Cytokine concentrations throughout pregnancy and risk for psychosis in adult offspring: a longitudinal case-control study.

BACKGROUND: Schizophrenia has been associated with pregnancy and birth complications and fetal exposure to inflammation is thought to be a common underlying mechanism. However, whether the risk is specific to particular phases of pregnancy is unclear. The aim of this study was to characterise and compare longitudinal patterns of maternal serum concentrations of cytokines across pregnancy between offspring who were later ascertained to have a psychotic disorder, non-psychotic siblings of these cases, and unrelated, non-psychotic individuals who served as controls. METHODS: The National Collaborative Perinatal Project was a large-scale prospective longitudinal study that assessed the effects of perinatal factors on infant and child development. At sites across the USA, over 50 000 pregnant women were enrolled during prenatal clinical visits between 1959 and 1965. The present study draws from the Philadelphia cohort, which includes 9236 surviving offspring of 6753 pregnant women. Psychotic disorder diagnoses in adulthood were assessed with review of medical records and were confirmed with a validation study. Concentrations of TNFα, IL-1ß, IL-5, IL-6, IL-8, IL-10, and IL-17a were assessed using a multiplex bead assay in archived maternal serum samples collected across prenatal visits and birth. We characterized cytokine patterns with linear mixed models. FINDINGS: Our final sample comprised 90 cases, 79 siblings (of 40 cases), and 273 matched controls. Concentrations of proinflammatory cytokines TNFα, IL-1ß, and IL-6 were significantly higher in maternal serum of offspring who later developed psychosis compared with maternal serum of matched controls. These differences were greatest in the first half of pregnancy (7-20 weeks), with no difference observed during the second half of pregnancy. INTERPRETATION: Our results suggest that exposure to high maternal proinflammatory cytokine concentrations in early pregnancy might play a part in psychosis. These findings place the timing of risk associated with maternal inflammation much earlier in prenatal development than previously documented in humans and provide insight into a potential developmental pathway to the disorder. FUNDING: National Institute of Mental Health (P50) Silvio O Conte Center at Johns Hopkins, Stanley Foundation, March of Dimes, Yale University, National Science Foundation, and National Institute of Child Health and Human Development/Division of Intramural Population Health Research.

Characterizing Covariant Trajectories of Individuals at Clinical High Risk for Psychosis Across Symptomatic and Functional Domains.

OBJECTIVE: The authors sought to characterize differences in outcomes among help-seeking individuals at clinical high risk for psychosis by identifying covariant longitudinal patterns of symptoms and functioning. METHODS: Group-based multitrajectory modeling was applied to longitudinal ratings of four symptom domains (positive, negative, disorganized, general) and general functioning among clinical high-risk individuals in an initial discovery sample (N=422). An independent sample (N=133) was used to test replicability. RESULTS: Three trajectory groups were identified among clinical high-risk individuals in the discovery sample: group 1 (30%) exhibited substantial improvement across all domains, with half reaching positive outcomes for both functioning and positive symptoms; group 2 (49%) exhibited moderate impairments across domains, with approximately one-quarter meeting criteria for positive outcomes; the remaining participants (group 3; 22%) exhibited consistent levels of severe impairment across domains and did not experience positive outcomes. These trajectory groups and remission patterns were replicated in an independent sample. CONCLUSIONS: Replicable subgroups of help-seeking clinical high-risk cases can be ascertained based on distinctive profiles of change over time in symptoms and functioning. Within each of the three identified subgroups, similar patterns of change (i.e., rapid, moderate, or no improvement) were observed across the four symptom domains and functioning. This consistency of change over time across domains within each subgroup is a novel observation supporting the syndrome consistency of clinical high-risk symptoms and signs. The observed trajectory subgroups are suggestive of different degrees of need for clinical interventions, ranging from minimal or supportive for about one-third of cases to increasingly intensive among the remainder.

Cortical abnormalities in youth at clinical high-risk for psychosis: Findings from the NAPLS2 cohort.

In a recent machine learning study classifying "brain age" based on cross-sectional neuroanatomical data, clinical high-risk (CHR) individuals were observed to show deviation from the normal neuromaturational pattern, which in turn was predictive of greater risk of conversion to psychosis and a pattern of stably poor functional outcome. These effects were unique to cases who were between 12 and 17 years of age when their prodromal and psychotic symptoms began, suggesting that neuroanatomical deviance observable at the point of ascertainment of a CHR syndrome marks risk for an early onset form of psychosis. In the present study, we sought to clarify the pattern of neuroanatomical deviance linked to this "early onset" form of psychosis and whether this deviance is associated with poorer premorbid functioning. T1 MRI scans from 378 CHR individuals and 190 healthy controls (HC) from the North American Prodrome Longitudinal Study (NAPLS2) were analyzed. Widespread smaller cortical volume was observed among CHR individuals compared with HC at baseline evaluation, particularly among the younger group (i.e., those who were 12 to 17 years of age). Moreover, the younger CHR individuals who converted or presented worsened clinical symptoms at follow-up (within 2 years) exhibited smaller surface area in rostral anterior cingulate, lateral and medial prefrontal regions, and parahippocampal gyrus relative to the younger CHR individuals who remitted or presented a stable pattern of prodromal symptoms at follow-up. In turn, poorer premorbid functioning in childhood was associated with smaller surface area in medial orbitofrontal, lateral frontal, rostral anterior cingulate, precuneus, and temporal regions. Together with our prior report, these results are consistent with the view that neuroanatomical deviance manifesting in early adolescence marks vulnerability to a form of psychosis presenting with poor premorbid adjustment, an earlier age of onset (generally prior to the age of 18 years), and poor long-term outcome.

Prenatal inflammation and risk for schizophrenia: A role for immune proteins in neurodevelopment.

Prenatal inflammation is an established risk factor for schizophrenia. However, the specific inflammatory pathways that mediate this association remain unclear. Potential candidate systems include inflammatory markers produced by microglia, such as cytokines and complement. Accumulating evidence suggests that these markers play a role in typical neurodevelopmental processes, such as synapse formation and interneuron migration. Rodent models demonstrate that altered marker levels during the prenatal period can cause lasting deficits in these systems, leading to cognitive deficits that resemble schizophrenia. This review assesses the potential role of prenatal cytokine and complement elevations on the etiology of schizophrenia. The current neurobiological understanding of the development of schizophrenia is reviewed to identify candidate cellular mechanisms that may be influenced by prenatal inflammation. We discuss the functions that cytokines and complement may play in prenatal neurodevelopment, review evidence that links exposure to these factors with risk for schizophrenia, and consider how these markers may interact with genetic vulnerabilities to influence the neurodevelopment of schizophrenia. We consider how prenatal inflammatory exposure may influence childhood and adolescent developmental risk trajectories for schizophrenia. Finally, we identify areas of further research needed to support the development of anti-inflammatory treatments to prevent the development of schizophrenia in at-risk neonates.

Complement Gene Expression Correlates with Superior Frontal Cortical Thickness in Humans.

Recent work suggests that genes encoding complement proteins that are active in the innate immune system may confer risk for schizophrenia by disrupting typical synaptic pruning in late adolescence. Alterations in the complement pathway may contribute to aberrant cortical thinning in schizophrenia prodromes and reduced prefrontal cortical thickness in chronic schizophrenia patients; however, this theory needs to be translated to humans. We conducted a series of analyses in a sample of adult Swedish twins enriched for schizophrenia (N=129) to assess the plausibility of a relationship between complement gene expression and cortical thickness that could go awry in the etiology of schizophrenia. First, we identified that peripheral mRNA expression levels of two complement genes (C5, SERPING1) made unique contributions to the variance in superior frontal cortical thickness among all participants. Vertex-wise maps of the association between gene expression levels and thickness across the cortex suggested that this relationship was especially strong with SERPING1 in the superior frontal region, consistent with the pattern of disruption in cortical thickness observed in schizophrenia. Additional analyses identified that these genes are expressed in the human superior frontal cortex, that heritable genetic factors influence SERPING1 gene expression levels, and that these associations are observed regardless of case status. These findings provide initial evidence linking the complement system with cortical thinning in humans, a process potentially involved in the pathogenesis of schizophrenia.

Elevated maternal cytokine levels at birth and risk for psychosis in adult offspring.

BACKGROUND: Pregnancy and birth complications, particularly those associated with maternal inflammation and fetal hypoxia, are associated with increased risk for schizophrenia later in life. However, the molecular mechanisms underlying these associations are not fully delineated. This study sought to examine the effect of exposure to maternal inflammation on risk of developing psychosis in adulthood. Maternal serum levels of pro-inflammatory Th1 cytokines (IL-2, interferon gamma [IFN-γ], IL-12) and Th17 cytokines (IL-1b, IL-6, IL-8, tumor necrosis factor alpha [TNF-α], granulocyte macrophage colony stimulating factor [gm-csf]) and anti-inflammatory Th2 cytokines (IL-4, IL-5, and IL-13) and Treg cytokines (IL-10) were evaluated for association with later psychosis in the offspring. METHODS: Subjects were 43 adults with psychoses and 43 matched controls followed from gestation as part of the Philadelphia cohort of the National Collaborative Perinatal Project. Adult symptoms of psychosis were assessed via medical records review and confirmed with a validation study. Archived maternal serum samples collected at the time of birth were analyzed for cytokine levels using a multiplex bead assay. RESULTS: Individuals exposed to elevated maternal levels of anti-inflammatory Th2 cytokines (≥75th percentile) were significantly less likely to develop psychosis in adulthood. CONCLUSIONS: These results may suggest that increased maternal levels of anti-inflammatory cytokines during the perinatal period could protect against the development of psychosis.

Gestational Age at Term, Delivery Circumstance, and Their Association with Childhood Attention Deficit Hyperactivity Disorder Symptoms.

BACKGROUND: Perinatal characteristics may identify subgroups of term-born children at risk for academic and behavioural difficulties. Using follow-up data from the Pregnancy Outcomes and Community Health Study, we subdivided term births according to two potential markers of perinatal risk (gestational age, delivery circumstance) and evaluated their association with attention deficit hyperactivity disorder (ADHD) symptoms. METHODS: We included children born at term whose mothers completed the Conners' Parent Rating Scales-Revised-Short Form (CPRS-R-S) (n = 610; ages: 3-9 years). The CPRS-R-S yields age and sex-referenced T-scores for the two primary dimensions of ADHD (inattention, hyperactivity) and an ADHD Index that reflects both dimensions. Using general linear models, we evaluated whether: (1) term delivery defined by gestational week (reference: 39-40 weeks), or (2) term delivery circumstance defined by labour onset type and mode of delivery (reference: spontaneous labour, vaginal delivery) was associated with these problems. RESULTS: Following adjustment for parity, sociodemographics, and maternal mental health both during pregnancy and at the child follow-up survey, the induced labour plus caesarean group exhibited higher inattention and ADHD Index scores relative to the spontaneous labour, vaginal delivery group (inattention: mean difference = 5.1, 95% CI 0.6, 9.7; ADHD Index: mean difference = 4.1, 95% CI 0.5, 7.8). Findings were primarily driven by male children. CONCLUSIONS: Among term-born children, only those whose mothers experienced induction of labour that culminated in caesarean delivery exhibited higher levels of ADHD symptoms. Prenatal, antepartum, and/or postnatal factors associated with this delivery profile may reflect increased risk for such problems.