presentation made by Dr. Robert Yolken on the 13th of November, 2012, at the Schizophrenia Research Forum (www.schizophreniaforum.org) live webinar.

1. Neurotropic Infectious Agents and
Cognitive Impairment in
Schizophrenia
Robert H Yolken
Johns Hopkins School of Medicine
Vishwajit Nimgaonkar
University of Pittsburgh

2. Outline of the webinar
This presentation, R Yolken:
Biology of schizophrenia and infectious agents
Presentation 2, K.Prasad:
‘Epidiagnostic’ risk for cognitive impairment
Presentation 3, V. Nimgaonkar:
Role of host genetic variation
Presentation 4, M. Pletnikov:
Effects of Toxoplasma gondii infection in rodent
models of cognition

3. Schizophrenia in the Human Population
Aspects 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)

4. 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

5. 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

6. 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.

7. Toxoplasma Life cycle
Cats are the
All other animals definitive
are dead-end host, where sexual
hosts. The life reproduction can
cycle can only be take place
completed by
getting back into a
cat
Having 2 methods of transmission makes Toxoplasma a highly successful parasite

8. T gondii Contains Genes which May Generate
Dopamine in Infected Brains
ToxoDB
Thanvi and Treadwell
Postgrad Med J 2004
Prandovszky et al, Plos
One, 2011

9. Infectious Agents and Animal Behavior
Mechanisms that increase transmission
 Malaria/Leishmania
Listlessness
Increased insect exposure
 Rabies Virus
Increased aggression
Transmission by biting
 Respiratory viruses
Coughing
Droplet transmission
 Herpesviruses/Retroviruses
Cognitive impairment
Sexual transmission
Many agents which have not yet been characterized in humans

10. Evolutionary Genetics of Human Psychiatric
Diseases-Conclusions
o Human psychiatric disorders are diseases involving multiple
genomes.
o Genomes involved include:
o Human genome
o 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.

11. Perinatal Infections and Schizophrenia
Collaborators
 Johns Hopkins University  Brown University
 Lorraine Jones-Brando  Steve Buka
 J-C Xiao  UCLA
 Flora Leister
 Ty Cannon
 Shuojia Yang
 Ann Cusic  University of Aarhaus
 Emily Severence  Preben Mortensen
 Emese O”Donnell  University of London
 Stanley Medical Research  Joanne Webster
Institute  University of Leeds
 E Fuller Torrey  Gerald McConkey
 Sheppard Pratt Hospital
 Faith Dickerson
This work was supported by the Stanley Medical Research Institute