Toxoplasma gondii IgG Serointensity and Cognitive Function in Bipolar Disorder

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Postolache, Nina Dalkner, Tatjana Stross, and 17 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4556766/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Aug, 2024 Read the published version in International Journal of Bipolar Disorders → Version 1 posted 9 You are reading this latest preprint version Abstract Background Alongside affective episodes, cognitive dysfunction is a core symptom of bipolar disorder. The intracellular parasite Toxoplasma gondii has been positively associated with both a diagnosis of bipolar disorder as well as poorer cognitive performance, across diagnostic boundaries. Methods A total of 76 participants with bipolar disorder were tested for Toxoplasma gondii -specific IgG and IgM antibodies and for cognitive performance with a neuropsychological test battery. Cognitive parameters were categorized into three cognitive domains (attention and processing speed, verbal memory, executive function). Statistical analysis of associations between continuous indicators of cognitive status as dependent variables in relationship to Toxoplasma gondii , included multivariate analyses of co-variance for seropositivity, and partial correlations with IgG serointensity in IgG seropositives. All analyses were controlled for age and premorbid IQ. Results In seropositives ( n = 27), individual parameters in the verbal memory domain showed significant inverse partial correlations with IgG antibody levels. Cognitive functioning did not differ between IgG seropositive and seronegative individuals in any of the cognitive domains ( n = 76). IgM positives ( n = 7) were too few to be analyzed. Conclusions This investigation is the first to show an association between Toxoplasma gondii IgG serointensity and memory function in a well-diagnosed bipolar disorder sample. While further research is necessary, latent Toxoplasma gondii infections could represent a risk factor for functional decline for patients with bipolar disorder and Toxoplasma gondii serointensity in seropositives may emerge as a biomarker for personalized treatment. bipolar disorder toxoplasmosis Toxoplasma gondii cognition Background Bipolar Disorder (BD) is a chronic psychiatric disorder causing recurring periods of depression and mania. BD has a lifetime prevalence of 1.02% ( 1 ) and causes an average of 12.89 years of potential life lost in affected patients ( 2 ). Beside pathological mood swings, a core symptom of BD is cognitive dysfunction that even persists during euthymia ( 3 , 4 ). Studies have shown that cognitive deficits predict decrements in psychosocial and occupational functioning ( 5 ), and reduced quality of life ( 6 ). Toxoplasma gondii (T. gondii) is a protozoan intracellular parasite with a worldwide distribution ( 7 ) that infects up to a third of the world’s population ( 8 ). While it infects all warm-blooded animals, the parasite can only sexually reproduce in cats. The parasite infection can be divided into three distinct stages: sporozoites - within sporulated oocysts, tachyzoites that rapidly invade and multiply, and bradyzoites that replicate slowly within tissue cysts. In approximately half of the cases of toxoplasmosis, humans become infected through a foodborne route consisting of ingestion of T. gondii oocysts shed in the feces of infected cats and contaminating food during food preparation, or tissue cysts from the meat of infected animals. Within the medical community, T. gondii is especially important in obstetrics, since vertical acute infections from the pregnant woman to the fetus can have long-term devastating effects in the offspring, resulting in chorioretinitis, intracranial calcifications, autism, and intellectual disability ( 9 ). Otherwise, T. gondii infection acquired postnatally is usually asymptomatic (“latent toxoplasmosis”) in immunocompetent individuals and rarely needs treatment. In only about 10%, it causes time-limited mild non-specific symptoms like isolated lymphadenopathy or fever. More severe manifestations are very infrequent in otherwise healthy individuals ( 8 ). Nevertheless, once an organism is infected with T. gondii , the clearance of the microorganism is virtually impossible. After the acute phase- the microorganisms (tachyzoites) travel via blood immune cells and infect several organs, in particular the brain and the skeletal muscle, where, under immune pressure, they transform into slow growing phenotypes- the bradyzoite, and intracellular cysts. Most adult infections therefore are chronic, with only minimal reactivations of the pathogen ( 10 ). Diagnosis of infection is commonly made with serological methods detecting T. gondii -specific antibodies. Acute infection is accompanied by elevated IgM, which can be detected as soon as one week after infection. It peaks after 1–3 months and usually disappears over the following months; yet, in some patients IgM can also be observed for many years after the acute infection ( 11 , 12 ). Subsequently, IgG appears around two weeks after infection and persists for life in immunocompetent hosts ( 13 ). Despite T. gondii being considered harmless in immunocompetent individuals for a long time, recent investigations highlight that the parasite might also be linked to a wide array of neuropsychiatric disorders ( 14 – 16 ). There is evidence of associations between the parasite and epilepsy ( 17 ), schizophrenia ( 18 ), as well as suicidal behavior, across diagnostic categories ( 19 – 22 ). Furthermore possible links to obsessive-compulsive disorder ( 16 ) and Alzheimer’s disease ( 23 , 24 ) have been reported. In contrast, studies examining associations with depression have shown heterogeneous and predominantly negative results ( 25 , 26 ). The association between T. gondii and BD has been reviewed by several meta-analyses identifying significant relationships in all ages ( 16 , 27 ), as well as in a subpopulation under 40 years of age ( 28 ). A recent publication with 12,690 participants (4,021 with BD and 8,669 controls) supported these findings and reported that persons with BD had significantly greater odds of seropositivity for T. gondii than controls ( 29 ). Although cognitive function is an important parameter of outcome in BD, to our knowledge only two studies have examined a link between T. gondii and cognitive performance, but with inconsistent results. Dickerson et al. ( n = 347) found significant associations between T. gondii IgM, but not IgG serointensity, and certain cognitive parameters (overall cognitive function, delayed memory and visuospatial/constructional), but not for immediate memory, language, or attention. Moreover, IgG serointensity and cognition scores showed no association in their study ( 30 ). Tanaka et al. ( n = 32) found no association between any antibody levels and overall neurocognitive function ( 31 ). Interestingly, in healthy individuals, a meta-analysis by de Haan et al. with 13,289 participants reported an association between T. gondii seropositivity and mild cognitive impairment. In this analysis, individuals with latent T. gondii infections had inferior performance in four cognitive domains: processing speed, working memory, short-term verbal memory, and executive function, relative to seronegative individuals ( 32 ). In summary, prior studies reported inconsistent results on associations between latent T. gondii infections and cognitive dysfunction in BD, while others were able to identify associations of T. gondii seropositivity with distinct cognitive domains. Therefore, the current investigation aimed to investigate the association between T. gondii seropositivity, serointensity, and cognitive domains in a well-diagnosed BD population. We hypothesized that in euthymic bipolar patients, the T. gondii -seropositive individuals would manifest more severe cognitive impairments relative to their seronegative individuals. In addition, we assumed that there would be negative associations between serointensity and measures of cognitive performance in T. gondii seropositives. Methods Sample Description and Inclusion Criteria We measured T. gondii -specific antibodies in a total of 126 individuals with BD as part of the ongoing “BIPLONG” study project at a dedicated BD outpatient clinic at the Medical University of Graz, Department of Psychiatry and Psychotherapeutic Medicine. BIPLONG aims to assess psychiatric symptoms and history in association with metabolic, lifestyle, genetic, biological, brain imaging, and cognitive parameters in individuals with BD in a longitudinal design. After baseline measurement, there are follow-up measurements every six months. In the current investigation, we used data from the baseline measurement. For more details about the BIPLONG project please see earlier publications by our study group ( 33 – 35 ). Participants were diagnosed with BD according to the Structured Clinical Interview for DSM IV (SCID-I) by a trained psychiatrist or psychologist with the German Version ( 36 ). Furthermore, participants had to be euthymic at the time of testing and had to have a complete cognition data set. Euthymia was determined by a score of ≤ 12 on the Hamilton Depression Rating Scale (HAMD) ( 37 ) and a score of ≤ 8 on the Young Mania Rating Scale (YMRS) ( 38 ). Exclusion criteria were a premorbid IQ of < 80 tested with the multiple choice vocabulary test (MWT-B) ( 39 ) and an age of ≥ 70 years. Out of the 126 individuals considered, 38 participants did not meet the criteria for euthymia; three were over 70 years of age, and nine participants had to be excluded because of missing cognition data. In total, we were able to include 76 participants in this investigation. Additionally, for computing correlations between serointensity and cognitive parameters, we used only the serointensity higher than positivity thresholds. Therefore, 49 patients who tested seronegative for T. gondii were excluded and, thus, the sample comprised of 27 participants for the serointensity component of the analysis. Serological Analysis For each participant, a blood sample was obtained on the day of cognitive testing. Plasma was isolated from blood samples, stored, and shipped at − 70°C until testing. The serological analysis was conducted by the Institute of Human Virology and Department of Pathology at the University of Maryland School of Medicine, Baltimore, USA. T. gondii antibodies, specific for IgG or IgM, were detected in subjects using commercial ELISA methods (IBL International, Hamburg, Germany). Briefly, diluted serum was added to antigen-coated plates, and the specific antibodies were detected using an anti-IgG or anti-IgM peroxidase-labeled conjugate, followed by the addition of a TMB substrate. Color development was detected at 450nm. Intensity was measured and the concentration of antibodies was determined as an Antibody Index based on the OD of a calibrator, a Calibrator Factor, and the sample OD. Sample results with an Antibody Index of greater than 1.1 were considered seropositive for IgG- or IgM-specific antibodies (as per the manufacturer’s guidelines). Neuropsychological Assessment We used a neuropsychological test battery including: (a) Attention and processing speed : Trail Making Test part A (TMT-A) ( 40 ), the word- and color-naming trials from the Color and Word Interference Test by J. R. Stroop ( 41 ), the d2 Test of Attention Revised (d2-R) ( 42 ), and the digit-symbol-coding test from the “Hamburg-Wechsler-Intelligenztest für Erwachsene” (HAWIE) ( 43 ). The latter is a German version of the “Wechsler Adult Intelligence Scale” (WAIS) ( 44 ). (b) Verbal memory : German Version of the California Verbal Learning Test (CVLT) with the subscales “immediate recall sum trial 1–5”, “short delay free recall”, “short delay cued recall”, “long delay free recall” and “long delay cued recall”( 45 ); and the digit span forward test from the WAIS. (c) Executive function : Trail Making Test Part B (TMT-B), digit span backwards test from the WAIS, and the interference trial from the Color and Word Interference Test by J. R. Stroop. Descriptive Analyses and Sample Characteristics For descriptive analyses, independent sample t -tests for metric data, the nonparametric Mann-Whitney U test for ordinal data, and chi-square tests for categorial data were used. A total of 76 patients were included in this study, of which 43 (56.6%) were male and 33 (43.4%) were female. The median age was 43.1 years ( SD 13.1) with an age range from 17.8 to 67.2 years. The median illness duration was 18.9 years ( SD 12.4). Seven (9.2%) participants were seropositive for IgM antibodies and 27 (35.5%) were seropositive for IgG antibodies. Statistical Analyses Due to the small sample size of the participants who were seropositive for IgM ( n = 7), we were not able to perform any statistical analyses in this sub-group because of limited power and substantial risk of type II error. For IgG antibody levels a natural logarithm transformation was performed to correct for the left-skewed distributions. Raw cognitive test scores were converted into z -scores. For higher scores to represent higher performance, variables initially oriented negatively were reversed. Neuropsychological tests used in the BIPLONG study project were categorized and summed up into three cognitive domain scores: (a) attention and processing speed (TMT-A, Stroop word- and color naming trials and d2-R); (b) verbal memory (CVLT subscales and digit span forward test); and (c) executive function (TMT-B, digit span backwards test and Stroop interference). These domain scores were again transformed into z -scores and functioned as primary cognitive outcome variables. Two-way multivariate analyses of co-variance controlling for age and IQ (MANCOVA) were computed with IgG seropositivity as the independent variable, and cognitive domain scores (attention and processing speed, verbal memory, executive function) as dependent variables. To evaluate for associations between IgG antibody serointensity and cognitive domain scores in seropositive participants, we used partial correlations controlling for age and premorbid IQ. Seronegative participants were excluded from this part of the analysis, since serointensity is only biologically meaningful in seropositive patients. All statistical analyses were computed using IBM SPSS version 27.0. Results Differences in cognitive domain scores between seropositive and seronegative groups MANCOVA analysis to test for differences in cognitive domain scores (attention and processing speed, verbal memory, executive function) between IgG seropositive and seronegative participants controlling for age and premorbid IQ showed no significant multivariate main effect for IgG positive relative to IgG negative individuals ( F ( 3 , 70 ) = 0.327, p = 0.806, n = 76); results are shown in Table 1 . Table 1 Demographic and clinical characteristics and cognitive domain scores among IgG seropositive and seronegative groups ( n = 76). Seropositive for IgG Seronegative for IgG Statistical Test, p value n = 27 (35.5%) n = 49 (64.5%) Demographics Age (years), mean ± SD 47.16 (12.682) 40.92 (12.869) t (54.39)=–2.041 , p = 0.046 Sex, n (%) Χ 2 ( 1 ) = 1.735, p = 0.188 Male 18 (41.9%) 25 (58.1%) Female 9 (27.3%) 24 (72.7%) Clinical Characteristics Illness Duration (years), mean ± SD 22.93 (13.032) 16.71 (11.589) U = 476.5 z =–2.009 , p = 0.044 HAMD, mean ± SD 4.67 (3.497) 5.12 (3.626) U = 615.0 z =–0.508, p = 0.612 YMRS, mean ± SD 0.67 (1.617) 1.33 (2.267) U = 567.0 z =–1.262, p = 0.208 BD Type, n (%) Χ 2 ( 1 ) = 0.910, p = 0.340 Type 1 17 (67.9%) 36 (32.1%) Type 2 10 (43.5%) 13 (56.5%) Cognitive Domain Scores* Attention and Processing Speed, mean ± SD –8.435 (3.422) 0.465 (3.356) F ( 1 ) = 0.696, p = 0.407 Verbal Memory, mean ± SD –0.653 (4.736) 0.360 (4.892) F ( 1 ) = 0.003, p = 0.955 Executive Function, mean ± SD –0.291 (2.233) 0.160 (2.113) F ( 1 ) = 0.015, p = 0.904 Note: Significant values are indicated in bold (p < 0.05); *Differences in cognitive domain scores, results corrected for age and IQ; IgG = Immunoglobulin G specific for T. gondii ; HAMD = Hamilton Depression Rating Scale, YMRS = Young Mania Rating Scale, BD = Bipolar Disorder Table 1 also presents further demographic and clinical characteristics and compares variables between IgG seropositive and seronegative groups. **Insert Table 1 about here*** Associations between T. gondii IgG serointensity in seropositives and Cognitive Domain Scores Partial correlation coefficients were computed to assess linear relationships between IgG serointensity and cognitive domain scores controlling for age and premorbid IQ ( n = 27). There were no significant correlations between IgG serointensity and both “attention and processing speed” ( r= –0.095, p = 0.651) and “executive function” ( r = 0.115, p = 0.586). There was a tendency towards a negative correlation, ( r= –0.396, p = 0.050) between IgG serointensity and “verbal memory”. Based on this tendency further correlations for individual parameters in the verbal memory domain were explored. Specifically, additional partial correlations between IgG antibody levels and the individual test scores in the verbal memory domain using the California Verbal Learning Test were done using Bonferroni corrected alpha levels of p = 0.008. Results showed a negative correlation between IgG serointensity and short delay free recall ( r= –0.539, p = 0.005), long delay free recall ( r= –0.423, p = 0.035), and immediate recall sum trial 1–5 ( r =–0.399, p = 0.048). No significant correlations were found between IgG serointensity, and short delay cued recall ( r= –0.364, p = 0.074) and long delay cued recall ( r= –0.215, p = 0.302). After Bonferroni correction for multiple comparisons, only negative correlation with short delay free recall remained significant ( p < 0.008). Coefficients and statistics of partial correlation analyses are presented in Table 2 . Table 2 Partial Correlation Results between IgG serointensity (in IgG seropositives) and Cognitive Parameters (n = 27). r p value Cognitive Domain Scores Attention and Processing Speed –0.095 0.651* Executive Function 0.115 0.586* Verbal Memory –0.396 0.050* Individual Parameters in the verbal memory domain CVLT immediate recall sum trial 1–5 –0.399 0.048 * CVLT Short Delay Free Recall –0.539 0.005 * CVLT Short Delay Cued Recall –0.364 0.074* CVLT Long Delay Free Recall –0.423 0.035 * CVLT Long Delay Cued Recall –0.215 0.302* WAIS Digit Span Forward Test 0.115 0.583* Note: All results are corrected for age and IQ; Significant values are indicated in bold (p < 0.05); *remains significant after Bonferroni correction ( p < 0.008); CVLT = California Verbal Learning Test, WAIS = Wechsler Adult Intelligence Scale **Insert Table 2 about here*** Discussion Key Findings Our investigation aimed to determine associations between T. gondii -specific antibodies and cognitive function in a well-diagnosed BD sample. While domain scores for “attention and processing speed” and “executive function” showed no partial correlations with IgG serointensity, we found inverse associations between T. gondii IgG serointensity and individual “verbal memory” scores. Higher T. gondii IgG titers were associated with lower performance in certain aspects of verbal memory. Notably, all free recall parameters showed significant negative correlations with IgG serointensity in seropositives; however, only short delayed free recall remained significant after Bonferroni correction. The free recall condition of CVLT assesses several memory processes such as encoding, learning, storage, and retrieval. Thus, our results suggest that the higher T. gondii IgG titers were, the lower the individual's short-term verbal learning abilities. We did not find differences between groups seropositive and seronegative for T. gondii IgG in any cognitive domain assessed (attention and processing speed, verbal memory, and executive function). This coincides with previous studies in BD samples ( 30 , 31 ). A small sample size of participants seropositive for IgM ( n = 7) precluded us from attempting to reevaluate previously reported positive association between T. gondii IgM serointensity and certain measures of cognitive dysfunction ( 30 ), which later was not replicated ( 31 ). Furthermore, seropositive individuals were on average older than seronegative individuals. Once infected, the host cannot eradicate T. gondii due to its ability to hide in intracellular cysts within neurons and glial cells, and to manipulate the immune system. Therefore, prevalence of chronic toxoplasmosis is known to increase with age ( 46 ), and thus we accounted for age by statistical adjustment. We observed no other group differences between seropositive and seronegative groups in any demographic or clinical parameters that might be capable of confounding our results. Strengths and Limitations Strengths of this study were its homogeneous and well-diagnosed BD study population, and a clearly defined euthymic state at the time of testing to avoid cognitive alterations caused by mood state episodes. Euthymia was a mandatory inclusion criterion, securing that the mood-state dependent cognitive deficits are not the driver of our associations. Another strength is the result of an association between serointensity in seropositive individuals specifically with verbal recall performance, in contrast to other cognitive domains. It has been reported in longitudinal studies that deterioration in many cognitive tasks in BD is often the result of confounding, except for memory recall ( 47 ). This study cannot provide evidence for cause-and-effect inferences due to its observational stance and cross-sectional design. Another limiting factor was the small sample size in the evaluation of associations with IgM seropositivity and serointensity ( n = 7) that precluded us from doing analyses in this sub-group. As IgM antibodies can persist years after infection, and could be elevated with reinfection with a different strain, and because the IgM can give false positive results and thus have a limited use in determining incidence, severity and timing of T. gondii infection ( 48 ), we have not integrated analysis of IgM seropositivity and serointensity into our analysis of IgG titers. Furthermore, we did not have a healthy control comparison. Therefore, we cannot estimate if shown cognitive effects differ in individuals with BD (having multiple and potentially interactive liabilities like the recurrent affective disorder, the treatment effects and finally the T. gondii infection) than in those reported in healthy controls ( 32 ). We also did not analyze effects of medications, and thus there is a possibility that medications commonly used in BD and known to impact both cognitive function and the risk of dementia, either inducing worsening or improvement ( 49 – 52 ), could have been differentially represented in the T. gondii positive versus negative groups, and thus either leading to spurious results or masking true associations. We also did not analyze a potential confounding, moderating or mediating role of body mass index (BMI) and metabolic factors such as dyslipidemia and diabetes type II, relevant due to the positive associations between obesity and metabolic dysregulation with both cognitive dysfunction in BD ( 53 , 54 ) and T. gondii infection ( 55 – 57 ). Furthermore, we did not analyze possible interacting effects of alcohol or drug abuse, as well as socioeconomical factors. The latter could represent T. gondii infection risk factors and also could represent factors previously associated with a poor cognitive status and increased risk of dementia ( 58 ). We also acknowledge not measuring markers of distinct serotype and especially markers of the oocyst infection that appear to be more virulent, more neurotropic, with more tissue damage and inflammation ( 59 , 60 ), and thus, potentially affecting cognition more strongly than the tissue cyst infection path would. In addition, in the absence of a longitudinal study, it is not possible to exclude an alternative explanation for the reported associations. A reverse causality would implicate BD, in particular with preexisting, developmental, preprodromal or post-onset cognitive deficits, as a risk factor for infection and a more extensive and virulent T. gondii infection, perhaps by elevating risk factors for acquiring toxoplasmosis. Clinical Implications With its worldwide distribution and high prevalence, T. gondii might impose an additional risk to BD populations, which are already affected by cognitive deficits due to their underlying illness ( 3 ). Higher T. gondii prevalence in BD has been shown in numerous meta-analyses ( 16 , 27 – 29 ) and, therefore, makes BD patients even more susceptible to possible negative effects caused by the parasite. This study adds to the existing literature on T. gondii infection in BD. Since cognitive impairment predicts psychosocial functioning and quality of life ( 5 , 6 ), identification of T. gondii as a risk factor and prognostic marker for cognitive outcome might lead to novel treatment approaches for BD patients. Measures to prevent infection and reactivation of the parasite in those already infected, as well as personalized interventions to sustain cognitive performance, could provide additional benefit to patients in a distinct subpopulation of BD, perhaps with high serointensity and documented mood state switches, known to increase cognitive risk. Furthermore, consideration of anti-toxoplasma effects of certain psychotropic medications already used in BD would be necessary. Directions for Future Research In future studies larger sample sizes or meta-analyses will be necessary to provide stronger evidence for associations reported in our study. Moreover, longitudinal designs will be necessary to confirm if T. gondii serointensity in seropositives can predict cognitive decline, function as a catalyst, or even be, at least in part, a causal factor of cognitive decline in a subgroup of BD patients. It might also be worthwhile to investigate the memory component in more detail and to use tests for figural recall and working memory in addition to verbal memory. Identification and targeting of the molecular and cellular mechanisms mediating the link between T. gondii and cognitive deficits may lead to novel targets and treatment modalities to be tested in their own right. Furthermore, broader serological testing could identify the serotype of T. gondii , the source of infection via more virulent oocysts versus tissue cysts, as well as co-occurring, and reciprocally potentiating, infections with other chronic latent pathogens. A Need for Broader Serological Testing to Identify Specific Serotypes of T. gondii. There is a need in future studies to use broader serological testing to identify specific serotypes of T. gondii . While evidence is emerging that some serotypes of T. gondii may confer worse clinically relevant outcomes ( 61 ), it is possible that certain strains ( 62 ) or modes of infection (e.g., tissue cyst versus oocyst) of T. gondii , under some conditions, serve as microbial “Old Friends”—promoting immunoregulation ( 63 , 64 ), and thus, reducing chronic low-grade immune activation, which has been associated with BD ( 65 ). Rationale for Long Term Plans for Personalized Treatment and Prevention of Cognitive Deficits in BD based on T. gondii Serointensity in Seropositives While psychotropic treatment is effective in reducing the frequency of mood switches as well as the severity and the duration of mood episodes, its effects on the progression of cognitive deficits in BD has demonstrated considerable variability between and within published studies. This is due to considerable etiological and pathophysiological heterogeneity of cognitive deficits associated with BD. This imposes a change from asking “does this treatment work” towards “what are the characteristics of individual patients with BD in whom a particular treatment is likely to yield strong cognitive protective or remediating effects”. Consistent with this vision, the sizable anti- T. gondii activity of a few psychotropics in the current clinical arsenal in BD might have a direct impact on preventing, slowing or reversing cognitive decline, specifically in T. gondii seropositive patients with BD who have a high T. gondii IgG serointensity, as a potential marker of virulence, with frequent reactivation, local and distant spread and induction of inflammation. For example, valproic acid has a considerable antiproliferative effect against T. gondii tachyzoites in vitro ( 66 ) relative to lithium or lamotrigine ( 67 ), resulting in reductions in tissue cyst load in glial nodules and perivascular infiltration of lymphocytes ( 68 ), and thus, could become, after confirming in randomized clinical trials, a mood stabilizer of choice in BD patients with high T. gondii serointensity. Consistently, Fond et al., ( 69 ) showed that the total number of recurrent depressive episodes was reduced in individuals with BD (but not major depressive disorder) who were T. gondii seropositive, if treated with psychotropics having anti- T. gondii activity (TATA+) as compared with medications that had no or minimal anti- T. gondii activity (TATA–) ( 67 ). The TATA + medications included valproate, paliperidone, risperidone, fluphenazine, haloperidol, levomepromazine, loxapine, thioridazine, zuclopenthixol, and cyamemazine. The TATA– drugs included lamotrigine, lithium carbonate, carbamazepine, olanzapine, quetiapine, aripiprazole, amisulpride, clozapine, and tiapride. The medications commonly used to prevent or treat severe exacerbated toxoplasmosis in immunocompromised hosts, or in acute severe infections (e.g., pyrimethamine and sulfadiazine) are not sufficiently effective against bradyzoites within tissue cysts, thus in chronic toxoplasmosis, and have considerable side effects. Widely used medications, statins, have previously demonstrated pleiotropic antiproliferative effects on T. gondii through inhibition of isoprenoid synthesis in the parasite. For instance, treatment with the lipophilic statins pravastatin and simvastatin reduced adhesion, infection, and proliferation of T. gondii in HeLa cells, in monotherapy ( 70 ) as well as in combination with anti-toxoplasmosis agents pyrimethamine and sulfadiazine ( 71 ). A chronic toxoplasmosis in vivo model has demonstrated that rosuvastatin, a hydrophilic statin, reverses the short term and long term memory impairment in BALB/c mice infected with ME-39 strain of T. gondii ( 72 ), also reducing the brain cyst load as well as markers neuroinflammation, including microglial proliferation, perivascular cuffs, and cell infiltration ( 72 , 73 ). Furthermore, novel compounds based on in silico structural and mechanistic short-listing have yielded promising anti- T. gondii pharmacological approaches ( 74 ). Of particular relevance is hydroxyzine, a first generation sedating antihistamine, widely used off label for insomnia, anxiety, and agitation in patients with recurrent mood disorders, which has recently demonstrated a specific capability not only to reduce tachyzoites infection and spread, but also to prevent reactivation of chronic infection by suppressing bradyzoites ( 75 ). These developments provide further support for the need for clinical trials investigating repurposing medications with anti- T. gondii activity, demonstrated in vitro after being short-listed by in silico analysis ( 76 ), to improve therapeutic control, to preserve or even enhance cognitive function and rehabilitate functioning in a specific subgroup of seropositive BD patients with high IgG serointensity, and to determine longitudinally documented overlap between indicators of T. gondii reactivation (including episodic elevations of IgG serointensity) and clinically-defined BD relapse, or symptomatic exacerbation of mood state switching, or worsening of cognitive deficits. In the longer term, regarding drug discovery based on mechanistic inferences, there are promising areas involving targeting autophagy dysregulation, which is actively induced and sustained by intracellular T. gondii bradyzoites ( 77 ) and contributes to cognitive deficits in BD, as a recent elegant postmortem study using a reverse translational approach has demonstrated ( 78 ). The high T. gondii IgG serointensity in seropositives could become one among many other predictive biomarkers for personalizing the treatment approach targeting cognitive dysfunction in BD. For instance, while valproate appears as inferior to lithium ( 49 , 79 ) in terms of preserving cognitive function and preventing dementia in patients with BD, in the subgroup with high T. gondii serointensity valproate might end up being advantageous, considering its TATA + activity. This could be evaluated in a targeted randomized interventional study. By extension, a possible next step of our current report is represented by a double-blind randomized study comparing cognitive function between those randomly treated with a TATA(+) versus TATA(–) psychotropic–in a sample including only individuals with high T. gondii IgG serointensity and mild cognitive deficits. This study will be positioned to test the causal hypothesis underlying our current result, and distinguish it from alternative explanations, including reverse causality or confounding. Conclusions This investigation is the first to show an association between T. gondii IgG serointensity in seropositives and specific cognitive deficits in a well-diagnosed BD sample. Specifically, verbal memory parameters, and in particular short delay free recall, were negatively correlated with IgG serointensity. Although further research is needed to confirm and expand our findings, eliminate potential sources of bias, and establish cause-effect relationships, latent T. gondii infection may emerge as a pharmacologically targetable contributory cause to decreased cognitive performance, functioning, and quality of life in patients with bipolar disorder. Abbreviations BD Bipolar Disorder CVLT California Verbal Learning Test d2-R d2 Test of Attention Revised ELISA Enzyme-linked Immunosorbent Assay HAMD Hamilton Depression Rating Scale HAWIE Hamburg-Wechsler-Intelligenztest für Erwachsene IgG Immunoglobulin G IgM Immunoglobulin M IQ Intelligence Quotient MANCOVA Multivariate Analyses of Co-Variance MWT-B Multiple Choice Vocabulary Test OD Optical Density SCID-I Structured Clinical Interview for DSM IV TATA+ Medications having anti-T. gondii Activity TATA- Medications having no or minimal anti-T. gondii Activity TMT-A Trail Making Test Part A TMT-B Trail Making Test Part B T. gondii Toxoplasma Gondii WAIS Wechsler Adult Intelligence Scale YRMS Young Mania Rating Scale Declarations Ethics approval and consent to participate The study was approved by the ethics committee of the Medical University of Graz (EC-number: 25-335 ex 12/13). Written informed consent was obtained from all subjects before participation in this study. Consent for publication Not applicable Availability of data and material The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding PR received a student scholarship from the Medical University of Graz to cover publication costs. Authors' contributions PRconceptualized the study, collected data as part of the BIPLONG study project, curated the data, undertook the statistical analyses and wrote the original draft of the manuscript. TTPsupported conceptualization, contributed to results interpretation and co-wrote intermediate drafts of the manuscript. NDsupported conceptualization, planned statistical analyses and coordinated the BIPLONG study project.TSsupervised statistical analyses.NC performed serological analysis of T. gondii antibodies and played a critical role in interpretation of results. ADorganized the database of biological material for serological analysis and managed data, and interpreted results. AB, FM, CAL, and JJ contributed to results interpretation and co-wrote intermediate drafts of the manuscript. AB, FTF, AF, ML, AM, AP, RQ, FS, SS, and ATBare part of the BIPLONG study group, were responsible for diagnostics and data collection. EZRis project lead and supported conceptualization. All authors contributed intellectual content to the manuscript, and also read, edited and approved its final version. Acknowledgements Not applicable References Moreira ALR, Van Meter A, Genzlinger J, Youngstrom EA. Review and Meta-Analysis of Epidemiologic Studies of Adult Bipolar Disorder. J Clin Psychiatry. 2017;78(9):e1259–69. Chan JKN, Tong CHY, Wong CSM, Chen EYH, Chang WC. Life expectancy and years of potential life lost in bipolar disorder: systematic review and meta-analysis. Br J Psychiatry. 2022;221(3):567–76. 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Cite Share Download PDF Status: Published Journal Publication published 23 Aug, 2024 Read the published version in International Journal of Bipolar Disorders → Version 1 posted Editorial decision: Revision requested 11 Jul, 2024 Reviews received at journal 11 Jul, 2024 Reviewers agreed at journal 08 Jul, 2024 Reviews received at journal 03 Jul, 2024 Reviewers agreed at journal 03 Jul, 2024 Reviewers invited by journal 24 Jun, 2024 Editor assigned by journal 10 Jun, 2024 Submission checks completed at journal 10 Jun, 2024 First submitted to journal 10 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Postolache","email":"","orcid":"","institution":"University of Maryland School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Teodor","middleName":"T.","lastName":"Postolache","suffix":""},{"id":318310038,"identity":"98735c59-0a59-43b9-8ef4-80f8f1c2f9c3","order_by":2,"name":"Nina Dalkner","email":"data:image/png;base64,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","orcid":"","institution":"Medical University of Graz","correspondingAuthor":true,"prefix":"","firstName":"Nina","middleName":"","lastName":"Dalkner","suffix":""},{"id":318310039,"identity":"59280a0f-22d5-4d5d-8f36-3b278b1b79c3","order_by":3,"name":"Tatjana Stross","email":"","orcid":"","institution":"Medical University of Graz","correspondingAuthor":false,"prefix":"","firstName":"Tatjana","middleName":"","lastName":"Stross","suffix":""},{"id":318310040,"identity":"6747c411-4421-45ba-9878-2c881c962114","order_by":4,"name":"Niel Constantine","email":"","orcid":"","institution":"University of Maryland School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Niel","middleName":"","lastName":"Constantine","suffix":""},{"id":318310041,"identity":"61bd1132-2984-4da8-a0dc-24827bdc4e44","order_by":5,"name":"Aline Dagdag","email":"","orcid":"","institution":"University of Maryland School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Aline","middleName":"","lastName":"Dagdag","suffix":""},{"id":318310042,"identity":"dbcb7c7b-e7d3-474e-a668-62289b884dfb","order_by":6,"name":"Abhishek Wadhawang","email":"","orcid":"","institution":"Saint Elizabeth's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Abhishek","middleName":"","lastName":"Wadhawang","suffix":""},{"id":318310043,"identity":"658986e6-b700-45f1-a76b-5f262e72247a","order_by":7,"name":"Farooq Mohyudding","email":"","orcid":"","institution":"Saint Elizabeth's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Farooq","middleName":"","lastName":"Mohyudding","suffix":""},{"id":318310044,"identity":"c893dead-6678-4560-81d9-00f652b4e156","order_by":8,"name":"Christopher A. Lowryd","email":"","orcid":"","institution":"University of Colorado Boulder","correspondingAuthor":false,"prefix":"","firstName":"Christopher","middleName":"A.","lastName":"Lowryd","suffix":""},{"id":318310045,"identity":"51276839-76c7-4ef4-b669-698c49bd0522","order_by":9,"name":"Joshua Josephb","email":"","orcid":"","institution":"University of Maryland School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Joshua","middleName":"","lastName":"Josephb","suffix":""},{"id":318310046,"identity":"7f781f67-f61c-4b16-b2f0-12655b258a20","order_by":10,"name":"Armin Birner","email":"","orcid":"","institution":"Medical University of Graz","correspondingAuthor":false,"prefix":"","firstName":"Armin","middleName":"","lastName":"Birner","suffix":""},{"id":318310047,"identity":"6ceea358-daa1-4c6c-a38d-2dd2a0f7c396","order_by":11,"name":"Frederike T. Fellendorf","email":"","orcid":"","institution":"Medical University of Graz","correspondingAuthor":false,"prefix":"","firstName":"Frederike","middleName":"T.","lastName":"Fellendorf","suffix":""},{"id":318310048,"identity":"ad25379f-a155-49fd-b23a-09393ec75b48","order_by":12,"name":"Alexander Finner","email":"","orcid":"","institution":"Medical University of Graz","correspondingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Finner","suffix":""},{"id":318310049,"identity":"adccbc7d-03d1-48de-8f30-9c2368de4bdb","order_by":13,"name":"Melanie Lenger","email":"","orcid":"","institution":"Medical University of Graz","correspondingAuthor":false,"prefix":"","firstName":"Melanie","middleName":"","lastName":"Lenger","suffix":""},{"id":318310050,"identity":"7e6bd357-89f1-4076-a95e-6eb14645cc87","order_by":14,"name":"Alexander Maget","email":"","orcid":"","institution":"Medical University of Graz","correspondingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Maget","suffix":""},{"id":318310051,"identity":"7f7411d5-4e0a-4da9-b022-27351e1dc93d","order_by":15,"name":"Annamaria Painold","email":"","orcid":"","institution":"Medical University of Graz","correspondingAuthor":false,"prefix":"","firstName":"Annamaria","middleName":"","lastName":"Painold","suffix":""},{"id":318310052,"identity":"1f255c6e-1dcf-4810-9650-61cf9ae839b8","order_by":16,"name":"Robert Queissner","email":"","orcid":"","institution":"Medical University of Graz","correspondingAuthor":false,"prefix":"","firstName":"Robert","middleName":"","lastName":"Queissner","suffix":""},{"id":318310053,"identity":"58266f67-fcc8-4e42-8921-e46c88095b05","order_by":17,"name":"Franziska Schmiedhofer","email":"","orcid":"","institution":"Medical University of Graz","correspondingAuthor":false,"prefix":"","firstName":"Franziska","middleName":"","lastName":"Schmiedhofer","suffix":""},{"id":318310054,"identity":"6648c5b8-ce40-4283-920d-80063713967a","order_by":18,"name":"Stefan Smolle","email":"","orcid":"","institution":"Medical University of Graz","correspondingAuthor":false,"prefix":"","firstName":"Stefan","middleName":"","lastName":"Smolle","suffix":""},{"id":318310055,"identity":"85978bd9-f97a-448a-b5d5-55b8c854cf29","order_by":19,"name":"Adelina Tmava-Berisha","email":"","orcid":"","institution":"Medical University of Graz","correspondingAuthor":false,"prefix":"","firstName":"Adelina","middleName":"","lastName":"Tmava-Berisha","suffix":""},{"id":318310056,"identity":"175e7302-6d5d-475b-8ef8-9ccc6f44e094","order_by":20,"name":"Eva Reininghaus","email":"","orcid":"","institution":"Medical University of Graz","correspondingAuthor":false,"prefix":"","firstName":"Eva","middleName":"","lastName":"Reininghaus","suffix":""}],"badges":[],"createdAt":"2024-06-10 08:37:45","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4556766/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4556766/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s40345-024-00353-8","type":"published","date":"2024-08-23T15:57:53+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":63300358,"identity":"221ee95c-a373-405a-901e-75ed4da63bbc","added_by":"auto","created_at":"2024-08-26 16:13:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":734335,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4556766/v1/00cc6d07-1f29-4d9b-bb98-1c0cf7b1b7fe.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Toxoplasma gondii IgG Serointensity and Cognitive Function in Bipolar Disorder","fulltext":[{"header":"Background","content":"\u003cp\u003eBipolar Disorder (BD) is a chronic psychiatric disorder causing recurring periods of depression and mania. BD has a lifetime prevalence of 1.02% (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) and causes an average of 12.89 years of potential life lost in affected patients (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Beside pathological mood swings, a core symptom of BD is cognitive dysfunction that even persists during euthymia (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Studies have shown that cognitive deficits predict decrements in psychosocial and occupational functioning (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), and reduced quality of life (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cem\u003eToxoplasma gondii (T. gondii)\u003c/em\u003e is a protozoan intracellular parasite with a worldwide distribution (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) that infects up to a third of the world\u0026rsquo;s population (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). While it infects all warm-blooded animals, the parasite can only sexually reproduce in cats. The parasite infection can be divided into three distinct stages: sporozoites - within sporulated oocysts, tachyzoites that rapidly invade and multiply, and bradyzoites that replicate slowly within tissue cysts. In approximately half of the cases of toxoplasmosis, humans become infected through a foodborne route consisting of ingestion of \u003cem\u003eT. gondii\u003c/em\u003e oocysts shed in the feces of infected cats and contaminating food during food preparation, or tissue cysts from the meat of infected animals.\u003c/p\u003e \u003cp\u003eWithin the medical community, \u003cem\u003eT. gondii\u003c/em\u003e is especially important in obstetrics, since vertical acute infections from the pregnant woman to the fetus can have long-term devastating effects in the offspring, resulting in chorioretinitis, intracranial calcifications, autism, and intellectual disability (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOtherwise, \u003cem\u003eT. gondii\u003c/em\u003e infection acquired postnatally is usually asymptomatic (\u0026ldquo;latent toxoplasmosis\u0026rdquo;) in immunocompetent individuals and rarely needs treatment. In only about 10%, it causes time-limited mild non-specific symptoms like isolated lymphadenopathy or fever. More severe manifestations are very infrequent in otherwise healthy individuals (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Nevertheless, once an organism is infected with \u003cem\u003eT. gondii\u003c/em\u003e, the clearance of the microorganism is virtually impossible. After the acute phase- the microorganisms (tachyzoites) travel via blood immune cells and infect several organs, in particular the brain and the skeletal muscle, where, under immune pressure, they transform into slow growing phenotypes- the bradyzoite, and intracellular cysts. Most adult infections therefore are chronic, with only minimal reactivations of the pathogen (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDiagnosis of infection is commonly made with serological methods detecting \u003cem\u003eT. gondii\u003c/em\u003e-specific antibodies. Acute infection is accompanied by elevated IgM, which can be detected as soon as one week after infection. It peaks after 1\u0026ndash;3 months and usually disappears over the following months; yet, in some patients IgM can also be observed for many years after the acute infection (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Subsequently, IgG appears around two weeks after infection and persists for life in immunocompetent hosts (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite \u003cem\u003eT. gondii\u003c/em\u003e being considered harmless in immunocompetent individuals for a long time, recent investigations highlight that the parasite might also be linked to a wide array of neuropsychiatric disorders (\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). There is evidence of associations between the parasite and epilepsy (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e), schizophrenia (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e), as well as suicidal behavior, across diagnostic categories (\u003cspan additionalcitationids=\"CR20 CR21\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Furthermore possible links to obsessive-compulsive disorder (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) and Alzheimer\u0026rsquo;s disease (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) have been reported. In contrast, studies examining associations with depression have shown heterogeneous and predominantly negative results (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe association between \u003cem\u003eT. gondii\u003c/em\u003e and BD has been reviewed by several meta-analyses identifying significant relationships in all ages (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e), as well as in a subpopulation under 40 years of age (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). A recent publication with 12,690 participants (4,021 with BD and 8,669 controls) supported these findings and reported that persons with BD had significantly greater odds of seropositivity for \u003cem\u003eT. gondii\u003c/em\u003e than controls (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlthough cognitive function is an important parameter of outcome in BD, to our knowledge only two studies have examined a link between \u003cem\u003eT. gondii\u003c/em\u003e and cognitive performance, but with inconsistent results. Dickerson et al. (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;347) found significant associations between \u003cem\u003eT. gondii\u003c/em\u003e IgM, but not IgG serointensity, and certain cognitive parameters (overall cognitive function, delayed memory and visuospatial/constructional), but not for immediate memory, language, or attention. Moreover, IgG serointensity and cognition scores showed no association in their study (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Tanaka et al. (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;32) found no association between any antibody levels and overall neurocognitive function (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eInterestingly, in healthy individuals, a meta-analysis by de Haan et al. with 13,289 participants reported an association between \u003cem\u003eT. gondii\u003c/em\u003e seropositivity and mild cognitive impairment. In this analysis, individuals with latent \u003cem\u003eT. gondii\u003c/em\u003e infections had inferior performance in four cognitive domains: processing speed, working memory, short-term verbal memory, and executive function, relative to seronegative individuals (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn summary, prior studies reported inconsistent results on associations between latent \u003cem\u003eT. gondii\u003c/em\u003e infections and cognitive dysfunction in BD, while others were able to identify associations of \u003cem\u003eT. gondii\u003c/em\u003e seropositivity with distinct cognitive domains. Therefore, the current investigation aimed to investigate the association between \u003cem\u003eT. gondii\u003c/em\u003e seropositivity, serointensity, and cognitive domains in a well-diagnosed BD population. We hypothesized that in euthymic bipolar patients, the \u003cem\u003eT. gondii\u003c/em\u003e-seropositive individuals would manifest more severe cognitive impairments relative to their seronegative individuals. In addition, we assumed that there would be negative associations between serointensity and measures of cognitive performance in \u003cem\u003eT. gondii\u003c/em\u003e seropositives.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eSample Description and Inclusion Criteria\u003c/h2\u003e\n \u003cp\u003eWe measured \u003cem\u003eT. gondii\u003c/em\u003e-specific antibodies in a total of 126 individuals with BD as part of the ongoing \u0026ldquo;BIPLONG\u0026rdquo; study project at a dedicated BD outpatient clinic at the Medical University of Graz, Department of Psychiatry and Psychotherapeutic Medicine. BIPLONG aims to assess psychiatric symptoms and history in association with metabolic, lifestyle, genetic, biological, brain imaging, and cognitive parameters in individuals with BD in a longitudinal design. After baseline measurement, there are follow-up measurements every six months. In the current investigation, we used data from the baseline measurement. For more details about the BIPLONG project please see earlier publications by our study group (\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eParticipants were diagnosed with BD according to the Structured Clinical Interview for DSM IV (SCID-I) by a trained psychiatrist or psychologist with the German Version (\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e). Furthermore, participants had to be euthymic at the time of testing and had to have a complete cognition data set. Euthymia was determined by a score of \u0026le;\u0026thinsp;12 on the Hamilton Depression Rating Scale (HAMD) (\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e) and a score of \u0026le;\u0026thinsp;8 on the Young Mania Rating Scale (YMRS) (\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e). Exclusion criteria were a premorbid IQ of \u0026lt;\u0026thinsp;80 tested with the multiple choice vocabulary test (MWT-B) (\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e) and an age of \u0026ge;\u0026thinsp;70 years.\u003c/p\u003e\n \u003cp\u003eOut of the 126 individuals considered, 38 participants did not meet the criteria for euthymia; three were over 70 years of age, and nine participants had to be excluded because of missing cognition data. In total, we were able to include 76 participants in this investigation.\u003c/p\u003e\n \u003cp\u003eAdditionally, for computing correlations between serointensity and cognitive parameters, we used only the serointensity higher than positivity thresholds. Therefore, 49 patients who tested seronegative for \u003cem\u003eT. gondii\u003c/em\u003e were excluded and, thus, the sample comprised of 27 participants for the serointensity component of the analysis.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003eSerological Analysis\u003c/h2\u003e\n \u003cp\u003eFor each participant, a blood sample was obtained on the day of cognitive testing. Plasma was isolated from blood samples, stored, and shipped at \u0026minus;\u0026thinsp;70\u0026deg;C until testing. The serological analysis was conducted by the Institute of Human Virology and Department of Pathology at the University of Maryland School of Medicine, Baltimore, USA. \u003cem\u003eT. gondii\u003c/em\u003e antibodies, specific for IgG or IgM, were detected in subjects using commercial ELISA methods (IBL International, Hamburg, Germany). Briefly, diluted serum was added to antigen-coated plates, and the specific antibodies were detected using an anti-IgG or anti-IgM peroxidase-labeled conjugate, followed by the addition of a TMB substrate. Color development was detected at 450nm. Intensity was measured and the concentration of antibodies was determined as an Antibody Index based on the OD of a calibrator, a Calibrator Factor, and the sample OD. Sample results with an Antibody Index of greater than 1.1 were considered seropositive for IgG- or IgM-specific antibodies (as per the manufacturer\u0026rsquo;s guidelines).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003eNeuropsychological Assessment\u003c/h2\u003e\n \u003cp\u003eWe used a neuropsychological test battery including:\u003c/p\u003e\u003cspan\u003e\n \u003cp\u003e(a) \u003cem\u003eAttention and processing speed\u003c/em\u003e: Trail Making Test part A (TMT-A) (\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e), the word- and color-naming trials from the Color and Word Interference Test by J. R. Stroop (\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e), the d2 Test of Attention Revised (d2-R) (\u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e), and the digit-symbol-coding test from the \u0026ldquo;Hamburg-Wechsler-Intelligenztest f\u0026uuml;r Erwachsene\u0026rdquo; (HAWIE) (\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e). The latter is a German version of the \u0026ldquo;Wechsler Adult Intelligence Scale\u0026rdquo; (WAIS) (\u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e).\u003c/p\u003e\n \u003c/span\u003e \u003cspan\u003e\n \u003cp\u003e(b) \u003cem\u003eVerbal memory\u003c/em\u003e: German Version of the California Verbal Learning Test (CVLT) with the subscales \u0026ldquo;immediate recall sum trial 1\u0026ndash;5\u0026rdquo;, \u0026ldquo;short delay free recall\u0026rdquo;, \u0026ldquo;short delay cued recall\u0026rdquo;, \u0026ldquo;long delay free recall\u0026rdquo; and \u0026ldquo;long delay cued recall\u0026rdquo;(\u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e); and the digit span forward test from the WAIS.\u003c/p\u003e\n \u003c/span\u003e \u003cspan\u003e\n \u003cp\u003e(c) \u003cem\u003eExecutive function\u003c/em\u003e: Trail Making Test Part B (TMT-B), digit span backwards test from the WAIS, and the interference trial from the Color and Word Interference Test by J. R. Stroop.\u003c/p\u003e\n \u003c/span\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003eDescriptive Analyses and Sample Characteristics\u003c/h2\u003e\n \u003cp\u003eFor descriptive analyses, independent sample \u003cem\u003et\u003c/em\u003e-tests for metric data, the nonparametric Mann-Whitney U test for ordinal data, and chi-square tests for categorial data were used.\u003c/p\u003e\n \u003cp\u003eA total of 76 patients were included in this study, of which 43 (56.6%) were male and 33 (43.4%) were female. The median age was 43.1 years (\u003cem\u003eSD\u003c/em\u003e 13.1) with an age range from 17.8 to 67.2 years. The median illness duration was 18.9 years (\u003cem\u003eSD\u003c/em\u003e 12.4). Seven (9.2%) participants were seropositive for IgM antibodies and 27 (35.5%) were seropositive for IgG antibodies.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical Analyses\u003c/h2\u003e\n \u003cp\u003eDue to the small sample size of the participants who were seropositive for IgM (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7), we were not able to perform any statistical analyses in this sub-group because of limited power and substantial risk of type II error.\u003c/p\u003e\n \u003cp\u003eFor IgG antibody levels a natural logarithm transformation was performed to correct for the left-skewed distributions. Raw cognitive test scores were converted into \u003cem\u003ez\u003c/em\u003e-scores. For higher scores to represent higher performance, variables initially oriented negatively were reversed.\u003c/p\u003e\n \u003cp\u003eNeuropsychological tests used in the BIPLONG study project were categorized and summed up into three cognitive domain scores: (a) \u003cem\u003eattention and processing speed\u003c/em\u003e (TMT-A, Stroop word- and color naming trials and d2-R); (b) \u003cem\u003everbal memory\u003c/em\u003e (CVLT subscales and digit span forward test); and (c) \u003cem\u003eexecutive function\u003c/em\u003e (TMT-B, digit span backwards test and Stroop interference). These domain scores were again transformed into \u003cem\u003ez\u003c/em\u003e-scores and functioned as primary cognitive outcome variables.\u003c/p\u003e\n \u003cp\u003eTwo-way multivariate analyses of co-variance controlling for age and IQ (MANCOVA) were computed with IgG seropositivity as the independent variable, and cognitive domain scores (attention and processing speed, verbal memory, executive function) as dependent variables.\u003c/p\u003e\n \u003cp\u003eTo evaluate for associations between IgG antibody serointensity and cognitive domain scores in seropositive participants, we used partial correlations controlling for age and premorbid IQ. Seronegative participants were excluded from this part of the analysis, since serointensity is only biologically meaningful in seropositive patients.\u003c/p\u003e\n \u003cp\u003eAll statistical analyses were computed using IBM SPSS version 27.0.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eDifferences in cognitive domain scores between seropositive and seronegative groups\u003c/h2\u003e \u003cp\u003eMANCOVA analysis to test for differences in cognitive domain scores (attention and processing speed, verbal memory, executive function) between IgG seropositive and seronegative participants controlling for age and premorbid IQ showed no significant multivariate main effect for IgG positive relative to IgG negative individuals (\u003cem\u003eF\u003c/em\u003e (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e)\u0026thinsp;=\u0026thinsp;0.327, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.806, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;76); results are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic and clinical characteristics and cognitive domain scores among IgG seropositive and seronegative groups (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;76).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSeropositive for IgG\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSeronegative for IgG\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eStatistical Test, \u003cem\u003ep value\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;27 (35.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;49 (64.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eDemographics\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years), mean\u0026thinsp;\u003cem\u003e\u0026plusmn;\u0026thinsp;SD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47.16 (12.682)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40.92 (12.869)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003et\u003c/b\u003e\u003cb\u003e(54.39)=\u0026ndash;2.041\u003c/b\u003e, \u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;0.046\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eΧ\u003c/em\u003e \u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u0026thinsp;=\u0026thinsp;1.735, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.188\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (41.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (58.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (27.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (72.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eClinical Characteristics\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIllness Duration (years), mean\u0026thinsp;\u003cem\u003e\u0026plusmn;\u0026thinsp;SD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22.93 (13.032)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.71 (11.589)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eU\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;476.5\u003c/b\u003e \u003cb\u003ez\u003c/b\u003e\u003cb\u003e=\u0026ndash;2.009\u003c/b\u003e, \u003cb\u003ep\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;0.044\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHAMD, mean\u0026thinsp;\u003cem\u003e\u0026plusmn;\u0026thinsp;SD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.67 (3.497)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.12 (3.626)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eU\u003c/em\u003e\u0026thinsp;=\u0026thinsp;615.0 \u003cem\u003ez\u003c/em\u003e=\u0026ndash;0.508, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.612\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYMRS, mean\u0026thinsp;\u003cem\u003e\u0026plusmn;\u0026thinsp;SD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.67 (1.617)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.33 (2.267)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eU\u003c/em\u003e\u0026thinsp;=\u0026thinsp;567.0 \u003cem\u003ez\u003c/em\u003e=\u0026ndash;1.262, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.208\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBD Type, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eΧ\u003c/em\u003e \u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u0026thinsp;=\u0026thinsp;0.910, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.340\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (67.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 (32.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (43.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (56.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eCognitive Domain Scores*\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAttention and Processing Speed, mean\u0026thinsp;\u003cem\u003e\u0026plusmn;\u0026thinsp;SD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;8.435 (3.422)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.465 (3.356)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eF\u003c/em\u003e(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u0026thinsp;=\u0026thinsp;0.696, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.407\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVerbal Memory, mean\u0026thinsp;\u003cem\u003e\u0026plusmn;\u0026thinsp;SD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.653 (4.736)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.360 (4.892)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eF\u003c/em\u003e(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u0026thinsp;=\u0026thinsp;0.003, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.955\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExecutive Function, mean\u0026thinsp;\u003cem\u003e\u0026plusmn;\u0026thinsp;SD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.291 (2.233)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.160 (2.113)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eF\u003c/em\u003e(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u0026thinsp;=\u0026thinsp;0.015, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.904\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eNote: Significant values are indicated in bold (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05); *Differences in cognitive domain scores, results corrected for age and IQ; IgG\u0026thinsp;=\u0026thinsp;Immunoglobulin G specific for \u003cem\u003eT. gondii\u003c/em\u003e; HAMD\u0026thinsp;=\u0026thinsp;Hamilton Depression Rating Scale, YMRS\u0026thinsp;=\u0026thinsp;Young Mania Rating Scale, BD\u0026thinsp;=\u0026thinsp;Bipolar Disorder\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e also presents further demographic and clinical characteristics and compares variables between IgG seropositive and seronegative groups.\u003c/p\u003e \u003cp\u003e**Insert Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e about here***\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eAssociations between T. gondii IgG serointensity in seropositives and Cognitive Domain Scores\u003c/h2\u003e \u003cp\u003ePartial correlation coefficients were computed to assess linear relationships between IgG serointensity and cognitive domain scores controlling for age and premorbid IQ (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;27). There were no significant correlations between IgG serointensity and both \u0026ldquo;attention and processing speed\u0026rdquo; (\u003cem\u003er=\u003c/em\u003e\u0026ndash;0.095, \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.651) and \u0026ldquo;executive function\u0026rdquo; (\u003cem\u003er\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.115, \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.586). There was a tendency towards a negative correlation, (\u003cem\u003er=\u003c/em\u003e\u0026ndash;0.396, \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.050) between IgG serointensity and \u0026ldquo;verbal memory\u0026rdquo;. Based on this tendency further correlations for individual parameters in the verbal memory domain were explored.\u003c/p\u003e \u003cp\u003eSpecifically, additional partial correlations between IgG antibody levels and the individual test scores in the verbal memory domain using the California Verbal Learning Test were done using Bonferroni corrected alpha levels of \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008. Results showed a negative correlation between IgG serointensity and short delay free recall (\u003cem\u003er=\u003c/em\u003e\u0026ndash;0.539, \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.005), long delay free recall (\u003cem\u003er=\u003c/em\u003e\u0026ndash;0.423, \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.035), and immediate recall sum trial 1\u0026ndash;5 (\u003cem\u003er\u003c/em\u003e=\u0026ndash;0.399, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.048). No significant correlations were found between IgG serointensity, and short delay cued recall (\u003cem\u003er=\u003c/em\u003e\u0026ndash;0.364, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.074) and long delay cued recall (\u003cem\u003er=\u003c/em\u003e\u0026ndash;0.215, \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.302). After Bonferroni correction for multiple comparisons, only negative correlation with short delay free recall remained significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.008). Coefficients and statistics of partial correlation analyses are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePartial Correlation Results between IgG serointensity (in IgG seropositives) and Cognitive Parameters (n\u0026thinsp;=\u0026thinsp;27).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003er\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ep value\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eCognitive Domain Scores\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAttention and Processing Speed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.095\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.651*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExecutive Function\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.115\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.586*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVerbal Memory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.396\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.050*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eIndividual Parameters in the verbal memory domain\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCVLT immediate recall sum trial 1\u0026ndash;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.399\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.048\u003c/b\u003e*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCVLT Short Delay Free Recall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.539\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.005\u003c/b\u003e*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCVLT Short Delay Cued Recall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.364\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.074*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCVLT Long Delay Free Recall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.423\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.035\u003c/b\u003e*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCVLT Long Delay Cued Recall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.215\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.302*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWAIS Digit Span Forward Test\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.115\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.583*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eNote: All results are corrected for age and IQ; Significant values are indicated in bold (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05); *remains significant after Bonferroni correction (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.008); CVLT\u0026thinsp;=\u0026thinsp;California Verbal Learning Test, WAIS\u0026thinsp;=\u0026thinsp;Wechsler Adult Intelligence Scale\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e**Insert Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e about here***\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eKey Findings\u003c/h2\u003e \u003cp\u003eOur investigation aimed to determine associations between \u003cem\u003eT. gondii\u003c/em\u003e-specific antibodies and cognitive function in a well-diagnosed BD sample. While domain scores for \u0026ldquo;attention and processing speed\u0026rdquo; and \u0026ldquo;executive function\u0026rdquo; showed no partial correlations with IgG serointensity, we found inverse associations between \u003cem\u003eT. gondii\u003c/em\u003e IgG serointensity and individual \u0026ldquo;verbal memory\u0026rdquo; scores. Higher \u003cem\u003eT. gondii\u003c/em\u003e IgG titers were associated with lower performance in certain aspects of verbal memory. Notably, all free recall parameters showed significant negative correlations with IgG serointensity in seropositives; however, only short delayed free recall remained significant after Bonferroni correction. The free recall condition of CVLT assesses several memory processes such as encoding, learning, storage, and retrieval. Thus, our results suggest that the higher \u003cem\u003eT. gondii\u003c/em\u003e IgG titers were, the lower the individual's short-term verbal learning abilities.\u003c/p\u003e \u003cp\u003eWe did not find differences between groups seropositive and seronegative for \u003cem\u003eT. gondii\u003c/em\u003e IgG in any cognitive domain assessed (attention and processing speed, verbal memory, and executive function). This coincides with previous studies in BD samples (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA small sample size of participants seropositive for IgM (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7) precluded us from attempting to reevaluate previously reported positive association between \u003cem\u003eT. gondii\u003c/em\u003e IgM serointensity and certain measures of cognitive dysfunction (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e), which later was not replicated (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFurthermore, seropositive individuals were on average older than seronegative individuals. Once infected, the host cannot eradicate \u003cem\u003eT. gondii\u003c/em\u003e due to its ability to hide in intracellular cysts within neurons and glial cells, and to manipulate the immune system. Therefore, prevalence of chronic toxoplasmosis is known to increase with age (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e), and thus we accounted for age by statistical adjustment. We observed no other group differences between seropositive and seronegative groups in any demographic or clinical parameters that might be capable of confounding our results.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and Limitations\u003c/h2\u003e \u003cp\u003eStrengths of this study were its homogeneous and well-diagnosed BD study population, and a clearly defined euthymic state at the time of testing to avoid cognitive alterations caused by mood state episodes. Euthymia was a mandatory inclusion criterion, securing that the mood-state dependent cognitive deficits are not the driver of our associations. Another strength is the result of an association between serointensity in seropositive individuals specifically with verbal recall performance, in contrast to other cognitive domains. It has been reported in longitudinal studies that deterioration in many cognitive tasks in BD is often the result of confounding, except for memory recall (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis study cannot provide evidence for cause-and-effect inferences due to its observational stance and cross-sectional design. Another limiting factor was the small sample size in the evaluation of associations with IgM seropositivity and serointensity (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7) that precluded us from doing analyses in this sub-group. As IgM antibodies can persist years after infection, and could be elevated with reinfection with a different strain, and because the IgM can give false positive results and thus have a limited use in determining incidence, severity and timing of \u003cem\u003eT. gondii\u003c/em\u003e infection (\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e), we have not integrated analysis of IgM seropositivity and serointensity into our analysis of IgG titers.\u003c/p\u003e \u003cp\u003eFurthermore, we did not have a healthy control comparison. Therefore, we cannot estimate if shown cognitive effects differ in individuals with BD (having multiple and potentially interactive liabilities like the recurrent affective disorder, the treatment effects and finally the \u003cem\u003eT. gondii\u003c/em\u003e infection) than in those reported in healthy controls (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). We also did not analyze effects of medications, and thus there is a possibility that medications commonly used in BD and known to impact both cognitive function and the risk of dementia, either inducing worsening or improvement (\u003cspan additionalcitationids=\"CR50 CR51\" citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e), could have been differentially represented in the \u003cem\u003eT. gondii\u003c/em\u003e positive versus negative groups, and thus either leading to spurious results or masking true associations. We also did not analyze a potential confounding, moderating or mediating role of body mass index (BMI) and metabolic factors such as dyslipidemia and diabetes type II, relevant due to the positive associations between obesity and metabolic dysregulation with both cognitive dysfunction in BD (\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e) and \u003cem\u003eT. gondii\u003c/em\u003e infection (\u003cspan additionalcitationids=\"CR56\" citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e). Furthermore, we did not analyze possible interacting effects of alcohol or drug abuse, as well as socioeconomical factors. The latter could represent \u003cem\u003eT. gondii\u003c/em\u003e infection risk factors and also could represent factors previously associated with a poor cognitive status and increased risk of dementia (\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e). We also acknowledge not measuring markers of distinct serotype and especially markers of the oocyst infection that appear to be more virulent, more neurotropic, with more tissue damage and inflammation (\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e), and thus, potentially affecting cognition more strongly than the tissue cyst infection path would.\u003c/p\u003e \u003cp\u003eIn addition, in the absence of a longitudinal study, it is not possible to exclude an alternative explanation for the reported associations. A reverse causality would implicate BD, in particular with preexisting, developmental, preprodromal or post-onset cognitive deficits, as a risk factor for infection and a more extensive and virulent \u003cem\u003eT. gondii\u003c/em\u003e infection, perhaps by elevating risk factors for acquiring toxoplasmosis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eClinical Implications\u003c/h2\u003e \u003cp\u003eWith its worldwide distribution and high prevalence, \u003cem\u003eT. gondii\u003c/em\u003e might impose an additional risk to BD populations, which are already affected by cognitive deficits due to their underlying illness (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Higher \u003cem\u003eT. gondii\u003c/em\u003e prevalence in BD has been shown in numerous meta-analyses (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) and, therefore, makes BD patients even more susceptible to possible negative effects caused by the parasite. This study adds to the existing literature on \u003cem\u003eT. gondii\u003c/em\u003e infection in BD. Since cognitive impairment predicts psychosocial functioning and quality of life (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), identification of \u003cem\u003eT. gondii\u003c/em\u003e as a risk factor and prognostic marker for cognitive outcome might lead to novel treatment approaches for BD patients. Measures to prevent infection and reactivation of the parasite in those already infected, as well as personalized interventions to sustain cognitive performance, could provide additional benefit to patients in a distinct subpopulation of BD, perhaps with high serointensity and documented mood state switches, known to increase cognitive risk. Furthermore, consideration of anti-toxoplasma effects of certain psychotropic medications already used in BD would be necessary.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eDirections for Future Research\u003c/h2\u003e \u003cp\u003eIn future studies larger sample sizes or meta-analyses will be necessary to provide stronger evidence for associations reported in our study. Moreover, longitudinal designs will be necessary to confirm if \u003cem\u003eT. gondii\u003c/em\u003e serointensity in seropositives can predict cognitive decline, function as a catalyst, or even be, at least in part, a causal factor of cognitive decline in a subgroup of BD patients. It might also be worthwhile to investigate the memory component in more detail and to use tests for figural recall and working memory in addition to verbal memory. Identification and targeting of the molecular and cellular mechanisms mediating the link between \u003cem\u003eT. gondii\u003c/em\u003e and cognitive deficits may lead to novel targets and treatment modalities to be tested in their own right. Furthermore, broader serological testing could identify the serotype of \u003cem\u003eT. gondii\u003c/em\u003e, the source of infection via more virulent oocysts versus tissue cysts, as well as co-occurring, and reciprocally potentiating, infections with other chronic latent pathogens.\u003c/p\u003e \u003cp\u003e \u003cem\u003eA Need for Broader Serological Testing to Identify Specific Serotypes of T. gondii.\u003c/em\u003e \u003c/p\u003e \u003cp\u003eThere is a need in future studies to use broader serological testing to identify specific serotypes of \u003cem\u003eT. gondii\u003c/em\u003e. While evidence is emerging that some serotypes of \u003cem\u003eT. gondii\u003c/em\u003e may confer worse clinically relevant outcomes (\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e), it is possible that certain strains (\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e) or modes of infection (e.g., tissue cyst versus oocyst) of \u003cem\u003eT. gondii\u003c/em\u003e, under some conditions, serve as microbial \u0026ldquo;Old Friends\u0026rdquo;\u0026mdash;promoting immunoregulation (\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e, \u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e), and thus, reducing chronic low-grade immune activation, which has been associated with BD (\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cem\u003eRationale for Long Term Plans for Personalized Treatment and Prevention of Cognitive Deficits in BD based on T. gondii Serointensity in Seropositives\u003c/em\u003e \u003c/p\u003e \u003cp\u003eWhile psychotropic treatment is effective in reducing the frequency of mood switches as well as the severity and the duration of mood episodes, its effects on the progression of cognitive deficits in BD has demonstrated considerable variability between and within published studies. This is due to considerable etiological and pathophysiological heterogeneity of cognitive deficits associated with BD. This imposes a change from asking \u0026ldquo;does this treatment work\u0026rdquo; towards \u0026ldquo;what are the characteristics of individual patients with BD in whom a particular treatment is likely to yield strong cognitive protective or remediating effects\u0026rdquo;. Consistent with this vision, the sizable anti-\u003cem\u003eT. gondii\u003c/em\u003e activity of a few psychotropics in the current clinical arsenal in BD might have a direct impact on preventing, slowing or reversing cognitive decline, specifically in \u003cem\u003eT. gondii\u003c/em\u003e seropositive patients with BD who have a high \u003cem\u003eT. gondii\u003c/em\u003e IgG serointensity, as a potential marker of virulence, with frequent reactivation, local and distant spread and induction of inflammation. For example, valproic acid has a considerable antiproliferative effect against \u003cem\u003eT. gondii\u003c/em\u003e tachyzoites \u003cem\u003ein vitro\u003c/em\u003e (\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e) relative to lithium or lamotrigine (\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e), resulting in reductions in tissue cyst load in glial nodules and perivascular infiltration of lymphocytes (\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e), and thus, could become, after confirming in randomized clinical trials, a mood stabilizer of choice in BD patients with high \u003cem\u003eT. gondii\u003c/em\u003e serointensity.\u003c/p\u003e \u003cp\u003eConsistently, Fond et al., (\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e) showed that the total number of recurrent depressive episodes was reduced in individuals with BD (but not major depressive disorder) who were \u003cem\u003eT. gondii\u003c/em\u003e seropositive, if treated with psychotropics having anti-\u003cem\u003eT. gondii activity\u003c/em\u003e (TATA+) as compared with medications that had no or minimal anti-\u003cem\u003eT. gondii activity\u003c/em\u003e (TATA\u0026ndash;) (\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e). The TATA\u0026thinsp;+\u0026thinsp;medications included valproate, paliperidone, risperidone, fluphenazine, haloperidol, levomepromazine, loxapine, thioridazine, zuclopenthixol, and cyamemazine. The TATA\u0026ndash; drugs included lamotrigine, lithium carbonate, carbamazepine, olanzapine, quetiapine, aripiprazole, amisulpride, clozapine, and tiapride.\u003c/p\u003e \u003cp\u003eThe medications commonly used to prevent or treat severe exacerbated toxoplasmosis in immunocompromised hosts, or in acute severe infections (e.g., pyrimethamine and sulfadiazine) are not sufficiently effective against bradyzoites within tissue cysts, thus in chronic toxoplasmosis, and have considerable side effects. Widely used medications, statins, have previously demonstrated pleiotropic antiproliferative effects on \u003cem\u003eT. gondii\u003c/em\u003e through inhibition of isoprenoid synthesis in the parasite. For instance, treatment with the lipophilic statins pravastatin and simvastatin reduced adhesion, infection, and proliferation of \u003cem\u003eT. gondii\u003c/em\u003e in HeLa cells, in monotherapy (\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e) as well as in combination with anti-toxoplasmosis agents pyrimethamine and sulfadiazine (\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e). A chronic toxoplasmosis \u003cem\u003ein vivo\u003c/em\u003e model has demonstrated that rosuvastatin, a hydrophilic statin, reverses the short term and long term memory impairment in BALB/c mice infected with ME-39 strain of \u003cem\u003eT. gondii\u003c/em\u003e (\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e), also reducing the brain cyst load as well as markers neuroinflammation, including microglial proliferation, perivascular cuffs, and cell infiltration (\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e, \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e). Furthermore, novel compounds based on in silico structural and mechanistic short-listing have yielded promising anti-\u003cem\u003eT. gondii\u003c/em\u003e pharmacological approaches (\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e). Of particular relevance is hydroxyzine, a first generation sedating antihistamine, widely used off label for insomnia, anxiety, and agitation in patients with recurrent mood disorders, which has recently demonstrated a specific capability not only to reduce tachyzoites infection and spread, but also to prevent reactivation of chronic infection by suppressing bradyzoites (\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThese developments provide further support for the need for clinical trials investigating repurposing medications with anti-\u003cem\u003eT. gondii\u003c/em\u003e activity, demonstrated \u003cem\u003ein vitro\u003c/em\u003e after being short-listed by in silico analysis (\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e), to improve therapeutic control, to preserve or even enhance cognitive function and rehabilitate functioning in a specific subgroup of seropositive BD patients with high IgG serointensity, and to determine longitudinally documented overlap between indicators of \u003cem\u003eT. gondii\u003c/em\u003e reactivation (including episodic elevations of IgG serointensity) and clinically-defined BD relapse, or symptomatic exacerbation of mood state switching, or worsening of cognitive deficits.\u003c/p\u003e \u003cp\u003eIn the longer term, regarding drug discovery based on mechanistic inferences, there are promising areas involving targeting autophagy dysregulation, which is actively induced and sustained by intracellular \u003cem\u003eT. gondii\u003c/em\u003e bradyzoites (\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e) and contributes to cognitive deficits in BD, as a recent elegant postmortem study using a reverse translational approach has demonstrated (\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe high \u003cem\u003eT. gondii\u003c/em\u003e IgG serointensity in seropositives could become one among many other predictive biomarkers for personalizing the treatment approach targeting cognitive dysfunction in BD. For instance, while valproate appears as inferior to lithium (\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e) in terms of preserving cognitive function and preventing dementia in patients with BD, in the subgroup with high \u003cem\u003eT. gondii\u003c/em\u003e serointensity valproate might end up being advantageous, considering its TATA\u0026thinsp;+\u0026thinsp;activity. This could be evaluated in a targeted randomized interventional study. By extension, a possible next step of our current report is represented by a double-blind randomized study comparing cognitive function between those randomly treated with a TATA(+) versus TATA(\u0026ndash;) psychotropic\u0026ndash;in a sample including only individuals with high \u003cem\u003eT. gondii\u003c/em\u003e IgG serointensity and mild cognitive deficits. This study will be positioned to test the causal hypothesis underlying our current result, and distinguish it from alternative explanations, including reverse causality or confounding.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis investigation is the first to show an association between \u003cem\u003eT. gondii\u003c/em\u003e IgG serointensity in seropositives and specific cognitive deficits in a well-diagnosed BD sample. Specifically, verbal memory parameters, and in particular short delay free recall, were negatively correlated with IgG serointensity. Although further research is needed to confirm and expand our findings, eliminate potential sources of bias, and establish cause-effect relationships, latent \u003cem\u003eT. gondii\u003c/em\u003e infection may emerge as a pharmacologically targetable contributory cause to decreased cognitive performance, functioning, and quality of life in patients with bipolar disorder.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Bipolar Disorder\u003c/p\u003e\n\u003cp\u003eCVLT\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;California Verbal Learning Test\u003c/p\u003e\n\u003cp\u003ed2-R\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;d2 Test of Attention Revised\u003c/p\u003e\n\u003cp\u003eELISA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Enzyme-linked Immunosorbent Assay\u003c/p\u003e\n\u003cp\u003eHAMD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Hamilton Depression Rating Scale\u003c/p\u003e\n\u003cp\u003eHAWIE\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Hamburg-Wechsler-Intelligenztest f\u0026uuml;r Erwachsene\u003c/p\u003e\n\u003cp\u003eIgG\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Immunoglobulin G\u003c/p\u003e\n\u003cp\u003eIgM\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Immunoglobulin M\u003c/p\u003e\n\u003cp\u003eIQ\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Intelligence Quotient\u003c/p\u003e\n\u003cp\u003eMANCOVA\u0026nbsp; \u0026nbsp;\u0026nbsp;Multivariate Analyses of Co-Variance\u003c/p\u003e\n\u003cp\u003eMWT-B\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Multiple Choice Vocabulary Test\u003c/p\u003e\n\u003cp\u003eOD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Optical Density\u003c/p\u003e\n\u003cp\u003eSCID-I\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Structured Clinical Interview for DSM IV\u003c/p\u003e\n\u003cp\u003eTATA+\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Medications having anti-T. gondii Activity\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTATA-\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Medications having no or minimal anti-T. gondii Activity\u003c/p\u003e\n\u003cp\u003eTMT-A\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Trail Making Test Part A\u003c/p\u003e\n\u003cp\u003eTMT-B\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Trail Making Test Part B\u003c/p\u003e\n\u003cp\u003eT. gondii\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Toxoplasma Gondii\u003c/p\u003e\n\u003cp\u003eWAIS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Wechsler Adult Intelligence Scale\u003c/p\u003e\n\u003cp\u003eYRMS \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Young Mania Rating Scale\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the ethics committee of the Medical University of Graz (EC-number: 25-335 ex 12/13). Written informed consent was obtained from all subjects before participation in this study.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data and material\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePR received a student scholarship from the Medical University of Graz to cover publication costs.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors\u0026apos; contributions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePRconceptualized the study, collected data as part of the BIPLONG study project, curated the data, undertook the statistical analyses and wrote the original draft of the manuscript. TTPsupported conceptualization, contributed to results interpretation and co-wrote intermediate drafts of the manuscript. NDsupported conceptualization, planned statistical analyses and coordinated the BIPLONG study project.TSsupervised statistical analyses.NC performed serological analysis of T. gondii antibodies and played a critical role in interpretation of results. ADorganized the database of biological material for serological analysis and managed data, and interpreted results. AB, FM, CAL, and JJ contributed to results interpretation and co-wrote intermediate drafts of the manuscript. AB, FTF, AF, ML, AM, AP, RQ, FS, SS, and ATBare part of the BIPLONG study group, were responsible for diagnostics and data collection. EZRis project lead and\u0026nbsp;supported conceptualization. All authors contributed intellectual content to the manuscript, and also read, edited and approved its final version.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMoreira ALR, Van Meter A, Genzlinger J, Youngstrom EA. Review and Meta-Analysis of Epidemiologic Studies of Adult Bipolar Disorder. J Clin Psychiatry. 2017;78(9):e1259\u0026ndash;69.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChan JKN, Tong CHY, Wong CSM, Chen EYH, Chang WC. Life expectancy and years of potential life lost in bipolar disorder: systematic review and meta-analysis. Br J Psychiatry. 2022;221(3):567\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBourne C, Aydemir \u0026Ouml;, Balanz\u0026aacute;-Mart\u0026iacute;nez V, Bora E, Brissos S, Cavanagh JT, et al. 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Vet Parasitol. 2006;140(1\u0026ndash;2):69\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEvangelista FF, de Sant'Ana L, Ferreira P, Ferreira WC, Dos Santos TA, de Souza ML. The Brazilian Toxoplasma gondii strain BRI caused greater inflammation and impairment in anxiogenic behavior in mice, which was reverted by rosuvastatin treatment. Parasitol Res. 2023;123(1):64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrito RMM, de Lima Bessa G, Bastilho AL, Dantas-Torres F, de Andrade-Neto VF, Bueno LL, et al. Genetic diversity of Toxoplasma gondii in South America: occurrence, immunity, and fate of infection. Parasit Vectors. 2023;16(1):461.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTenorio EP, Fern\u0026aacute;ndez J, Castellanos C, Olgu\u0026iacute;n JE, Saavedra R. 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Effect of valproate and lithium on dementia onset risk in bipolar disorder patients. Sci Rep. 2022;12(1):14142.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-bipolar-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijbd","sideBox":"Learn more about [International Journal of Bipolar Disorders](http://journalbipolardisorders.springeropen.com/)","snPcode":"40345","submissionUrl":"https://submission.nature.com/new-submission/40345/3","title":"International Journal of Bipolar Disorders","twitterHandle":"@SpringerOpen","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"bipolar disorder, toxoplasmosis, Toxoplasma gondii, cognition","lastPublishedDoi":"10.21203/rs.3.rs-4556766/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4556766/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAlongside affective episodes, cognitive dysfunction is a core symptom of bipolar disorder. The intracellular parasite \u003cem\u003eToxoplasma gondii\u003c/em\u003e has been positively associated with both a diagnosis of bipolar disorder as well as poorer cognitive performance, across diagnostic boundaries.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA total of 76 participants with bipolar disorder were tested for \u003cem\u003eToxoplasma gondii\u003c/em\u003e -specific IgG and IgM antibodies and for cognitive performance with a neuropsychological test battery. Cognitive parameters were categorized into three cognitive domains (attention and processing speed, verbal memory, executive function). Statistical analysis of associations between continuous indicators of cognitive status as dependent variables in relationship to \u003cem\u003eToxoplasma gondii\u003c/em\u003e, included multivariate analyses of co-variance for seropositivity, and partial correlations with IgG serointensity in IgG seropositives. All analyses were controlled for age and premorbid IQ.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn seropositives (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;27), individual parameters in the verbal memory domain showed significant inverse partial correlations with IgG antibody levels. Cognitive functioning did not differ between IgG seropositive and seronegative individuals in any of the cognitive domains (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;76). IgM positives (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7) were too few to be analyzed.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThis investigation is the first to show an association between \u003cem\u003eToxoplasma gondii\u003c/em\u003e IgG serointensity and memory function in a well-diagnosed bipolar disorder sample. While further research is necessary, latent \u003cem\u003eToxoplasma gondii\u003c/em\u003e infections could represent a risk factor for functional decline for patients with bipolar disorder and \u003cem\u003eToxoplasma gondii\u003c/em\u003e serointensity in seropositives may emerge as a biomarker for personalized treatment.\u003c/p\u003e","manuscriptTitle":"Toxoplasma gondii IgG Serointensity and Cognitive Function in Bipolar Disorder","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-25 11:02:27","doi":"10.21203/rs.3.rs-4556766/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-11T08:29:03+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-11T07:36:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"298674299718087963576821840041630853136","date":"2024-07-08T06:18:42+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-03T20:19:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"246470427012105528122427754702329772814","date":"2024-07-03T12:13:06+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-24T12:38:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-10T13:05:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-10T13:05:10+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Bipolar Disorders","date":"2024-06-10T08:36:26+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-bipolar-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijbd","sideBox":"Learn more about [International Journal of Bipolar Disorders](http://journalbipolardisorders.springeropen.com/)","snPcode":"40345","submissionUrl":"https://submission.nature.com/new-submission/40345/3","title":"International Journal of Bipolar Disorders","twitterHandle":"@SpringerOpen","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d1abd6e5-7b55-4056-8512-36853ccb4ea5","owner":[],"postedDate":"June 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-26T16:04:33+00:00","versionOfRecord":{"articleIdentity":"rs-4556766","link":"https://doi.org/10.1186/s40345-024-00353-8","journal":{"identity":"international-journal-of-bipolar-disorders","isVorOnly":false,"title":"International Journal of Bipolar Disorders"},"publishedOn":"2024-08-23 15:57:53","publishedOnDateReadable":"August 23rd, 2024"},"versionCreatedAt":"2024-06-25 11:02:27","video":"","vorDoi":"10.1186/s40345-024-00353-8","vorDoiUrl":"https://doi.org/10.1186/s40345-024-00353-8","workflowStages":[]},"version":"v1","identity":"rs-4556766","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4556766","identity":"rs-4556766","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}