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Progressive grey matter loss and temporal changes in cognitive functions associated with exposure to HSV1 in schizophrenia: A longitudinal study
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Abstracts / Brain, Behavior, and Immunity 24 (2010) S1–S71
Abstract # 456 Determination of T-cell subpopulations in CSF and peripheral blood in patients with affective and schizophrenic spectrum disorders to assess immunosurveillance and to apply as a diagnostic approach K. Bechter a,b, H. Maxeiner b, M. Rojewski b, A. Schmitt b, H. Tumani b, M. Schmitt b a
BKH Guenzburg, Ludwig-Heilmeyer-Str. 2, Guenzburg, Bayern 89312, Germany b Ulm University, Germany To investigate lymphocyte activation and T regulatory cells (Tregs) cell surface markers in patients with psychiatric disorders and subgroups of patients with neurological diseases in paired samples of CSF and blood (PB), we used modern flow cytometers which allows with high sensitivity to detect up to eight parameters per cell. CSF and PBMC were collected simultaneously from 45 patients, 17 patients with major psychoses (MPD), 16 with non-inflammatory neurological diseases (NIND), 7 with meningitis (MEN) and 5 with chronic inflammatory diseases (CIND). Peripheral Blood Mononuclear Cells (PBMC) were isolated by Ficoll, CSF-cells were centrifuged. Samples were stained with monoclonal antibodies directed against CD4, CD8, CD25, CD45, CD69, CD127 (BD and Caltag-Invitrogen). Stained cell samples were analysed using BD FACSAria™ cytometer and BD FACSDiva software. Significant differences (p < 0.05) were observed in PB for CD4+ cells (MEN: 45.8% versus NIND: 33.06%/CIND: 31.03%); in PB for CD4+CD45RO+ cells (MEN: 24.08% versus CIND:11.12%); in PB for CD4+CD25+ (MEN:0.89% versus CIND: 0.28%/MPD: 0.39%); and in CSF for CD4+CD127dim cells (MEN: 5.15% versus MPD: 10.18%). A significantly higher frequency of CD4+CD25+CD127dim, representing Tregs were observed in PB of MEN (0.25%) versus CIND (0.09%). In summary, multiparameter FACS analysis of CSF versus PB is feasible and distinct patterns of T-cell subsets were identified in both neurological and psychiatric disorders. doi:10.1016/j.bbi.2010.07.191
Abstract # 457 Systemic challenge with the TLR3 agonist poly I:C induces amplified IFN-a/b and IL-1b responses in the diseased brain and exacerbates chronic neurodegeneration R. Field a, S. Campion b, C. Warren a, C. Murray a, C. Cunningham a a
Trinity College Institute of Neuroscience, Dublin, Ireland Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
b
The role of inflammation in the progression of neurodegenerative disease remains unclear. We have shown that systemic bacterial insults accelerate progression of neurodegenerative disease in animals and in patients with Alzheimer’s disease. The impact of systemic viral insults on existing neurodegenerative disease has not been investigated. Polyinosinic:polycytidylic acid (poly I:C) is a toll-like receptor 3 agonist and induces type I interferons, thus mimicking inflammatory responses to systemic viral infection. We hypothesized that systemic challenge with poly I:C, during chronic neurodegenerative disease, would amplify CNS inflammation and exacerbate disease. Systemic challenge with poly I:C (12 mg/kg
i.p.) induced amplified expression of IFN-a/b and of the pro-inflammatory genes IL-1b and IL-6 in ME7 animals relative to NBH controls. Similarly amplified expression of IFN-dependent genes confirmed type I IFN secretion and action in the brain with apparent antiinflammatory consequences. However, prion-diseased animals experienced heightened acute sickness behaviour and acute neurological impairments in response to poly I:C. Furthermore, these challenges accelerated disease progression in ME7 mice without lasting effects in normal animals. Increased apoptosis coupled with doublestranded RNA-dependent protein kinase (PKR) and FAS transcription suggested activation of interferon-dependent, pro-apoptotic pathways in the brain of ME7 + poly I:C animals. That systemic poly I:C accelerates neurodegeneration has implications for the control of systemic viral infection during chronic neurodegeneration and indicates that type I interferon responses in the brain merit further study. doi:10.1016/j.bbi.2010.07.192
Abstract # 458 Progressive grey matter loss and temporal changes in cognitive functions associated with exposure to HSV1 in schizophrenia: A longitudinal study K.M. Prasad a, S. Eack b, D. Goradia c, K.M. Pancholi a, M.S. Keshavan a,d, R.H. Yolken e, V.L. Nimgaonkar a a
University of Pittsburgh School of Medicine, 3811 O’Hara St, Pittsburgh, PA 15213, USA b University of Pittsburgh, Dept of Social Work, USA c Wayne State University School of Medicine, Detroit, MI, USA d Harvard Medical School, Boston, MA, USA e Johns Hopkins University School of Medicine, Baltimore, MD, USA There is replicable association of exposure to herpes simplex virus, subtype 1 (HSV1) – a neurotropic virus with smaller prefrontal regions and cognitive impairments, especially in executive functions and working memory domains in schizophrenia (SZ). Here, we concurrently examined the longitudinal trajectory of grey matter volumes and executive functions among first episode antipsychotic naive SZ subjects and healthy subjects (HS) over 1 year. We tested the hypothesis that HSV1 exposed subjects will show longitudinal grey matter loss and decline in executive functions measured using the Wisconsin Card Sorting Test (WCST) over 1 year. Age, gender, socioeconomic status (SES) and exposure to cytomegalovirus (CMV) – another neurotropic virus, were the covariates. Using deformation fields analysis, we observed grey matter loss in seropositive SZ subjects but not seronegative SZ or HS in the left posterior cingulate gyrus at 1 year compared to baseline. Binomial random mixed effects growth models showed that over 1 year, a significantly higher number of HSV1 positive SZ subjects were committing more errors and completing fewer categories compared to HSV1 negative SZ and HS regardless of the serological status; the three-way interaction (time * diagnosis * HSV1 status) for categories completed (p = 0.0004) and perseverative errors were significant (p = 0.042). These observations suggest that SZ subjects exposed to HSV1 may show longitudinal grey matter volume loss in PCG and decline in executive functions in contrast to the comparison groups. doi:10.1016/j.bbi.2010.07.193
Abstracts / Brain, Behavior, and Immunity 24 (2010) S1–S71
Abstract # 456 Determination of T-cell subpopulations in CSF and peripheral blood in patients with affective and schizophrenic spectrum disorders to assess immunosurveillance and to apply as a diagnostic approach K. Bechter a,b, H. Maxeiner b, M. Rojewski b, A. Schmitt b, H. Tumani b, M. Schmitt b a
BKH Guenzburg, Ludwig-Heilmeyer-Str. 2, Guenzburg, Bayern 89312, Germany b Ulm University, Germany To investigate lymphocyte activation and T regulatory cells (Tregs) cell surface markers in patients with psychiatric disorders and subgroups of patients with neurological diseases in paired samples of CSF and blood (PB), we used modern flow cytometers which allows with high sensitivity to detect up to eight parameters per cell. CSF and PBMC were collected simultaneously from 45 patients, 17 patients with major psychoses (MPD), 16 with non-inflammatory neurological diseases (NIND), 7 with meningitis (MEN) and 5 with chronic inflammatory diseases (CIND). Peripheral Blood Mononuclear Cells (PBMC) were isolated by Ficoll, CSF-cells were centrifuged. Samples were stained with monoclonal antibodies directed against CD4, CD8, CD25, CD45, CD69, CD127 (BD and Caltag-Invitrogen). Stained cell samples were analysed using BD FACSAria™ cytometer and BD FACSDiva software. Significant differences (p < 0.05) were observed in PB for CD4+ cells (MEN: 45.8% versus NIND: 33.06%/CIND: 31.03%); in PB for CD4+CD45RO+ cells (MEN: 24.08% versus CIND:11.12%); in PB for CD4+CD25+ (MEN:0.89% versus CIND: 0.28%/MPD: 0.39%); and in CSF for CD4+CD127dim cells (MEN: 5.15% versus MPD: 10.18%). A significantly higher frequency of CD4+CD25+CD127dim, representing Tregs were observed in PB of MEN (0.25%) versus CIND (0.09%). In summary, multiparameter FACS analysis of CSF versus PB is feasible and distinct patterns of T-cell subsets were identified in both neurological and psychiatric disorders. doi:10.1016/j.bbi.2010.07.191
Abstract # 457 Systemic challenge with the TLR3 agonist poly I:C induces amplified IFN-a/b and IL-1b responses in the diseased brain and exacerbates chronic neurodegeneration R. Field a, S. Campion b, C. Warren a, C. Murray a, C. Cunningham a a
Trinity College Institute of Neuroscience, Dublin, Ireland Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
b
The role of inflammation in the progression of neurodegenerative disease remains unclear. We have shown that systemic bacterial insults accelerate progression of neurodegenerative disease in animals and in patients with Alzheimer’s disease. The impact of systemic viral insults on existing neurodegenerative disease has not been investigated. Polyinosinic:polycytidylic acid (poly I:C) is a toll-like receptor 3 agonist and induces type I interferons, thus mimicking inflammatory responses to systemic viral infection. We hypothesized that systemic challenge with poly I:C, during chronic neurodegenerative disease, would amplify CNS inflammation and exacerbate disease. Systemic challenge with poly I:C (12 mg/kg
i.p.) induced amplified expression of IFN-a/b and of the pro-inflammatory genes IL-1b and IL-6 in ME7 animals relative to NBH controls. Similarly amplified expression of IFN-dependent genes confirmed type I IFN secretion and action in the brain with apparent antiinflammatory consequences. However, prion-diseased animals experienced heightened acute sickness behaviour and acute neurological impairments in response to poly I:C. Furthermore, these challenges accelerated disease progression in ME7 mice without lasting effects in normal animals. Increased apoptosis coupled with doublestranded RNA-dependent protein kinase (PKR) and FAS transcription suggested activation of interferon-dependent, pro-apoptotic pathways in the brain of ME7 + poly I:C animals. That systemic poly I:C accelerates neurodegeneration has implications for the control of systemic viral infection during chronic neurodegeneration and indicates that type I interferon responses in the brain merit further study. doi:10.1016/j.bbi.2010.07.192
Abstract # 458 Progressive grey matter loss and temporal changes in cognitive functions associated with exposure to HSV1 in schizophrenia: A longitudinal study K.M. Prasad a, S. Eack b, D. Goradia c, K.M. Pancholi a, M.S. Keshavan a,d, R.H. Yolken e, V.L. Nimgaonkar a a
University of Pittsburgh School of Medicine, 3811 O’Hara St, Pittsburgh, PA 15213, USA b University of Pittsburgh, Dept of Social Work, USA c Wayne State University School of Medicine, Detroit, MI, USA d Harvard Medical School, Boston, MA, USA e Johns Hopkins University School of Medicine, Baltimore, MD, USA There is replicable association of exposure to herpes simplex virus, subtype 1 (HSV1) – a neurotropic virus with smaller prefrontal regions and cognitive impairments, especially in executive functions and working memory domains in schizophrenia (SZ). Here, we concurrently examined the longitudinal trajectory of grey matter volumes and executive functions among first episode antipsychotic naive SZ subjects and healthy subjects (HS) over 1 year. We tested the hypothesis that HSV1 exposed subjects will show longitudinal grey matter loss and decline in executive functions measured using the Wisconsin Card Sorting Test (WCST) over 1 year. Age, gender, socioeconomic status (SES) and exposure to cytomegalovirus (CMV) – another neurotropic virus, were the covariates. Using deformation fields analysis, we observed grey matter loss in seropositive SZ subjects but not seronegative SZ or HS in the left posterior cingulate gyrus at 1 year compared to baseline. Binomial random mixed effects growth models showed that over 1 year, a significantly higher number of HSV1 positive SZ subjects were committing more errors and completing fewer categories compared to HSV1 negative SZ and HS regardless of the serological status; the three-way interaction (time * diagnosis * HSV1 status) for categories completed (p = 0.0004) and perseverative errors were significant (p = 0.042). These observations suggest that SZ subjects exposed to HSV1 may show longitudinal grey matter volume loss in PCG and decline in executive functions in contrast to the comparison groups. doi:10.1016/j.bbi.2010.07.193