Neurotropic Infectious Agents and Cognitive Impairment in Schizophrenia

Robert H YolkenJohns Hopkins School of Medicine

Vishwajit NimgaonkarUniversity of Pittsburgh

Outline of the webinar

This presentation, R Yolken: Biology of schizophrenia and infectious agentsPresentation 2, K.Prasad: ‘Epidiagnostic’ risk for cognitive impairmentPresentation 3, V. Nimgaonkar: Role of host genetic variationPresentation 4, M. Pletnikov: Effects of Toxoplasma gondii infection in rodent models of cognition

Schizophrenia in the Human PopulationAspects Not Consistent with Gene-Only Effects

Events during pregnancy and birth Seasonality (Increased rates during winter) Urban birth Maternal Fever/Infection/Pre-eclampsia Famine Migration

Discordance among monozygotic twins Common occurrence of disorders in individuals without an

affected first degree relative Increased levels of antibodies to infectious agents and food

antigens Evolutionary persistence of a trait associated with low rates of

reproduction (Torrey and Yolken, Scz Bulletin, 2010)

Microbial agents in Psychiatric Disorders Likely Biological characteristics

Capable of long term persistence within the CNS Associated with cognitive impairments Biological effects on brain cell functioning

Dopamine metabolism Ion channels Immune system activation

Capable of interaction with host genes Genetic susceptibility (HLA, Micb) Epigenetic modifications Cross species infections

Possible relationship to known neurotropic agents: Similar Variant strains Novel agents

4

Infections and Schizophrenia-Associations with infectious agents and inflammatory factors

Perinatal Associations Rubella Brown et al, 2001; Odds Ratio (OR)~3.5 Enteroviruses Jones et al, 1998; OR~4 Herpesvirus type 2 Buka et al 2001; OR~4 Toxoplasma gondii Brown, Mortensen; 2005/7; OR~3 ) Fever in Pregnancy Torrey et al 2000; OR~3 Pre-eclampsia Dalman et al, 1999; OR~2.5 Antibodies to food antigens Karlsson et al 2012; OR~2

Adult Associations Toxoplasma gondii Torrey and Yolken 2012; OR ~2.5 Endogenous Retroviruses Karlsson et al 2001; OR~2 Circulating Immune Complexes Severance et al 2012; OR~3 Antibodies to food antigens Dickerson et al 2011; OR~3

Toxoplasma Gondii and Schizophrenia Forest plot of 23 previous and 15 new studies and their combination.

Torrey E F et al. Schizophr Bull 2012;38:642-647

© The Author 2012. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Toxoplasma Life cycle

Cats are the definitive host, where sexual reproduction can take place

All other animals are dead-end hosts. The life cycle can only be completed by getting back into a cat

Having 2 methods of transmission makes Toxoplasma a highly successful parasite

T gondii Contains Genes which May Generate Dopamine in Infected Brains

Prandovszky et al, Plos One, 2011

Thanvi and TreadwellPostgrad Med J 2004

ToxoDB

Infectious Agents and Animal BehaviorMechanisms that increase transmission

Malaria/LeishmaniaListlessnessIncreased insect exposure

Rabies VirusIncreased aggressionTransmission by biting

Respiratory virusesCoughingDroplet transmission

Herpesviruses/RetrovirusesCognitive impairmentSexual transmissionMany agents which have not yet been characterized in humans

Evolutionary Genetics of Human Psychiatric Diseases-Conclusions

o Human psychiatric disorders are diseases involving multiple genomes.

o Genomes involved include:o Human genomeo Replicating zoonotic protozoa capable of altering

neurotransmission o Viruses persisting in the brain

o The prevention of these infections may result in a dramatic decrease in the massive personal, social and economic impact of these disorders.

Perinatal Infections and Schizophrenia Collaborators

Johns Hopkins University Lorraine Jones-Brando J-C Xiao Flora Leister Shuojia Yang Ann Cusic Emily Severence Emese O”Donnell

Stanley Medical Research Institute E Fuller Torrey

Sheppard Pratt Hospital Faith Dickerson

Brown University Steve Buka

UCLA Ty Cannon

University of Aarhaus Preben Mortensen

University of London Joanne Webster

University of Leeds Gerald McConkey

This work was supported by the Stanley Medical Research Institute