G Fond1, L Boyer2, F Schürhoff3, F Berna4, O Godin5, E Bulzacka3, M Andrianarisoa3, L Brunel3, B Aouizerate6, D Capdevielle7, I Chereau8, N Coulon3, T D'Amato9, C Dubertret10, J Dubreucq11, C Faget2, C Lançon2, S Leignier11, J Mallet10, D Misdrahi12, C Passerieux13, R Rey9, A Schandrin7, M Urbach13, P Vidailhet14, P M Llorca8, M Leboyer3. 1. Fondation FondaMental, Créteil, France; Aix-Marseille Univ, Faculté de Médecine - Secteur Timone, EA 3279: CEReSS -Centre d'Etude et de Recherche sur les Services de Santé et la Qualité de vie, 27 Boulevard Jean Moulin, 13005 Marseille, France. Electronic address: guillaume.fond@ap-hm.fr. 2. Fondation FondaMental, Créteil, France; Aix-Marseille Univ, Faculté de Médecine - Secteur Timone, EA 3279: CEReSS -Centre d'Etude et de Recherche sur les Services de Santé et la Qualité de vie, 27 Boulevard Jean Moulin, 13005 Marseille, France. 3. Fondation FondaMental, Créteil, France; INSERM U955, équipe de psychiatrie translationnelle, Créteil, France; Université Paris-Est Créteil, DHU Pe-PSY, Pôle de Psychiatrie des Hôpitaux Universitaires H Mondor, Créteil, France. 4. Fondation FondaMental, Créteil, France; Hôpitaux Universitaires de Strasbourg, Université de Strasbourg, INSERM U1114, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France. 5. Fondation FondaMental, Créteil, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, F-75013 Paris, France; INSERM, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, F-75013 Paris, France. 6. Fondation FondaMental, Créteil, France; Université de Bordeaux, Centre Hospitalier Charles Perrens, F-33076 Bordeaux, France; INRA, NutriNeuro, University of Bordeaux, U1286 F-33076 Bordeaux, France. 7. Fondation FondaMental, Créteil, France; Service Universitaire de Psychiatrie Adulte, Hôpital la Colombière, CHRU Montpellier, Université Montpellier 1, Inserm 1061, Montpellier, France. 8. Fondation FondaMental, Créteil, France; CMP B, CHU, EA 7280 Faculté de Médecine, Université d'Auvergne, BP 69 63003 Clermont-Ferrand Cedex 1, France. 9. Fondation FondaMental, Créteil, France; INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, Université Claude Bernard Lyon 1, Equipe PSYR2, Centre Hospitalier Le Vinatier, Pole Est, 95 bd Pinel, BP 30039, 69678 Bron Cedex, France. 10. Fondation FondaMental, Créteil, France; AP-HP, Department of Psychiatry, Louis Mourier Hospital, Colombes, Inserm U894, Université Paris Diderot, Sorbonne Paris Cité, Faculté de médecine, France. 11. Fondation FondaMental, Créteil, France; Centre Référent de Réhabilitation Psychosociale, CH Alpes Isère, Grenoble, France. 12. Fondation FondaMental, Créteil, France; Université de Bordeaux, Centre Hospitalier Charles Perrens, F-33076 Bordeaux, France; CNRS UMR 5287-INCIA, France. 13. Fondation FondaMental, Créteil, France; Centre Hospitalier de Versailles, Service de psychiatrie et d'addictologie adulte, Le Chesnay, EA 4047 HANDIReSP, UFR des Sciences de la Santé Simone Veil, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France. 14. Hôpitaux Universitaires de Strasbourg, Université de Strasbourg, INSERM U1114, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France.
Abstract
OBJECTIVE: Latent Toxoplasma infection has been associated with widespread brain immune activation, increased blood brain barrier permeability, neural disruption, increased dopamine release in dopaminergic neurons, with NMDA activation and with schizophrenia (SZ) onset risk. Toxoplasma has been suggested to be a source of chronic low-grade inflammation and this inflammation has been associated with cognitive impairment in SZ. The objective of the present study were (i) to determine if latent Toxoplasma infection was associated with specific clinical features in stabilized SZ subjects, with cognitive impairment and with increased low-grade peripheral inflammation and (ii) to determine if Treatments with Anti-Toxoplasmic Activity (TATA) were associated with improved outcomes in subjects with latent Toxoplasma infection. METHODS: A comprehensive 2 daylong clinical and neuropsychological battery was administered in 250 SZ subjects included between 2015 and 2017 in the national FondaMental Expert Center (FACE-SZ) Cohort. Solid phase-enzyme microplate immunoassay methods were used to measure IgG class of antibodies to T. gondii in blood sample. Latent Toxoplasma infection was defined by T. gondii IgG ratio ≥0.8, equivalent to ≥10 international units. Chronic peripheral inflammation was defined by highly sensitive C reactive protein blood level ≥ 3 mg/L. RESULTS: Latent Toxoplasma infection has been found in 184 (73.6%) of this national multicentric sample. In the multivariate analyses, latent Toxoplasma infection has been significantly associated with higher PANSS negative (aOR = 1.1 [1.1-1.1], p = 0.04) and excitement subscores (aOR = 1.3 [1.1-1.6], p = 0.01), with two specific symptoms (i.e., reference delusion (aOR = 3.6 [1.2-10.6] p = 0.01) and alogia (aOR = 16.7 [2.0-134.7], p = 0.008)) and with chronic low-grade peripheral inflammation (27.2% vs. 7.6%, aOR = 3.8 [1.4-10.3], p = 0.004). Extrapyramidal symptoms remained significantly associated with latent Toxoplasma infection. On the opposite, no significant association of latent Toxoplasma infection with age, gender, age at SZ onset, suicide behavior or cognitive deficits has been found in these models (all p > 0.05). TATA were associated with lower depressive symptoms (aOR = 0.8[0.7-0.9], p = 0.01), and with lower rates of chronic peripheral inflammation (20.9% vs. 48.6%, aOR = 3.5 [1.5-7.9], p = 0.003) but not with higher cognitive scores (p > 0.05). CONCLUSION: The present findings suggest that Toxoplasma is almost 3 times more frequent in SZ population compared to general population in France. The potential cerebral underpinnings of the association of latent Toxoplasma infection and the above-mentioned outcomes have been discussed. Future studies should confirm that TATA may be effective to reduce Toxoplasma-associated depressive symptoms and low-grade peripheral inflammation.
OBJECTIVE: Latent Toxoplasma infection has been associated with widespread brain immune activation, increased blood brain barrier permeability, neural disruption, increased dopamine release in dopaminergic neurons, with NMDA activation and with schizophrenia (SZ) onset risk. Toxoplasma has been suggested to be a source of chronic low-grade inflammation and this inflammation has been associated with cognitive impairment in SZ. The objective of the present study were (i) to determine if latent Toxoplasma infection was associated with specific clinical features in stabilized SZ subjects, with cognitive impairment and with increased low-grade peripheral inflammation and (ii) to determine if Treatments with Anti-Toxoplasmic Activity (TATA) were associated with improved outcomes in subjects with latent Toxoplasma infection. METHODS: A comprehensive 2 daylong clinical and neuropsychological battery was administered in 250 SZ subjects included between 2015 and 2017 in the national FondaMental Expert Center (FACE-SZ) Cohort. Solid phase-enzyme microplate immunoassay methods were used to measure IgG class of antibodies to T. gondii in blood sample. Latent Toxoplasma infection was defined by T. gondii IgG ratio ≥0.8, equivalent to ≥10 international units. Chronic peripheral inflammation was defined by highly sensitive C reactive protein blood level ≥ 3 mg/L. RESULTS: Latent Toxoplasma infection has been found in 184 (73.6%) of this national multicentric sample. In the multivariate analyses, latent Toxoplasma infection has been significantly associated with higher PANSS negative (aOR = 1.1 [1.1-1.1], p = 0.04) and excitement subscores (aOR = 1.3 [1.1-1.6], p = 0.01), with two specific symptoms (i.e., reference delusion (aOR = 3.6 [1.2-10.6] p = 0.01) and alogia (aOR = 16.7 [2.0-134.7], p = 0.008)) and with chronic low-grade peripheral inflammation (27.2% vs. 7.6%, aOR = 3.8 [1.4-10.3], p = 0.004). Extrapyramidal symptoms remained significantly associated with latent Toxoplasma infection. On the opposite, no significant association of latent Toxoplasma infection with age, gender, age at SZ onset, suicide behavior or cognitive deficits has been found in these models (all p > 0.05). TATA were associated with lower depressive symptoms (aOR = 0.8[0.7-0.9], p = 0.01), and with lower rates of chronic peripheral inflammation (20.9% vs. 48.6%, aOR = 3.5 [1.5-7.9], p = 0.003) but not with higher cognitive scores (p > 0.05). CONCLUSION: The present findings suggest that Toxoplasma is almost 3 times more frequent in SZ population compared to general population in France. The potential cerebral underpinnings of the association of latent Toxoplasma infection and the above-mentioned outcomes have been discussed. Future studies should confirm that TATA may be effective to reduce Toxoplasma-associated depressive symptoms and low-grade peripheral inflammation.
Authors: Graham L Cromar; Jonathan R Epp; Ana Popovic; Yusing Gu; Violet Ha; Brandon J Walters; James St Pierre; Xuejian Xiong; John G Howland; Sheena A Josselyn; Paul W Frankland; John Parkinson Journal: PLoS Negl Trop Dis Date: 2022-07-20
Authors: Mariana Acquarone; A Poleto; A F Perozzo; P F R Gonçalves; R Panizzutti; J R L Menezes; G A Neves; Helene Santos Barbosa Journal: Sci Rep Date: 2021-07-07 Impact factor: 4.379
Authors: Teodor T Postolache; Abhishek Wadhawan; Dan Rujescu; Andrew J Hoisington; Aline Dagdag; Enrique Baca-Garcia; Christopher A Lowry; Olaoluwa O Okusaga; Lisa A Brenner Journal: Front Psychiatry Date: 2021-06-11 Impact factor: 4.157