Cognitive deficits in schizophrenia are detectable at the onset of illness and during the preceding prodromal period. Additionally, adolescents and young adults at clinical high risk for psychosis (CHR-P) demonstrate cognitive impairment regardless of future conversion. The cortical substrates of these deficits have yet to be established within CHR-P samples, including the differential relations of cortical thickness (CTh) versus surface area (SA) as they differ in underlying cytoarchitecture and genetic influences. Youth at CHR-P (N = 463) and healthy control participants (N = 210) from the second cohort of the North American Prodrome Longitudinal Study (ages 12-35) completed the two-subtest form of the Wechsler Abbreviated Scale of Intelligence and structural MRI scans at baseline. The associations between regional cortical morphometry and Full-Scale IQ (FSIQ-2) were examined using multiple linear regression. Increased CTh in frontoparietal regions (left lateral orbitofrontal cortex; left precentral gyrus; left postcentral gyrus; right supramarginal gyrus) and lateral occipital areas associated with better cognitive functioning in CHR-P. In contrast, among healthy control participants, no associations between CTh and cognitive functioning were observed. Additionally, increased SA across the cortex was associated with better cognitive functioning for both groups, though people at CHR-P demonstrated a more diffuse pattern of associations. These results underscore the importance of decomposing cortical volume into CTh and SA and how variation in cognitive functioning may be potentially supported by shared and group-specific substrates. Results generate hypotheses about how aberrant neurodevelopmental processes, such as cortical thinning, may disturb cognitive functioning in the early stage of psychosis.

BACKGROUND & HYPOTHESIS:Prior studies suggest that cognitive batteries normed in the U.S. may not be suitable for populations that differ in English proficiency and/or cultural background. Here, we investigated how cultural variables (i.e., length of residence, native English speaker) influence cognitive performance within a U.S. and Canadian sample of people at clinical high risk for psychosis (CHR-P) and healthy control (HC) participants. STUDY DESIGN:The sample consisted of 925 adolescents and adults (664 CHR-P, 261 HC) from the second cohort of the North American Prodromal Longitudinal Study, including 73 (7.9 %) foreign-born participants and 94 (10.2 %) who reported a language other than English as their first language. Multigroup structural equation modeling was used to estimate effects of cultural variables on MATRICS Consensus Cognitive Battery (MCCB) subtests, separately in each diagnostic group. STUDY RESULTS:A structural model that generated unique estimates for all parameters in group models was selected. For CHR-P, longer length of residence in U.S./Canada related to better performance on Animal Naming (β = 0.09, p = .01), whereas being a native English speaker related to better performance on Letter-Number Span (β = 0.14, p = .001) and Hopkins Verbal Learning Test - Revised (β = 0.10, p = .03). In contrast, no such relationships were observed among HCs. CONCLUSIONS:Findings extend our understanding of how cultural variables may influence presentation of psychosis-risk syndromes and suggest that being a non-native English speaker or having recently immigrated may hinder performance on certain verbal neuropsychological measures.

The 3q29 deletion (3q29Del) is a copy number variant (CNV) with one of the highest effect sizes for psychosis-risk (>40-fold). Systematic research offers avenues for elucidating mechanism; however, compared to CNVs like 22q11.2Del, 3q29Del remains understudied. Emerging findings indicate that posterior fossa abnormalities are common among carriers, but their clinical relevance is unclear. We report the first in-depth evaluation of psychotic symptoms in participants with 3q29Del (N=23), using the Structured Interview for Psychosis-Risk Syndromes, and compare this profile to 22q11.2Del (N=31) and healthy controls (N=279). We also explore correlations between psychotic symptoms and posterior fossa abnormalities. Cumulatively, 48% of the 3q29Del sample exhibited a psychotic disorder or attenuated positive symptoms, with a subset meeting criteria for clinical high-risk. 3q29Del had more severe ratings than controls on all domains and only exhibited less severe ratings than 22q11.2Del in negative symptoms; ratings demonstrated select sex differences but no domain-wise correlations with IQ. An inverse relationship was identified between positive symptoms and cerebellar cortex volume in 3q29Del, documenting the first clinically-relevant neuroanatomical connection in this syndrome. Our findings characterize the profile of psychotic symptoms in the largest 3q29Del sample reported to date, contrast with another high-impact CNV, and highlight cerebellar involvement in psychosis-risk.

Research on serious mental disorders, particularly psychosis, has revealed highly variable symptom profiles and developmental trajectories prior to illness-onset. As Dante Cicchetti pointed out decades before the term "transdiagnostic" was widely used, the pathways to psychopathology emerge in a system involving equifinality and multifinality. Like most other psychological disorders, psychosis is associated with multiple domains of risk factors, both genetic and environmental, and there are many transdiagnostic developmental pathways that can lead to psychotic syndromes. In this article, we discuss our current understanding of heterogeneity in the etiology of psychosis and its implications for approaches to conceptualizing etiology and research. We highlight the need for examining risk factors at multiple levels and to increase the emphasis on transdiagnostic developmental trajectories as a key variable associated with etiologic subtypes. This will be increasingly feasible now that large, longitudinal datasets are becoming available and researchers have access to more sophisticated analytic tools, such as machine learning, which can identify more homogenous subtypes with the ultimate goal of enhancing options for treatment and preventive intervention.

Among high-impact genomic variants associated with severe neurodevelopmental disorders, the 3q29 deletion (3q29Del) stands out, conferring a 40-100-fold elevated risk of schizophrenia, alongside a heightened susceptibility to autism, intellectual disability and ADHD. Despite growing knowledge of its clinical associations, its neurobiological consequences are largely unknown.

BACKGROUND:3q29 deletion syndrome (3q29del) is a rare (~1:30 000) genomic disorder associated with a wide array of neurodevelopmental and psychiatric phenotypes. Prior work by our team identified clinically significant executive function (EF) deficits in 47% of individuals with 3q29del; however, the nuances of EF in this population have not been described. METHODS:We used the Behavior Rating Inventory of Executive Function (BRIEF) to perform the first in-depth assessment of real-world EF in a cohort of 32 individuals with 3q29del (62.5% male, mean age = 14.5 ± 8.3 years). All participants were also evaluated with gold-standard neuropsychiatric and cognitive assessments. High-resolution structural magnetic resonance imaging was performed on a subset of participants (n = 24). RESULTS:We found global deficits in EF; individuals with 3q29del scored higher than the population mean on the BRIEF global executive composite (GEC) and all subscales. In total, 81.3% of study subjects (n = 26) scored in the clinical range on at least one BRIEF subscale. BRIEF GEC T scores were higher among 3q29del participants with a diagnosis of attention deficit/hyperactivity disorder (ADHD), and BRIEF GEC T scores were associated with schizophrenia spectrum symptoms as measured by the Structured Interview for Psychosis-Risk Syndromes. BRIEF GEC T scores were not associated with cognitive ability. The BRIEF-2 ADHD form accurately (sensitivity = 86.7%) classified individuals with 3q29del based on ADHD diagnosis status. BRIEF GEC T scores were correlated with cerebellar white matter and subregional cerebellar cortex volumes. CONCLUSIONS:Together, these data expand our understanding of the phenotypic spectrum of 3q29del and identify EF as a core feature linked to both psychiatric and neuroanatomical features of the syndrome.

Objective: Cohort studies demonstrate that people who later develop schizophrenia, on average, present with mild cognitive deficits in childhood and endure a decline in adolescence and adulthood. Yet, tremendous heterogeneity exists during the course of psychotic disorders, including the prodromal period. Individuals identified to be in this period (known as CHR-P) are at heightened risk for developing psychosis (~35%) and begin to exhibit cognitive deficits. Cognitive impairments in CHR-P (as a singular group) appear to be relatively stable or ameliorate over time. A sizeable proportion has been described to decline on measures related to processing speed or verbal learning. The purpose of this analysis is to use data-driven approaches to identify latent subgroups among CHR-P based on cognitive trajectories. This will yield a clearer understanding of the timing and presentation of both general and domain-specific deficits. Participants and Methods: Participants included 684 young people at CHR-P (ages 12–35) from the second cohort of the North American Prodromal Longitudinal Study. Performance on the MATRICS Consensus Cognitive Battery (MCCB) and the Wechsler Abbreviated Scale of Intelligence (WASI-I) was assessed at baseline, 12-, and 24-months. Tested MCCB domains include verbal learning, speed of processing, working memory, and reasoning & problem-solving. Sex- and age-based norms were utilized. The Oral Reading subtest on the Wide Range Achievement Test (WRAT4) indexed pre-morbid IQ at baseline. Latent class mixture models were used to identify distinct trajectories of cognitive performance across two years. One- to 5-class solutions were compared to decide the best solution. This determination depended on goodness-of-fit metrics, interpretability of latent trajectories, and proportion of subgroup membership (>5%). Results: A one-class solution was found for WASI-I Full-Scale IQ, as people at CHR-P predominantly demonstrated an average IQ that increased gradually over time. For individual domains, one-class solutions also best fit the trajectories for speed of processing, verbal learning, and working memory domains. Two distinct subgroups were identified on one of the executive functioning domains, reasoning and problem-solving (NAB Mazes). The sample divided into unimpaired performance with mild improvement over time (Class I, 74%) and persistent performance two standard deviations below average (Class II, 26%). Between these classes, no significant differences were found for biological sex, age, years of education, or likelihood of conversion to psychosis (OR = 1.68, 95% CI 0.86 to 3.14). Individuals assigned to Class II did demonstrate a lower WASI-I IQ at baseline (96.3 vs. 106.3) and a lower premorbid IQ (100.8 vs. 106.2). Conclusions: Youth at CHR-P demonstrate relatively homogeneous trajectories across time in terms of general cognition and most individual domains. In contrast, two distinct subgroups were observed with higher cognitive skills involving planning and foresight, and they notably exist independent of conversion outcome. Overall, these findings replicate and extend results from a recently published latent class analysis that examined 12-month trajectories among CHR-P using a different cognitive battery (Allott et al., 2022). Findings inform which individuals at CHR-P may be most likely to benefit from cognitive remediation and can inform about the substrates of deficits by establishing meaningful subtypes.

Background: The 3q29 deletion (3q29Del) is a copy number variant (CNV) with the highest known effect size for psychosis-risk (>40-fold increased risk). Systematic research on this CNV offers promising avenues for identifying mechanisms underlying psychosis and related disorders. Relative to other high-impact CNVs like 22q11.2Del, far less is known about the phenotypic presentation and pathophysiology of 3q29Del. Emerging findings indicate that posterior fossa abnormalities are common among 3q29Del carriers; however, their clinical relevance is unknown. Methods: Here, we report the first in-depth evaluation of psychotic symptoms in study participants with 3q29Del ( N =23), using the Structured Interview for Psychosis-Risk Syndromes (SIPS), and compare to SIPS data from 22q11.2Del participants ( N =31) and healthy controls ( N =279). We also investigate the relationship between psychotic symptoms, cerebellar morphology, and cystic/cyst-like malformations of the posterior fossa in 3q29Del by structural brain imaging. Results: Cumulatively, 48% of the 3q29Del sample exhibited a psychotic disorder ( N =4) or attenuated positive symptoms ( N =7), with three individuals with attenuated symptoms meeting the frequency and timing criteria for clinical high risk for psychosis. Males with 3q29Del scored higher in negative symptoms than females. 3q29Del participants had more severe ratings than controls on all domains and exhibited less severe negative symptoms than 22q11.2Del participants. An inverse relationship was identified between positive symptom severity and cerebellar cortex volume in 3q29Del, while cystic/cyst-like malformations yielded no clinical link with psychosis. Conclusions: Overall, our findings establish the unique and shared profiles of psychotic symptoms across two CNVs and highlight cerebellar involvement in elevated psychosis-risk in 3q29Del. FOV=256x256mm, resolution=0.8mm isotropic. T2-weighted 3D images were acquired in the sagittal plane using a SPACE sequence with the following parameters: TE=563ms, TR=3200ms, bandwidth=745Hz/pixel, FOV=256x256mm, resolution=0.8mm isotropic. Further details on neuroimaging parameters have been described (10, 33). Furthermore, our results establish the unique and shared profiles of psychotic symptoms across 3q29Del and 22q11.2 DS and highlight cerebellar involvement in elevated psychosis-risk in 3q29Del.

Individuals with psychotic disorders largely demonstrate moderate-to-severe cognitive deficits. Deficits are detectable throughout the illness, including the “prodrome” immediately preceding clinical onset. The cortical determinants of impairments have yet to be established, and samples at clinical high risk for psychosis (CHR-P) are ideal for addressing this issue, given their reduced exposure to confounds (e.g. prolonged anti-psychotic use).

This exploratory study reports on borderline symptomatology within a sample of individuals at clinical high risk for psychosis (CHR‐P) through a validated, self‐report instrument, the short version of the Borderline Symptom List (BSL‐23).

Despite substantial efforts aimed at the detection and intervention for early symptoms of mental illness, there is relatively limited research on the clinical overlap between borderline personality disorder (BPD) and early psychosis, for example, clinical high risk (CHR) for psychosis, in young people. We present a narrative review of the clinical overlap between BPD and psychosis spectrum symptoms. Both conditions have unstable temporal course, and both are marked by functional impairment, increased suicide risk, and higher rates of psychiatric inpatient services. We then review evidence-based treatments for psychosis and BPD, emphasizing treatments for early presentations of these symptoms and initial research considering treatments for the overlap. Psychotherapies with the strongest empirical support include cognitive behavioral models, with BPD showing limited response to adjunctive pharmacotherapy. We end by discussing specific recommendations for future research, including longitudinal studies to determine the predictors of the course of illness and the development of treatments to target comorbid BPD and CHR symptoms.

The 3q29 deletion is a recurrent copy number variant (CNV) that confers a ∼40-fold increased risk for schizophrenia (SZ), the largest known effect size for any SZ-associated genetic variant. Recent findings by the Emory 3q29 Project (http://genome.emory.edu/3q29/) revealed that cerebellar hypoplasia is a common feature of 3q29 deletion syndrome (3q29DS). This is coincident with emerging SZ literature implicating the cerebellum as a central site of neuropathology. We investigated the relationship between cerebellar volume and psychotic and sub-threshold psychotic symptoms in 3q29DS.

Purpose To understand the consequences of the 3q29 deletion on medical, neurodevelopmental, psychiatric, brain structural, and neurological sequalae by systematic evaluation of affected individuals. To develop evidence-based recommendations using these data for effective clinical care. Methods Thirty-two individuals with the 3q29 deletion were evaluated using a defined phenotyping protocol and standardized data collection instruments. Results Medical manifestations were varied and reported across nearly every organ system. The most severe manifestations were congenital heart defects (25%) and the most common were gastrointestinal symptoms (81%). Physical examination revealed a high proportion of musculoskeletal findings (81%). Neurodevelopmental phenotypes represent a significant burden and include intellectual disability (34%), autism spectrum disorder (38%), executive function deficits (46%), and graphomotor weakness (78%). Psychiatric illness manifests across the lifespan with psychosis prodrome (15%), psychosis (20%), anxiety disorders (40%), and attention deficit–hyperactivity disorder (ADHD) (63%). Neuroimaging revealed structural anomalies of the posterior fossa, but on neurological exam study subjects displayed only mild or moderate motor vulnerabilities. Conclusion By direct evaluation of 3q29 deletion study subjects, we document common features of the syndrome, including a high burden of neurodevelopmental and neuropsychiatric phenotypes. Evidence-based recommendations for evaluation, referral, and management are provided to help guide clinicians in the care of 3q29 deletion patients.