- Email: [email protected]
Biomarkers of vulnerability and progression in the psychosis prodrome
e6
Abstracts
Woodberry, K.A., Giuliano, A.J., Seidman, L.J., 2008. Premorbid IQ in schizophrenia: a meta-analytic review. Am. J. Psychiatry 165 (5), 579–587. Wykes, T., Huddy, V., Cellard, C., McGurk, S.R., Czobor, P., 2011. A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes. Am. J. Psychiatry 168 (5), 472–485. Kraepelin, E., 1919. Dementia Praecox and Paraphrenia. E & S Livingston, Edinburgh, Scotland. Seidman, L.J., Cassens, G., Kremen, W.S., Pepple, J.R., 1992. The neuropsychology of schizophrenia. In: White, R.W. (Ed.), Clinical Syndromes in Adult Neuropsychology: The Practitioner's Handbook. Elsevier, Amsterdam, pp. 381–450.
doi:10.1016/j.schres.2014.09.067
Biomarkers of vulnerability and progression in the psychosis prodrome Tyrone D. Cannon1 Department of Psychology, Yale University, United States; Department of Psychiatry, Yale University, United States 1 On behalf of the North American Prodrome Longitudinal Study (NAPLS) Consortium. E-mail: [email protected] Identification of the fundamental mechanisms underlying onset of psychosis is critical for the development of targeted pre-emptive interventions. This talk presented findings on clinical risk prediction algorithms as well as biomarkers assessed longitudinally in youth at clinical high-risk for psychosis as part of the second phase of the North American Prodrome Longitudinal Study (NAPLS2) (Addington et al., 2012). The study cohort consists of 765 clinical high-risk (CHR) participants and 260 healthy control subjects. The primary outcome was conversion to psychosis over 2 years from initial evaluation. Participants were evaluated with structural MRI, electrophysiology (mismatch negativity [MMN], auditory P300), and cortisol assays at baseline and at 12 months or at conversion to psychosis. Smaller subgroups were evaluated with functional MRI (resting state, verbal working memory, associative learning, emotion processing) and plasma analytes (indexing inflammatory and oxidative stress markers) at baseline. Multivariate models incorporating risk factors from clinical, demographic, neurocognitive, and psychosocial assessments achieved high levels of predictive accuracy when applied to individuals who meet criteria for a prodromal risk syndrome. A risk calculator was created that can be used to scale the risk for newly ascertained cases based on this set of predictors (Cannon, 2014). With respect to biomarkers, at risk individuals who converted to psychosis showed elevated levels of cortisol (Walker et al., 2013) and pro-inflammatory cytokines (Perkins et al., in press), as well as lower MMN and P300 amplitude (Mathalon et al., 2014) and disrupted resting state thalamo-cortical functional connectivity (Anticevic et al., 2014) at baseline, compared to those who do not. Further, converters showed a steeper rate of gray matter reduction, most prominent in prefrontal cortex that in turn was predicted by higher levels of cortisol and inflammatory markers as well as by lower MMN amplitude at baseline (Cannon et al., in press). Each biomarker was a significant predictor of psychosis on its own, and several improved predictions over and above the level achieved by the clinical, demographic, and cognitive algorithm (Cannon, 2014). Microglia, resident immune cells in the brain, have recently been discovered to influence synaptic plasticity in health (Schafer et al., 2013; Zhang et al., 2014) and impair plasticity in disease (Takano et al., 2014). Processes that modulate microglial activation may represent convergent mechanisms that influence brain dysconnectivity and risk for onset of psychosis. Inflammatory markers are elevated in postmortem neural tissue from patients with schizophrenia (Catts et al., 2014; Fillman et al., 2013; Fung et al., 2014; Rao et al., 2013) and these same markers are associated with microglialmediated synaptic pruning and dendritic retraction in animal models (Milatovic et al., 2011; Schafer et al., 2013), thus, providing a potential mechanism for the reduced neuropil and disrupted functional connectivity seen in patients (Glausier and Lewis, 2013; Selemon and Goldman-Rakic, 1999; Selemon et al., 1998). Although prenatal neuroinflammatory processes could “program” for vulnerability (Meyer, 2013), subsequent exposure to stress, infection, autoimmune processes and/or synaptic pruning during adolescent brain development represents influences more proximal to psychosis onset (Frick et al., 2013; Glausier and Lewis, 2013; McGlashan and Hoffman, 2000; Meyer, 2013). Future work is encouraged to target these
mechanisms in longitudinal studies of CHR subjects; results will help to identify targets for preventative intervention.
References Addington, J., Cadenhead, K., Cornblatt, B., Mathalon, D., McGlashan, T., Perkins, D., Seidman, L., Tsuang, M., Walker, E., Woods, S., Addington, J., Cannon, T.D., 2012. North American Prodrome Longitudinal Study 2 (NAPLS-2): overview and recruitment. Schizophr. Res. 142 (1–3), 77–82. Anticevic, A., Haut, K., Cole, M.W., Repovs, G., Yang, G., McEwen, S., Cannon, T.D., 2014. Thalamic dysconnectivity predicts risk for conversion to schizophrenia. Biol. Psychiatry 75 (9 Supplement). Cannon, T.D., 2014. The development and implementation of a psychosis risk prediction algorithm. Biol. Psychiatry 75 (9 Supplement). Cannon, T.D., Chung, Y., He, G., Sun, D., Jacobson, A., van Erp, T.G.M., McEwen, S., Addington, J., Bearden, C.E., Cadenhead, K., Cornblatt, B., Mathalon, D.H., McGlashan, T., Perkins, D., Jeffries, C., Seidman, L.J., Tsuang, M., Walker, E., Woods, S.W., Heinssen, R., 2014. Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk. Biol. Psychiatry (in press). Catts, V.S., Wong, J., Fillman, S.G., Fung, S.J., Weickert, C.S., 2014. Increased expression of astrocyte markers in schizophrenia: association with neuroinflammation. Aust. N. Z. J. Psychiatry 48 (8), 722–734. Fillman, S.G., Cloonan, N., Catts, V.S., Miller, L.C., Wong, J., McCrossin, T., Cairns, M., Weickert, C.S., 2013. Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol. Psychiatry 18 (2), 206–214. Frick, L.R., Williams, K., Pittenger, C., 2013. Microglial dysregulation in psychiatric disease. Clin. Dev. Immunol. 2013, 608654. Fung, S.J., Joshi, D., Fillman, S.G., Weickert, C.S., 2014. High white matter neuron density with elevated cortical cytokine expression in schizophrenia. Biol. Psychiatry 75 (4), e5–e7. Glausier, J.R., Lewis, D.A., 2013. Dendritic spine pathology in schizophrenia. Neuroscience 251, 90–107. Mathalon, D.H., Perkins, D., Walker, E., Addington, J., Bearden, C., Cadenhead, K., Cornblatt, B., McGlashan, T., Seidman, L., Tsuang, M., Woods, S., Cannon, T.D., 2014. Impaired synaptic plasticity, synaptic over-pruning, inflammation, and stress: a pathogenic model of the transition to psychosis in clinical high risk youth. Biol. Psychiatry 75 (9 Supplement). McGlashan, T.H., Hoffman, R.E., 2000. Schizophrenia as a disorder of developmentally reduced synaptic connectivity. Arch. Gen. Psychiatry 57 (7), 637–648. Meyer, U., 2013. Developmental neuroinflammation and schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 42, 20–34. Milatovic, D., Gupta, R.C., Yu, Y., Zaja-Milatovic, S., Aschner, M., 2011. Protective effects of antioxidants and anti-inflammatory agents against manganese-induced oxidative damage and neuronal injury. Toxicol. Appl. Pharmacol. 256 (3), 219–226. Perkins, D.O., Jeffries, C.D., Addington, J., Bearden, C.E., Cadenhead, K.S., Cannon, T.D., Cornblatt, B.A., Mathalon, D.H., McGlashan, T.H., Seidman, L.J., Tsuang, M.T., Walker, E.F., Woods, S.W., Heinssen, R., 2014. Towards a psychosis risk blood diagnostic for persons experiencing high-risk symptoms: preliminary results from the NAPLS project. Schizophr. Bull. (in press). Rao, J.S., Kim, H.W., Harry, G.J., Rapoport, S.I., Reese, E.A., 2013. Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in the postmortem frontal cortex from schizophrenia patients. Schizophr. Res. 147 (1), 24–31. Schafer, D.P., Lehrman, E.K., Stevens, B., 2013. The “quad-partite” synapse: microgliasynapse interactions in the developing and mature CNS. Glia 61 (1), 24–36. Selemon, L.D., Goldman-Rakic, P.S., 1999. The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol. Psychiatry 45 (1), 17–25. Selemon, L.D., Rajkowska, G., Goldman-Rakic, P.S., 1998. Elevated neuronal density in prefrontal area 46 in brains from schizophrenic patients: application of a threedimensional, stereologic counting method. J. Comp. Neurol. 392 (3), 402–412. Takano, M., Kawabata, S., Komaki, Y., Shibata, S., Hikishima, K., Toyama, Y., Okano, H., Nakamura, M., 2014. Inflammatory cascades mediate synapse elimination in spinal cord compression. J. Neuroinflammation 11, 40. Walker, E.F., Trotman, H.D., Pearce, B.D., Addington, J., Cadenhead, K.S., Cornblatt, B. A., Heinssen, R., Mathalon, D.H., Perkins, D.O., Seidman, L.J., Tsuang, M.T., Cannon, T.D., McGlashan, T.H., Woods, S.W., 2013. Cortisol levels and risk for psychosis: initial findings from the North American prodrome longitudinal study. Biol. Psychiatry 74 (6), 410–417. Zhang, J., Malik, A., Choi, H.B., Ko, R.W., Dissing-Olesen, L., MacVicar, B.A., 2014. Microglial CR3 activation triggers long-term synaptic depression in the hippocampus via NADPH oxidase. Neuron 82 (1), 195–207.
doi:10.1016/j.schres.2014.09.068
Dopamine dysfunction in schizophrenia Anissa Abi-Dargham Department of Psychiatry, Columbia University, New York State Psychiatric Institute, NY, USA E-mail: [email protected]
Abstracts
Woodberry, K.A., Giuliano, A.J., Seidman, L.J., 2008. Premorbid IQ in schizophrenia: a meta-analytic review. Am. J. Psychiatry 165 (5), 579–587. Wykes, T., Huddy, V., Cellard, C., McGurk, S.R., Czobor, P., 2011. A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes. Am. J. Psychiatry 168 (5), 472–485. Kraepelin, E., 1919. Dementia Praecox and Paraphrenia. E & S Livingston, Edinburgh, Scotland. Seidman, L.J., Cassens, G., Kremen, W.S., Pepple, J.R., 1992. The neuropsychology of schizophrenia. In: White, R.W. (Ed.), Clinical Syndromes in Adult Neuropsychology: The Practitioner's Handbook. Elsevier, Amsterdam, pp. 381–450.
doi:10.1016/j.schres.2014.09.067
Biomarkers of vulnerability and progression in the psychosis prodrome Tyrone D. Cannon1 Department of Psychology, Yale University, United States; Department of Psychiatry, Yale University, United States 1 On behalf of the North American Prodrome Longitudinal Study (NAPLS) Consortium. E-mail: [email protected] Identification of the fundamental mechanisms underlying onset of psychosis is critical for the development of targeted pre-emptive interventions. This talk presented findings on clinical risk prediction algorithms as well as biomarkers assessed longitudinally in youth at clinical high-risk for psychosis as part of the second phase of the North American Prodrome Longitudinal Study (NAPLS2) (Addington et al., 2012). The study cohort consists of 765 clinical high-risk (CHR) participants and 260 healthy control subjects. The primary outcome was conversion to psychosis over 2 years from initial evaluation. Participants were evaluated with structural MRI, electrophysiology (mismatch negativity [MMN], auditory P300), and cortisol assays at baseline and at 12 months or at conversion to psychosis. Smaller subgroups were evaluated with functional MRI (resting state, verbal working memory, associative learning, emotion processing) and plasma analytes (indexing inflammatory and oxidative stress markers) at baseline. Multivariate models incorporating risk factors from clinical, demographic, neurocognitive, and psychosocial assessments achieved high levels of predictive accuracy when applied to individuals who meet criteria for a prodromal risk syndrome. A risk calculator was created that can be used to scale the risk for newly ascertained cases based on this set of predictors (Cannon, 2014). With respect to biomarkers, at risk individuals who converted to psychosis showed elevated levels of cortisol (Walker et al., 2013) and pro-inflammatory cytokines (Perkins et al., in press), as well as lower MMN and P300 amplitude (Mathalon et al., 2014) and disrupted resting state thalamo-cortical functional connectivity (Anticevic et al., 2014) at baseline, compared to those who do not. Further, converters showed a steeper rate of gray matter reduction, most prominent in prefrontal cortex that in turn was predicted by higher levels of cortisol and inflammatory markers as well as by lower MMN amplitude at baseline (Cannon et al., in press). Each biomarker was a significant predictor of psychosis on its own, and several improved predictions over and above the level achieved by the clinical, demographic, and cognitive algorithm (Cannon, 2014). Microglia, resident immune cells in the brain, have recently been discovered to influence synaptic plasticity in health (Schafer et al., 2013; Zhang et al., 2014) and impair plasticity in disease (Takano et al., 2014). Processes that modulate microglial activation may represent convergent mechanisms that influence brain dysconnectivity and risk for onset of psychosis. Inflammatory markers are elevated in postmortem neural tissue from patients with schizophrenia (Catts et al., 2014; Fillman et al., 2013; Fung et al., 2014; Rao et al., 2013) and these same markers are associated with microglialmediated synaptic pruning and dendritic retraction in animal models (Milatovic et al., 2011; Schafer et al., 2013), thus, providing a potential mechanism for the reduced neuropil and disrupted functional connectivity seen in patients (Glausier and Lewis, 2013; Selemon and Goldman-Rakic, 1999; Selemon et al., 1998). Although prenatal neuroinflammatory processes could “program” for vulnerability (Meyer, 2013), subsequent exposure to stress, infection, autoimmune processes and/or synaptic pruning during adolescent brain development represents influences more proximal to psychosis onset (Frick et al., 2013; Glausier and Lewis, 2013; McGlashan and Hoffman, 2000; Meyer, 2013). Future work is encouraged to target these
mechanisms in longitudinal studies of CHR subjects; results will help to identify targets for preventative intervention.
References Addington, J., Cadenhead, K., Cornblatt, B., Mathalon, D., McGlashan, T., Perkins, D., Seidman, L., Tsuang, M., Walker, E., Woods, S., Addington, J., Cannon, T.D., 2012. North American Prodrome Longitudinal Study 2 (NAPLS-2): overview and recruitment. Schizophr. Res. 142 (1–3), 77–82. Anticevic, A., Haut, K., Cole, M.W., Repovs, G., Yang, G., McEwen, S., Cannon, T.D., 2014. Thalamic dysconnectivity predicts risk for conversion to schizophrenia. Biol. Psychiatry 75 (9 Supplement). Cannon, T.D., 2014. The development and implementation of a psychosis risk prediction algorithm. Biol. Psychiatry 75 (9 Supplement). Cannon, T.D., Chung, Y., He, G., Sun, D., Jacobson, A., van Erp, T.G.M., McEwen, S., Addington, J., Bearden, C.E., Cadenhead, K., Cornblatt, B., Mathalon, D.H., McGlashan, T., Perkins, D., Jeffries, C., Seidman, L.J., Tsuang, M., Walker, E., Woods, S.W., Heinssen, R., 2014. Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk. Biol. Psychiatry (in press). Catts, V.S., Wong, J., Fillman, S.G., Fung, S.J., Weickert, C.S., 2014. Increased expression of astrocyte markers in schizophrenia: association with neuroinflammation. Aust. N. Z. J. Psychiatry 48 (8), 722–734. Fillman, S.G., Cloonan, N., Catts, V.S., Miller, L.C., Wong, J., McCrossin, T., Cairns, M., Weickert, C.S., 2013. Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol. Psychiatry 18 (2), 206–214. Frick, L.R., Williams, K., Pittenger, C., 2013. Microglial dysregulation in psychiatric disease. Clin. Dev. Immunol. 2013, 608654. Fung, S.J., Joshi, D., Fillman, S.G., Weickert, C.S., 2014. High white matter neuron density with elevated cortical cytokine expression in schizophrenia. Biol. Psychiatry 75 (4), e5–e7. Glausier, J.R., Lewis, D.A., 2013. Dendritic spine pathology in schizophrenia. Neuroscience 251, 90–107. Mathalon, D.H., Perkins, D., Walker, E., Addington, J., Bearden, C., Cadenhead, K., Cornblatt, B., McGlashan, T., Seidman, L., Tsuang, M., Woods, S., Cannon, T.D., 2014. Impaired synaptic plasticity, synaptic over-pruning, inflammation, and stress: a pathogenic model of the transition to psychosis in clinical high risk youth. Biol. Psychiatry 75 (9 Supplement). McGlashan, T.H., Hoffman, R.E., 2000. Schizophrenia as a disorder of developmentally reduced synaptic connectivity. Arch. Gen. Psychiatry 57 (7), 637–648. Meyer, U., 2013. Developmental neuroinflammation and schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 42, 20–34. Milatovic, D., Gupta, R.C., Yu, Y., Zaja-Milatovic, S., Aschner, M., 2011. Protective effects of antioxidants and anti-inflammatory agents against manganese-induced oxidative damage and neuronal injury. Toxicol. Appl. Pharmacol. 256 (3), 219–226. Perkins, D.O., Jeffries, C.D., Addington, J., Bearden, C.E., Cadenhead, K.S., Cannon, T.D., Cornblatt, B.A., Mathalon, D.H., McGlashan, T.H., Seidman, L.J., Tsuang, M.T., Walker, E.F., Woods, S.W., Heinssen, R., 2014. Towards a psychosis risk blood diagnostic for persons experiencing high-risk symptoms: preliminary results from the NAPLS project. Schizophr. Bull. (in press). Rao, J.S., Kim, H.W., Harry, G.J., Rapoport, S.I., Reese, E.A., 2013. Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in the postmortem frontal cortex from schizophrenia patients. Schizophr. Res. 147 (1), 24–31. Schafer, D.P., Lehrman, E.K., Stevens, B., 2013. The “quad-partite” synapse: microgliasynapse interactions in the developing and mature CNS. Glia 61 (1), 24–36. Selemon, L.D., Goldman-Rakic, P.S., 1999. The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol. Psychiatry 45 (1), 17–25. Selemon, L.D., Rajkowska, G., Goldman-Rakic, P.S., 1998. Elevated neuronal density in prefrontal area 46 in brains from schizophrenic patients: application of a threedimensional, stereologic counting method. J. Comp. Neurol. 392 (3), 402–412. Takano, M., Kawabata, S., Komaki, Y., Shibata, S., Hikishima, K., Toyama, Y., Okano, H., Nakamura, M., 2014. Inflammatory cascades mediate synapse elimination in spinal cord compression. J. Neuroinflammation 11, 40. Walker, E.F., Trotman, H.D., Pearce, B.D., Addington, J., Cadenhead, K.S., Cornblatt, B. A., Heinssen, R., Mathalon, D.H., Perkins, D.O., Seidman, L.J., Tsuang, M.T., Cannon, T.D., McGlashan, T.H., Woods, S.W., 2013. Cortisol levels and risk for psychosis: initial findings from the North American prodrome longitudinal study. Biol. Psychiatry 74 (6), 410–417. Zhang, J., Malik, A., Choi, H.B., Ko, R.W., Dissing-Olesen, L., MacVicar, B.A., 2014. Microglial CR3 activation triggers long-term synaptic depression in the hippocampus via NADPH oxidase. Neuron 82 (1), 195–207.
doi:10.1016/j.schres.2014.09.068
Dopamine dysfunction in schizophrenia Anissa Abi-Dargham Department of Psychiatry, Columbia University, New York State Psychiatric Institute, NY, USA E-mail: [email protected]