Impaired olfactory ability associated with larger left hippocampus and rectus volumes at earliest stages of schizophrenia:a sign of neuroinflammation?

Impaired olfactory identification has been reported as a first sign of schizophrenia during the earliest stages of illness, including before illness onset. The aim of this study was to examine the relationship between volumes of these regions (amygdala, hippocampus, gyrus rectus and orbitofrontal cortex) and olfactory ability in three groups of participants: healthy control participants (Ctls), patients with first-episode schizophrenia (FE-Scz) and chronic schizophrenia patients (Scz). Exploratory analyses were performed in a sample of individuals at ultra-high risk (UHR) for psychosis in a co-submission paper (Masaoka et al., 2020). The relationship to brain structural measures was not apparent prior to psychosis onset, but was only evident following illness onset, with a different pattern of relationships apparent across illness stages (FE-Scz vs Scz). Path analysis found that lower olfactory ability was related to larger volumes of the left hippocampus and gyrus rectus in the FE-Scz group. We speculate that larger hippocampus and rectus in early schizophrenia are indicative of swelling, potentially caused by an active neurochemical or immunological process, such as inflammation or neurotoxicity, which is associated with impaired olfactory ability. The volumetric decreases in the chronic stage of Scz may be due to degeneration resulting from an active immune process and its resolution

Plasma neurofilament light in behavioural variant frontotemporal dementia compared to mood and psychotic disorders

OBJECTIVE: Blood biomarkers of neuronal injury such as neurofilament light (NfL) show promise to improve diagnosis of neurodegenerative disorders and distinguish neurodegenerative from primary psychiatric disorders (PPD). This study investigated the diagnostic utility of plasma NfL to differentiate behavioural variant frontotemporal dementia (bvFTD, a neurodegenerative disorder commonly misdiagnosed initially as PPD), from PPD, and performance of large normative/reference data sets and models. METHODS: Plasma NfL was analysed in major depressive disorder (MDD, n = 42), bipolar affective disorder (BPAD, n = 121), treatment-resistant schizophrenia (TRS, n = 82), bvFTD (n = 22), and compared to the reference cohort (Control Group 2, n = 1926, using GAMLSS modelling), and age-matched controls (Control Group 1, n = 96, using general linear models). RESULTS: Large differences were seen between bvFTD (mean NfL 34.9 pg/mL) and all PPDs and controls (all < 11 pg/mL). NfL distinguished bvFTD from PPD with high accuracy, sensitivity (86%), and specificity (88%). GAMLSS models using reference Control Group 2 facilitated precision interpretation of individual levels, while performing equally to or outperforming models using local controls. Slightly higher NfL levels were found in BPAD, compared to controls and TRS. CONCLUSIONS: This study adds further evidence on the diagnostic utility of NfL to distinguish bvFTD from PPD of high clinical relevance to a bvFTD differential diagnosis, and includes the largest cohort of BPAD to date. Using large reference cohorts, GAMLSS modelling and the interactive Internet-based application we developed, may have important implications for future research and clinical translation. Studies are underway investigating utility of plasma NfL in diverse neurodegenerative and primary psychiatric conditions in real-world clinical settings

Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ): Rationale and Study Design of the Largest Global Prospective Cohort Study of Clinical High Risk for Psychosis

This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals

Neural correlates of memory dysfunction across stages of schizophrenia-spectrum disorder

© 2020 Cassandra Marie Joanne WannanSchizophrenia-spectrum disorders are severe mental illnesses characterised by hallucinations, delusions, blunted affect and disorganised thought patterns. A core feature of these disorders is cognitive deficits, which are associated with functional disability. Episodic memory, in particular, is one of the most severely impacted areas of cognitive functioning in schizophrenia-spectrum disorder, and memory deficits predict poorer clinical prognosis and increased functional disability. However, the longitudinal course of episodic memory deficits in schizophrenia-spectrum disorders is currently poorly defined, with the focus to date being on areas of functioning that are already impaired in early illness stages, such as verbal memory. In order to better understand trajectories, it may be important to examine areas of functioning that are preserved early in the illness, such as visual associative memory. Furthermore, there is currently a poor understanding of the neural underpinnings of memory impairment in schizophrenia-spectrum disorders, making it difficult to develop targeted interventions aimed at ameliorating these deficits. It is plausible that episodic memory impairments in these disorders is related to underlying dysfunction in the brain regions and networks that underlie this ability – namely, the hippocampus and its connections to the prefrontal cortex. This thesis utilised longitudinal cognitive assessment and cross-sectional multi modal neuroimaging to address three primary research aims: 1. To investigate the longitudinal course of episodic memory ability over a 5-11-year follow-up period in individuals with first-episode psychosis. 2. To investigate relationships between visual associative memory performance and hippocampal subfield volumes in FEP individuals and individuals with chronic schizophrenia-spectrum disorders. 3. to investigate whether visuospatial associative memory ability is related to white matter microstructure in the hippocampal-prefrontal pathway in FEP individuals and individuals with chronic schizophrenia-spectrum disorders. Results showed that visual associative memory ability was preserved in in individuals who had recently experienced a first psychotic episode, but deteriorated over a 5-11 year follow-up period. Conversely, verbal associative memory ability improved over the follow-up period to the same degree in FEP individuals and healthy controls. In a subsequent cross-sectional study, we found that, while hippocampal subfield volume reductions were present only in individuals with chronic schizophrenia-spectrum disorder, poorer episodic memory performance was associated with reduced subfield volumes in the CA4/dentate gyrus (DG) and in the stratum layers in both FEP individuals and those with chronic schizophrenia-spectrum disorder. Finally, we found that abnormal white matter microstructure in a number of memory-related ROIs and hippocampal-prefrontal pathways was present only in individuals with chronic schizophrenia-spectrum disorder. Furthermore, microstructural abnormalities in the fornix and the hippocampal-thalamic pathway were associated with poorer memory performance in individuals with chronic schizophrenia-spectrum disorder, but not FEP individuals. These findings provide new insights into the neural underpinnings of episodic memory impairment across stages of schizophrenia-spectrum disorder, and suggest that hippocampal structure may be more relevant to memory impairment in FEP individuals, with memory-related white matter abnormalities emerging in later illness stages

An Interleukin-1 beta (IL1B) haplotype linked with psychosis transition is associated with IL1B gene expression and brain structure

We investigated IL1B genetic variation previously associated with risk for transition to psychosis for its association with gene expression in human post-mortem dorsolateral prefrontal cortex (DLPFC) from 74 (37 schizophrenia, 37 control) individuals and brain structure in 92 (44 schizophrenia, 48 control) living individuals. The IL1B A-G-T `risk for psychosis transition&apos; haplotype (rs16944 vertical bar rs4848306 vertical bar rs12621220) was associated with upregulation of IL1B mRNA expression in the DLPFC as well as reduced total grey matter and left middle frontal volumes and enlarged left lateral ventricular volume. Our results suggest IL1B genetic variation may confer psychosis risk via elevated mRNA expression and/or brain structure abnormalities. (C) 2018 Elsevier B.V. All rights reserved

Risk and resilience brain networks in treatment-resistant schizophrenia

Background Genes, molecules and neural circuits that are associated with, or confer risk to developing schizophrenia have been studied and mapped. It is hypothesized that certain neural systems may counterbalance familial risk of schizophrenia, and thus confer resilience to developing the disorder. This study sought to identify resting-state functional brain connectivity (rs-FC) representing putative risk or resilience endophenotypes in schizophrenia. Methods Resting-state functional magnetic resonance imaging (rs-fMRI) was performed in 42 individuals with treatment resistant schizophrenia (TRS), 16 unaffected first-degree family members (UFM) and 42 healthy controls. Whole-brain rs-FC networks were mapped for each individual and analysed graph theoretically to identify network markers associated with schizophrenia risk or resilience. Results The ~ 900 functional connections showing between-group differences were operationalized as conferring: i) resilience, ii) risk, or iii) precipitating risk and/or illness effects. Approximately 95% of connections belonged to the latter two categories, with substantially fewer connections associated with resilience. Schizophrenia risk primarily involved reduced frontal and occipital rs-FC, with patients showing additional reduced frontal and temporal rs-FC. Functional brain networks were characterized by greater local efficiency in UFM, compared to TRS and controls. Conclusions TRS and UFM share frontal and occipital rs-FC deficits, representing a ‘risk’ endophenotype. Additional reductions in frontal and temporal rs-FC appear to be associated with risk that precipitates psychosis in vulnerable individuals, or may be due to other illness-related effects, such as medication. Functional brain networks are more topologically resilient in UFM compared to TRS, which may protect UFM from psychosis onset despite familial liability