Psychological Medicine

Original Articles

Persistent infection with neurotropic herpes viruses and cognitive impairment

A. M. M. Watsona1, K. M. Prasada1, L. Kleia1, J. A. Wooda1, R. H. Yolkena2, R. C. Gura3a4, L. D. Bradforda5, M. E. Calkinsa3, J. Richarda3, N. Edwardsa6, R. M. Savagea7, T. B. Allena8, J. Kwentusa9, J. P. McEvoya8, A. B. Santosa10, H. W. Wienera11, R. C. P. Goa11, R. T. Perrya11, H. A. Nasrallaha12, R. E. Gura3, B. Devlina13 and V. L. Nimgaonkara1a13 c1

a1 Departments of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA

a2 Stanley Division of Developmental Neurovirology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

a3 Department of Psychiatry, Neuropsychiatry Section, University of Pennsylvania, Philadelphia, PA, USA

a4 Philadelphia Veteran's Affairs Medical Center, Philadelphia, PA, USA

a5 Department of Psychiatry, Morehouse School of Medicine, Atlanta, GA, USA

a6 Department of Psychiatry, University of Tennessee, College of Medicine, Memphis, TN, USA

a7 Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA

a8 Duke University Medical Center, John Umstead Hospital, Butner, NC, USA

a9 Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA

a10 Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA

a11 Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA

a12 Departments of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH, USA

a13 Departments of Human Genetics, University of Pittsburgh School of Medicine and Graduate School of Public Health, Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA

Background Herpes virus infections can cause cognitive impairment during and after acute encephalitis. Although chronic, latent/persistent infection is considered to be relatively benign, some studies have documented cognitive impairment in exposed persons that is untraceable to encephalitis. These studies were conducted among schizophrenia (SZ) patients or older community dwellers, among whom it is difficult to control for the effects of co-morbid illness and medications. To determine whether the associations can be generalized to other groups, we examined a large sample of younger control individuals, SZ patients and their non-psychotic relatives (n=1852).

Method Using multivariate models, cognitive performance was evaluated in relation to exposures to herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2) and cytomegalovirus (CMV), controlling for familial and diagnostic status and sociodemographic variables, including occupation and educational status. Composite cognitive measures were derived from nine cognitive domains using principal components of heritability (PCH). Exposure was indexed by antibodies to viral antigens.

Results PCH1, the most heritable component of cognitive performance, declines with exposure to CMV or HSV-1 regardless of case/relative/control group status (p = 1.09 × 10−5 and 0.01 respectively), with stronger association with exposure to multiple herpes viruses (β = −0.25, p = 7.28 × 10−10). There were no significant interactions between exposure and group status.

Conclusions Latent/persistent herpes virus infections can be associated with cognitive impairments regardless of other health status.

(Received April 16 2012)

(Revised July 18 2012)

(Accepted July 23 2012)

(Online publication September 14 2012)

Key words

  • Cognition;
  • cytomegalovirus;
  • HSV-1;
  • HSV-2;
  • schizophrenia


c1 Address for correspondence: V. L. Nimgaonkar, M.D., Ph.D., TDH, Room 441, 3811 O'Hara St., Pittsburgh, PA 15213, USA. (Email: