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Persistent infection with neurotropic herpes viruses and cognitive impairment

  • A. M. M. Watson (a1), K. M. Prasad (a1), L. Klei (a1), J. A. Wood (a1), R. H. Yolken (a2), R. C. Gur (a3) (a4), L. D. Bradford (a5), M. E. Calkins (a3), J. Richard (a3), N. Edwards (a6), R. M. Savage (a7), T. B. Allen (a8), J. Kwentus (a9), J. P. McEvoy (a8), A. B. Santos (a10), H. W. Wiener (a11), R. C. P. Go (a11), R. T. Perry (a11), H. A. Nasrallah (a12), R. E. Gur (a3), B. Devlin (a13) and V. L. Nimgaonkar (a1) (a13)...



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).


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.


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.


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


Corresponding author

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


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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, 10461054.
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, 3244.
Almasy, L, Blangero, J (1998). Multipoint quantitative-trait linkage analysis in general pedigrees. American Journal of Human Genetics 62, 11981211.
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, 10201029.
Baringer, JR, Pisani, P (1994). Herpes simplex virus genomes in human nervous system tissue analyzed by polymerase chain reaction. Annals of Neurology 36, 823829.
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, 201208.
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, 5356.
Brown, AS, Derkits, EJ (2010). Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. American Journal of Psychiatry 167, 261280.
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, 77217727.
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, 459472.
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.
Cheeran, MC, Lokensgard, JR, Schleiss, MR (2009). Neuropathogenesis of congenital cytomegalovirus infection: disease mechanisms and prospects for intervention. Clinical Microbiology Reviews 22, 99126.
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, 757763.
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, 11031107.
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, 588593.
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, 466472.
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.
Goodkin, ML, Morton, ER, Blaho, JA (2004). Herpes simplex virus infection and apoptosis. International Reviews of Immunology 23, 141172.
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, 766776.
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, 813819.
Itzhaki, R (2004). Herpes simplex virus type 1, apolipoprotein E and Alzheimer's disease. Herpes 11 (Suppl. 2), 77A82A.
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, 224227.
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, 241247.
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, 919.
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, 809817.
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, 321326.
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, 459464.
Ott, J, Rabinowitz, D (1999). A principal-components approach based on heritability for combining phenotype information. Human Heredity 49, 106111.
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, 105113.
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.
Schmutzhard, E (2001). Viral infections of the CNS with special emphasis on herpes simplex infections. Journal of Neurology 248, 469477.
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, 224231.
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, 268274.
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, S3S28.
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, 11431151.
Steiner, I, Kennedy, PG, Pachner, AR (2007). The neurotropic herpes viruses: herpes simplex and varicella-zoster. Lancet Neurology 6, 10151028.
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, 117123.
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, 10011004.
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, 21262131.
Taylor, GH (2003). Cytomegalovirus. American Family Physician 67, 519524.
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, 905913.
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 (
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.
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, 7079.
Zeger, SL, Liang, KY (1986). Longitudinal data analysis for discrete and continuous outcomes. Biometrics 42, 121130.


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Persistent infection with neurotropic herpes viruses and cognitive impairment

  • A. M. M. Watson (a1), K. M. Prasad (a1), L. Klei (a1), J. A. Wood (a1), R. H. Yolken (a2), R. C. Gur (a3) (a4), L. D. Bradford (a5), M. E. Calkins (a3), J. Richard (a3), N. Edwards (a6), R. M. Savage (a7), T. B. Allen (a8), J. Kwentus (a9), J. P. McEvoy (a8), A. B. Santos (a10), H. W. Wiener (a11), R. C. P. Go (a11), R. T. Perry (a11), H. A. Nasrallah (a12), R. E. Gur (a3), B. Devlin (a13) and V. L. Nimgaonkar (a1) (a13)...


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