Cognitive and inflammatory heterogeneity in severe mental illness: Translating findings from blood to brain.

Recent findings link cognitive impairment and inflammatory-immune dysregulation in schizophrenia (SZ) and bipolar (BD) spectrum disorders. However, heterogeneity and translation between the periphery and central (blood-to-brain) mechanisms remains a challenge. Starting with a large SZ, BD and healthy control cohort (n = 1235), we aimed to i) identify candidate peripheral markers (n = 25) associated with cognitive domains (n = 9) and elucidate heterogenous immune-cognitive patterns, ii) evaluate the regulation of candidate markers using human induced pluripotent stem cell (iPSC)-derived astrocytes and neural progenitor cells (n = 10), and iii) evaluate candidate marker messenger RNA expression in leukocytes using microarray in available data from a subsample of the main cohort (n = 776), and in available RNA-sequencing deconvolution analysis of postmortem brain samples (n = 474) from the CommonMind Consortium (CMC). We identified transdiagnostic subgroups based on covariance between cognitive domains (measures of speed and verbal learning) and peripheral markers reflecting inflammatory response (CRP, sTNFR1, YKL-40), innate immune activation (MIF) and extracellular matrix remodelling (YKL-40, CatS). Of the candidate markers there was considerable variance in secretion of YKL-40 in iPSC-derived astrocytes and neural progenitor cells in SZ compared to HC. Further, we provide evidence of dysregulated RNA expression of genes encoding YKL-40 and related signalling pathways in a high neuroinflammatory subgroup in the postmortem brain samples. Our findings suggest a relationship between peripheral inflammatory-immune activity and cognitive impairment, and highlight YKL-40 as a potential marker of cognitive functioning in a subgroup of individuals with severe mental illness.

Neurocognitive function and delusion severity in schizophrenia spectrum disorders.

The role of basic neurocognitive function in delusions is unclear despite the association to difficulties in reasoning and decision-making. We investigated 812 individuals with schizophrenia spectrum disorders (SSD) using a broad neuropsychological test battery encompassing motor and mental processing speed, working memory, learning and memory, and executive function. Premorbid and current intellectual function was assessed with NART and WASI. Delusion level and other clinical symptoms were measured with the PANSS and GAF. Hierarchical and k-means cluster analysis using standardized scores showed the presence of two separate clusters where the group with the higher delusion level (n = 291) was characterized by more severe neurocognitive deficits (>1.5 standard deviations below the healthy control mean), higher PANSS scores, lower GAF scores, and lower intelligence levels compared to the cluster with mild impairments (n = 521). We conclude that a higher delusion level is related to neurocognitive deficits across domains. Further, the validity of the two separate clusters was indicated by significant differences in clinical symptoms, everyday function, and intellectual ability. Compared to those with mild delusion levels, SSD patients with higher delusion levels seem particularly disadvantaged, with co-occurring general symptoms and lower daily function, underscoring the need for clinical and psychosocial support programs. A limitation of this study is the cross sectional design. Longitudinal studies are needed to determine the causal relationship between delusions and neurocognitive function.

A 10-Year Longitudinal Study of Brain Cortical Thickness in People with First-Episode Psychosis Using Normative Models.

BACKGROUND: Clinical forecasting models have potential to optimize treatment and improve outcomes in psychosis, but predicting long-term outcomes is challenging and long-term follow-up data are scarce. In this 10-year longitudinal study, we aimed to characterize the temporal evolution of cortical correlates of psychosis and their associations with symptoms. DESIGN: Structural magnetic resonance imaging (MRI) from people with first-episode psychosis and controls (n = 79 and 218) were obtained at enrollment, after 12 months (n = 67 and 197), and 10 years (n = 23 and 77), within the Thematically Organized Psychosis (TOP) study. Normative models for cortical thickness estimated on public MRI datasets (n = 42 983) were applied to TOP data to obtain deviation scores for each region and timepoint. Positive and Negative Syndrome Scale (PANSS) scores were acquired at each timepoint along with registry data. Linear mixed effects models assessed effects of diagnosis, time, and their interactions on cortical deviations plus associations with symptoms. RESULTS: LMEs revealed conditional main effects of diagnosis and time × diagnosis interactions in a distributed cortical network, where negative deviations in patients attenuate over time. In patients, symptoms also attenuate over time. LMEs revealed effects of anterior cingulate on PANSS total, and insular and orbitofrontal regions on PANSS negative scores. CONCLUSIONS: This long-term longitudinal study revealed a distributed pattern of cortical differences which attenuated over time together with a reduction in symptoms. These findings are not in line with a simple neurodegenerative account of schizophrenia, and deviations from normative models offer a promising avenue to develop biomarkers to track clinical trajectories over time.

Long-term Outcomes of People With DSM Psychotic Disorder NOS.

Introduction: The Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV diagnostic category "Psychotic disorder not otherwise specified" (PNOS) is seldom investigated, and we lack knowledge about long-term outcomes. We examined long-term symptom severity, global functioning, remission/recovery rates, and diagnostic stability after the first treatment for PNOS. Methods: Participants with first-treatment PNOS (n = 32) were reassessed with structured interviews after 7 to 10 years. The sample also included narrow schizophrenia spectrum disorders (SSD, n = 94) and psychotic bipolar disorders (PBD, n = 54). Symptomatic remission was defined based on the Remission in Schizophrenia Working Group criteria. Clinical recovery was defined as meeting the criteria for symptomatic remission and having adequate functioning for the last 12 months. Results: Participants with baseline PNOS or PBD had lower symptom severity and better global functioning at follow-up than those with SSD. More participants with PNOS and PBD were in symptomatic remission and clinical recovery compared to participants with SSD. Seventeen (53%) PNOS participants retained the diagnosis, while 15 participants were diagnosed with either SSD (22%), affective disorders (19%), or substance-induced psychotic disorders (6%). Those rediagnosed with SSD did not differ from the other PNOS participants regarding baseline clinical characteristics. Conclusions: Long-term outcomes are more favorable in PNOS and PBD than in SSD. Our findings confirm diagnostic instability but also stability for a subgroup of participants with PNOS. However, it is challenging to predict diagnostic outcomes of PNOS based on clinical characteristics at first treatment.

Intra- and inter-individual cognitive variability in schizophrenia and bipolar spectrum disorder: an investigation across multiple cognitive domains.

There is substantial cognitive heterogeneity among patients with schizophrenia (SZ) and bipolar disorders (BD). More knowledge about the magnitude and clinical correlates of performance variability could improve our understanding of cognitive impairments. Using double generalized linear models (DGLMs) we investigated cognitive mean and variability differences between patients with SZ (n = 905) and BD spectrum disorders (n = 522), and healthy controls (HC, n = 1170) on twenty-two variables. The analysis revealed significant case-control differences on 90% of the variables. Compared to HC, patients showed larger intra-individual (within subject) variability across tests and larger inter-individual (between subject) variability in measures of fine-motor speed, mental processing speed, and inhibitory control (SZ and BD), and in verbal learning and memory and intellectual functioning (SZ). In SZ, we found that lager intra -and inter (on inhibitory control and speed functions) individual variability, was associated with lower functioning and more negative symptoms. Inter-individual variability on single measures of memory and intellectual function was additionally associated with disorganized and positive symptoms, and use of antidepressants. In BD, there were no within-subject associations with symptom severity. However, greater inter-individual variability (primarily on inhibitory control and speeded functions) was associated with lower functioning, more negative -and disorganized symptoms, earlier age at onset, longer duration of illness, and increased medication use. These results highlight larger individual differences in patients compared to controls on various cognitive domains. Further investigations of the causes and correlates of individual differences in cognitive function are warranted.