Elsa Gilbert

Shared Neurocognitive Dysfunctions in Young Offspring at Extreme Risk for Schizophrenia or Bipolar Disorder in Eastern Quebec Multigenerational Families

BACKGROUND Adult patients having schizophrenia (SZ) or bipolar disorder (BP) may have in common neurocognitive deficits. Former evidence suggests impairments in several neuropsychological functions in young offspring at genetic risk for SZ or BP. Moreover, a dose-response relation may exist between the degree of familial loading and cognitive impairments. This study examines the cognitive functioning of high-risk (HR) offspring of parents having schizophrenia (HRSZ) and high-risk offspring of parents having bipolar disorder (HRBP) descending from densely affected kindreds. METHODS The sample consisted of 45 young offspring (mean age of 17.3 years) born to a parent having SZ or BP descending from large multigenerational families of Eastern Québec that are densely affected by SZ or BP and followed up since 1989. The offspring were administered a lifetime best-estimate diagnostic procedure (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV]) and an extensive standard neuropsychological battery. Raw scores were compared with age- and gender-matched controls. RESULTS The offspring displayed differences in memory and executive functions when compared with controls. Moderate to large effect sizes (Cohen d) ranging from 0.65 to 1.25 (for IQ and memory) were observed. Several of the cognitive dysfunctions were present in both HRSZ and HRBP, even when considering DSM-IV clinical status. CONCLUSIONS HRSZ and HRBP shared several aspects of their cognitive impairment. Our data suggest that the extremely high genetic and familial loading of these HRs may have contributed to a quantitatively increased magnitude of the cognitive impairments in both HR subgroups, especially in memory. These offspring at heightened risk present difficulties in processing information that warrant preventive research.

Verbal and Visual Memory Impairments Among Young Offspring and Healthy Adult Relatives of Patients With Schizophrenia and Bipolar Disorder: Selective Generational Patterns Indicate Different Developmental Trajectories

Objective: Memory deficits have been shown in patients affected by schizophrenia (SZ) and bipolar (BP)/mood disorder. We recently reported that young high-risk offspring of an affected parent were impaired in both verbal episodic memory (VEM) and visual episodic memory (VisEM). Understanding better the trajectory of memory impairments from childhood to adult clinical status in risk populations is crucial for early detection and prevention. In multigenerational families densely affected by SZ or BP, our aim was to compare the memory impairments observed in young nonaffected offspring with memory functioning in nonaffected adult relatives and patients. Methods: For 20 years, we followed up numerous kindreds in the Eastern Québec population. After having characterized the Diagnostic and Statistical Manual of Mental Disorders phenotypes, we assessed cognition (N = 381) in 3 subsamples in these kindreds and in controls: 60 young offspring of a parent affected by SZ or BP, and in the adult generations, 92 nonaffected adult relatives and 40 patients affected by SZ or BP. VEM was assessed with the California Verbal Learning Test and VisEM with the Rey figures. Results: The VEM deficits observed in the offspring were also found in adult relatives and patients. In contrast, the VisEM impairments observed in the young offspring were present only in patients, not in the adult relatives. Conclusion: Implications for prevention and genetic mechanisms can be drawn from the observation that VEM and VisEM would show distinct generational trajectories and that the trajectory associated with VisEM may offer a better potential than VEM to predict future risk of developing the disease.

Cluster analysis of cognitive deficits may mark heterogeneity in schizophrenia in terms of outcome and response to treatment

Abstract Cognitive impairments are central to schizophrenia, but their clinical utility for tagging heterogeneity in lifetime outcome and response to treatment is not conclusive. By exploiting four cognitive domains consistently showing large deficits in studies, we tested whether cluster analysis would define separate subsets of patients and then whether the disease heterogeneity marked by these clusters would be related to lifetime outcome and response to treatment. A total of 112 schizophrenia patients completed a neuropsychological evaluation. The PANSS, GAF-S and GAF-F were rated at the onset and endpoint of the illness trajectory. A blind judgment of the lifetime response to treatment was made. The first cluster presented near-normal cognitive performance. Two other clusters of severely impaired patients were identified: one generally impaired in the four cognitive domains and another selectively impaired in visual episodic memory and processing speed, each relating to a different lifetime evolution of disease and treatment response. Although the two impaired clusters were clinically indistinguishable in symptom severity and functioning at disease onset, patients with selective cognitive impairments demonstrated better improvement at outcome, whereas the generally impaired patients were more likely to be treatment refractory. The findings have implications for the management of patients and for clinical trials since particular combinations of cognitive deficits in patients would influence their treatment response.

Young offspring at genetic risk of adult psychoses: the form of the trajectory of IQ or memory may orient to the right dysfunction at the right time.

Objective Neurocognitive dysfunctions analogous to those of adult patients have been detected in children at risk of schizophrenia and bipolar disorder. This led to the following developmental question: Do IQ and memory impairments exhibit different developmental courses from childhood to young adulthood in terms of stability or fluctuations? Methods In a high risk sample, we used a step by step sampling approach to narrow-down the early disease mechanisms. Upstream, we started with a 20-year follow-up of 48 densely affected multigenerational kindreds, including 1500 clinically characterized adult members. We then identified 400 adult members affected by a DSM-IV schizophrenia or bipolar disorder. Downstream, we finally focused on 65 offspring (of an affected parent) aged 7 to 22, who were administered a neuropsychological battery. We then constructed cross-sectional trajectories that were compared to those of controls. Results The childhood IQ deficit displayed a stability until young adulthood. The delay in visual memory exhibited a non-linear two-stage trajectory: a lagging period during childhood followed by a recuperation period from adolescence until adulthood, as supported by a significant Group x Age Periods interaction. No data suggested deterioration between 7 and 22. Conclusion In these offspring at genetic risk, the developmental trajectory of global IQ impairment may not apply to specific domains of cognition such as episodic memory. Different cognitive dysfunctions would mark different developmental courses. The shape of the trajectories might itself have a meaning and provide empirical leads for targeting the right dysfunction at the right time in future prevention research.

Liability indicators aggregate many years before transition to illness in offspring descending from kindreds affected by schizophrenia or bipolar disorder

Objectives Offspring born to patients with affective and non-affective psychoses display indicators of brain dysfunctions that affected parents carry. Such indicators may help understand the risk trajectory. Methods We followed up the clinical/developmental trajectories of 84 young offspring born to affected parents descending from the Quebec kindreds affected by schizophrenia or bipolar disorder. We longitudinally characterized childhood trajectories using 5 established risk indicators: cognitive impairments, psychotic-like experiences, non-psychotic DSM diagnosis and episodes of poor functioning, trauma and drug use. Results Overall, offspring individually presented a high rate of risk indicators with 39% having 3 or more indicators. Thirty-three offspring progressed to an axis 1 DSM-IV disorder, 15 of whom transitioned to a major affective or non-affective disorder. The relative risks for each risk indicator were low in these vulnerable offspring (RR = 1.92 to 2.99). Remarkably, transitioners accumulated more risk indicators in childhood-adolescence than non-transitioners (Wilcoxon rank test; Z = 2.64, p = 0.008). Heterogeneity in the risk trajectories was observed. Outcome was not specific to parents diagnosis. Conclusion Young offspring descending from kindreds affected by major psychoses would accumulate risk indicators many years before transition. A clustering of risk factors has also been observed in children at risk of metabolic-cardiovascular disorders and influences practice guidelines in this field. Our findings may be significant for the primary care surveillance of millions of children born to affected parents in the G7 nations. Future longitudinal risk research of children at genetic risk should explore concurrently several intrinsic and environmental risk modalities to increase predictivity.

A feasibility study of a new computerised cognitive remediation for young adults with schizophrenia

Cognitive remediation therapy is effective for improving cognition, symptoms and social functioning in individuals with schizophrenia; however, the impact on visual episodic memory remains unclear. The objectives of this feasibility study were: (1) to explore whether or not CIRCuiTS—a new computerised cognitive remediation therapy programme developed in England—improves visual episodic memory and other cognitive domains in young adults with early course schizophrenia; and (2) to evaluate acceptability of the CIRCuiTS programme in French-Canadians. Three participants with visual episodic memory impairments at baseline were recruited from clinical settings in Canada, and consented to participate. Neuropsychological, clinical and social functioning was evaluated at baseline and post-treatment. Intervention involved 40 sessions of cognitive remediation. First, the reliable change index (RCI) revealed that each participant demonstrated significant post-therapy change in episodic memory and in other cognitive domains. The response profile was characterised by the use of organisational strategies. Second, the treatment was considered acceptable to participants in terms of session frequency (number of sessions per week), intensity (hours per week; total hours), and number of missed sessions and total completed sessions. This preliminary study yielded encouraging data demonstrating the feasibility of the CIRCuiTS programme in French-Canadian young adults with schizophrenia.

VERBAL AND VISUAL MEMORY IMPAIRMENTS AMONGST YOUNG OFFSPRING AND HEALTHY ADULT RELATIVES OF PATIENTS WITH SCHIZOPHRENIA AND BIPOLAR-DEPRESSION: SELECTIVE GENERATIONAL PATTERNS INDICATE DIFFERENT PREDICTIVE PATHWAYS

Michel Maziade, Nancie Rouleau, Chantal Merette, Marco Battaglia, Cecilia Marino, Valerie Jomphe, Elsa Gilbert, Caroline Cellard, Amelie Achim, Roch-Hugo Bouchard, Marie-Eve Paradis, Marc-Andre Roy Centre de recherche Universite, Laval Robert-Giffard, Quebec, Quebec, Canada; Ecole de psychologie, Universite Laval Quebec, Quebec, Canada; Academic Centre for the Study of Behavioural Plasticity, Vita-Salute San Raffaele University, Milan, Italy; Eugenio Medea Institute, Department of Child Psychiatry, Bosisio, Parini, Italy

T88. CLUSTER ANALYSIS IDENTIFIES TWO NEUROCOGNITIVE PROFILES AMONG OFFSPRING AT GENETIC RISK OF A MAJOR MENTAL DISORDER

Abstract Background Offspring of patients diagnosed with Schizophrenia (SZ) or Bipolar Disorder (BP) are at high risk (HR) of developing either SZ or BP and show impairment in various cognitive domains (Mortiz et al 2017, Gilbert et al 2014,). Also, the performance gradually decreases from relatives of patients with psychosis to individuals at prodromal phase and finally to subjects at first episode of psychosis (Hou et al. 2016). Recently a meta-analysis found that various cognitive domains were impaired in a pooled sample of subjects including clinical high risk for psychosis and first episode of psychosis with effect sizes ranging from -0.30 to -0.85 (Hauser et al. 2017). However, theses deficits were obtained from data of the entire sample of subjects at risk even though only a small percentage of all offspring at HR risk transit toward to a major mental disorder (Rasic et al.2014). Hence, the effect size reported may represent a mixture of larger and smaller deficits, referring to those who will eventually convert versus those who won’t, respectively. This present study addresses this issue by attempting to separate offspring of individuals with SZ or BP into two subgroups according to their cognitive profile in order to differentiate a subgroup with healthy or close to healthy cognitive performance from another having a lower performance. Methods Our sample was composed of a HR group of 131 offspring from 6 to 24 years old. The sample was drawn from previous independent studies that targeted all multigenerational families densely affected by SZ or BP in the Eastern Québec (Canada) catchment area for genetic analysis purposes (Maziade et al. 2011). All subjects were assessed on: Processing speed, Verbal memory (VEM), Visual Memory (VISEM), Working memory and Executive functioning. An average hierarchical cluster analysis, using the Ward’s method, was performed by age group on all five cognitive domains to separate the HR group into two subgroups according to their cognitive functioning. The pseudo F statistics and Pseudo T square index were used to estimate the number of clusters and ANOVA was also performed by age group to verify that the two clusters differed in their average cognitive scores. Then, both subgroups were compared to a control group of n= 131 subjects that matched the HR group by age and gender. Results The cluster analysis yielded two different groups, referred to as HR1 and HR2. For Processing speed and VEM, differences between HR1 and HR2 were statistically significant in almost all age groups (6-10,11-15,16–20 years old), for VISEM the two groups were different from 11 to 24 years old, while for Working memory and Executive functioning, HR1 differed from HR2 from age 16 to 24. Moreover, the HR1 group performed very similarly to the control group in all functions, while the HR2 group presented significant differences from control subjects in most cognitive performance with effect sizes often exceeding those previously seen and even reaching -2.3 for VISEM. Discussion One of the most striking results from our study was to detect one subgroup of HR with cognitive performance very similar to non at risk individuals, while the other subgroup performed even worse than what was presented in the literature. To our knowledge, this is the first study to reveal such two neurocognitive profiles across different age groups in the HR population. Still, further research is needed in longitudinal studies to investigate whether these findings are associated with the transition to a psychiatric disorder in the following years. Nevertheless, our study suggests that interventions with a neurocognitive target should be addressed earlier, due to the apparition of a breach in cognitive performance at very early stages in life.

T71. CHANGE AND STABILITY IN COGNITIVE TRAJECTORIES FROM CHILDHOOD TO LATE ADOLESCENCE IN YOUNG OFFSPRING AT GENETIC RISK OF SCHIZOPHRENIA AND MOOD DISORDER: IMPLICATIONS FOR THE RISK STATUS

Abstract Background Cognitive impairments are a core feature of schizophrenia (SZ).1 The few existing retrospective or prospective population-based studies indicate that patients who develop psychoses have cognitive impairments in childhood and adolescence.2,3 Offspring at high genetic risk also present neurocognitive impairments before the age of disease incidence.4,5 The form of the childhood cognitive trajectory may be a predictor of transition to illness but more data are needed on the early cognitive trajectories in children at genetic risk to inform about the most sensitive periods in risk progression to psychosis and to orient interventions.6 The objective was to investigate the cognitive trajectories in children born to a parent affected by a SZ or BP from early childhood to late adolescence, in terms of changes in cognitive 4 domains known to be impaired in major psychosis. A special attention was given to the timing of changes in childhood, and their association with well documented clinical risk indicators. Methods The sample consisted of 79 offspring (age from 6 to 21) born to parents affected by SZ or BP from our multi-affected kindreds of Eastern Quebec. Our cognitive battery covered: episodic memory, working memory, speed of processing and executive functioning evaluated at two-time points (mean duration between assessments +/- 6y). A Cognitive domain was considered impaired when mean performance was below -1 SD. We had measurements of established childhood risk indicators [4]: psychotic-like experiences, non-psychotic DSM diagnoses and social functioning (GAF). Results Three distinct developmental trajectories were identified according to the progression in number of impaired cognitive domains from baseline to follow-up: i) A “steady” trajectory with stable and intact performances across all cognitive domains (n=52; 66%); ii) a “deteriorating” trajectory with an accumulation of cognitive impairments (n=18; 23%) and; iii) an “improving” trajectory with a diminishing number of cognitive impairments at follow-up (n=9; 11%). IQ and neuropsychological performances were similar at baseline between the “deteriorating” and “improving” trajectories (p=.4), while the steady group performed best. The 3 subgroups were comparable in terms of the parent diagnosis and offspring gender. Regarding clinical risk indicators, the deteriorating subgroup presented a worsening of social functioning between the two-time points (-7 GAF points vs -0.8 for steady, +0.56 for improving) and a higher rate of childhood non-psychotic DSM diagnosis (p≤.01). Importantly, we observed striking differences in cognitive trajectories among siblings suggesting that change or stability go beyond the heritability of cognitive capacities. Discussion Our results suggest three types of cognitive developmental trajectories among offspring of parents affected by SZ or BP. The progressive deteriorating trajectory was associated with an aggregation of other clinical risk indicators shown to predict transition.4 Cognitive deterioration was slightly more frequent in childhood and pre-adolescence than in late adolescence which has implications for the timing of detection, the need of care, the type of longitudinal surveillance and the design of future prevention research.6 References 1. Keefe & Kahn, JAMA Psychiatry, 2017 2. Meier et al., Am J Psychiatry, 2014 3. MacCabe et al., JAMA Psychiatry 2013 4. Paccalet et al., Schizophr Res, 2016 5. Maziade et al., Schizophr Bull, 2011 6. Maziade, N Eng J Med, 2017

7.2 ELECTRORETINOGRAPHIC ANOMALIES SEEN IN PATIENTS AFFECTED BY SCHIZOPHRENIA OR BIPOLAR DISORDER ARE DETECTABLE EARLY IN CHILDREN BORN TO AN AFFECTED PARENT: IMPLICATIONS FOR THE STAGING OF RISK STATUS IN CHILDHOOD-ADOLESCENCE

Abstract Background Adult patients having schizophrenia, bipolar disorder or major depression display indicators of brain dysfunctions that may be detectable in healthy children-adolescents at genetic risk, such as those born to an affected parent (Maziade, New Eng J Med 2017; Schizophr Res 2013). For instance, cognitive deficits are displayed by both adult patients and children at risk (Maziade, Schizophr Bull 2011). We had reported that schizophrenia patients present diminished amplitudes and delayed latencies of rod and cone photoreceptor responses (Hébert, Schizophr Res, 2015) and we recently found that bipolar patients have similar ERG anomalies. We had also reported preliminary data in a small sample of 29 children born to an affected parent showing that young offspring had rod diminished amplitudes (Hébert, Biol Psychiatry 2010). The present objectives were i) under the hypothesis that offspring would display many of the ERG anomalies that schizophrenia or mood disorder patients carry (Hébert, Schizophr Res 2015; Prog Neuropsychopharmacol Biol Psychiatry 2017), to look for cone and rod response anomalies in a large sample of young high-risk offspring; ii) to describe the relationship between ERG anomalies and other risk endophenotypes in the offspring; and iii) look at the relationship between ERG anomalies and the risk clusters already shown to predict later transition to illness. Methods The sample consisted of 84 young offspring (aged 6 to 27) of a parent affected by schizophrenia or bipolar disorder, compared to 224 healthy controls balanced for age and sex. Full-field cone and rod ERG was measured in non-dilated eyes for all subjects. In the young offspring, we also collected measures of different cognitive domains, attenuated symptoms of psychosis, non-psychotic DSM diagnosis and/or an episode of poor GAF functioning in childhood-adolescence, childhood trauma, and cannabis use (Paccalet, Schizophr Res 2016). Results In comparison to controls the offspring displayed three ERG anomalies that were observed in adult patients: prolonged cone b-wave latency (p=0.04), diminished rod b-wave amplitude (p=0.04) and prolonged rod b-wave latency (p=0.006). These ERG anomalies were shared by offspring of a parent with schizophrenia or bipolar disorder, an observation of ERG commonality that we had made in adult patients. The three ERG amplitude and latency anomalies tended to aggregate in a child at risk, a trend we also observed in another endophenotype modality such as deficits in different cognitive domains. However, in these high-risk children and adolescents, the patterns of aggregation suggest that ERG anomalies would depict another risk pathway than that marked by cognitive deficits. Discussion First, ERG anomalies in high-risk children have neurobiological implications for future research on the illness neurodevelopment. Second, as found for other modalities of risk endophenotypes in children at genetic risk (Maziade, New Eng J Med 2017), multiple rod and cone ERG anomalies tended to cluster together in a child. Such an aggregation may be compatible with the multifactorial polygenic theory with a threshold. Remarkably, a clustering of risk indicators is also observed in children at risk of metabolic cardiovascular disorders and is presently considered in practice guidelines for these children. The clustering of risk indicators may provide an empirical basis for the staging of the risk status of children at genetic risk and has immediate implications for their longitudinal surveillance in the clinic.