Hostname: page-component-745bb68f8f-kw2vx Total loading time: 0 Render date: 2025-01-25T18:35:09.490Z Has data issue: false hasContentIssue false
  • English
  • Français

Persistent infection with neurotropic herpes viruses and cognitive impairment

Published online by Cambridge University Press:  14 September 2012

A. M. M. Watson ,
K. M. Prasad ,
L. Klei ,
J. A. Wood ,
R. H. Yolken ,
R. C. Gur ,
L. D. Bradford ,
M. E. Calkins ,
J. Richard  and
N. Edwards
...Show all authors
A. M. M. Watson
Affiliation:
Departments of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA
K. M. Prasad
Affiliation:
Departments of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA
L. Klei
Affiliation:
Departments of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA
J. A. Wood
Affiliation:
Departments of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA
R. H. Yolken
Affiliation:
Stanley Division of Developmental Neurovirology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
R. C. Gur
Affiliation:
Department of Psychiatry, Neuropsychiatry Section, University of Pennsylvania, Philadelphia, PA, USA Philadelphia Veteran's Affairs Medical Center, Philadelphia, PA, USA
L. D. Bradford
Affiliation:
Department of Psychiatry, Morehouse School of Medicine, Atlanta, GA, USA
M. E. Calkins
Affiliation:
Department of Psychiatry, Neuropsychiatry Section, University of Pennsylvania, Philadelphia, PA, USA
J. Richard
Affiliation:
Department of Psychiatry, Neuropsychiatry Section, University of Pennsylvania, Philadelphia, PA, USA
N. Edwards
Affiliation:
Department of Psychiatry, University of Tennessee, College of Medicine, Memphis, TN, USA
R. M. Savage
Affiliation:
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA
T. B. Allen
Affiliation:
Duke University Medical Center, John Umstead Hospital, Butner, NC, USA
J. Kwentus
Affiliation:
Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA
J. P. McEvoy
Affiliation:
Duke University Medical Center, John Umstead Hospital, Butner, NC, USA
A. B. Santos
Affiliation:
Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA
H. W. Wiener
Affiliation:
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA
R. C. P. Go
Affiliation:
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA
R. T. Perry
Affiliation:
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA
H. A. Nasrallah
Affiliation:
Departments of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH, USA
R. E. Gur
Affiliation:
Department of Psychiatry, Neuropsychiatry Section, University of Pennsylvania, Philadelphia, PA, USA
B. Devlin
Affiliation:
Departments of Human Genetics, University of Pittsburgh School of Medicine and Graduate School of Public Health, Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA
V. L. Nimgaonkar*
Affiliation:
Departments of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA Departments of Human Genetics, University of Pittsburgh School of Medicine and Graduate School of Public Health, Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA
*
*Address for correspondence: V. L. Nimgaonkar, M.D., Ph.D., TDH, Room 441, 3811 O'Hara St., Pittsburgh, PA 15213, USA. (Email: nimga@pitt.edu)
Get access Rights & Permissions [Opens in a new window]

Abstract

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.

Keywords

CognitioncytomegalovirusHSV-1HSV-2schizophrenia
Type
Original Articles
Information
Psychological Medicine , Volume 43 , Issue 5 , May 2013 , pp. 1023 - 1031
Copyright
Copyright © Cambridge University Press 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Aiello, AE, Haan, M, Blythe, L, Moore, K, Gonzalez, JM, Jagust, W (2006). The influence of latent viral infection on rate of cognitive decline over 4 years. Journal of the American Geriatrics Society 54, 1046–1054.CrossRefGoogle ScholarPubMed
Aliyu, MH, Calkins, ME, Swanson, CL Jr., Lyons, PD, Savage, RM, May, R, Wiener, H, McLeod-Bryant, S, Nimgaonkar, VL, Ragland, JD, Gur, RE, Gur, RC, Bradford, LD, Edwards, N, Kwentus, J, McEvoy, JP, Santos, AB, McCleod-Bryant, S, Tennison, C, Go, RC, Allen, TB (2006). Project among African-Americans to explore risks for schizophrenia (PAARTNERS): recruitment and assessment methods. Schizophrenia Research 87, 32–44.CrossRefGoogle ScholarPubMed
Almasy, L, Blangero, J (1998). Multipoint quantitative-trait linkage analysis in general pedigrees. American Journal of Human Genetics 62, 1198–1211.CrossRefGoogle ScholarPubMed
Alvarez, G, Aldudo, J, Alonso, M, Santana, S, Valdivieso, F (2012). Herpes simplex virus type 1 induces nuclear accumulation of hyperphosphorylated tau in neuronal cells. Journal of Neuroscience Research 90, 1020–1029.CrossRefGoogle ScholarPubMed
Baringer, JR, Pisani, P (1994). Herpes simplex virus genomes in human nervous system tissue analyzed by polymerase chain reaction. Annals of Neurology 36, 823–829.CrossRefGoogle ScholarPubMed
Bertrand, P, Guillaume, D, Hellauer, K, Dea, D, Lindsay, J, Kogan, S, Gauthier, S, Poirier, J (1993). Distribution of herpes simplex virus type 1 DNA in selected areas of normal and Alzheimer's disease brains: a PCR study. Neurodegeneration 2, 201–208.Google Scholar
Borgo, F, Sgaramella, TM, Penello, B, L'Erario, R, Toso, V (2000). A componential analysis of visual object recognition deficits in patients with herpes simplex virus encephalitis. Brain and Cognition 43, 53–56.Google ScholarPubMed
Brown, AS, Derkits, EJ (2010). Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. American Journal of Psychiatry 167, 261–280.CrossRefGoogle ScholarPubMed
Buursma, AR, de Vries, EF, Garssen, J, Kegler, D, van Waarde, A, Schirm, J, Hospers, GA, Mulder, NH, Vaalburg, W, Klein, HC (2005). [18F]FHPG positron emission tomography for detection of herpes simplex virus (HSV) in experimental HSV encephalitis. Journal of Virology 79, 7721–7727.CrossRefGoogle ScholarPubMed
Calkins, ME, Tepper, P, Gur, RC, Ragland, JD, Klei, L, Wiener, HW, Richard, J, Savage, RM, Allen, TB, O'Jile, J, Devlin, B, Kwentus, J, Aliyu, MH, Bradford, LD, Edwards, N, Lyons, PD, Nimgaonkar, VL, Santos, AB, Go, RC, Gur, RE (2010). Project among African-Americans to explore risks for schizophrenia (PAARTNERS): evidence for impairment and heritability of neurocognitive functioning in families of schizophrenia patients. American Journal of Psychiatry 167, 459–472.CrossRefGoogle ScholarPubMed
Carter, C (2011). Alzheimer's disease: APP, gamma secretase, APOE, CLU, CR1, PICALM, ABCA7, BIN1, CD2AP, CD33, EPHA1, and MS4A2, and their relationships with herpes simplex, C. pneumoniae, other suspect pathogens, and the immune system. International Journal of Alzheimer's Disease. Published online: 29 December 2011, doi:10.4061/2011/501862.CrossRefGoogle Scholar
Cheeran, MC, Lokensgard, JR, Schleiss, MR (2009). Neuropathogenesis of congenital cytomegalovirus infection: disease mechanisms and prospects for intervention. Clinical Microbiology Reviews 22, 99–126.CrossRefGoogle ScholarPubMed
Delisi, LE, Smith, SB, Hamovit, JR, Maxwell, ME, Goldin, LR, Dingman, CW, Gershon, ES (1986). Herpes simplex virus, cytomegalovirus and Epstein-Barr virus antibody titres in sera from schizophrenic patients. Psychological Medicine 16, 757–763.CrossRefGoogle ScholarPubMed
Dickerson, F, Stallings, C, Sullens, A, Origoni, A, Leister, F, Krivogorsky, B, Yolken, R (2008). Association between cognitive functioning, exposure to Herpes Simplex Virus type 1, and the COMT Val158Met genetic polymorphism in adults without a psychiatric disorder. Brain, Behavior, and Immunity 22, 1103–1107.CrossRefGoogle ScholarPubMed
Dickerson, FB, Boronow, JJ, Stallings, C, Origoni, AE, Cole, S, Krivogorsky, B, Yolken, RH (2004). Infection with herpes simplex virus type 1 is associated with cognitive deficits in bipolar disorder. Biological Psychiatry 55, 588–593.CrossRefGoogle ScholarPubMed
Dickerson, FB, Boronow, JJ, Stallings, C, Origoni, AE, Ruslanova, I, Yolken, RH (2003). Association of serum antibodies to herpes simplex virus 1 with cognitive deficits in individuals with schizophrenia. Archives of General Psychiatry 60, 466–472.CrossRefGoogle ScholarPubMed
Féart, C, Helmer, C, Fleury, H, Béjot, Y, Ritchie, K, Amouyel, P, Schraen-Maschke, S, Buée, L, Lambert, JC, Letenneur, L, Dartigues, JF (2011). Association between IgM anti-herpes simplex virus and plasma amyloid-beta levels. PLoS ONE 6, e29480.CrossRefGoogle ScholarPubMed
Goodkin, ML, Morton, ER, Blaho, JA (2004). Herpes simplex virus infection and apoptosis. International Reviews of Immunology 23, 141–172.CrossRefGoogle ScholarPubMed
Gur, RC, Ragland, JD, Moberg, PJ, Turner, TH, Bilker, WB, Kohler, C, Siegel, SJ, Gur, RE (2001). Computerized neurocognitive scanning: I. Methodology and validation in healthy people. Neuropsychopharmacology 25, 766–776.CrossRefGoogle ScholarPubMed
Gur, RE, Nimgaonkar, VL, Almasy, L, Calkins, ME, Ragland, JD, Pogue-Geile, MF, Kanes, S, Blangero, J, Gur, RC (2007). Neurocognitive endophenotypes in a multiplex multigenerational family study of schizophrenia. American Journal of Psychiatry 164, 813–819.CrossRefGoogle Scholar
Itzhaki, R (2004). Herpes simplex virus type 1, apolipoprotein E and Alzheimer's disease. Herpes 11 (Suppl. 2), 77A–82A.Google Scholar
Jamieson, GA, Maitland, NJ, Wilcock, GK, Craske, J, Itzhaki, RF (1991). Latent herpes simplex virus type 1 in normal and Alzheimer's disease brains. Journal of Medical Virology 33, 224–227.CrossRefGoogle ScholarPubMed
Kaufman, HE, Azcuy, AM, Varnell, ED, Sloop, GD, Thompson, HW, Hill, JM (2005). HSV-1 DNA in tears and saliva of normal adults. Investigative Ophthalmology and Visual Science 46, 241–247.CrossRefGoogle ScholarPubMed
Klei, L, Luca, D, Devlin, B, Roeder, K (2008). Pleiotropy and principal components of heritability combine to increase power for association analysis. Genetic Epidemiology 32, 9–19.CrossRefGoogle ScholarPubMed
Licastro, F, Carbone, I, Ianni, M, Porcellini, E (2011). Gene signature in Alzheimer's disease and environmental factors: the virus chronicle. Journal of Alzheimer's Disease 27, 809–817.CrossRefGoogle ScholarPubMed
McGrath, N, Anderson, NE, Croxson, MC, Powell, KF (1997). Herpes simplex encephalitis treated with acyclovir: diagnosis and long term outcome. Journal of Neurology, Neurosurgery, and Psychiatry 63, 321–326.CrossRefGoogle ScholarPubMed
McKenna, DB, Neill, WA, Norval, M (2001). Herpes simplex virus-specific immune responses in subjects with frequent and infrequent orofacial recrudescences. British Journal of Dermatology 144, 459–464.CrossRefGoogle ScholarPubMed
Ott, J, Rabinowitz, D (1999). A principal-components approach based on heritability for combining phenotype information. Human Heredity 49, 106–111.CrossRefGoogle ScholarPubMed
Prasad, KM, Shirts, BH, Yolken, RH, Keshavan, MS, Nimgaonkar, VL (2007). Brain morphological changes associated with exposure to HSV1 in first-episode schizophrenia. Molecular Psychiatry 12, 105–113.CrossRefGoogle ScholarPubMed
Prasad, KM, Watson, AM, Dickerson, FB, Yolken, RH, Nimgaonkar, VL (2012). Exposure to herpes simplex virus type 1 and cognitive impairments in individuals with schizophrenia. Schizophrenia Bulletin. Published online: 6 April 2012. doi:10.1093/schbul/sbs046.CrossRefGoogle Scholar
Schmutzhard, E (2001). Viral infections of the CNS with special emphasis on herpes simplex infections. Journal of Neurology 248, 469–477.CrossRefGoogle ScholarPubMed
Schretlen, DJ, Vannorsdall, TD, Winicki, JM, Mushtaq, Y, Hikida, T, Sawa, A, Yolken, RH, Dickerson, FB, Cascella, NG (2010). Neuroanatomic and cognitive abnormalities related to herpes simplex virus type 1 in schizophrenia. Schizophrenia Research 118, 224–231.CrossRefGoogle ScholarPubMed
Shirts, BH, Prasad, KM, Pogue-Geile, MF, Dickerson, F, Yolken, RH, Nimgaonkar, VL (2008). Antibodies to cytomegalovirus and Herpes Simplex Virus 1 associated with cognitive function in schizophrenia. Schizophrenia Research 106, 268–274.CrossRefGoogle ScholarPubMed
Smith, JS, Robinson, NJ (2002). Age-specific prevalence of infection with herpes simplex virus types 2 and 1: a global review. Journal of Infectious Diseases 186, S3–S28.CrossRefGoogle ScholarPubMed
Staras, SA, Dollard, SC, Radford, KW, Flanders, WD, Pass, RF, Cannon, MJ (2006). Seroprevalence of cytomegalovirus infection in the United States, 1988–1994. Clinical Infectious Diseases 43, 1143–1151.CrossRefGoogle ScholarPubMed
Steiner, I, Kennedy, PG, Pachner, AR (2007). The neurotropic herpes viruses: herpes simplex and varicella-zoster. Lancet Neurology 6, 1015–1028.CrossRefGoogle ScholarPubMed
Stevens, JG, Haarr, L, Porter, DD, Cook, ML, Wagner, EK (1988). Prominence of the herpes simplex virus latency-associated transcript in trigeminal ganglia from seropositive humans. Journal of Infectious Diseases 158, 117–123.CrossRefGoogle ScholarPubMed
Strandberg, TE, Pitkala, K, Eerola, J, Tilvis, R, Tienari, PJ (2005). Interaction of herpesviridae, APOE gene, and education in cognitive impairment. Neurobiology of Aging 26, 1001–1004.CrossRefGoogle ScholarPubMed
Strandberg, TE, Pitkala, KH, Linnavuori, KH, Tilvis, RS (2003). Impact of viral and bacterial burden on cognitive impairment in elderly persons with cardiovascular diseases. Stroke 34, 2126–2131.CrossRefGoogle ScholarPubMed
Taylor, GH (2003). Cytomegalovirus. American Family Physician 67, 519–524.Google ScholarPubMed
Toulopoulou, T, Goldberg, TE, Mesa, IR, Picchioni, M, Rijsdijk, F, Stahl, D, Cherny, SS, Sham, P, Faraone, SV, Tsuang, M, Weinberger, DR, Seidman, LJ, Murray, RM (2010). Impaired intellect and memory: a missing link between genetic risk and schizophrenia? Archives of General Psychiatry 67, 905–913.CrossRefGoogle ScholarPubMed
Whitley, RJ (1996). Herpesviruses. In: Medical Microbiology 4th edn [e-book] (ed. Baron, S.), chapter 68. Galveston (TX): University of Texas Medical Branch at Galveston (http://www.ncbi.nlm.nih.gov/books/NBK8157/).Google Scholar
Wiener, H, Klei, L, Calkins, M, Wood, J, Nimgaonkar, V, Gur, R, Bradford, LD, Richard, J, Edwards, N, Savage, R, Kwentus, J, Allen, T, McEvoy, J, Santos, A, Devlin, B, Go, R (2012). Principal components of heritability from neurocognitive domains differ between families with schizophrenia and control subjects. Schizophrenia Bulletin. Published online 10 January 2012. doi:10.1093/schbul/sbr161V.Google ScholarPubMed
Wiener, HW, Klei, L, Irvin, MD, Perry, RT, Aliyu, MH, Allen, TB, Bradford, LD, Calkins, ME, Devlin, B, Edwards, N, Gur, RE, Gur, RC, Kwentus, J, Lyons, PD, McEvoy, JP, Nasrallah, HA, Nimgaonkar, VL, O'Jile, J, Santos, AB, Savage, RM, Go, RC (2009). Linkage analysis of schizophrenia in African-American families. Schizophrenia Research 109, 70–79.CrossRefGoogle ScholarPubMed
Zeger, SL, Liang, KY (1986). Longitudinal data analysis for discrete and continuous outcomes. Biometrics 42, 121–130.CrossRefGoogle ScholarPubMed
Supplementary material: File

Watson Supplementary Material

Tables

Download Watson Supplementary Material(File)
File 91.1 KB