Iraqi J Pharm Sci, Vol.30(2) 2021 Toxoplasmosis in parkinson’s disease patients DOI: https://doi.org/10.31351/vol30iss2pp99-105 99 Seroprevalence of Toxoplasma Gondii in Parkinson’s Disease Iraqi Patients Maysoon Abdul-Zahra Merdaw*, Ali A.Kasim*,1 and Mahmood Kahtan Salih** *Department of Clinical Laboratory Sciences, College of Pharmacy, University of Baghdad, Baghdad-Iraq **Department of Pharmacology and Toxicology, College of Pharmacy, University of Baghdad, Baghdad-Iraq Abstract Several studies have addressed the prevalence of Toxoplasma gondii (T. gondii), among Parkinson’s disease (PD) patients in different countries, and the potential association between the infection and PD; the results of these studies were conflicting. The study aims to investigate the prevalence of Toxoplasma infection among sample of Iraqi PD patients. Also, to examine the potential association of age, PD duration, gender, smoking habit, zone of residence and family history of PD, with the prevalence of Toxoplasma infection in PD patients. Seventy-four PD patients attaining Dr. Saad Al-Witry Neuroscience Hospital in Baghdad/ Iraq for routine follow up, from different Iraqi governorates, were enrolled in this cross-sectional study. Detection of T. gondii was performed by detection of anti-Toxoplasma IgG and IgM antibodies in serum by ELISA method. The frequency rate of anti-Toxoplasma IgG antibodies in Iraqi PD patients was 43.2% (32/74); while, none of the participants was seropositive for anti-Toxoplasma IgM antibody. Age, PD duration, smoking habit and zone of residences were not shown to be risk factors for Toxoplasma infection in PD patients (P>0.05); meanwhile, female gender and positive family history of PD were shown to have a protective effect; (OR, 0.309; 95% CI, 0.099-0.966; P= 0.043) and (OR, 0.162; 95% CI, 0.037-0.705; P=0.015); respectively. The prevalence rate of Toxoplasma infection in Iraqi PD patients is 43.2%, female gender and positive family history of PD might protect against Toxoplasma infection in PD patients. Key words: Iraq, Neurodegeneration, Parkinson’s disease, Prevalence, Toxoplasma gondii العراقيين باركنسون داء مرضى في الغوندية المقوسة انتشار **محمود قحطان صالح و 1 *،، علي عبد الحسين قاسم *و اميسون عبد الزهرة مرد فرع العلوم المختبرية السريرية، كلية الصيدلة، جامعة بغداد، بغداد، العراق * ، بغداد، العراق. كلية الصيدلة، جامعة بغداد االدوية والسموم، فرع ** الخالصة مختلفة، والعالقة المحتملة في بلدان ، بين مرضى داء باركنسونأو المقوسة الغوندية التوكسوبالزماتناولت العديد من الدراسات انتشار تهدف الدراسة الحالية إلى معرفة مدى انتشار عدوى التوكسوبالزما . كانت نتائج هذه الدراسات متضاربة .بين عدوى التوكسوبالزما وداء باركنسون ن والجنس والتدخين ومنطقة بين عينة من مرضى داء باركنسون في العراق باإلضافة لفحص االرتباط المحتمل بين العمر ومدة مرض باركنسو . اإلقامة والتاريخ العائلي لمرض باركنسون، مع ايجابية المصل للتوكسوبالزما في مرضى داء باركنسون م تم تسجيل أربعة وسبعين مريضاً من مرضى داء باركنسون في هذه الدراسة المقطعية المستعرضة من مراجعي مستشفى الدكتور سعد الوترى للعلو عن طريق التوكسوبالزما تم إجراء الكشف عن اصابة. العراق الحاضرين للمتابعة الروتينية ، من مختلف المحافظات العراقية /بغداد العصبية في . االمتزاز المناعي المرتبط باالنزيم المضادة للتوكسوبالزما في مصل الدم بطريقة IgM و IgG الكشف عن األجسام المضادة تواتر معدل المضادةبلغ مرضى IgG األجسام في للتوكسوبالزما باركنسون المضادة من (. 32/74)٪ 43.2العراقيين داء أي يكن لم بينما، والتدخين ومنطقة اإلقامة االصابة بداء باركنسون لم يُظهر العمر ومدة. المضادة للتوكسوبالزما IgM المشاركين إيجابي المصل لألجسام المضادة ؛ بينما تبين أن للجنس األنثوي والتاريخ العائلي اإليجابي لداء باركنسون (P> 0.05) التوكسوبالزما في مرضى داء باركنسون كعوامل خطر لعدوى تأثير وقائي (OR, 0.162; 95% CI, 0.037-0.705; P=0.015)و (OR, 0.309; 95% CI, 0.099-0.966; P= 0.043) على التوالي. ٪ ، والجنس األنثوي والتاريخ العائلي اإليجابي لمرض باركنسون 43.2العراقيين هو باركنسون ءداى التوكسوبالزما في مرضمعدل انتشار عدوى . قد يحميان من عدوى التوكسوبالزما في مرضى داء باركنسون العراق، التنكس العصبي، مرض باركنسون، االنتشار، التوكسوبالزما جوندي :الكلمات المفتاحية 1Corresponding author E-mail: E-mail: ali.qasem@copharm.uobaghdad.edu.iq Received: 6/1/2021 Accepted: 15/3 /2021 Published Online First: 2021-12-09 Iraqi Journal of Pharmaceutical Science https://doi.org/10.31351/vol30iss2pp99-105 Iraqi J Pharm Sci, Vol.30(2) 2021 Toxoplasmosis in parkinson’s disease patients 100 Introduction Toxoplasma gondii (T. gondii) is an obligate intracellular parasitic protozoan that causes a zoonotic disease known as toxoplasmosis. T. gondii can infect most worm-blooded mammals including human (1). The infection is transmitted to the humans by consumption of raw or undercooked meat comprising the parasites’ cysts, ingestion of oocysts, and from the infected mother to the fetus (2). Moreover, T. gondii is transmitted through blood transfusion and organ or stem cell transplantation (3). It is estimated that over one third of the world population is infected with T. gondii, thus, it is considered the etiological cause of the most prevalent infection in humans (4). The infection is mostly asymptomatic in individuals with competent immune responses, and tissue cysts of the parasite are formed principally in the brain and skeletal muscles (5). The infection remains latent until when the hosts’ immune responses are challenged where tissue cysts rupture causes release of the quiescent parasite that rapidly divide (6). The reactivated infections might result in neurological damage and inflammation (7, 8). Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder, just preceded by Alzheimer’s disease. PD affects about 1% of the world population aged 60 years or older (9, 10). The pathological hallmarks in PD involve dopaminergic and non-dopaminergic neurodegeneration and cytoplasmic accumulation of misfolded proteins known as Lewy bodies. Many pathological mechanisms have been proposed to explain these events (11-17). The prevalence of T. gondii infection in Parkinson’s disease patients has been studied in many epidemiological studies in an attempt to investigate whether T. gondii infection is associated with increased risk for Parkinson’s disease; and the results have been very inconsistent. Ramezani et al. has reported a significantly higher frequency rate of anti‐toxoplasmosis seropositivity in the idiopathic PD patients compared to healthy individuals and patients with other neurological disorders; and has suggested that T. gondii infection contributed to an increased risk of idiopathic PD (18). Similarly, Miman et al. has considered toxoplasma infection might contribute to the pathogenesis of PD (19). Contrariwise, other studies have reported no association between Toxoplasma infection and PD (2,20, 21). Actually, Fallahi et al. has suggested that T. gondii infection could not be a risk factor for PD and that patients with PD are at more risk to acquire Toxoplasma infection (2). To date, the prevalence of Toxoplasma in Iraqi PD patients is not documented. Thus, this study aims to investigate the prevalence of anti-Toxoplasma antibodies in a sample of Iraqi PD patients; and to examine the potential association of age, PD duration, gender, smoking habits, zone of residence and family history of PD, with the prevalence of Toxoplasma infection in PD patients. Patients and Methods This cross-sectional study was conducted at Dr. Saad Al-Witry Neuroscience Hospital in Baghdad/ Iraq, during the period extending from May to December 2019. The study was approved by the Research Committee and by the Ethics Committee of the College of Pharmacy/University of Baghdad. Seventy-four patients with an established diagnosis of PD, according to The United Kingdom Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria for idiopathic PD (22); who were attending the hospital for routine follow up, were enrolled in the study. Patients with other neurological diseases and people with a history of brain surgery were excluded from the study. Sociodemographic data regarding patients’ age, gender, zone of residence, and smoking habits; in addition to PD duration and family history of PD were collected by one of the researchers. A consent was obtained from each patient after being informed about all aspects of the study. A five millilitres venous blood samples were collected from the patients and left at room temperature to clot, then the samples were centrifuged at 3000 rpm for 15 minutes to obtain sera. Sera were separated and kept frozen at (-20 °C) until assayed. Anti-Toxoplasma IgM and IgG levels were assayed using a readily available enzyme- linked immunosorbent assay (ELISA) kit purchased from (ACON laboratories, San Diego, USA). Calibration curve was drawn to obtain serum anti- Toxoplasma IgG and IgM levels from their absorbance. For qualitative assessment of anti- Toxoplasma IgG and IgM seropositivity, Index value >1.1was interpreted as positive, also according to the manufacturer recommendations. Statistical analysis Statistical analyses were performed using SPSS, version 22 (SPSS Inc., Chicago, IL, USA), software for windows. Descriptive statistics, mainly mean values and standard deviation (SD), were presented for numerical variables, and frequencies and percentages were used for categorical variables. Independent student t-test was conducted to examine the significance of the difference in the means of numerical variables between anti- Toxoplasma IgG -positive and -negative groups. Iraqi J Pharm Sci, Vol.30(2) 2021 Toxoplasmosis in parkinson’s disease patients 101 While, chi-square test was used to check the significance of the difference in the frequencies of the categorical variables between anti-Toxoplasma IgG-positive and -negative groups. Univariate and multivariate logistic regression were used to identify risk factors associated with the seropositivity of anti- Toxoplasma IgG in PD patients. Variables with P- values less than 0.05 in the univariate logistic model were included in the multivariate logistic model. The confidence interval was set to 95%, and the default level of statistical significance was based on P < 0.05 Results In this study, the mean age of PD patients was 60.65 ± 10.67. Forty-three patients (58.1 %) were males and 31 (41.9%) were females. In terms of zone of residence, 60 patients (81.1%) were living rural areas and 14 (18.9%) were living in urban areas. The mean duration of disease was 6.41 ± 3.75 years; only 17 patients (23%) have a family history of PD and only 16 patients (21.6%) were smokers; (Table 1). The overall prevalence of Toxoplasma in PD patients was 32/74 (43.2%); Toxoplasma positive patients were found positive for anti- Toxoplasma IgG antibody, which reflects chronic Toxoplasma infections. All PD patients were found as negative for anti-Toxoplasma IgM antibody. None of the samples was in the equivocal range for anti-Toxoplasma IgG or IgM antibody. The mean serum levels of anti-Toxoplasma IgG antibody in seropositive PD patients was 3.538 ± 2.164 (Table 2). Table 1. Characteristics of 74 Parkinson’s disease patients Age (year) 60.65 ± 10.67 PD duration (year) 6.41 ± 3.75 Gender [n (%)] Male 43 (58.1%) Female 31 (41.9%) Smoking [n (%)] No 58 (78.4%) Yes 16 (21.6%) Zone of residence [n (%)] Rural 60 (81.1%) Urban 14 (18.9%) Family history of Parkinson’s disease [n (%)] No 57 (77%) Yes 17 (23%) Table 2. Frequency and serum levels of anti T. gondii antibodies in Parkinson’s disease patients Serum anti-Toxoplasma IgG antibody Serum anti-Toxoplasma IgM antibody Frequency Level Range Frequency Level Range Toxoplasma Positive 32 (43.2%) 3.538 ± 2.164 1.30-7.54 0 (0%) ------- ------- Toxoplasma Negative 42 (56.8%) 0.473 ± 0.134 0.31-0.79 100 (100%) 0.232 ± 0.048 0.18-0.36 The means of age and PD duration were significantly different between anti-Toxoplasma IgG antibody seropositive and seronegative patients (P<0.001). Moreover, there was a significant difference between the frequency of Toxoplasma between male and female PD patients and between those with positive and negative family history of PD (P = 0.036 and 0.015; respectively); (Table 3). Table 3. Patients’ characteristics by prevalence of toxoplasmosis Variable Toxoplasma positive n=32 Toxoplasma negative n=42 P value Age (year) 64.31 ± 10.17 57.86 ± 9.87 0.000 PD duration (year) 7.16 ± 4.89 5.83 ± 2.49 0.000 Gender Male 23 (71.9%) 20 (47.6%) 0.036 Female 9 (28.1%) 22 (52.4%) Smoking No 23 (71.9%) 35 (83.3%) 0.236 Yes 9 (28.1%) 7 (16.7) Zone of residence Rural 28 (87.5%) 32 (76.2%) 0.218 Urban 4 (12.5%) 10 (23.8%) Family history of PD No 29 (90.6%) 28 (66.7%) 0.015 Yes 3 (9.4%) 14 (33.3%) Iraqi J Pharm Sci, Vol.30(2) 2021 Toxoplasmosis in parkinson’s disease patients 102 Univariate logistic regression analysis showed that the older age, female gender and positive family history of PD are significantly related to anti-Toxoplasma IgG antibody seropositivity; (Table 4). Multivariate logistic regression analysis of these variables showed that female gender and positive family history of PD reduce the risk of anti-Toxoplasma IgG antibody seropositivity in PD patients; (OR 0.309, 95% CI: 0.99-0.966, P = 0.043) and (OR 0.162, 95% CI: 0.037-0.705, P = 0.015); respectively; (Table 4). Table 4.Multiple logistic regression analysis to predict potential independent risk factors for prevalence of toxoplasmosis in Pakinson’s disease patients Variable Unadjusted Adjusted OR (95% CI) P value OR (95% CI) P value Age 1.069 (1.014-1.127) 0.014 1.041 (0.983-1.102) 0.169 PD duration 1.103 (0.968-1.257) 0.141 -------- ------ Gender Male (Reference group) Female 0.356 (0.134-0.948) 0.039 0.309 (0.099-0.966) 0.043 Smoking No (Reference group) Yes 1.957 (0.637-5.991) 0. 240 -------- ------ Zone of residence Rural (Reference group) Urban 0.457 (0.129-1.621) 0.225 -------- ------ Family history of PD No (Reference group) Yes 1.036 (0.054-0.799) 0.022 0.162 (0.037-0.705) 0.015 Discussion Latent Toxoplasma infection has been shown to be associated with neurodegeneration (23). The exact mechanism by which Toxoplasma infection results in neurodegeneration is not well elucidated; however, neuroinflammation has been proposed to be a major contributor (24). In chronic Toxoplasma infection, the cysts tend to concentrate in the neurons (25), where they are subjected to persistent local cellular immune reactions (26). Neuroinflammation might continue for years if Toxoplasma infection is not eradicated (23). Many studies have addressed the prevalence of Toxoplasma infection among PD patients in different countries, and the potential association between the infection and PD; the results of these studies were conflicting (2,18-21,27,28). Except for Ramezani et al.(18) and Miman et al.(19) who have reported significant difference in seroprevalence of Toxoplasma infection between PD patients and healthy control, other studies did not report such finding. In a recent meta-analysis, Zhou et al. reported no correlation between PD and anti- Toxoplasma IgG antibody seropositivity (29). This meta-analysis has attributed the positive correlation that has been reported in some studies (18, 19), to the small sample sizes and sampling bias that these studies were conducted in a nearby geographical area. To the best of our knowledge, this is the first study investigating the prevalence of Toxoplasma infection and PD in Iraq. In the present study, 43.2% of PD patients were seropositive for anti-Toxoplasma IgG antibody, indicating chronic latent infection. While, all PD patients were seronegative for anti-Toxoplasma IgM antibody, indicating no acute Toxoplasma infection among participants (Table 2). These results occur in agreement with studies that have reported seroprevalence, based on anti-Toxoplasma IgG antibody, in Turkey (42.3%)(19), Egypt (43.3%)(27), Iran (53%)(2). Ramezani et al.(18) and Mahami et al.(21) have reported higher seroprevelance rates in Iran (82.5% and 85%; respectively). Low seroprevalence rates has been reported by Alvarado- Esquivel et al. (9.2%) in Mexico(20) and by Çelik et al. (18%) in Turkey(28). In the present study, the age of seropositive PD patients was significantly higher than their seronegative counterparts (Table 3). Age has been reported to be a risk factor for Toxoplasma infection(30, 31). The increase in Toxoplasma seroprevalence with age can be attributed to the increase in the likelihood of contact with the parasites’ oocyts with time, due to occupational factors for example. Moreover, the improvement in the knowledge about Toxoplasma infection and its routes of transmission might reduce the prevalence Iraqi J Pharm Sci, Vol.30(2) 2021 Toxoplasmosis in parkinson’s disease patients 103 of Toxoplasma infection among younger individuals. The duration of PD in Toxoplasma seropositive patients in the present study, was significantly higher than that of their seronegative counterparts (Table 3). However, PD duration was not a risk factor for the seroprevalence of Toxoplasma in PD patients (Table 4). Typically, onset and diagnosis of PD occur ages higher than 55 years, thus, the higher PD duration in Toxoplasma seropositive PD patients might reflects the higher age of those patients rather than of pointing a pathological significance. Regarding gender, the results showed significant difference between males and females of Toxoplasma seropositive and seronegative PD patients (Table 3), and female PD patients were shown to be at lower risk for Toxoplasma infection (Table 4), which disagree with Mahami et al.(21) who reported no association between gender and Toxoplasma infection in PD patients. Female gonadal sex hormones in rats have been shown to modulate the dopaminergic actions in the striatum and nucleus accumbens of the brain(32). Dluzen et al. has showed that estrogen protects against neurodegeneration of the striatal dopaminergic system, probably by inhibiting the uptake of neurotoxins(33). The Toxoplasma-induced dopamine manipulation, which has long been suggested(34), might be inhibited by estrogen, hence, contributing to the lower prevalence and risk of Toxoplasma infection in female PD patients reported in the study. The results of the present study showed that PD patients with positive family history of the disease are at lower risk for Toxoplasma infection (Table 4). Up to our knowledge, this is the first study reporting such a relationship and further studies are required for confirmation. If confirmed, this finding may highlight a genetic role in protecting against, Toxoplasma infection in PD patients. It is worthy to mention that, several studies have linked genetic polymorphisms with increased(35, 36), or decreased(37) susceptibility to Toxoplama infection. Finally, smoking and zone of residence were not associated with Toxoplasma infection in PD patients that occur in agreement with other studies(20, 21). 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Cytotoxic T-Lymphocyte Associated Antigen-4 (+49A/G) Gene Polymorphism as a Protective Factor against Toxoplasmosis. Medical Journal of Babylon. 2017;14(2):240-6. Baghdad Iraqi Journal Pharmaceutical Sciences by bijps is licensed under a Creative Commons Attribution 4.0 International License. Copyrights© 2015 College of Pharmacy - University of Baghdad. http://bijps.uobaghdad.edu.iq/index.php/bijps.com http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/