not clear, it is currently unknown whether T. gondii
harvests enough to affect cognitive functioning. With these data, it is also impossible to determine the time of initial infection by T. gondii
or the frequency with which individuals have encountered the parasite in their lifetime. It is possible that the effects of T. gondii
on folate availability and on cognition could vary based on the length of infection with the parasite or based on the number of exposures to the parasite. Finally, folate and vitamin B-12 availability can vary for a multitude of reasons including genetic mutations in key folate-cycle enzymes [7
]. Although the NHANES III does include genetic data, access to the data is restricted and requires funding to obtain it. Therefore, additional research is needed to identify other factors that might modify the effects observed in this study.
This study is strengthened by using multiple controls that limit the number of potential confounds that might explain the observed effects. Specifically, by controlling for demographic and other health factors, we were more confident that the interactions between T. gondii and concentrations of folate, vitamin B-12, or homocysteine were associated with the variation in SDL or RT scores. Finally, use of the NHANES III data sets resulted in a large sample size that increases the generalizability of the findings and study power.
This study consisting of 2037 U.S. adults presents evidence of an interaction effect between T. gondii seropositivity and concentrations of multiple folate-cycle factors on cognitive functioning in adult humans. Additional research is recommended to explore the specific mechanisms involved in this association and to determine any additional potential consequences to folate and/or vitamin B-12 availability following T. gondii infection.