RR:C19 Evidence Scale rating by reviewer:
Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.
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Review: The study analyzed associations between toxoplasmosis and cytomegalovirus on the one hand and intelligence, memory functions and action control on the other hand in young healthy adults. The results show a stronger association between toxoplasmosis and intelligence predominantly in males with positive rhesus factor. Cytomegalovirus shows a negative association with memory and processing speed in women. Furthermore, it was hypothesized that the strength of the correlations between antibody concentrations and cognitive changes provides information about the duration of the infection.
General evaluation:
This is an interesting and novel study that examines two types of infections toxoplasmosis and cytomegalovirus, considering potential confounders such as age, sex, and rhesus factor on the cognitive abilities of young adults. The manuscript is quite complex and sometimes not straightforward. While several studies have been published in recent years reporting an association between T. gondii seropositivity and cognitive function, CMV status and its relationship to cognition has rarely been studied. I will go through the manuscript and shortly comment each section. The introduction is short and concise. However, the theoretical background was not fully presented as some relevant literature on toxoplasmosis and cognitive function across the lifespan was not mentioned.
The method section sounds well, and the procedures, cognitive tests, and statistical analysis seem valid. The only methodological shortcoming is the relatively long period between the blood samples and the cognitive tests (2-24 months). There are also some minor points that could be improved in the method description, for example some sociodemographic parameters or the age range. Another interesting point that could be outlined in more detail in the method section is the relationship between the IgG concentration as proxy of the duration of latent infection. It would also be interesting to know how long this association persists (months, years, decades).
The results section includes the prevalence of infection for each subgroup and shows the effects of gender, age and toxoplasmosis on cognition, whereas this relationship was less consistent for CMV. Unfortunately, the mean concentrations of IgG antibodies were not reported. Yet, is also important to recognize that significant results were reported with and without correction for multiple testing. In the next step both types of infection were related to different cognitive domains after controlling for age and sex. This analysis revealed that toxoplasmosis has a negative impact on different aspects of intelligence, memory, and even a positive effect on action control task exclusively in men, even after correction for multiple testing, while CMV was only marginally associated with memory decline in women. Furthermore, in section 3.4 it was hypothesized, that IgG antibody level is a proxy for the time elapsed since infection and that high concentrations indicate early stage of the disease. The negative relationship in infected men and intelligence, memory as well as faster reaction times as a function of IgG was interpreted in terms of changes of these functions in the course of infection. However, the time point of infection is unknown, and second Table 3 provided no significant dose-effect association between IgG concentration and cognitive performance (unless in the pre-pulse test in women). Therefore, in my view this interpretation is rather speculative, and the hypothesis can be only evaluated in a longitudinal study design with a known time point of acute infection. Information about the IgG concentration in each group would be helpful to assess the severity of infection in the groups. Additionally, scatter plots indicating the IgG concentrations in relation to the most relevant cognitive parameters would help to visualize relationships and to detect potential outliers. Section 3.5 focuses on the mechanisms of superior action control in infected individuals basing on previous findings. The present study confirms superior inhibitory control in the group with toxoplasmosis and proposed the hypothesis that slower reaction times could be a cause for reduced error rates in infected subjects using structural equation modeling. However, this may be a result of a speed-accuracy tradeoff that can be simply tested by a correlational analysis: negative correlation would indicate speed-accuracy tradeoff. In the last part the role of rhesus factor in toxoplasmosis and CMV infected men and women on the different cognitive tests was analyzed. According to Table 4, the previously found effects of toxoplasmosis on cognition in men were confirmed in Rh positive men only, whereas CMV infection affected mostly Rh-negative men and women.
The data were discussed appropriately. However, the non-significant, albeit negative, relationship between Toxoplasma IgG and intelligence was interpreted that intelligence was lowest shortly after infection due to high antibody concentration. This point already mentioned above needs more attention. Please explain this assumption in more detail, as the actual time of infection was not known. Why can the reduction in intelligence not be due to cumulative effects of toxoplasmosis, such as reaction times, if the infection occurred in childhood? Please explain the reasoning and the conditions for diminishing and cumulative effects. Are negative associations between concentrations indication for cumulative effects?
There are some limitations of the study that have not been considered. It seems to be a sex-related differences in some dimensions of the IST-2000R. Please comment accordingly. Although IST 2000R is a comprehensive test to assess IQ it provides limited measures of specific cognitive functions that classic neuropsychological tests do. For example, functions such as working memory, selective attention or some executive functions cannot be reliably measured. Computer-based tasks with several trials provides even more reliable measures. Additionally, age was included in the analysis although only young adults (students) participated in the study and the age range was relatively narrow. Finally, some ideas to explain the effects of toxoplasmosis and CMV on brain, behavior and cognition would be helpful.
Minor:
Correct nonreactions of action control account presumably means the ratio of correct No/Go trials. The most common measures in such paradigm are false alarms, (i.e. non-successful inhibited responses (1 – p(No/Go)).
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